Prep 2015

PREP ID 2015 Dr YAMEEN ALMATAWAH
Question: 1
You are treating a previously healthy 14-year-old adolescent with linezolid for a severe community
acquired pneumonia caused by methicillin-resistant Staphylococcus aureus. The infection was
complicated by the development of necrotizing pneumonia and empyema. The patient received a 2-
week course of vancomycin and you have transitioned him to linezolid in hopes of avoiding a long
term intravascular catheter and further hospitalization. He is on no other medications. The family in
concerned about the possible adverse effects of linezolid therapy.
Of the following, the MOST common adverse effect related to linezolid therapy is
A. arthropathy
B. bone marrow suppression
C. hepatitis
D. renal failure
E. seizures
Question: 1
You are treating a previously healthy 14-year-old adolescent with linezolid for a severe community
acquired pneumonia caused by methicillin-resistant Staphylococcus aureus. The infection was
complicated by the development of necrotizing pneumonia and empyema. The patient received a 2-
week course of vancomycin and you have transitioned him to linezolid in hopes of avoiding a long
term intravascular catheter and further hospitalization. He is on no other medications. The family in
concerned about the possible adverse effects of linezolid therapy.
Of the following, the MOST common adverse effect related to linezolid therapy is
A. arthropathy
B. bone marrow suppression
C. hepatitis
D. renal failure
E. seizures
8d5515a9-245a-4
Linezolid is the first antibiotic of the oxazolidinone class to be approved for use in the United
States and to be approved and used in children. This agent has activity limited to Gram-positive
organisms, including methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, and
vancomycin-resistant enterococci. The agent has excellent bioavailability when administered orally and
can be used to treat resistant Gram-positive infections as an alternative to more traditional
intravenous therapies. Linezolid appears to have a good safety profile. The most concerning possible
toxicity related to this agent is the development of neutropenia and thrombocytopenia. This adverse
effect, however, appears to be fully reversible and dependent on the dose and duration of
administration. The bone marrow toxicity has mainly been documented in patients receiving high dose
therapy for more than 2 weeks duration. Other toxicities, such as arthropathy, hepatitis, renal
dysfunction, do not appear to be problematic with linezolid therapy. Neurologic effects such as
peripheral neuropathy and optic neuritis have been described, but appear to be uncommon.
By virtue of being a fully synthetic compound, the risk of naturally occurring resistance against this
agent is less than against other agents. Furthermore, linezolid has a unique mechanism of action that
protects against cross-resistance with other antimicrobial agents. Unlike other agents that inhibit
protein synthesis, linezolid inhibits protein synthesis by binding to an area close to the ribosomal
peptidyl transferase center and prevents the formation of the initiation complex of elongation factors
at this center. The end result of this mechanism is to prevent the coupling of amino acids and
lengthening of the peptide chain.
In the pediatric population, linezolid has mainly been studied for the treatment of community acquired
pneumonia and uncomplicated skin and soft tissue infections, where it generally has been shown to be
comparable to vancomycin. Limited data has also documented successful treatment of bone and joint
and central nervous system infection. Thus, linezolid is an alternative in treating resistant Gram-
positive infections in situations where more standard therapies are not available, not tolerated, or
where there is an advantage to treating these infections with an oral agent.
* Completed *Take Survey

PREP Pearls
 Linezolid can be used to treat gram-positive infections, including resistant organisms such as
methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.
 Bone marrow toxicity is a reversible adverse effect of linezolid that occurs with high dosages
given over a long duration.
American Board of Pediatrics Content Specification(s)
 Recognize that linezolid inhibits bacterial protein synthesis through a mechanism of action
different from that of other antibacterial agents (eg, unlikely cross-resistance with other
antimicrobials)
 Understand that linezolid is a therapeutic option for resistant gram positive organisms
 Plan appropriate monitoring (eg, blood counts) in patients receiving oxazolidinone therapy
Suggested Readings
 Bozdogan B, Appelbaum PC. Oxazolidinones: activity, mode of action, and mechanism of

resistance. Int J Antimicrob Agents. 2004;23(2):113-119. DOI:
10.1016/j.ijantimicag.2003.11.003
 Chiappini E, Conti C, Galli L, de Martino M. Clinical efficacy and tolerability of linezolid in
pediatric patients: a systematic review. Clin Ther. 2010;32(1):66-88. DOI:
10.1016/j.clinthera.2010.01.019
 Kaplan SL, Deville JG, Yogev R, et al. Linezolid versus vancomycin for treatment of resistant
Gram-positive infections in children. Pediatr Infect Dis J. 2003;22(8):677-686.
Question: 2
You are discussing the clinical features and complications of bacterial skin and skin structure infections
with the pediatric residents. They seem familiar with complications of staphylococcal skin infections,
but are less familiar with serious consequences of group A streptococcal skin infections. To give them
perspective on the relative incidence of serious consequences of group A streptococcal skin pyoderma,
you present cases of complications of Streptococcus pyogenes you have seen in your career, many of
these from the years prior to universal varicella vaccination.
Of the following, the MOST common serious consequence of S pyogenes pyoderma is
A. ecthyma gangrenosum
B. necrotizing fasciitis
C. osteoarticular infection
D. post-streptococcal glomerulonephritis
E. toxic shock syndrome

Question: 2
You are discussing the clinical features and complications of bacterial skin and skin structure infections
with the pediatric residents. They seem familiar with complications of staphylococcal skin infections,
but are less familiar with serious consequences of group A streptococcal skin infections. To give them
perspective on the relative incidence of serious consequences of group A streptococcal skin pyoderma,
you present cases of complications of Streptococcus pyogenes you have seen in your career, many of
these from the years prior to universal varicella vaccination.
Of the following, the MOST common serious consequence of S pyogenes pyoderma is
A. ecthyma gangrenosum
B. necrotizing fasciitis
C. osteoarticular infection
D. post-streptococcal glomerulonephritis
E. toxic shock syndrome
Superficial skin infections include impetigo or pyoderma, folliculitis, furuncles and carbuncles,
usually caused by Staphylococcus aureus or Streptococcus pyogenes. Occasionally folliculitis is caused
by Pseudomonas species or other Gram-negative enteric bacteria. Lymphangitis, suppurative
lymphadenitis, cellulitis, ecthyma, necrotizing soft tissue infection with bulla formation, necrotizing
fasciitis, and necrotizing myositis are locally invasive consequences of untreated superficial skin
infections. Bloodstream seeding by S aureus or S pyogenes can result in septicemia or organ infection
such as pneumonia and musculoskeletal infection (pyomyositis, pyogenic arthritis, osteomyelitis).
Toxic shock syndrome can complicate superficial S aureus or S pyogenes infections.
Serious consequences of S pyogenes skin infections are uncommon in the current era, partly because
varicella infection was a leading predisposing factor, therefore post-streptococcal glomerulonephritis
(APSGN), is the most common among diagnoses in the vignette. Post-streptococcal glomerulonephritis
is a later consequence of nephritogenic S pyogenes strains that occurs about 3 weeks after the
primary infection. S pyogenes causes a very small proportion of toxic shock syndrome, necrotizing soft
tissue infection, osteoarticular infection, or ecthyma gangrenosum. Moreover, the portal of entry is the
site of minimal local trauma, or is unknown in many cases, rather than skin infection.
Ecthyma presents as a deep skin infection that heals as a crusted ulcer usually without purple and
black color changes. Ecthyma gangrenosum is a serious skin infection that progresses rapidly from
erythematous, indurated, well-circumscribed, raised, or flat lesions to purple and black, necrotic
―punched-out‖ soft tissue ulcers because of tissue infarction. P aeruginosa is the most common
organism but other gram-negative bacilli, S aureus, S pyogenes and some pathogenic molds and
yeasts can cause ecthyma gangrenosum. It occurs mostly in immunocompromised hosts especially in
the setting of neutropenia, and septicemia is a life-threatening complication in these patients. The
pathogenesis involves seeding of skin blood vessels either hematogenously or by local inoculation at a
traumatized site.
Cutaneous anthrax is a superficial skin infection with surrounding edema and bulla formation that can
form an ulcer with a black eschar once the bulla ruptures. Constitutional symptoms and regional
lymphadenopathy are common, but bacteremia is rare, although it can be iatrogenically induced by
incision and drainage.
A plan of treatment for a superficial skin infection will vary according to the severity and extent of the
infection. Mild impetigo can be treated with topical antibiotics, such as mupirocin for staphylococcal
infection. All forms of deep tissue extension and systemic infection require systemic antibiotic therapy,
administered orally or parenterally depending upon the patient‘s condition.
PREP Pearls
 Serious consequences of superficial skin infections include locally invasive complications,

bloodstream and organ seeding, toxic shock syndrome, or acute post-streptococ¬cal
glomerulonephritis
 Understand possible serious consequences of superficial skin infection (eg, systemic spread,
glomerulonephrits)
 Plan the treatment of superficial skin infections
Suggested Readings
 Lawrence HS, Nopper AJ. Superficial bacterial skin infections and cellulitis. In: Long S,
Pickering LK, Prober CG, ed. Principles and Practice of Pediatric Infectious Diseases. 4th ed.
Philadelphia, PA: Saunders Elsevier; 2012:427-434.
Question: 3
You are speaking to a group of medical students, who are leaving on a medical mission trip to rural
Southeast Asia, about diseases that can be contracted through the ingestion of contaminated raw or
inadequately cooked aquatic animals.
Of the diseases discussed, paragonimiasis is caused by the ingestion of raw or inadequately cooked:
A. crayfish
B. fish
C. frogs
D. oysters
E. shrimp
Question: 3
You are speaking to a group of medical students, who are leaving on a medical mission trip to rural
Southeast Asia, about diseases that can be contracted through the ingestion of contaminated raw or
inadequately cooked aquatic animals.
Of the diseases discussed, paragonimiasis is caused by the ingestion of raw or inadequately cooked:
A. crayfish
B. fish
C. frogs
D. oysters
E. shrimp
There are a number of infections that may be contracted through the ingestion of raw
or inadequately cooked aquatic food animals in many areas of the world. Infection
with Paragonimus species occurs through the ingestion of raw or undercooked
crustaceans, especially crayfish and crabs. Diphyllobothrium latum is the fish tape
worm that is acquired by eating uncooked freshwater fish containing the parasite’s
pleroceroid cysts. Sparganosis caused by Spirometra mansonoides may be acquired through the
consumption of prolonged exposure to uncooked meat of infected animals containing plerocercoid
cysts. It is most commonly acquired in association with the traditional use of frog or snake poultices.
Clinical presentation usually involves local inflammation at the site of invasion with the skin and eye
being the most common sites for the application of poultices. Hepatitis A virus is ubiquitous worldwide
and infection may occur through the ingestion of hepatitis A virus contaminated food or water. Multiple
outbreaks have occurred secondary to ingestion of contaminated raw oysters and clams. Vibrio
parahaemolyticus is ubiquitous in coastal waters throughout the temperate and tropical zones of the
world. It may contaminant raw or inadequately cooked seafood, especially shrimp and crab meat, and
causes an acute diarrheal illness.
Paragonimiasis, oriental lung fluke disease, is a zoonotic infection caused by trematode parasites of the
genus Pargonimus in which humans may act as definitive hosts. Paragonimus species are found in
tropical, subtropical, and temperate climates and occur throughout east and southeast Asia, sub-
Saharan Africa, and in the Americas from Peru to Canada. At least 9 species have been identified that
cause infections in humans. These include: Paragonimus westermani (Korea, Japan, Taiwan, China,
Phillipines, India, New Guinea), P kellicotti (North America), P africanus (Central and West Africa), P
heterotremus (China, Thailand, southeast Asia), P mexicanus (Central and South America), P siamensis
(Thailand), P skrjabini (China), P skrjabini miyazakii (Japan), and P urterobilateralis (Central and West
Africa). P westermani is the most common species causing infection in southeast Asia and China, while
most North American cases of paragonimiasis are caused by P kellicotti. Paragonimus species have
complex life cycles that require 2 intermediate hosts: primarily, snails and crustaceans (eg, crabs,
crayfish), and a definitive mammalian host. In addition to humans, other definitive mammalian hosts
include monkeys, dogs, foxes, wolves, cats, tigers, leopards, pigs, wild boars, and rats. The life cycle of
Paragonimus species (Figure 1) begins with the eggs being released from the definitive hosts via sputum
or feces. When the miracidia are fully developed within the eggs, the eggs hatch in water and the
miracidia swim to infect a snail host. The miracidia penetrate the tissues of the snail and localize in the
hemocele where it becomes a sporocyst. The sporocyst produces rediae asexually and then daughter
rediae. The daughter rediae produce cercariae with a short tail (microcercus cercariae). The cercariae in
water then infect the crustacean hosts. The life cycle of Paragonimus is perpetuated in nature in
omnivorous and carnivorous crustacean-eating mammals, which are the definitive hosts.
The estimated number of people infected with Paragonimus around the world is 20.7 million. The
prevalence of infection is generally higher in men than in women, and higher in young children than
adults. Humans most commonly become infected through ingestion of raw or undercooked crustaceans
(eg, crabs or crayfish) or products derived from these animals (eg, crab or crayfish juice), which are used
in folk medicine practices that contain infective metacercariae. In Asia, the dishes most commonly
associated with human paragonimiasis include drunken crab in China, Kejang (sauced crab) in Korea,
crab juice soup in Japan, raw crayfish salad in Thailand, and raw crab in the Philippines. In the United
States, raw, frozen, or pickled crabs and crayfish are the major sources of infection. In Africa, Peru and
Mexico, eating uncooked crabs and other crustaceans (eg, in ceviche) are the principal mode of
infection. Other ways that humans may become infected are via contamination of fingers with
metacercariae while handling and cooking the crabs or crawfish; the chopping board or other cooking
utensils may also be contaminated and serve as a source of exposure.
After penetration of the intestinal wall, juvenile worms immediately enter the inner wall of the
abdominal cavity where they mature, and then after 5 to 7 days, reappear in the abdominal cavity.
These worms penetrate the diaphragm and appear in the pleural cavity about 14 days after infection.
Worms mate in the pleural cavity and then move to the lung parenchyma where a fibrous cyst develops
around the worms. The worms produce eggs that escape from the cyst into small bronchioles and
eventually to the external environment via sputum or feces. Patients may manifest a number of
different symptoms and clinical findings depending on the location of the worms because of the
complex migration route, as shown in the Table. Most patients are asymptomatic or have subclinical
disease and are unaware of the infection, while others have mild to moderate symptoms for many
months to years before they come to medical attention, if they come to medical attention at all.
General laboratory findings are nonspecific, but may be suggestive of an infection with a helminthic
parasite. These findings include: eosinophilia, which is very commonly seen with two-third of the
patients having eosinophils greater than 500/µL (0.5 x 109/L); elevated immunoglobulin E levels; one-
third of patients will have leukocytosis with white blood cell counts of greater than 10,000/µL (10 x
109/L), while two-thirds of the patients will have leukocyte counts of less than 10,000/µL (10 x 109/L);
eosinophils, Charcot-Leyden crystals, and eggs may be found in respiratory secretions and stools;
neutrophils and macrophages may also be present in the respiratory secretions.
Enzyme-linked immunosorbent assay (ELISA) and immunoblotting are the 2 major serodiagnostic tests
for paragonimiasis. Pleural fluid specimens can be used to test for the presence of anti-
Paragonimusspecific antibody. DNA probes, polymerase chain reaction (PCR), and PCR-based restriction
fragment length polymorphism (PCR-RFLP) analysis can also be used for the diagnosis of paragonimiasis.
The eggs of Paragonimus may be seen in the histologic examination of excised tissues and cytologic
preparations of respiratory specimens and their presence can be used to make a diagnosis. The eggs
(Figure 2) are generally yellowish-brown in color, thick-shelled, and vary in size from 70 to 90 µm long
and 40 to 50 µm wide. They are operculated (have a cap or lid) and asymmetric in shape; they are wide
at the operculum level and tapered at the posterior end. The pathologic findings in the tissue are
dependent on the stage of infection, but can aid in the diagnosis. In the late acute or chronic states of
pleuropulmonary disease, parenchymal lung nodules and cysts, pleural-based lesions, or both may be
seen. The walls of the cysts, which contain the adult parasites, become progressively fibrotic with time.
After the worms die, the cyst contracts and becomes a scar that contains residual eggs entrapped in the
fibrous tissue and may calcify.
The drug of choice for the treatment of paragonimiasis, including cerebral infections, is praziquantel 25
mg/kg per dose 3 times daily for 3 days. In severe disease and in patients with high ELISA titers or
multiple pulmonary lesions, a second course of treatment may be needed to completely cure the
infection. Triclabendazole (not commercially available in the United States or Canada) is another drug
that has been used to treat paragonimiasis. The dosing is 10 mg/kg per dose twice a day.
PREP Pearls
 Paragonimus species (lung fluke) are found in tropical, subtropical, and temperate climates and
occur throughout east and southeast Asia, sub-Saharan Africa, and in the Americas from Peru to
Canada.
 Humans most commonly become infected through ingestion of raw or undercooked crustaceans
(eg, crabs or crayfish) or products derived from these animals (eg, crab or crayfish juice), which
are used in folk medicine practices that contain infective metacercariae.
 Most patients are asymptomatic or have subclinical disease and are unaware of the infection,
while others have mild to moderate symptoms for many months to years before they come to
medical attention. Pleuropulmonary and cerebral disease are the most common manifestations
of infection.
 Recognize the epidemiology (ingestion of raw or uncooked freshwater crabs or crayfish

containing larvae) and clinical manifestations of paragonimiasis, including insidious onset, a
chronic course, eosinophilic response, and pathologic lesions
Suggested Readings
 Chai JY. Paragonimiasis. Neuroparasitology and tropical neurology. In: Garcia HH, Tanowitz HB,
Del Brutto OH, ed. Handbook of Clinical Neurology. Amsterdam, The Netherlands: Elsevier;
2013;Vol 114 (3rd series):283-296.
Question: 4
A previously healthy 14-month-old girl developed a temperature to 39.3°C, red eyes, cough, runny nose,
and fussiness 4 days ago. Last night, a red rash developed on her face and this morning it has spread to
the rest of her body. Physical examination is pertinent for a miserable-appearing child, bilateral bulbar
conjunctivitis, rhinorrhea, and a diffuse morbilliform rash.
Of the following, the agent MOST likely to lessen her morbidity and mortality when administered is
A. intravenous immunoglobulin
B. ribavirin
C. vitamin A
D. vitamin C
E. zinc
Question: 4
A previously healthy 14-month-old girl developed a temperature to 39.3°C, red eyes, cough, runny
nose, and fussiness 4 days ago. Last night, a red rash developed on her face and this morning it has
spread to the rest of her body. Physical examination is pertinent for a miserable-appearing child,
bilateral bulbar conjunctivitis, rhinorrhea, and a diffuse morbilliform rash.
Of the following, the agent MOST likely to lessen her morbidity and mortality when administered is
A. intravenous immunoglobulin
B. ribavirin
C. vitamin A
D. vitamin C
E. zinc
Vitamin A treatment is recommended for all children with measles infection, regardless of
whether or not a child is known to be vitamin A deficient. The evidence for this recommendation
originates largely from studies in developing countries showing more severe measles in children with
vitamin A deficiency, as well as improved outcomes when those children are treated with vitamin A.
Additionally, children in developing countries without vitamin A deficiency appear to have better
outcomes with measles when they receive vitamin A supplementation. Although complementary
studies in developed countries are lacking, vitamin A-deficient children are represented in these
populations, and treatment is therefore recommended universally. Both intramuscular and intravenous
immunoglobulin contain anti-measles antibody and can be used for prophylaxis after exposure to
measles, but these preparations have not been shown to have a role in treatment of measles.
Similarly, ribavirin has in vitro activity against measles virus, but has no clear clinical role. Vitamin C
and zinc have been touted as therapeutic agents for some viral infections, but have not been
demonstrated to be effective for measles.
Micronutrients, such as vitamins and trace elements, have been shown to alter immune function in
vitro in many studies. For example, vitamin A deficiency is associated with decreased response of T
cells to mitogen stimulation, decreased antigen-specific immunoglobulin A and immunoglobulin G
production, decreased ability of CD4+ T lymphocytes to stimulate Th2 responses, and decreased
neutrophil phagocytosis. Vitamin D may play a role in Toll-like receptor-mediated defense against
mycobacterial infection, and zinc plays a role in multiple components of the immune system.
Evidence for clinical effects of vitamins and micronutrients on human infection is lacking in most
instances. A Cochrane review of vitamin C and the common cold did not find a consistent positive
effect, though the authors acknowledged a possible role in individual patients. So far, prophylactic
vitamin C has not been shown to have a role in pneumonia. Zinc might have a role in reducing
symptom severity of the common cold, as well as in preventing pneumonia in children in developing
countries.
PREP Pearls
 Vitamin A therapy is indicated for all children with measles, regardless of vitamin A deficiency
status or country of origin.
 Many micronutrients can impact in vitro immune function, but evidence of a significant impact
for supplementation in human disease is lacking for most substances.
 Know that specific nutritional deficiencies (eg, vitamin A, zinc) contribute to increased severity
of respiratory and gastrointestinal tract infections
Question: 5
A 2-month-old male infant presents with a 2-week history of skin rash. His past medical history is
remarkable for intermittent diarrhea and failure to appropriately gain weight. Physical examination
shows a small, afebrile, well-perfused, alert infant with normal vital signs. Lung fields are clear on
auscultation and cardiovascular examination revealed normal rate and rhythm and no murmurs.
Abdomen showed a soft, nontender abdomen with a liver palpable 4 cm below the right costal margin.
A maculopapular, lichenous, and desquamative rash is present on the extremities and chest.
Laboratory evaluation shows a peripheral blood white blood cell count of 6,200/µL (6.2 x 109/L) with
15% lymphocytes, 80% polymorphonuclear cells, and 5% monocytes. Hemoglobin level is 12 g/dL
(120 g/L). Serum aspartate aminotransferase is 100 U/L (1.7 µkat/L) and alanine aminotransferase is
150 U/L (2.5 µkat/L).
Chest radiographs are performed and shown in Figure 1A and Figure 1B.
Of the following, the MOST likely factor causing this infant‘s condition is
A. bacterial sepsis
B. disseminated adenovirus infection
C. graft-versus-host disease
D. iron overload state
E. X-linked lymphoproliferative disease

Question: 5
A 2-month-old male infant presents with a 2-week history of skin rash. His past medical history is
remarkable for intermittent diarrhea and failure to appropriately gain weight. Physical examination
shows a small, afebrile, well-perfused, alert infant with normal vital signs. Lung fields are clear on
auscultation and cardiovascular examination revealed normal rate and rhythm and no murmurs.
Abdomen showed a soft, nontender abdomen with a liver palpable 4 cm below the right costal margin.
A maculopapular, lichenous, and desquamative rash is present on the extremities and chest.
Laboratory evaluation shows a peripheral blood white blood cell count of 6,200/µL (6.2 x 109/L) with
15% lymphocytes, 80% polymorphonuclear cells, and 5% monocytes. Hemoglobin level is 12 g/dL (120
g/L). Serum aspartate aminotransferase is 100 U/L (1.7 µkat/L) and alanine aminotransferase is 150 U/L
(2.5 µkat/L).
Chest radiographs are performed and shown in Figure 1A and Figure 1B.
Of the following, the MOST likely factor causing this infant’s condition is
A. bacterial sepsis
B. disseminated adenovirus infection
C. graft-versus-host disease
D. iron overload state
E. X-linked lymphoproliferative disease
This infant exhibits absolute lymphopenia and absence of a thymic shadow on chest
radiograph. These findings strongly suggest the diagnosis of severe combined immune
deficiency disorder (SCID), an inherited primary immunodeficiency disorder of T- and
B-lymphocytes and natural killer (NK) cell function. The severe T-cell lymphopenia and
decreased T lymphocyte function observed in infants with SCID cause an inability to
reject foreign material from the body. Therefore, these infants can develop clinically apparent graft-
versus-host disease (GvHD) mediated by transplacentally acquired alloreactive maternal T-lymphocytes,
which occurred in this infant. Additional causes of GvHD in infants with SCID include reactive T cells
present in nonirradiated blood product transfusions and hematopoietic stem cell transplantation, which
is the treatment of choice for most types of SCID. Symptoms of GvHD in infants with SCID include skin
rash, hepatitis, and gastrointestinal inflammation, which were all exhibited by this infant.
Infants with SCID also have a marked susceptibility to life-threatening opportunistic infections, as well as
severe, protracted, or fatal courses of common bacterial, viral, and fungal infections. Bacterial sepsis is
unlikely to be the cause of this infant’s presenting illness because the infant was not acutely ill and did
not show signs of sepsis or septic shock. In addition, bacterial infection in infants with SCID is less
common before the age of 3 to 6 months because of the presence of transplacentally derived protective
maternal immunoglobulin G antibody.
Life-threatening, disseminated viral infections may also be the presenting illness in infants with SCID.
The viruses causing these infections include herpes simplex virus, cytomegalovirus, varicella zoster virus
(both wild type and vaccine strain), Epstein-Barr virus (EBV), rotavirus (both wild type and vaccine
strain), respiratory syncytial virus, influenza virus, and parainfluenza virus. The lack of a systemic
inflammatory response or signs of viral sepsis, as well as the desquamative and lichenous characteristic
of the infant’s rash, make adenovirus less likely.
Iron overload state is characteristic of hemoglobinopathies, such as sickle cell disease (SCD). These
infants are at risk for serious infections, especially infections caused by encapsulated and intracellular
organisms, because of a functional asplenia and decreased opsonic activity. This infant had a normal
hemoglobin, making SCD unlikely.
X-linked lymphoproliferative disease is an inherited primary immune disorder characterized by the lack
of ability to control infection with EBV, causing a serious, potentially fatal lymphoproliferative disease.
An infant with SCID and EBV infection may have rash and hepatitis, but the rash exhibited by this infant
is not characteristic of EBV.
PREP Pearls
 Noninfectious conditions may complicate the course of infants with severe combined immune
deficiency (SCID).
 Infants with SCID, because of their lack of T-cell numbers and function, may exhibit clinically
apparent graft-versus-host disease (GvHD) caused by transplacental maternally derived reactive
T cells.
 Irradiated blood products reduce the risk of GvHD in patients with SCID.
 Understand the role of T-cell immunity in protecting the body from immunologically active graft
cells
Question: 6
A previously healthy 14-year-old male adolescent presents to the office with a 6-day history of fever,
nasal congestion, frontal headache, and fatigue. He has a known history of migraines, but told his
mother that the current headaches are far worse than he has experienced previously. On physical
examination, he is febrile to 41°C. He is very sleepy and when aroused, he appeared confused, holds his
head, and complains that the light hurts his eyes and makes his headache worse. He has tenderness
overlying the frontal sinus. There is no papilledema or focal findings on a complete neurologic
examination.
Of the following, the diagnostic test that MOST clearly elucidates the cause of his current complaints is
A. blood culture
B. cerebrospinal fluid culture
C. computed tomography of the brain
D. cultures from the middle nasal meatus
E. sinus radiographs
Question: 6
A previously healthy 14-year-old male adolescent presents to the office with a 6-day history of fever,
nasal congestion, frontal headache, and fatigue. He has a known history of migraines, but told his
mother that the current headaches are far worse than he has experienced previously. On physical
examination, he is febrile to 41°C. He is very sleepy and when aroused, he appeared confused, holds his
head, and complains that the light hurts his eyes and makes his headache worse. He has tenderness
overlying the frontal sinus. There is no papilledema or focal findings on a complete neurologic
examination.
Of the following, the diagnostic test that MOST clearly elucidates the cause of his current complaints is
A. blood culture
B. cerebrospinal fluid culture
C. computed tomography of the brain
D. cultures from the middle nasal meatus
E. sinus radiographs
The patient has a history and physical examination findings of a paranasal (frontal)
bacterial sinus infection complicated by local direct extension to the subdural space or
brain parenchyma. While cultures from the middle nasal meatus and sinus
radiographs may indicate the sinus origin and microbiologic cause of the current
infection, they will not reveal the extension of the infection to the brain parenchyma,
where it has now caused a frontal lobe abscess.
The most common predisposing clinical feature for the development of a parameningeal abscess in a
child who is previously well is the presence of sinus or middle ear infection. Children with moderate-to
severe mastoiditis can develop sigmoid or cavernous sinus thrombosis with resultant “otitic
hydrocephalus,” even when the infection itself has not (yet) extended to the brain parenchyma. This
form of hydrocephalus is associated with thromboses of the dural sinuses and is characterized by a
marked increase in cerebrospinal fluid pressure, resulting in a neurosurgical emergency to re-establish
cerebrospinal fluid flow.
Parameningeal infections include abscesses, effusions, and empyemas, which occur in the epidural or
subdural spaces surrounding the brain and spinal cord, or in the brain parenchyma itself. Subdural
empyema is a focal purulent collection of fluid between the dura mater and the arachnoid mater. More
than 95% of clinical cases are found in the intracranial space rather than along the spinal axis. Epidural
abscesses develop between the skull and the dura mater. The majority of epidural infections spread to
the subdural space as the infection progresses.
Subdural empyema develops by local direct extension of an infection rather than through
hematogenous seeding. In infants, most cases of subdural empyema result from the infection of reactive
subdural effusions that collect in response to bacterial meningitis. Local spread in older children and in
adults occurs from infected frontal, ethmoid, or sphenoid sinuses. Less commonly, direct spread from an
adjacent osteomyelitis can occur.
The usual clinical presentation of subdural empyema is fever with headache. Symptoms of acute
sinusitis may or may not be evident. As the infection progresses, the patient will typically develop
altered mental status, sometimes with overt clinical symptoms suggesting bacterial meningitis, such as
meningismus, cranial nerve palsy, or other localizing neurologic signs. The presence of papilledema
indicates elevated intracranial pressure. Seizures occur in up to 20% of cases. While brain abscesses can
occur anywhere in the parenchyma, the most frequent sites are the frontal, temporal, and parietal
lobes. Abscesses caused by a direct extension of sinus disease are typically located in the frontal lobes,
while those extending from mastoiditis will infect the temporal lobe.
Two other clinical scenerios that represent significant anatomic risk factors for the development of brain
abscess are cyanotic congenital heart disease and hereditary hemorrhagic telangiectasia. Hereditary
hemorrhagic telangiectasia dramatically increases the risk for brain abscess, likely as a result of
paradoxical emboli from pulmonary arteriovenous malformation.
During the diagnostic evaluation of a child with suspected meningeal or parameningeal infection, a
lumbar puncture is usually performed. The procedure should be deferred in patients with clinical signs
or symptoms of increased intracranial pressure or when paramenigeal pressure is suspected. When
cerebrospinal fluid is collected for cellular and biochemical characteristics, the results are often
nonspecific. Gram stain and cultures are negative in the majority of cases, although total protein
concentrations are usually elevated. There may be a mild-to-moderate pleocytosis. Most of the
infiltrating cells are polymorphonuclear leukocytes. Sterile intraoperative cultures are reported in
approximately half of cases, presumably at least in part, because of the preoperative administration of
antibiotics. Infections that extend from the paranasal or mastoid sinuses can be expected to be
polymicrobial in nature. When cultures are positive, Gram-positive aerobic organisms (including
Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus anginosus,
and other α-hemolytic Streptococcus) with or without Gram-positive and Gram-negative anaerobes are
characteristic. Less commonly, aerobic Gram-negative rods are found.
Computed tomography (CT) is often the first neuroimaging obtained in patients with suspected
parameningeal infection. The study will reveal the presence of the mass lesions with surrounding
edema. On CT, peripheral rim enhancement is seen on contrast studies. On magnetic resonance
imaging, the presence of restricted diffusion within an enhancing ring strongly implicates a pyogenic
abscess (Figure).
Antimicrobial options for the empiric treatment of subdural, epidural, or brain abscess should include a
combination of anti-infectives that target the likely causative agents. Vancomycin, metronidazole, and a
third generation cephalosporin such as ceftriaxone or cefotaxime are typically used. The duration of
therapy is usually 4 to 6 weeks, but should be extended to 6 to 8 weeks (or longer) if adjacent bone is
also infected.
PREP Pearls
 Most brain abscesses in previously healthy children arise from local direct extension of a sinus or
middle ear infection.
 Cyanotic congenital heart disease and hereditary hemorrhagic telangiectasia are known risk
factors for the development of bacterial brain abscess.
 Sterile cerebrospinal fluid cultures do not exclude parameningeal infection.

Question: 7
There is an outbreak of gastroenteritis in a local child care center. The attendees range in age from 2
months to 5 years. Stool cultures from several children are positive for Salmonella enterica subspecies
enterica. The childcare center management contacts your office for recommendations regarding
treatment for the attendees and staff.
Of the following, the BEST approach to treatment of Salmonella gastroenteritis in this situation is to
treat
A. children as well as the staff
B. children younger than 3 months of age
C. children younger than 3 months of age and all others with gastroenteritis
D. children younger than 3 months of age and all staff members
E. no one because the illness is usually self limited

Question: 7
There is an outbreak of gastroenteritis in a local child care center. The attendees range in age from 2
months to 5 years. Stool cultures from several children are positive for Salmonella enterica subspecies
enterica. The childcare center management contacts your office for recommendations regarding
treatment for the attendees and staff.
Of the following, the BEST approach to treatment of Salmonella gastroenteritis in this situation is to
treat
A. children as well as the staff
B. children younger than 3 months of age
C. children younger than 3 months of age and all others with gastroenteritis
D. children younger than 3 months of age and all staff members
E. no one because the illness is usually self limited
Nontyphoidal Salmonella gastroenteritis is generally self limited in nature.

Antimicrobial treatment usually does not shorten the duration of the illness and may
prolong fecal excretion. Therefore, antibiotic treatment is not indicated for normal
healthy children older than 3 months of age or the staff, even when they are
symptomatic with diarrhea. Treatment should be considered for children younger
than 3 months of age because of the increased risk of invasive disease, as well as individuals who are
immunocompromised, have chronic gastrointestinal disease, hemoglobinopathies, HIV infection, or
malignant neoplasms.
Most cases of gastroenteritis in children in the United States are viral in origin, therefore antimicrobial
treatment would not be indicated. Indications for antimicrobial treatment are multifactorial and depend
on several factors, including the age of the patient, whether they are immunocompromised or not,
history of travel, pet or animal exposure, childcare attendance, and history of any antibiotic use or
recent hospitalization. Other factors that may be helpful include the immunization history because
severe diarrhea caused by Rotavirus would be unlikely in a child who has been immunized. A history of
hepatitis A vaccination would also make that very unlikely as a cause of diarrhea. Knowledge of any
specific local epidemiological factors such as a foodborne or recreational facility-related outbreak in the
community may also be helpful.
The nature of the diarrhea itself may be helpful in determining whether antimicrobial agents would be
indicated, ie, diarrhea caused by viruses (and some parasites such as Cryptosporidium) is usually profuse
and watery, while bacterial diarrhea tends to be mucoid with blood and may be accompanied by a
history of small frequent stools with tenesmus.
The mainstay of treatment for acute bacterial gastroenteritis in immune competent hosts is adequate
rehydration therapy because most cases are self-limited. Anti-motility agents may be used in select
cases with watery diarrhea, but should be avoided in young children, as well as in cases where there is a
history of blood and mucus in the stool because of the concern for hemolytic uremic syndrome. Use of
probiotics should also be considered in cases of watery diarrhea. Antimicrobial agents may however be
indicated in certain select circumstances. The Table lists the clinical indications and antimicrobial agents
indicated by the specific microorganism.
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PREP Pearls
 Most cases of gastroenteritis in children are viral in origin and self limited. The use of probiotics
should be considered in these cases
 Gastroenteritis caused by bacteria is also often self limited in normal healthy hosts
 Treatment is usually reserved for cases with dysentery usually caused by Shigella, in severe
cases of traveler’s diarrhea, or in immunocompromised hosts
 Know the clinical indication and choice of antimicrobial agents in gastroenteritis

Question: 8
The pediatric fellows at your institution are hosting a conference on bioethics, with an emphasis upon
clinical research in pediatrics. The pediatric infectious diseases service is invited to attend because your
division is very involved with clinical trials involving new antibiotic drug development, vaccines, and
antiviral and retroviral therapies for infants, children, and adolescents. The principles for research on
children were reviewed, including the history of the creation of current guidelines, which emphasize the
need for parental approval for research, for children older than 7 years of age to assent, for protection
of children in special care, and the creation of the current Institutional Review Board (IRB) system.
Of the following, the name of the guideline enacted to protect the rights of children is
A. Belmont Report
B. Declaration of Geneva
C. Declaration of Helsinki
D. Hippocratic Oath
E. Nuremberg Code
Question: 8
The pediatric fellows at your institution are hosting a conference on bioethics, with an emphasis upon
clinical research in pediatrics. The pediatric infectious diseases service is invited to attend because your
division is very involved with clinical trials involving new antibiotic drug development, vaccines, and
antiviral and retroviral therapies for infants, children, and adolescents. The principles for research on
children were reviewed, including the history of the creation of current guidelines, which emphasize the
need for parental approval for research, for children older than 7 years of age to assent, for protection
of children in special care, and the creation of the current Institutional Review Board (IRB) system.
Of the following, the name of the guideline enacted to protect the rights of children is
A. Belmont Report
B. Declaration of Geneva
C. Declaration of Helsinki
D. Hippocratic Oath
E. Nuremberg Code
The correct response is A, the Belmont Report (respect for persons, beneficence, and
justice). On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into
law, thereby creating the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research. The Belmont Report attempts to summarize
the basic ethical principles identified by the Commission in the course of its
deliberations. It is the outgrowth of an intensive 4-day period of discussions that were held in February
1976 at the Smithsonian Institution's Belmont Conference Center and is a statement of basic ethical
principles and guidelines that assist in resolving the ethical problems that surround the conduct of
research with human subjects. Any researcher receiving US Department of Health and Human Services
(HHS) funds and experimenting on human subjects is mandated to comply with these guidelines; these
guidelines ultimately led to the creation of the current Institutional Review Board (IRB) system and its
set of regulations. They proposed and emphasized the need for parents to approve any research on
their child(ren), including informed consent, for children older than 7 years of age to assent to research,
and for children in special care (either medical, psychiatric, or because they were orphans or had
committed juvenile crimes) generally to be subjects of research only if there was some direct connection
between the reasons for their special care and the objectives of the research. The Commission's work
was capped by the Belmont Report (1978), entitled Ethical Principles and Guidelines for the Protection of
Human Subjects of Research, which has since set the standard for ethical considerations related to
research on human subjects. The Belmont Report, the general recommendations of the Commission,
and the specific recommendations about research involving children have been largely sustained for the
past thirty years, and they now apply to the biomedical, behavioral, and social sciences, not only for all
federally-funded research, but by extension, virtually all academic and much other research conducted
in the United States. One of the charges to the Belmont report was to identify the basic ethical
principles that should underlie the conduct of biomedical and behavioral research involving human
subjects and to develop guidelines, which should be followed to assure that such research be conducted
in accordance with those principles. Three principles, or general prescriptive judgments, that are
relevant to research involving human subjects are identified in this Report. These 3 are comprehensive
and are stated at a level of generalization that should assist scientists, subjects, reviewers, and
interested citizens to understand the ethical issues inherent in research involving human subjects. These
principles cannot always be applied so as to resolve beyond dispute particular ethical problems. The
objective is to provide an analytical framework that will guide the resolution of ethical problems arising
from research involving human subjects.
The expression "basic ethical principles" refers to those general judgments that serve as a basic
justification for the many particular ethical prescriptions and evaluations of human actions. Three basic
principles are particularly relevant to the ethics of research involving human subjects: the principles of
respect of persons, beneficence, and justice.
1. Respect for Persons. Respect for persons incorporates at least 2 ethical convictions: first, that
individuals should be treated as autonomous agents, and second, that persons with diminished
autonomy are entitled to protection. Respect for persons requires that subjects, to the degree
that they are capable, be given the opportunity to choose what shall or shall not happen to
them. This opportunity is provided when adequate standards for informed consent are satisfied.
2. Beneficence. Persons are treated in an ethical manner not only by respecting their decisions and
protecting them from harm, but also by making efforts to secure their well-being. Such
treatment falls under the principle of beneficence. The term "beneficence" is often understood
to cover acts of kindness or charity that go beyond strict obligation. Two general rules have
been formulated as complementary expressions of beneficent actions in this sense: (1) do not
harm and (2) maximize possible benefits and minimize possible harms.
3. Justice. The question of justice is who ought to receive the benefits of research and bear its
burden, in the sense of "fairness in distribution" or "what is deserved." An injustice occurs when
some benefit to which a person is entitled is denied without good reason or when some burden
is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be
treated equally. However, this raises the question about who is equal and who is unequal, and
what considerations justify departure from equal distribution. The Belmont Report does allow
distinctions based on experience, age, deprivation, competence, merit, and position, which
sometimes constitute criteria justifying differential treatment for certain purposes. There are
several widely accepted formulations of just ways to distribute burdens and benefits. Each
formulation mentions some relevant property on the basis of which burdens and benefits
should be distributed. These formulations are (1) to each person an equal share, (2) to each
person according to individual need, (3) to each person according to individual effort, (4) to each
person according to societal contribution, and (5) to each person according to merit.
The Commission's deliberations took place during the post-World War II period of rapid changes in
understandings of childhood and adolescence, brought on in part by institutionalized children's highly
visible roles in hepatitis experimentation, poliovirus clinical trials, as well as the civil rights movement,
by the children's rights movement and court decisions granting children and adolescents greater
autonomy in divorce cases, in delinquency and mental health hearings, among other rights, and finally
by a movement for child protection led by parents of disabled children and by polio survivors
themselves. The National Commission's recommendations emphasized the need for informed consent,
for children to assent to research, and to protect children in special care. Ultimately, in these
recommendations, the National Commission charted a middle ground between the children's rights
movement, which advocated enhanced self-determination for children, and the disability rights
movement, which urged greater protection for children.
In 1947, after World War II, trials focused on doctors in Nazi Germany involved in the human
experiments in concentration camps. The trial verdict adopted 10 points, which constituted the
"Nuremberg Code." Although the legal force of the document was not established and it was not
incorporated directly into either American or German law, the Nuremberg Code and the related
Declaration of Helsinki became the basis for the Code of Federal Regulations (CFR) relating to human
subjects. The Nuremberg Code includes such principles as the voluntary consent of the human, that
experiment(s) should yield fruitful results for the good of society, to avoid all unnecessary physical and
mental suffering and injury, and that the human subject should be at liberty to bring the experiment to
an end if he or she chooses. The CFR is an annual codification of the general and permanent rules
published in the Federal Register by the executive departments and agencies of the federal government,
which are the regulations issued by the HHS governing federally-funded human subjects research in the
United States.
The Declaration of Helsinki was originally adopted in June 1964 in Helsinki, Finland, and has since
undergone numerous revisions. The Declaration is an important document in the history of research
ethics as it is the first significant effort of the medical community to regulate research itself, and forms
the basis of most subsequent documents. Prior to the 1947 Nuremberg Code, there was no generally
accepted code of conduct governing the ethical aspects of human research, although some countries,
notably Germany and Russia, had national policies. The Declaration developed the ten principles first
stated in the Nuremberg Code, and tied them to the Declaration of Geneva, a statement of physicians'
ethical duties. The Declaration of Helsinki more specifically addressed clinical research, reflecting
changes in medical practice from the term “Human Experimentation” used in the Nuremberg Code. A
notable change from the Nuremberg Code was a relaxation of the conditions of consent, which was
“absolutely essential” under Nuremberg, to be able to obtain consent where a proxy consent, such as a
legal guardian, was available. The Declaration of Geneva (Physician's Oath) was adopted by the General
Assembly of the World Medical Association at Geneva in 1948, and has been amended numerous times.
It is a declaration of the humanitarian goals of medicine and intended as a revision of the Hippocratic
Oath, so that the oath's moral truths could be comprehended and acknowledged in a modern way.
PREP Pearls
 The Belmont Report is a statement of basic ethical principles and guidelines that should assist in
resolving the ethical problems that surround the conduct of research with human subjects.
 The 3 basic principles of the Belmont Report are particularly relevant to the ethics of research
involving human subjects: the principles of respect of persons, beneficence, and justice.
 Any researcher receiving Department of Health and Human Services funds and experimenting
on human subjects is mandated to comply with these guidelines.
 These guidelines ultimately led to the creation of the current Institutional Review Board system
and its set of regulations.
 The Belmont Report emphasizes the need for informed consent, for assent to research, and for
protection of children in special care in research.
 Understand and apply the three main principles of research ethics articulated in the Belmont
Report (ie, respect for persons, beneficence, and justice)
February
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Assessment History Reset Assessment
Mode: Learner Exam
Assessment Progress: Total Questions: 8 Questions Answered: 0 Correct Answers: 0
You currently have 8 questions unanswered in this assessment
Question: 1
You are assisting the local health department in investigating an ongoing measles outbreak in a
nearby immigrant community. The index case was a 4-month-old male infant who recently returned
from overseas. Subsequently, his 2 older siblings, a 6-month-old cousin, 1 parent were all
unimmunized and developed the disease. A postexposure immunization campaign for community
contacts is underway.
Of the following, the postexposure strategy MOST likely to be recommended for this community is
A. Measles Vaccine
should be given to all exposed children 1 year of age or older without evidence of 2 measles
containing vaccines
Measles immune globulin
should be given to all exposed infants younger than 1 year of age, exposed pregnant
women, and children who are immune compromised within 2 days of exposure
B. Measles Vaccine
containing vaccines within 6 days of exposure
should only be given to children who are immune compromised within 3 days of exposure
C. Measles Vaccine
should be given to all exposed children regardless of age within 3 days of exposure of
without evidence of 2 measles containing vaccines
should only be given to children who are immune compromised and pregnant women within
6 days of exposure
D. Measles Vaccine
should be given to all exposed children 6 months of age or older within 3 days of exposure
of without evidence of 2 measles containing vaccines
should be given to those younger than 6 months of age, pregnant women, and children who
are immune compromised within 6 days of exposure
E. Measles Vaccine
should be given to all exposed children regardless of immunization status or immune

compromising condition
should be given to all exposed pregnant women within 6 days of exposure

Question: 1
You are assisting the local health department in investigating an ongoing measles outbreak in a nearby
immigrant community. The index case was a 4-month-old male infant who recently returned from
overseas. Subsequently, his 2 older siblings, a 6-month-old cousin, 1 parent were all unimmunized and
developed the disease. A postexposure immunization campaign for community contacts is underway.
Of the following, the postexposure strategy MOST likely to be recommended for this community is
A. Measles Vaccine
containing vaccines
should be given to all exposed infants younger than 1 year of age, exposed pregnant women,
and children who are immune compromised within 2 days of exposure
B. Measles Vaccine
containing vaccines within 6 days of exposure
should only be given to children who are immune compromised within 3 days of exposure
C. Measles Vaccine
should be given to all exposed children regardless of age within 3 days of exposure of without
evidence of 2 measles containing vaccines
should only be given to children who are immune compromised and pregnant women within 6
days of exposure
D. Measles Vaccine
should be given to all exposed children 6 months of age or older within 3 days of exposure of
without evidence of 2 measles containing vaccines
should be given to those younger than 6 months of age, pregnant women, and children who are
immune compromised within 6 days of exposure
E. Measles Vaccine
should be given to all exposed children regardless of immunization status or immune

compromising condition
should be given to all exposed pregnant women within 6 days of exposure
Measles is a highly contagious virus with most of the disease transmission occurring
prior to symptom onset. Measles cases have increased in the United States over the
last 5 years with a record number of cases reported in 2014 (n=592 as of August 25,
2014). Eighteen separate outbreaks have been identified involving 21 different states.
The majority of people who developed measles were unimmunized and many index
cases developed infection while out of the country and then became ill upon return to the United States,
thus spreading infection in their communities.
In the setting of a community outbreak, measles-containing vaccine should be offered to all exposed
people without evidence of immunity (ie, serologic evidence or evidence of 2 doses of vaccine) within 3
days of exposure. However, in a community outbreak that involves infants, immunization may be given
to infants 6 to 11 months of age. Seroconversion rates after immunization in this setting are lower, and
thus measles-containing vaccines provided before 12 months of age cannot be counted. Thus, any
patient who receives a measles vaccine between 6 to 11 months of age will still need 2 more measles-
containing vaccines at 12 to 15 months and 4 to 5 years, and at least 28 days following the prior vaccine.
Measles immune globulin should be provided to all exposed infants less than 6 months of age, exposed
pregnant women, and exposed immune compromised persons who cannot take a live virus vaccine (eg,
oncology patient undergoing immune suppressive chemotherapy) within 6 days of exposure. Measles
immune globulin may be given beyond the 6 day period, but may be less effective in preventing or
ameliorating disease. Therefore, the preferred response for the community described in the vignette is
that measles vaccine should be given to all exposed children 6 months of age or older within 3 days of
exposure, and measles immune globulin should be given to those younger than 6 months of age,
pregnant women, and children who are immune compromised within 6 days of exposure. Additional
considerations during a community outbreak include identifying immunization status in all community
members, alerting health care personnel who work in these communities, and coordinating efforts with
the local health department to aid in source control. In circumstances in which measles immunization or
measles immune globulin cannot be given within the recommended time frame, exposed persons
should be excluded from school, work, and other public settings for the entire 21 day incubation period.
The efficacy of measles vaccine in an outbreak setting has been shown to be as high as 90% when
provided within 72 hours of exposure, but not in children who received vaccine on day 4 to 5 after
exposure. Approximately 95% of children develop measles antibodies after 1 dose of measles vaccine
when given at 12 months of age or older, and in 98% of children immunized at 15 months of age.
Approximately 2% to 5% of children fail to respond and have primary immunization failure after 1 dose
of vaccine. Primary vaccine failure may occur because of circulating passive antibody in the vaccine
recipient, improperly stored vaccine, or other reasons. Protection is durable in most people, although
some will lose protection several years after initial immunization. Greater than 99% of people who
receive 2 measles containing vaccines separated by at least 28 days at 12 months of age or older
develop measles immunity.
Historically, the measles vaccine is derived from an attenuated strain of an infected individual and is
termed the Edmonston strain. This strain was made famous by Enders and colleagues who further
passaged the Edmonston strain in primary kidney cells 24 times, primary human amnion cells 28 times,
and then adapted it to chicken embryos with 6 passages in chick embryo cells. This strain was
administered in the United States between 1963 and 1975, but had a high side effect profile, with 20%
to 40% of children developing fever to 39.4°C and 50% developing a rash. Thus, 2 further attenuated
vaccines became available in the 1960s. The Schwartz strain became available in 1965 and underwent
an additional 85 passages in chicken embryo cells, and the Moraten strain became available in 1968 and
had an additional 40 passages in chicken embryo cells. These vaccines are better tolerated with only 5%
to 15% developing fever to 39.4°C and rash in only 3% to 5% of recipients. Currently, the only vaccine
available in the United States is the Moraten strain, which is currently only available in the combination
vaccines measles, mumps, and rubella (MMR) and measles, mumps, rubella, and varicella (MMRV),
while the Schwartz strain is available in many European countries. The MMR and MMRV vaccines are
supplied as a freeze dried powder and are reconstituted with sterile, preservative-free water. The
vaccines contain a small amount of human albumin, neomycin, sorbitol, and gelatin.
PREP Pearls
 In a community outbreak setting measles vaccine should be provided to exposed infants and
children older than 6 months of age within 72 hours of exposure.
 In a community outbreak setting measles immune globulin should be provided to infants

younger than 6 months of age and immune compromised persons and pregnant women within
6 days of exposure.
 Current measles vaccine is further attenuated in chicken embryo cells.
 Know the means of prevention of measles in exposed and unexposed, susceptible patients,
including the appropriate measures for control of a rubeola outbreak
 Know the composition of measles vaccine, including its nature, tissue culture source, and
vaccine constituents
 Know the immunogenicity and potential efficacy of measles vaccine in the prevention of
infection
Question: 2
A new patient arrives at your office. He is an HIV-infected boy who recently immigrated to the United
States and he comes to the office visit with documentation of his current antiretroviral regimen. His
regimen includes zalcitabine (ddC). Although you recall that this is a nucleoside analog reverse
transcriptase inhibitor, you are otherwise unfamiliar with this antiretroviral and you search for
information about this drug.
Of the following, the MOST accurate statement about ddC is that :
A. formulations include both a liquid and a capsule
B. is an analog of purine
C. is associated with peripheral neuropathy
D. is significantly more potent than other nucleoside analog reverse transcriptase inhibitors
E. it exhibits limited cross resistance with other nucleoside analog reverse transcriptase inhibitors
Question: 2
A new patient arrives at your office. He is an HIV-infected boy who recently immigrated to the United
States and he comes to the office visit with documentation of his current antiretroviral regimen. His
regimen includes zalcitabine (ddC). Although you recall that this is a nucleoside analog reverse
transcriptase inhibitor, you are otherwise unfamiliar with this antiretroviral and you search for
information about this drug.
Of the following, the MOST accurate statement about ddC is that :
A. formulations include both a liquid and a capsule
B. is an analog of purine
C. is associated with peripheral neuropathy
D. is significantly more potent than other nucleoside analog reverse transcriptase inhibitors
E. it exhibits limited cross resistance with other nucleoside analog reverse transcriptase inhibitors
Zalcitabine (ddC) is associated with peripheral neuropathy, most frequently affecting the distal
extremities and especially the feet. Neuropathy among ddC patients usually begins with numbness or
paresthesias and can persist for weeks after discontinuation of ddC. Other adverse events among
patients using ddC include headache, abdominal pain, fever, fatigue, nausea, vomiting diarrhea, rash,
painful swallowing, and difficulty sleeping. Pancreatitis and painful oral ulcerations are reported rarely.
An analog of pyrimidine, ddC (2’-3’-dideoxycytidine) is a nucleoside analog reverse transcriptase

inhibitor (NRTI). The active metabolite (dideoxycitidine triphosphate) functions as a substrate for the
reverse transcriptase enzyme of HIV. Its incorporation into viral DNA results in termination of chain
elongation. In terms of antiviral activity, ddC is similar to another NRTI: didanosine (ddI).
In the United States, ddC was used relatively infrequently in children for 3 reasons:
1. There was no liquid formulation (a capsule formulation was utilized by adults with HIV)
2. The adverse events associated with its use
3. Extensive cross-resistance between ddC and other NRTIs, especially ddI and 3TC.
Thus, there was little utility in changing to ddC if an HIV-infected individual had previously used ddI or
3TC, and viral resistance had developed to 1 or both of these drugs.
The US Food and Drug Administration approved ddC in 1992. Sales of ddC in the United States were
discontinued by the manufacturer in 2006; this decision was attributed to the widespread availability
and use of other, more effective antiretrovirals.
PREP Pearls
 Zalcitabine (ddC) is a reverse transcriptase inhibitor.
 ddC is associated with peripheral neuropathy and other adverse events.
 The sale of ddC was discontinued in the United States in 2006, and this antiretroviral is not
included in current guidelines for the use of antiretrovirals in pediatric patients.
 Know the mechanism of action of dideoxycytosine (ddC)
 Know the adverse effects and toxicity of dideoxycytosine (ddC) in children versus adults
 Know the possible indications for dideoxycytosine (ddC) therapy for children
Question: 3
You are asked by a general pediatrician for advice regarding immunizations for a 2-year-old boy who was
diagnosed with pre-B cell acute lymphocytic leukemia at 12 months of age. The boy had undergone
induction chemotherapy with vincristine, PEG L-asparaginase, and corticosteroids, followed by
consolidation chemotherapy with 6-mercaptopurine and vincristine. The child has done well and is now
receiving maintenance chemotherapy of daily 6-MP, weekly oral methotrexate, monthly vincristine, and
monthly corticosteroid bursts. His absolute neutrophil count and lymphocyte counts have been
consistently around 1,000/mm³. The child had received age-appropriate immunizations through 6
months of age and has not received further vaccinations.
Of the following vaccines being considered by the pediatrician, it is MOST appropriate to vaccinate this
boy with
A. inactivated influenza vaccine
B. live attenuated influenza vaccine
C. measles-mumps-rubella vaccine
D. meningococcal vaccine
E. varicella vaccine
Question: 3
You are asked by a general pediatrician for advice regarding immunizations for a 2-year-old boy who was
diagnosed with pre-B cell acute lymphocytic leukemia at 12 months of age. The boy had undergone
induction chemotherapy with vincristine, PEG L-asparaginase, and corticosteroids, followed by
consolidation chemotherapy with 6-mercaptopurine and vincristine. The child has done well and is now
receiving maintenance chemotherapy of daily 6-MP, weekly oral methotrexate, monthly vincristine, and
monthly corticosteroid bursts. His absolute neutrophil count and lymphocyte counts have been
consistently around 1,000/mm³. The child had received age-appropriate immunizations through 6
months of age and has not received further vaccinations.
Of the following vaccines being considered by the pediatrician, it is MOST appropriate to vaccinate this
boy with
A. inactivated influenza vaccine
B. live attenuated influenza vaccine
C. measles-mumps-rubella vaccine
D. meningococcal vaccine
E. varicella vaccine
The safety and efficacy of vaccines in children with cancer varies according to the
degree of immunosuppression and the underlying disease. Published experience
regarding the safety and efficacy of vaccines in children with specific cancers is
limited. Accordingly, recommendation guidelines have recently been developed by
the Infectious Diseases Society of America (IDSA). In general, inactivated vaccines are
safe in children with cancer and should be used when appropriate. For the child in the vignette, who is
receiving maintenance immunosuppressive therapies, it is most important to recommend inactivated
influenza vaccine (as early as 4 months after transplant). Annual inactivated influenza vaccine is
indicated for any patient 6 months of age or older that has a hematological or solid tumor malignancy,
provided the patient is not receiving anti-B-cell antibodies or intensive chemotherapy, such as for
induction or consolidation chemotherapy for acute lymphocytic leukemia (ALL), because of poor
response rates of vaccination administered during these periods. Although inactivated vaccinations are
less immunogenic when administered during maintenance chemotherapy as compared to children who
have completed chemotherapy, they are not harmful and appear to provide some protection. Similarly,
pneumococcal vaccine (13-valent conjugate vaccine and/or polysaccharide vaccine—depending on the
age and history of vaccination) should be administered to children with malignancies. Other inactivated
vaccines routinely recommended in the immunization schedule can be considered for children who are
receiving maintenance chemotherapy, although vaccines received during this time should not be
counted as valid doses unless there is documentation of a protective antibody level. Live viral vaccines
(such as live attenuated influenza, measles-mumps-rubella, and varicella vaccines) are contraindicated
because of the risk of disseminated infection and prolonged shedding. Although varicella vaccine has
been studied in children with ALL who are receiving maintenance chemotherapy, it generally is not
recommended for children receiving such therapy. Although meningococcal vaccine would not be
contraindicated for the child in the vignette, it is not recommended because the child is not considered
at increased risk for meningococcal disease.
In general, adequate responses to vaccines appear to occur between 3 and 12 months after
discontinuation of immunosuppressive therapies. Recent IDSA recommendations state that the routine
immunization schedule (both inactivated and live vaccines) for children with cancer can be reinitiated 3
months after completion of chemotherapy. However, children who received regimens that included
anti-B cell antibodies should have vaccinations delayed at least 6 months. For children who have
undergone hematopoietic stem cell transplantation (HSCT), inactivated vaccines may be administered 6
to 12 months after HSCT (as early as 4 months for inactivated influenza vaccine), while live virus vaccines
may be administered 24 months after HSCT, provided the child does not have graft-versus-host disease
or ongoing immunosuppression.
Passive immunoprophylaxis has been shown to be effective for patients with cancer and can be used to
prevent or ameliorate infection in susceptible patients who cannot receive active immunization. An
infection-specific example is the use of varicella-zoster immune globulin (VZIG) to prevent or modify
varicella infection in susceptible children. Administration of VZIG (or IVIG if VZIG is not available) should
be performed as soon as possible (but within 10 days) to children with cancer who are exposed to
varicella, have no history of varicella, and have unknown or negative serologic test results.
Chemoprophylaxis has also been used to prevent infections in children with cancer. The use of
trimethroprim-sulfamethoxazole for prophylaxis against Pneumocystis jirovecii (PCP) in children with
cancer has been shown to be extremely effective and has resulted in a significant reduction of PCP in
children with malignancies. Acyclovir prophylaxis has been shown to be effective in preventing recurrent
herpes simplex virus infections in patients receiving intensive chemotherapy or bone marrow
transplantation, and varicella reactivation after bone marrow transplantation. The use of prophylactic
antibiotics, mainly fluoroquinolones, to prevent infections in patients who have prolonged neutropenia
has been studied in adults. In these trials, prophylactic antibiotics have been shown to reduce the
frequency of febrile episodes and possibly all cause mortality. The risk-benefit ratio of prophylactic
fluoroquinolone therapy in children with prolonged neutropenia has not been studied adequately
however. Clinical practice guidelines from the IDSA state that it may be reasonable to consider
fluoroquinolone prophylaxis for children in very high risk situations, such as allogeneic transplantation
or induction therapy for acute leukemia. Musculoskeletal toxicity and increasing rates of antimicrobial
resistance are possible risks of such prophylaxis; thus, vigilant monitoring for these is imperative if
prophylaxis is implemented for these patients.
Antifungal prophylaxis is often considered and/or instituted for patients with cancer who have
prolonged neutropenia (≥ 7 days). While fluconazole prophylaxis has been shown to be effective in
reducing the risk of Candida infections in neutropenic patients, broad use of this agent has led to an
increase in Candida species that are less susceptible to fluconazole, such as C glabrata and C krusei.
Thus, the IDSA recommends prophylaxis for patients who have substantial risk of invasive Candida
infections, such as allogeneic HSCT recipients or those undergoing intensive chemotherapy for acute
leukemia. At the present time, prophylaxis against invasive Aspergillus infection with posaconazole
should be considered for selected patients 13 years of age or older who are undergoing intensive
chemotherapy for acute myelocytic leukemia/myelodysplastic syndrome.
PREP Pearls
 Inactivated vaccines are safe, but may not be effective in children who are undergoing
treatment for cancer.
 Live viral vaccines are contraindicated in children receiving chemotherapy because of the risk of
disseminated infection and prolonged shedding.
 Passive immunoprophylaxis may be effective in preventing or ameliorating infection in

susceptible hosts.
 Chemoprophylaxis, such as the use of trimethoprim-sulfamethoxazole to prevent Pneumocystis

infection, may be used in certain situations to prevent infections in children with cancer.
 Know specific measures, and their effectiveness for immuno- and chemoprophylaxis, of
infection in patients with cancer
Question: 4
You are consulted for advice on choice of antistaphylococcal agents for a 2-year-old girl with pneumonia
who continues to need oxygen therapy after 7 days of intravenous vancomyin therapy and has a new
finding of pneumatoceles on chest radiograph. She has a history of severe eczema with recurrent
staphylococcal abscesses since the newborn period, has been treated for sinusitis 5 times, has had 2
prior hospitalizations for pneumonia requiring antibiotics, and has sustained a fracture of her humerus
after minimal trauma, attributed to osteoporosis. A review of laboratory tests performed during prior
hospitalizations reveals white blood cell counts in the normal range, normal total lymphocyte and
neutrophil counts, and persistent eosinophilia.
After you complete your consult, you conclude that the girl has an underlying disorder that MOST likely
is :
A. chronic granulomatous disease
B. eczema-thrombocytopenia-immunodeficiency syndrome
C. hyper-immunoglobulin E syndrome
D. severe atopic dermatitis
E. severe combined immunodeficiency with hypereosinophilia
The girl in the vignette has autosomal dominant hyper-IgE syndrome (AD-HIES, STAT3
deficiency or Job syndrome) because she has a characteristic skeletal abnormality
(osteoporosis) and eczema that began soon after birth. The genetic hyper-
immunoglobulin E (IgE) syndromes are characterized by eczema, persistent and
markedly elevated serum IgE levels, recurrent sinopulmonary infections, and other
severe infections. They are multisystem disorders with bone, dental, central nervous system, joint, and
vascular abnormalities, and older children have a “coarse facies.” Autosomal recessive hyper-IgE
syndrome (AR-HIES, DOCK8 deficiency) is distinguishable from AD-HIES by chronic, widespread

cutaneous viral infections caused by human papillomavirus (verrucous warts) and Molluscum
contagiosum (umbilicated papules) (Table). Eczema in DOCK8 deficiency typically becomes obvious at
several months of age, similar to the time course in atopic dermatitis. Patients with atopic dermatitis
may have IgE levels comparable to those seen in hyper IgE syndromes, but lack the other clinical
stigmata, and have documented allergies. Elevated IgE levels can be a component of other
immunodeficiency syndromes, but these manifest early in infancy with severe infections other than
Staphylococcus aureus: Wiskott–Aldrich syndrome (eczema-thrombocytopenia-immunodeficiency
syndrome), which is usually an X-linked disorder, and Omenn syndrome (severe combined
immunodeficiency with hypereosinophilia), which usually manifests with histiocytic reticulocytosis.
Elevated IgE levels are not a component of CGD, a disorder of phagocyte function of variable age onset
although diagnosed most often in toddlers; skeletal abnormalities and eczema are not features.
The management of AD-HIES and AR-HIES is primarily supportive, but prophylactic antibiotics, eg,
trimethoprim–sulfamethoxazole decrease the frequency and severity of S aureus skin abscesses and of
bacterial pneumonia. Prevention of staphylococcal pneumonia decreases the risk of parenchymal lung
damage. Use of dilute bleach baths or swimming in chlorinated pools is helpful in diminishing S aureus
colonization. Antifungal prophylaxis with fluconazole has some efficacy in decreasing the recurrences or
severity of chronic Candida infections, and voriconazole, posaconazole, or itraconazole is indicated in
patients with proven Aspergillus lung infection. The frequent need for immunosuppressive therapy,
most commonly corticosteroids, to control eczema increases the risk and severity of Molluscum and of
opportunistic infections. The role of immunoglobulin replacement therapy remains unproven, but is
generally used in patients who have breakthrough infections on prophylactic antibiotic therapy. To date,
bone marrow transplantation has not been curative, although anecdotally, some patients had resolution
of Molluscum infections.
PREP Pearls
 Eosinophilia and markedly elevated immunoglobulin E (IgE) can be seen in many conditions, but
stigmata of congenital hyper-IgE syndromes (HIES) should be recognized, eg, lung disease is one
of the criteria for diagnosis of HIES.
 Genetic mutations for autosomal dominant and autosomal recessive hyper-IgE syndromes have
recently been identified.
 Prophylactic antibiotic therapy (trimethoprim-sulfamethoxazole) is beneficial in hyper-IgE

syndromes.
 Plan specific long-term preventive therapy for a patient with hyperimmunoglobulin E syndrome
Question: 5
You are speaking to a group of residents about various common antibiotics used frequently in practice
and their spectrum of activity.
Of the following, clindamycin does not have any activity against
A. Actinomyces israelii
B. Babesia species
C. Enterococcus faecalis
D. Peptostreptococcus species
E. Streptococcus agalactiae
Question: 5
You are speaking to a group of residents about various common antibiotics used frequently in practice
and their spectrum of activity.
Of the following, clindamycin does not have any activity against
A. Actinomyces israelii
B. Babesia species
D. Peptostreptococcus species
E. Streptococcus agalactiae
Clindamycin is active against most aerobic Gram-positive cocci and even though
Enterococcus faecalis is a Gram-positive coccal organism, clindamycin has no activity
against this microorganism. Clindamycin has activity against all the other organisms
listed.
Clindamycin is a semisynthetic lincosamide antibiotic that is composed of the amino acid trans-1-4-n
propylhygrinic acid attached to a sulfur-containing derivative of an octose. Clindamycin works primarily
by binding to the 50S ribosomal subunit of the bacteria. The agent disrupts protein synthesis by
interfering with the transpeptidation reaction, which inhibits early chain elongation. This causes
alterations in the bacterial cell surface, resulting in decreased adherence to the host cells and increasing
their susceptibility to intracellular killing by leukocytes. Clindamycin exerts an extended postantibiotic
effect against some strains of bacteria, which may be attributed to the persistence of the drug at the
ribosomal binding site. Clindamycin inhibits the production of exotoxin associated with toxic shock
syndromes and facilitates opsonization and phagocytosis, even at low drug concentrations. It is
considered a bacteriostatic agent; however, it is bactericidal against some strains of staphylococci,
streptococci, and anaerobes (eg, Bacteroides fragilis). Killing activity may vary with drug concentration,
bacterial species, and inoculum.
Clindamycin in hydrochloride salt or palmitate ester form is well-absorbed after oral administration,
reaching peak serum concentrations within 1 hour; it is approximately 90% bioavailable with neither
food nor gastric pH significantly altering absorption. Following intravenous administration, peak levels
are achieved in 20 to 45 min. The drug generally distributes well into body tissues and penetrates well
into bone, but does not achieve significant levels in the cerebrospinal fluid, even with inflamed
meninges, or in bile when there is biliary obstruction. Given that the drug is actively transported into
polymorphonuclear leukocytes and macrophages, it has excellent penetration into abscesses.
Clindamycin is mainly metabolized in the liver to active (eg, N-demethyl-clindamycin and sulfoxide) and
inactive metabolites. Clindamycin and its metabolites are mostly eliminated in the bile and, to a lesser
extent, excreted in urine. Urinary excretion in adults is about 5% to 10%, while in children it is 10% to
20%. The half-life in patients with normal renal function is 2.4 hours, but this is extended to about 6
hours in patients with renal insufficiency and 8 to 12 hours in hepatic failure. The drug in not removed in
any appreciable amount by peritoneal dialysis or hemodialysis. Dose adjustment is recommended for
patients with severe liver failure or combined liver and renal failure, but no dose adjustment is usually
needed for patients with isolated renal failure.
Clindamycin generally is active against most aerobic Gram-positive cocci, numerous anaerobic
organisms, and some protozoa. Sensitive species include: staphylococci (S aureus and S epidermidis),
viridans group streptococci, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus
pneumoniae. It also has potent activity against anaerobic bacteria such as Bacteroides fragilis,
Clostridium perfringens, Fusobacterium species, Prevotella melaninogenicus, Propionibacterium,
Porphyromonas, and Peptostreptococcus species. However, increasing rates of resistance among B
fragilis have limited its utility in the treatment of infections because of this organism. Clindamycin
(usually in combination with other agents) is active in vitro against Actinomyces israelii and Nocardia
asteroides. Clindamycin also has activity against various protozoa including: Plasmodium falciparum and
P vivax (both chloroquine-sensitive and resistant strains), Toxoplasma gondii, Babesia species, and
Pneumocystis jiroveci. It is not active against strains of enterococcus or most aerobic Gram-negative
bacteria.
There are several mechanisms of bacterial resistance to clindamycin, including modification of the
target, inactivation of the drug, or efflux of the drug. Resistance is conferred by both plasmid and
chromosomally mediated mechanisms, as shown in the Table.
Streptococcus pneumoniae resistance to clindamycin has historically been low (< 5%) until 2004 with the
emergence of penicillin-resistant serotype 19A, when resistance rates increased significantly, with 1
study showing resistance rates of 26.7%. For most nonserotype 19A isolates, clindamycin resistance
rates remain at less than 10%.
Clindamycin has been used successfully in many clinical settings including treatment of:
1. Skin and soft tissue infections, including cellulitis, carbuncle, folliculitis, furunculosis, impetigo,
ecthyma, hidradenitis suppurativa, necrotizing fasciitis and Clostridium perfringens infections
2. Acne bacteria, primarily Propionibacterium acnes and P granulosum

3. Osteomyelitis
4. Intra-abdominal infections including appendicitis, diverticulitis, perforated ulcer, penetrating

trauma, biliary tree infections, infections related to intestinal fistula or ischemic bowel, liver
abscess, pancreatic abscess, and other intra-abdominal abscesses
5. Pelvic infections including pelvic inflammatory disease, tuboovarian abscess, postpartum

endometritis, septic abortion, posthysterectomy vaginal cuff infections, and Bartholin gland
abscess
6. Chronic sinusitis or chronic otitis media, bacterial pharyngitis, and eliminating the carrier state
of Corynebacterium diphtheriae
7. Odontogenic infections, including Ludwig angina (infection of the floor of the mouth), maxillary
sinusitis, retropharyngeal and parapharyngeal abscesses, mediastinitis, cavernous sinus
thrombosis, and hematogenous dissemination
8. Pleuropulmonary infections such as aspiration pneumonia, lung abscess, and empyema
9. Diabetic foot and decubitus ulcer infections
10. Bacterial vaginosis
11. Bacillus species (B cereus and B subtilis) endophthalmitis
12. Toxoplasma infections as an alternative agent for treatment
13. Babesia microti infections
14. Malaria caused by chloroquine-sensitive and chloroquine-resistant strains of Plasmodium

falciparum
PREP Pearls
 Clindamycin is a semisynthetic lincosamide antibiotic that works primarily by binding to the 50S
ribosomal subunit of the bacteria. The agent disrupts protein synthesis by interfering with the
transpeptidation reaction, which inhibits early chain elongation. This causes alterations in the
bacterial cell surface, resulting in decreased adherence to the host cells and increasing their
susceptibility to intracellular killing by leukocytes.
 Clindamycin generally is active against most aerobic Gram-positive cocci, numerous anaerobic
organisms, and some protozoa. It is not active against strains of Enterococcus or most aerobic
Gram-negative bacteria.
 Clindamycin has some activity against various protozoa including Plasmodium falciparum and P
vivax (both chloroquine-sensitive and resistant strains), Toxoplasma gondii, Babesia species, and
Pneumocystis jiroveci.
 Know the major site of action, the gastrointestinal absorption, and the route of elimination of
clindamycin
 Know the indications for clindamycin therapy
 Know the spectrum of antibacterial and antiprotozoal activity of clindamycin
 Know the activity of clindamycin against penicillin-resistant Streptococcus pneumoniae
Question: 6
Your microbiology lab director asks for your advice on a new laboratory test to diagnose invasive
aspergillosis in children. In the study cited by the test manufacturer, the prevalence of invasive
aspergillosis in the study population was 1 out of 1,000, the false positive rate was 5%, and there were
no false negatives.
What is the chance that a child found to have a positive result actually has invasive aspergillosis,
assuming you know nothing about the child’s symptoms or signs?
A. 0.1%
B. 2%
C. 25%
D. 50%
E. 95%
Question: 6
Your microbiology lab director asks for your advice on a new laboratory test to diagnose invasive
aspergillosis in children. In the study cited by the test manufacturer, the prevalence of invasive
aspergillosis in the study population was 1 out of 1,000, the false positive rate was 5%, and there were
no false negatives.
What is the chance that a child found to have a positive result actually has invasive aspergillosis,
assuming you know nothing about the child’s symptoms or signs?
A. 0.1%
B. 2%
C. 25%
D. 50%
E. 95%
The question wording is simply asking for the positive predictive value of this new
test. In fact, this question is a variation of a question first posed in a formal study of
attending physicians, residents, and fourth year medical students in 1978, repeated in
a similar fashion in 2014. Sadly, on both occasions, the most popular answer was 95%,
which is incorrect.
Predictive values (PVs) are highly dependent on disease prevalence. What might sound like a very good
test performance number, such as a false positive rate of only 5% (equivalent to 95% specificity), might
not be good enough. Any question regarding diagnostic test sensitivity, specificity, predictive value, or
likelihood ratios can best be worked out with a standardized approach in a 2 x 2 table.
A second method is to use standard formulas to calculate PVs, and perhaps the best way to do this is to
construct your own 2 x 2 table based on the test information provided. It is easiest to construct the “test
positive” row first, since that is the information you have, then fill in the rest for a sample size of 1,000.
Consistently constructing the table in this manner will help answer questions such as the one posed in
the vignette. Note that this method allows you to determine sensitivity, specificity, and likelihood ratios
(LR), as well as PVs. Table 1 shows generically what such a table may look like.
If the table is constructed in this manner, with the “gold standard” of whether or not aspergillosis is
present used as the column headings, then sensitivity and specificity easily follow from the columns, and
PVs from the rows. Table 2 demonstrates how the 2 x 2 table should be constructed for the example in
the vignette.
Sensitivity, which is simply the true positives divided by the total numbers of children with aspergillosis,
is 1/1 or 100%. Similarly, specificity (true negatives divided by total children without aspergillosis) is
949/999, or 95%. For positive PV, take the number of true positives divided by the total number with a
positive test: 1/51 = 1.96%. Negative PV is great, 949/949 = 100%, because the test has no false
negatives. It is an easy step to calculate the LR from sensitivity and specificity numbers. The LR of a
positive test is sensitivity/(1-specificity), in this case 1/(1-0.95) = 20. The LR for a negative test is (1-
sensitivity)/specificity = 0.
If you’re feeling uncertain about your answer, try a common sense approach to double check. Imagine
trying out this test in 1,000 children. One of those would have a true positive, the 1 in 1,000 who
actually has invasive aspergillosis. Additionally, from that pool of 1000, 50 more (0.05 X 1000) will have
positive tests, which will be false positives. Thus, 51 individuals will test positive in the sample, but only
1 will be true, which is about 2%.
How does one use all these numbers in practice? The PVs are popular because the numbers are more
intuitive than LRs, but the problem is that disease prevalence must be known. If one is trying to apply
PVs obtained from 1 population to a potentially different population where disease prevalence is very
different, it becomes a very misleading figure. Likelihood ratios avoid that problem because they are
derived solely from sensitivity and specificity, which are (virtually) independent of disease prevalence
and thus can be applied more broadly. The LRs must be combined with some sense of how likely your
patient has the disease in question (ie, pre-test probability), and then with the use of a Fagan nomogram
(a graphical tool used to calculate LRs) or calculator, the post-test probability of disease can be
estimated. In the example in the vignette, both LRs are excellent, but if you apply this in a population
with a very low disease prevalence, it is nott likely to change the disease probabilities very much. This
would indicate that you should not have ordered the test in the first place.
PREP Pearls
 Positive and negative predictive values vary significantly with the disease prevalence in a
population, and therefore must be used with care in different circumstances.
 Likelihood ratios are much less altered by disease prevalence and therefore may be more useful
clinically. However, their use requires a nomogram or calculator.
 Diagnostic tests should not be utilized if the predictive values are poor for a given population.
 Estimate the post-test probability of a disease, given the pretest probability of the disease and
the likelihood ratio for the test
 Calculate and interpret likelihood ratios
Question: 7
A healthy 5-year-old girl presents with her parents to the pediatrician’s office 3 months prior to a
planned trip to a polio-endemic area where an outbreak of active cases of poliomyelitis has been
reported. A review of the child’s immunization record shows she has received the recommended
vaccines for her age, including 4 doses of inactivated poliovirus vaccine. The parents inquire specifically
about their child’s immunity to paralytic poliomyelitis.
Of the following, the BEST explanation as to why this child is protected against paralytic poliomyelitis is
A. complement-mediated lysis
B. mucosal antibody
C. mucosal and serum antibody
D. natural killer cell recognition
E. serum antibody
Question: 7
A healthy 5-year-old girl presents with her parents to the pediatrician’s office 3 months prior to a
planned trip to a polio-endemic area where an outbreak of active cases of poliomyelitis has been
reported. A review of the child’s immunization record shows she has received the recommended
vaccines for her age, including 4 doses of inactivated poliovirus vaccine. The parents inquire specifically
about their child’s immunity to paralytic poliomyelitis.
Of the following, the BEST explanation as to why this child is protected against paralytic poliomyelitis is
A. complement-mediated lysis
B. mucosal antibody
C. mucosal and serum antibody
D. natural killer cell recognition
E. serum antibody
This child is protected against paralytic poliomyelitis by both poliovirus-specific

immunoglobulin A antibody-mediated mucosal immunity and poliovirus specific
immunoglobulin G-neutralizing serum antibody induced by the administration of
inactivated poliovirus vaccine (IPV). Both IPV and oral poliovirus vaccine (OPV) are
highly immunogenic, induce protective levels of poliovirus-specific, serum-neutralizing
antibody, and are protective against paralytic poliomyelitis. Poliovirus-specific immunoglobulin A (IgA)
antibody can be detected in all children who receive either IPV or OPV; however, OPV-immunized
children have higher levels of IgA mucosal antibody against polioviruses, providing a higher level of
intestinal immunity. In addition, children immunized with OPV shed vaccine strains of poliovirus, which
facilitates herd immunity through person-to-person transmission of vaccine strains.
The 4 major approaches currently available for active immunization to protect against viral infection and
disease are live attenuated vaccines, inactivated viruses, purified subunit components of viruses, and
recombinant vaccines. Most vaccines against viruses use 1 of these approaches; however, active
immunization strategies against poliovirus and influenza virus use both live attenuated and inactivated
viruses.
Live attenuated viral vaccines are traditionally produced through serial passage in culture or through
animals of a wild type or virulent strain of virus. This passage produces a strain of virus that is less
pathogenic towards humans, but still induces an immunologic response. Live attenuated vaccines also
may contain attenuated viral strains reassorted with viral antigens from more pathogenic strains. Live
attenuated viral vaccines multiply in the host and produce a complex immunologic response in the host,
which closely mimics natural infection with the virus, generating both systemic and local mucosal
humoral immunity, as well as simultaneous cell-mediated immunity. Live attenuated viral vaccines
include oral poliovirus and rotavirus vaccines, intranasal live influenza, and parenterally administered
measles, mumps, rubella, yellow fever, and varicella vaccines.
Inactivated viral vaccines contain whole viruses inactivated by heat or formalin, and include IPV,
hepatiitis A, rabies, and Japanese encephalitis vaccines. Viral vaccines also may contain purified viral
proteins, such as those contained in trivalent inactivated influenza vaccine, or viral antigenic subunits,
such as including the recombinant hepatitis B and human papillomavirus vaccines. Immunization
produces both a humoral and cellular T-cell immune response because the virus in these inactivated or
subunit vaccines or recombinant vaccines is not capable of replicating in the host, but the nature of the
local mucosal humoral immune response is less than the systemic humoral immunity.
Complement mediated lysis is an important part of the innate immune system’s defense against
bacteria, and initiation of immunity involving the complement pathway to lyse organisms or promote
phagocytosis is induced by pneumococcal vaccine, a polysaccharide bacterial vaccine.
Natural killer cells are part of the innate immune response, but would not be an important protective
mechanism produced by polio vaccine and are important first-line defenses against tumor cells and
virus-infected cells, especially herpes simplex virus, cytomegalovirus, and HIV.
PREP Pearls
 Both inactivated poliovirus vaccine and oral poliovirus vaccine produce mucosal and systemic
humoral immunity protective against paralytic poliomyelitis.
 Viral vaccines may come in several different forms: live attenuated, inactivated whole virus, or
purified subunits.
 Influenza virus and poliovirus vaccines are available in both live attenuated and inactivated
forms of vaccine.
 Understand the mechanism of mucosal and/or serum antiviral antibody in resistance to

reinfection and efficacy of viral vaccines
Question: 8
A mother calls your office to ask about her 12-year-old daughter who is attending summer camp. She
was alerted by the camp staff that 40 of the 100 children attending the camp have developed vomiting
and diarrhea. Some of the campers also have fever. Her daughter is feeling well. Your patient’s mother is
asking whether this could be food poisoning. You explain that the camp is likely experiencing an
outbreak of a gastrointestinal viral infection, and while the infection is unpleasant, most children
recover in a day or two.
Of the following, the virus MOST likely implicated is
A. Lagovirus
B. Norovirus
C. Rotavirus
D. Sapovirus
E. Vesivirus
Question: 8
A mother calls your office to ask about her 12-year-old daughter who is attending summer camp. She
was alerted by the camp staff that 40 of the 100 children attending the camp have developed vomiting
and diarrhea. Some of the campers also have fever. Her daughter is feeling well. Your patient’s mother is
asking whether this could be food poisoning. You explain that the camp is likely experiencing an
outbreak of a gastrointestinal viral infection, and while the infection is unpleasant, most children
recover in a day or two.
Of the following, the virus MOST likely implicated is
A. Lagovirus
B. Norovirus
C. Rotavirus
D. Sapovirus
E. Vesivirus
Caliciviruses include 5 genera, noroviruses, sapoviruses, lagoviruses, neboviruses, and

vesiviruses. While it’s clear that examples from the first 2 genera cause human
diarrheal disease, lagoviruses, neboviruses, and vesiviruses are currently thought to
be restricted to nonhuman hosts.
Epidemiologic studies have demonstrated that Norovirus infections are now the common cause of
gastroenteritis in the United States. Serologic testing has demonstrated that as many as 60% of infants
have already experienced their first infection. By early adulthood, nearly all individuals have serologic
evidence of a past norovirus infection. Moreover, individuals are likely to be infected by multiple virus
types as prior infection with 1 Norovirus type does not appear to offer complete immunologic protection
against another. Similarly, Sapovirus infections are very common, but unlike Norovirus, nearly all
children experience one or more Sapovirus infection prior to 4 years of age.
Norwalk agent (now norovirus, the prototypical agent in the norovirus genus) was first described in 1968
as “winter vomiting disease” during an epidemic of gastroenteritis in an elementary school affecting half
of all the students and teachers. Nearly one-third of household contacts were also infected
demonstrating the contagion of this agent. The virus was identified in 1972 and was not classified until
1990 following successful cloning and sequencing of the virus genome. Norovirus and related
caliciviruses do not grow in cell culture, therefore these noncultivatable agents had long been difficult to
track epidemiologically or to diagnosis with confirmatory testing. The cloning and sequencing of the
Norovirus genome has resulted in the development of assays and reagents that permit such
epidemiologic studies.
Noroviruses are recognized as the most common cause of epidemic gastroenteritis in the United States,
Europe, and Japan, and represent a major cause of diarrheal morbidity around the world. Each year in
the United States, noroviruses infect an estimated 21 million people and result in 70,000 hospitalizations
and 800 deaths. When outbreaks occur, they are typically family or communitywide, affecting all ages.
Known common source outbreaks following the ingestion of contaminated water, ice, shellfish, and a
variety of prepared foods are well described from recreational camps, cruise ships, communities,
hospitals, elementary schools, universities, military, and nursing homes. Attack rates during outbreaks
are as high as 90%. Most prevalent in the fall and winter, outbreaks can occur any time during the year.
Seasonal patterns for Sapovirus infections are less clear, but several studies suggest outbreaks are more
typical in the wintertime.
Both the noroviruses and sapoviruses cause acute gastroenteritis, although asymptomatic infection and
shedding is common across all age groups. In young children, the clinical triad of fever, vomiting, and
diarrhea do not distinguish norovirus infection from other causes of acute gastroenteritis like Rotavirus,
although the duration and severity of a norovirus infection is typically less than a rotavirus infection.
Fever and vomiting abate in 1 day or less. Diarrhea may continue for a day or so longer. Treatment is
supportive. Some children may require hospitalization for dehydration if the symptoms persist.
Mortality is rare. Vaccines have yet to be developed.
PREP Pearls
 Norovirus is now the most common cause of medically attended acute gastroenteritis in US
children.
 Understand the epidemiology of calicivirus infections, including age-related factors and

prevalence
 Evaluate the relative importance of calicivirus in causing gastroenteritis and outbreaks of

gastroenteritis in various age groups
Question: 1
You are seeing a 15-year-old adolescent in the clinic with a recent diagnosis of HIV infection. He was
started on highly active antiretroviral therapy approximately 1 month ago. He says that in general he is
tolerating the medications well; however, he is bothered by the fact that his eyes have turned yellow
(Figure).
Of the following, the protease inhibitor MOST likely to be associated with this adverse effect is
A. atazanavir
B. darunavir
C. lopinavir
D. nelfinavir
E. ritonavir
Question: 1
You are seeing a 15-year-old adolescent in the clinic with a recent diagnosis of HIV infection. He was
started on highly active antiretroviral therapy approximately 1 month ago. He says that in general he is
tolerating the medications well; however, he is bothered by the fact that his eyes have turned yellow
(Figure).
Of the following, the protease inhibitor MOST likely to be associated with this adverse effect is
A. atazanavir
B. darunavir
C. lopinavir
D. nelfinavir
E. ritonavir
While hyperbilirubinemia may be associated with a number of protease inhibitors

(PIs), it is seen most commonly with atazanavir (ATV) particularly when it is boosted
with ritonavir (RTV). This is because of ATV inhibition of the enzyme uridine-
glucuronosyl transferase 1A1, which is involved in bilirubin conjugation. The degree of
hyperbilirubinemia generally correlates with ATV levels. It should be noted that
isolated hyperbilirubinemia without impairment of hepatic function (ie, normal
hepatic enzymes) is not a contraindication to the use of ATV in HIV-infected individuals who are
otherwise tolerating the medication.
Protease inhibitors, in combination with nucleoside/tide reverse transcriptase inhibitors (NRTI) and non-
nucleoside reverse transcriptase inhibitors (NNRTI), constitute the back bone of therapy for HIV
infection. Other drugs in this class (PIs) include darunavir (DRV), lopinavir-ritonavir (LPR/v), nelfinavir
(NFV), tipranavir (TPV), saquinavir (SQV), fosamprenavir (FPV) and indinavir (IDV). RTV is used solely as a
boosting agent with other PIs since it is a potent inhibitor of cytochrome P450 (CYP) 3A enzyme.
Inhibition of CYP3A by RTV leads to increased serum drug levels of other concomitantly used PIs.
The mechanism of action of PIs is based on the fact that HIV replication is dependent on the production
of certain proteins from specific HIV genes- gag, pol, and env. PIs bind to HIV-1 protease thus preventing
the production of mature virions through the suppression of protease-based viral processing of gag and
gag-pol polyproteins.
PIs are indicated for the treatment of HIV infection both for primary treatment as well as when options
for treatment with other available agents become limited, either due to the presence of resistant
mutations or adverse effects. For treatment-naïve patients, PIs are generally used in combination with
NRTIs. In treatment-experienced patients they may be used in combination with other antiretroviral
(ARV) agents such as NNRTIs or integrase inhibitors. Dual PI-based regimens may also be used
occasionally in highly treatment experienced patients. Table 1 details the indications for the use of
antiretroviral agents in the treatment of pediatric HIV infection.
The age at which different PIs may be used varies based on available pharmacologic data, drug
tolerability, availability of liquid formulations, as well as safety and efficacy. In general, PIs represent a
class of medications that are extremely potent, generally well tolerated despite multiple reported
adverse effects, and have a high genetic barrier to resistance. The latter also makes them an excellent
choice for use in patients when noncompliance is anticipated during treatment.
Administration of PIs may be associated with multiple adverse effects. Most commonly seen with all PIs
at the onset of treatment are rash, nausea, diarrhea, vomiting, abdominal pain, arthralgias, headache,
and fatigue. However, most individuals develop tolerance to these adverse effects and usually do not
require discontinuation of the medication. Numerous other drug-specific or class-associated adverse
effects may be seen. These are described in Table 2.
In addition to adverse effects associated with the use of PIs themselves, multiple drug interactions may
occur when they are used with certain classes of medications because PIs interact with the hepatic CYP
enzyme system, acting both as inhibitors, as well as substrates at different concentrations. In general,
drug interactions, as well as altered serum drug levels, may be seen when PIs are used concomitantly
with proton pump inhibitors, macrolides, azoles, tricyclic antidepressants, oral contraceptives, lipid
lowering agents, rifampin/rifabutin, and oral anticoagulants. Consultation with a pharmacologist
experienced in the use of these medications may be warranted, particularly in complicated cases.
In combination with other ARV medications, PIs have revolutionized the treatment of HIV infection and,
despite all the listed adverse effects and drug interactions, they are generally well tolerated in children.
PREP Pearls
 Protease inhibitors (PIs) can be used for the treatment of HIV infection both in the treatment-
naïve, as well as treatment experienced individual
 Most common side effects of PIs include rash, gastrointestinal events (nausea,
diarrhea,vomiting, abdominal pain), arthralgias, fatigue, and headache.
 Other adverse effects associated with most PIs include elevation of hepatic enzymes,
dyslipidemia, and hyperglycemia.
 Multiple drug interactions are also common and consultation with an experienced pharmacist
when prescribing these medications in individuals with other chronic conditions is generally
recommended.
 Know the adverse effects and toxicity of HIV-1 protease inhibitors (indinavir, ritonavir,
saquinavir, amprenavir, atazanavir, lopinavir, nelfinavir)
 Know the mechanism of action of HIV-1 protease inhibitors (indinavir, ritonavir, saquinavir,
amprenavir, atazanavir, lopinavir, nelfinavir)
 Know the possible indications for HIV-1 protease inhibitor therapy (indinavir, ritonavir,
saquinavir, amprenavir, atazanavir, lopinavir, nelfinavir) for children
Question: 2
The School of Pharmacy and Department of Pediatrics is scheduled to hold a joint conference at your
local medical school to discuss various drug and treatment options in tuberculosis. The Division of
Pediatric Infectious Diseases is invited to review anti-tuberculosis medications, including the medication
pyrazinamide.
Of the following, the MOST common adverse event during the use of pyrazinamide is
A. hyperuricemia
B. inhibition of pyridoxine metabolism
C. optic neuritis
D. orange urine, sweat, and tears
E. otic and vestibular toxicity

Question: 2
The School of Pharmacy and Department of Pediatrics is scheduled to hold a joint conference at your
local medical school to discuss various drug and treatment options in tuberculosis. The Division of
Pediatric Infectious Diseases is invited to review anti-tuberculosis medications, including the medication
pyrazinamide.
Of the following, the MOST common adverse event during the use of pyrazinamide is
A. hyperuricemia
B. inhibition of pyridoxine metabolism
C. optic neuritis
D. orange urine, sweat, and tears
E. otic and vestibular toxicity
Pyrazinamide (PZA) is a first-line agent for the treatment of all forms of

Mycobacterium tuberculosis infection caused by organisms with known or presumed
susceptibility to the drug; it is only used in combination with other drugs such as
isoniazid (INH) and rifampin (RIF). Pyrazinamide routinely causes an increase in serum
uric acid concentrations by inhibiting uric acid excretion through the kidneys.
Hyperuricemia is usually asymptomatic, an expected effect of the drug, and is generally without adverse
consequence. Serum uric acid measurements are not recommended routinely but may serve as a
surrogate marker for compliance. Inhibition of pyridoxine metabolism may be caused by INH;
ethambutol (EMB) can cause reversible or irreversible optic neuritis; RIF causes orange urine, sweat, and
tears; and streptomycin (STM) may lead to otic and vertibular toxicity.
Pyrazinamide is usually well tolerated (Table); hepatotoxicity can occur at high doses. Toxic reactions
occur more frequently in adults and include flushing, cutaneous hypersensitivity, arthralgia, and overt
gout. In children, PZA has revealed few problems. Isoniazid, RIF, and PZA can cause hepatitis that may
result in additional liver damage in patients with preexisting liver disease. However, because of the
effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the
presence of preexisting liver disease. If serum transaminase levels are more than 3 times normal before
the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis),
treatment options avoiding the use of both INH and PZA may be considered. For patients with severe
liver disease a regimen with only 1 hepatotoxic agent is preferred, and consultation with a tuberculosis
expert is recommended. In all patients with preexisting liver disease, frequent clinical and laboratory
monitoring should be performed to detect drug-induced hepatic injury.
Pyrazinamide diffuses readily into all areas, attaining therapeutic cerebrospinal fluid concentrations, is
detectable in macrophages, is administered orally, and is metabolized by the liver. Pyrazinamide
contributes to the killing of Mycobacterium tuberculosis, by exerting its greatest activity against the
population of dormant or semidormant organisms contained within macrophages or the acidic
environment of caseous foci. In vitro, PZA has no effect on extracellular tubercle bacilli, but clearly
contributes to the killing of intracellular bacilli. Pyrazinamide appears to exert its maximal effect during
the first 2 months of therapy. When 3 or more antituberculosis drugs are used initially, treatment
durations of 6 months are routinely successful. Regimens using INH, RIF, and PZA, (+/-STM or EMB)
during the initial phase (2 months) of treatment for pulmonary tuberculosis, followed by INH and RIF in
the continuation phase (4 months), routinely yield cure rates of greater than 98% and relapse rates
below 4%. If PZA is excluded from the initial phase, the rate of failure rises to 7% to 10%. Use of PZA
beyond 2 months of therapy does not add any benefit.
PREP Pearls
 Hyperuricemia is usually asymptomatic, an expected effect of the drug pyrazinamide (PZA), and
is generally without adverse consequence. Serum uric acid measurements are not
recommended routinely, but may serve as a surrogate marker for compliance.
 In children, PZA is well tolerated; hepatotoxicity is rare and more frequently occurs at high
doses. Toxic reactions occur more frequently in adults and include flushing, cutaneous
hypersensitivity, arthralgia, and overt gout.
 Use of PZA beyond 2 months of therapy does not add any benefit in the routine treatment of
tuberculosis.
 Pyrazinamide exerts greatest activity against the population of dormant or semidormant

tuberculosis organisms contained within macrophages or the acidic environment of caseous
foci.
 Know the antibacterial properties of pyrazinamide, including type of activity
 Know the pharmacologic properties of pyrazinamide, including gastrointestinal absorption and

distribution in body fluids such as cerebrospinal fluid and toxicities
 Know the adverse effects of pyrazinamide therapy

March
Question: 3
While working with infection prevention and control nurses to develop a visitation policy for your
hospital, one of the infectious diseases fellows asks what factors are important to consider when
determining whether a sibling may visit their brother or sister while in the hospital.
Of the following, the BEST statement regarding sibling visitation is
A. a fully immunized, 6-year-old sibling who reports a recent case of varicella infection in the
second grade classroom cannot visit their brother or sister
B. a fully immunized sibling who has recently traveled domestically during influenza season
cannot visit their brother or sister
C. a sibling may come up to the hospital to join their brother or sister at the unit tea party
being held in the playroom
D. a sibling should be assessed for symptoms of acute infection prior to visiting their brother or
sister regardless of the time of year
E. a sibling who has recently received their 5 year old immunizations, including MMR and
varicella vaccine cannot visit their brother or sister
Question: 3
While working with infection prevention and control nurses to develop a visitation policy for your
hospital, one of the infectious diseases fellows asks what factors are important to consider when
determining whether a sibling may visit their brother or sister while in the hospital.
Of the following, the BEST statement regarding sibling visitation is
A. a fully immunized, 6-year-old sibling who reports a recent case of varicella infection in the
second grade classroom cannot visit their brother or sister
B. a fully immunized sibling who has recently traveled domestically during influenza season cannot
visit their brother or sister
C. a sibling may come up to the hospital to join their brother or sister at the unit tea party being
held in the playroom
D. a sibling should be assessed for symptoms of acute infection prior to visiting their brother or
sister regardless of the time of year
E. a sibling who has recently received their 5 year old immunizations, including MMR and varicella
vaccine cannot visit their brother or sister
Hospital guidelines should be established to maximize opportunities to visit a sibling in the hospital and
minimize risk of transmission of a contagious infection to the patient. There is increasing recognition
that siblings should be included in family visitations, including settings in which a long neonatal intensive
care unit stay is expected. Sibling visits to birthing centers, postpartum rooms, pediatric wards, and
intensive care units are also encouraged.
While guidelines may be modified for specific situations (eg, obstetrics versus neonatal intensive care
unit or community outbreaks) and for specific hospitals (eg, pediatric versus primarily adult), there are
basic principles which should be followed (Table 1). Visiting children should only be visiting their sibling
and not be in playrooms when other patients are there. Therefore, the sibling in this vignette should not
be attending the unit tea party where other hospitalized children will be present. Siblings may play in a
playroom or other designated area when there are no other patients present, but should not be in other
patient rooms.
It is important for the healthcare worker to assess the sibling for acute infection prior to visiting the
hospitalized patient in order to minimize risk of transmitting a communicable disease throughout the
year, and visitation should not be permitted if there is evidence of acute or contagious infection.
Likewise, it is important to ascertain the sibling’s immunization status prior to visiting the hospitalized
patient. It is ideal that the visiting sibling is current with Advisory Committee on Immunization Practices
recommendations, including influenza vaccine during influenza season. There is no reason to exclude a
sibling visit on the basis of receiving recent live virus vaccines. In addition to immunization status, it is
important to screen for exposure to communicable diseases (eg, measles, influenza) prior to sibling
visitation. While direct exposure to someone with influenza, chicken pox, or measles would prohibit a
sibling visit to some units (eg, bone marrow transplant unit), travel during influenza season would not.
Further, remote exposure to varicella in a different grade level would not be a cause to refuse sibling
visitation.
The importance of hand hygiene cannot be overstated in the setting of sibling visitation, and all family
members and healthcare workers should use proper hand hygiene technique before and after any
patient contact occurs. Appropriate hand hygiene is equally important during pet visitation.
Pet visitation is increasingly being recognized to have an important role in the mental health of the
patient. This may include visitation of the patient or family pet, or a more organized pet visitation
program through child life. As with sibling visitation, guidelines are necessary to limit the risk of spread
of infection, as well as to limit the risk of injury from the pet. The level of concern for zoonotic disease
transmission (eg, bone marrow transplant unit) will influence the ability to allow pet visitation. Pet
visitation policies should be written in conjunction with infectious diseases specialists, infection control
and preventionists, nursing, a hospital epidemiologist, and a veterinarian. Some specific
recommendations are listed in Table 2.
Physician approval should be obtained prior to pet visitation and contact should be confined to holding
and petting of the animal. All visits should be supervised and supervisors should be familiar with clean
up after pet urine, feces, and emesis. Consideration of patient allergies should be taken before allowing
pet visitation, and in patients who are immune compromised, the risk of infection from exposure to the
animal’s flora may outweigh the benefits of pet contact. Finally, indwelling catheter sites should be
completely covered with a dressing with clothing overlying to serve as a barrier to licking, biting, or
chewing on catheter material.
PREP Pearls
 Children should be screened for signs and symptoms of acute infection prior to visiting a
hospitalized sibling.
 Children who have direct exposure to a communicable infection, to which they are susceptible,
should not be allowed to visit a hospitalized sibling.
 Physician approval should be obtained before all pet visits and all visits should be monitored for
safety.
 Formulate a visitation policy for the siblings and/or pets of hospitalized children
Question: 4
You are asked to evaluate a previously healthy, 5-year-old boy for persistent, severe nasal drainage and
cough. He was well until 14 days ago, when he developed rhinorrhea and a mild sore throat. Over the
past 5 days, he has developed more profuse nasal drainage, worsening cough, and fever (up to 39.0°C).
His cough is significant during the daytime, but slightly worse at night. He is not having other respiratory
symptoms. He saw his primary care physician 7 days after the onset of his symptoms and was diagnosed
with a viral illness. On physical examination, his temperature is 38.8°C, his pulse rate is 100 beats/min,
his respiratory rate is 24 breaths/min, and his blood pressure is 90/60 mm Hg. He has mucopurulent
drainage from both nostrils and his posterior pharynx and erythematous nasal mucosa bilaterally. His
lungs are clear to auscultation. He has no facial tenderness, lymphadenopathy, or periorbital edema.
Of the following, the BEST plan of action is to
A. obtain a computed tomography of his sinuses
B. obtain a plain radiograph of his sinuses
C. perform a diagnostic sinus aspiration
D. prescribe an inhaled corticosteroid
E. prescribe an oral antibiotic

Question: 4
You are asked to evaluate a previously healthy, 5-year-old boy for persistent, severe nasal drainage and
cough. He was well until 14 days ago, when he developed rhinorrhea and a mild sore throat. Over the
past 5 days, he has developed more profuse nasal drainage, worsening cough, and fever (up to 39.0°C).
His cough is significant during the daytime, but slightly worse at night. He is not having other respiratory
symptoms. He saw his primary care physician 7 days after the onset of his symptoms and was diagnosed
with a viral illness. On physical examination, his temperature is 38.8°C, his pulse rate is 100 beats/min,
his respiratory rate is 24 breaths/min, and his blood pressure is 90/60 mm Hg. He has mucopurulent
drainage from both nostrils and his posterior pharynx and erythematous nasal mucosa bilaterally. His
lungs are clear to auscultation. He has no facial tenderness, lymphadenopathy, or periorbital edema.
Of the following, the BEST plan of action is to
A. obtain a computed tomography of his sinuses
B. obtain a plain radiograph of his sinuses
C. perform a diagnostic sinus aspiration
D. prescribe an inhaled corticosteroid
E. prescribe an oral antibiotic
The 2013 American Academy of Pediatrics (AAP) clinical practice guidelines for the
management of acute bacterial sinusitis (ABS) in children stress the importance of
making a clinical diagnosis and initiating appropriate antimicrobial treatment
according to clinical criteria. The diagnosis of ABS can be made in a child who has
upper respiratory symptoms that are either:
1. Persistent (lasting longer than 10 days and not improving);
2. Severe (high fever *≥ 38.9ºC+ and purulent nasal drainage present for 3 to 4 consecutive days in
a generally ill-appearing child);
3. Worsening (defined as worsening of respiratory symptoms or new onset of nasal discharge,

daytime cough, or fever after improvement).
The respiratory symptoms may include nasal or postnasal discharge of any quality and a cough that may
be worse at night. Although some children with uncomplicated viral upper respiratory tract infection
(URI) will have residual symptoms at 10 days after onset, the persistence of symptoms without
improvement is indicative of ABS. The physical examination does not generally contribute substantially
to the diagnosis of ABS because the physical findings in a child with an uncomplicated URI are very
similar to those of a child with ABS. Facial pain and tenderness are not reliable indicators of ABS in the
pediatric population. Thus, based on clinical criteria, the child in the vignette likely has ABS.
The diagnosis can be made on stringent clinical grounds, therefore antibiotic therapy should be initiated
for a child who meets clinical criteria for ABS. Intranasal steroids as an adjunct to oral antibiotic therapy
appear to have a very modest beneficial effect on symptoms, although the data in children are limited.
Two studies of intranasal steroids performed exclusively in children showed a modest benefit, compared
to placebo and oral decongestants. However, these studies had substantial methodological flaws, which
make definite conclusions regarding the benefit of intranasal corticosteroids difficult. Radiographic
testing, such as plain radiographs or computed tomography (CT), and invasive diagnostic studies, such as
sinus aspiration, are not indicated for uncomplicated ABS.
Imaging studies, which historically have been used as confirmatory or diagnostic modalities for the
diagnosis of ABS, are no longer recommended. This is based on the fact that plain radiographs, contrast-
enhanced CT or magnetic resonance imaging (MRI) in children will not differentiate between bacterial
sinusitis and uncomplicated URI. Thus, abnormal images cannot confirm the diagnosis of ABS. Imaging
studies, specifically contrast-enhanced CT and MRI with contrast, should be reserved for children who
are suspected of having a complication of ABS, such as orbital cellulitis or central nervous system
complication. The gold standard for the diagnosis of ABS is the recovery of bacteria in high density (≥ 104
colony-forming units/mL) from a paranasal sinus cavity. However, this procedure is invasive, time-
consuming, requires sedation, and requires performance by an otolaryngologist. Therefore, this is not a
practical method of diagnosis and not recommended for routine diagnosis of ABS in children. Indications
for sinus aspiration include lack of response to multiple courses of antibiotics, severe facial pain, orbital
or intracranial complications, and evaluation of an immunocompromised host. Transillumination of the
sinuses to assess for the presence of fluid for the diagnosis of ABS is unreliable in children and not
recommended.
According to the 2013 AAP guidelines, children who have ABS defined by a severe onset or a worsening
course (as defined previously) should receive antibiotic therapy as soon as possible. Children whose
diagnosis of ABS is based on persistent symptoms can either be immediately treated with antibiotics or
observed for 3 additional days. The recommendation for immediate antibiotic therapy for the child with
severe or worsening symptoms is based on randomized trials showing a clear benefit of therapy and the
theoretical risk of suppurative complications in this group of children compared to those with persistent
symptoms. The decision for treatment versus observation of the child with persistent symptoms can be
based on the severity of the symptoms, effect of the infection on the quality of life, caregiver
preference, and risk of adverse events. Although antibiotics appear to be beneficial for those with
persistent symptoms, some children improve without treatment and the risk of suppurative
complications is low.
The principal pathogens causing ABS include Streptococcus pneumoniae (30%), nontypeable
Haemophilus influenzae (30%), and Moraxella catarrhalis (10%). Staphylococcus aureus and anaerobes
are very rarely recovered from children with ABS. About half of infections caused by H influenzae and
50% to 75% of infections caused by M catarrhalis will resolve spontaneously, while only about 15% of
pneumococcal ABS will resolve spontaneously. About 15% to 40% of pneumococcal strains exhibit
nonsusceptibility to penicillins, with half of these strains being highly resistant. Except for the highly
resistant strains of pneumococci, most strains will respond to conventional dosages of amoxicillin.
Amoxicillin remains the agent of choice for children with uncomplicated ABS in situations where the
antimicrobial resistance is not suspected. This is based on the safety, tolerability, low cost, and narrow
antimicrobial spectrum of this agent. Standard dose amoxicillin (45 mg/kg per day) is recommended for
children older than 2 years of age who have mild or moderate symptoms, do not attend child care
centers, and who have not received antibiotic therapy during the previous 4 weeks. Higher doses of
amoxicillin (80-90 mg/kg per day) may be used in communities with a high prevalence of nonsusceptible
Streptococcus pneumoniae. High dose amoxicillin-clavulanate (80-90mg/kg per day) may be used for
children with ABS who have moderate-to-severe illness, those younger than 2 years of age, those
attending child care centers, or those who have recently been treated with an antimicrobial agent.
Children who are allergic to penicillin (nontype I hypersensitivity reaction) may be safely treated with a
second or third generation cephalosporin such as cefuroxime, cefdinir, or cefpodoxime. Children who
have a history of type I immediate or accelerated reaction to penicillin can also be treated with these
cephalosporins, although referral to an allergist for skin testing before initiation of therapy may be
preferred by some clinicians. Alternative antimicrobial agents for the treatment of ABS in young children
who have moderate or severe symptoms and who have type I hypersensitivity reactions to penicillin
include broader spectrum antimicrobial agents such as clindamycin, linezolid, or levofloxacin. The
optimal duration of treatment for ABS has not been systematically studied. A common approach is to
continue treatment for 7 days after signs and symptoms have resolved. Adjuvant therapies such as
antihistamines, decongestants, mucolytics, and nasal irrigations agents have not been studied
systematically and are not recommended for the primary indication of ABS in children.
PREP Pearls
 The diagnosis of acute bacterial sinusitis should be based on clinical criteria.
 Imaging studies of the sinuses in children will not differentiate between bacterial sinusitis and
uncomplicated upper respiratory tract infection and are not recommended for the diagnosis of
uncomplicated acute bacterial sinusitis (ABS).
 Amoxicillin remains the agent of choice for children with uncomplicated ABS in situations where
antimicrobial resistance is not suspected.
 Appreciate the relative value and accuracy of diagnostic tests for sinusitis
 Plan antimicrobial and other aspects of therapy for acute sinusitis

Question: 5
You are consulted on an 8-year-old boy who emigrated from India 4 weeks ago. He is admitted after a 5-
day history of fever, left-sided inguinal and distal leg swelling, and a limp that did not improve on oral
cephalexin. The parents state that their son has been generally healthy, has never been hospitalized, but
did have a similar but milder episode 3 months ago. On examination, he is uncomfortable but not toxic
appearing, has an oral temperature of 38.3°C, has multiple enlarged and tender inguinal and femoral
lymph nodes on the left side, prominent red streaking of the anterior thigh, and mild distal leg swelling.
He has scars of past insect bites, but no other skin lesions. A complete blood cell count profile is within
normal limits.
Of the following, the MOST likely etiologic agent causing illness in this boy is
A. Brugia malayi
B. Francisella tularensis
C. Leishmania brasiliensis
D. Wuchereria bancrofti
E. Yersinia pestis
Question: 5
You are consulted on an 8-year-old boy who emigrated from India 4 weeks ago. He is admitted after a 5-
day history of fever, left-sided inguinal and distal leg swelling, and a limp that did not improve on oral
cephalexin. The parents state that their son has been generally healthy, has never been hospitalized, but
did have a similar but milder episode 3 months ago. On examination, he is uncomfortable but not toxic
appearing, has an oral temperature of 38.3°C, has multiple enlarged and tender inguinal and femoral
lymph nodes on the left side, prominent red streaking of the anterior thigh, and mild distal leg swelling.
He has scars of past insect bites, but no other skin lesions. A complete blood cell count profile is within
normal limits.
Of the following, the MOST likely etiologic agent causing illness in this boy is
A. Brugia malayi
B. Francisella tularensis
C. Leishmania brasiliensis
D. Wuchereria bancrofti
E. Yersinia pestis
The boy is experiencing an acute episode of filariasis (filarial fever), which is most
commonly caused by Wuchereria bancrofti infection. The other filarial species in India,
Brugia malayi, is limited to causing disease in small endemic regions of the country.
Cutaneous leishmaniasis due to Leishmania brasiliensis can present with
lymphadenitis and lymphangitis, but is not common in India, where instead visceral
leishmania is hyperendemic. Francisella tularensis infection (ulceroglandular tuleraemia) and Yersinia
pestis infection (bubonic plague) would not present as a recurrent episode, and the patient usually has
large suppurative lymph nodes; tick-borne tularemia is not common in India, and bubonic plague would
be accompanied with sudden onset of high fever, chills, headache, often with manifestations of sepsis.
Lymphatic filariasis, which is classified as a neglected tropical disease, affects over 120 million people in
tropical and subtropical regions of Asia and Pacific regions, Africa, and in the Americas (Haiti, the
Dominican Republic, Guyana, and Brazil). About 40% of infected people live in India and about 33% in
Africa. The filariae are nematodes that reside in lymphatic vessels and lymph nodes. Mosquitoes are the
vectors and intermediate hosts. Adult worms live for at least 5 to 8 years and release larval microfilariae
into the bloodstream periodically, which are infective for mosquitoes. Individual microfilariae have a
lifespan up to 1.5 years (Figure), therefore the patient can be infective for more than a year after death
of adult worms. Microfilariae, but not the adult worm, are transmissible by blood transfusion.
Ninety percent of cases worldwide are caused by Wuchereria bancrofti (Bancroft filaria), which has a
solely human reservoir (Table). Brugia malayi (Malayan or Brugian filaria) has a reservoir in cats and
monkeys as well. B malayi is found mostly in Southeast Asia and parts of India. B timori is restricted to
islands at the eastern tip of Indonesia.
The majority of infected individuals have asymptomatic microfilaremia. In symptomatic patients, the
acute manifestation is adenolymphangitis, also called filarial fever. Patients experience up to week-long
episodes of fever, malaise, and chills that resemble malaria, often accompanied by enlarged, mildly
painful axillary or inguinal lymph nodes. Lymphangitis, provoked by adult worms and developing larvae,
is a cardinal feature of the acute stage of filariasis, and usually precedes the lymphadenitis, in contrast
to the opposite progression that occurs in bacterial cellulitis. The lower limbs are mainly affected, and
less commonly, arms, breasts, and genitals (epididymitis and orchitis). “Filarial abscess” can occur in the
affected part, with sterile pus or secondary bacterial infection, frequently caused by Streptococcus
pyogenes. Symptoms persist for several weeks, and recurrences occur over several months. Host
inflammatory response results in death of the worm, which leads to obliterative endolymphangitis with
ultimate fibrosis of lymph vessels and nodes. The resultant chronic lymphedema can cause hydroceles
and massive hypertrophy of limb tissues and scrotal enlargement termed “elephantiasis,” which is a
major cause of long term disability in endemic regions. Chyluria from rupture of dilated lymphatic
vessels into the genitourinary tract occurs uncommonly. Further complications result from skin
roughness, verrucae, and fissures caused by varicosity and sclerosis of lymphatic vessels, with risk of
secondary bacterial infection. In brugian filariasis, there is less genital involvement and elephantiasis is
usually restricted to below the knees.
Treatment of filariasis consists of drugs directed against microfilariae (microfilaricidal) and adult worms
(macrofilaricidal), and symptomatic treatment. The drug of choice for lymphatic filariasis is
diethylcarbamazine (DEC), which is both microfilaricidal and macrofilaricidal. Diethylcarbamazine is
administered as 6 mg/kg dose daily for 12 days, either as a single daily dose or divided 3 times a day,
along with doxycycline that is given for 6 weeks. It is recommended for both asymptomatic and
symptomatic persons, but it does not reverse symptoms of acute adenolymphangitis or chronic
sequelae of lymphedema and fibrosis, except possibly in B malayi infection in children. Systemic adverse
reactions (fever, myalgia, headache, malaise) secondary to larval killing are common, and some patients
experience local tender nodules at the site of the dying adult worm. In areas endemic for onchocerciasis
or loaiasis, co-infection should be ruled out before initiating treatment because killing those
microfilariae can cause blindness and encephalopathy respectively. The onchocerciasis is pretreated
with ivermectin, and in Loa loa co-infection, the DEC is spread over 21 days, and some experts prescribe
prednisone concomitantly. Ivermectin is only microfilaricidal and is employed in community-wide
control programs in Africa. There is some evidence that albendazole augments the microfilaricidal
activity of DEC and ivermectin. Bacterial superinfections, which are mostly streptococcal or
staphylococcal and can cause filarial abscess, should be treated with antibiotics. Additional symptomatic
therapy includes bandaging of wounds, physiotherapy and elevation to optimize limb mobility, skin care
to prevent secondary infection, surgical repair of hydroceles, and bladder fulguration for chyluria. In the
United States, DEC is available only from the drug service of the US Centers for Disease Control and
Prevention.
PREP Pearls
 Filariasis is very common worldwide and is transmitted by several mosquito vectors.
 Lymphangitis is a characteristic feature of acute filariasis, with retrograde progression from

lymphadenitis.
 Diethylcarbamazine may cause permanent sequelae in patients co-infected with Onchocerca

volvulus or Loa loa.
 Identify the geographic distribution, vector, and clinical manifestations of filariasis
 Know that microfilaria may remain in a patient's blood for more than one year after death of
adult worms
 Plan an appropriate treatment regimen for filariasis, including diethylcarbamazine, ivermectin,

and corticosteroids
Question: 6
You are called by a pediatrician caring for a 2-year-old boy with bilateral cochlear implants. The patient
inadvertently received a dose of the pneumococcal polysaccharide 23-valent vaccine (PPSV23) and his
fourth dose of 13-valent pneumococcal conjugate vaccine (PCV13) at the same visit. The pediatrician
wants to know what should be done.
Of the following, the MOST appropriate advice is to
A. consider both vaccine doses as NOT valid
B. consider both vaccine doses as valid
C. count the PCV13 dose as valid and repeat the PPSV23 dose
D. count the PPSV23 dose as valid and repeat the PCV13 dose
E. give a supplemental dose of PPSV23 in 2 years

Question: 6
You are called by a pediatrician caring for a 2-year-old boy with bilateral cochlear implants. The patient
inadvertently received a dose of the pneumococcal polysaccharide 23-valent vaccine (PPSV23) and his
fourth dose of 13-valent pneumococcal conjugate vaccine (PCV13) at the same visit. The pediatrician
wants to know what should be done.
Of the following, the MOST appropriate advice is to
A. consider both vaccine doses as NOT valid
B. consider both vaccine doses as valid
C. count the PCV13 dose as valid and repeat the PPSV23 dose
D. count the PPSV23 dose as valid and repeat the PCV13 dose
E. give a supplemental dose of PPSV23 in 2 years
Pneumococcal polysaccharide 23-valent vaccine (PPSV23) and 13-valent

pneumococcal conjugate vaccine (PCV13) should not be administered at the same
visit. When the 2 vaccines are given at the same visit, they affect each other by
decreasing vaccine immune response, especially to the PCV13. In the situation where
the 2 vaccines are given to a child at the same time, the recommendation is to count
the PPSV23 dose as being valid and administer another dose of PCV13 8 weeks after
the PPSV23 was administered. A supplemental dose of PPSV23 is not recommended for the cochlear
implant population after an initial dose of PPSV23 is given.
Antigens (Ags) are classified as T-cell dependent (TD) or T-cell independent (TI), depending on whether
T-cell help is needed to induce an antibody (Ab) response. T-cell independent Ags are further classified
into TI types 1 and 2. T-cell dependent Ags require B cells to have direct contact with T-helper cells in
order to form antibodies. An antigen presenting cell presents antigen to a T-helper cell, the T-helper cell
can then present antigen to the B cell and it is activated to produce antibodies. T-cell independent Ags
activate B cells by other mechanisms. The TI-1 Ags, such as lipopolysaccharide, are B-cell mitogens,
which function by polyclonally activating most B cells regardless of their antigenic specificity. The TI-2
Ags, such as polysaccharides, are large molecules with repeating arrays of antigenic epitopes that are
typically able to activate complement, but lack the ability to induce major histocompatibility complex-
dependent T-cell help. T-cell independent-2 Ags activate B cells by linking the membrane-bound
immunoglobulin expressed on the surface of the B cell. This bypasses the need for T cells to activate the
B cell to produce antibodies.
There are currently 2 different types of pneumococcal vaccines that are licensed for use: a
polysaccharide vaccine and a protein conjugated vaccine. The licensed pneumococcal polysaccharide
vaccine contains the purified pneumococcal polysaccharide capsular Ags of the 23 most common
disease causing serotypes. Polysaccharide Ags induce antibodies primarily by a T-cell independent
mechanism. These Ags do not induce immunologic memory and fail to prime for an anamnestic or
booster response with subsequent re-exposure. Therefore, children younger than 2 years of age either
do not respond or respond very poorly to vaccination with these vaccines because of an immature
immune system that does not respond well to T-cell independent Ags. After 1 dose of PPSV23, infants
develop fairly good antibody responses to types 3, 4, 8, 9N, and 18C; intermediate responses to types 1,
2, 7F, 19F, and 25; and poor responses to all the remaining serotypes in the vaccine. The antibody levels
decrease very rapidly in a few months after immunization and are short lived. Polysaccharide vaccines
are effective at preventing invasive pneumococcal disease, but fail to reduce nasopharyngeal carriage of
pneumococcal organisms, therefore, they do not provide any significant protection against mucosal
infections (eg, otitis media, sinusitis), and do not protect against the spread of resistant pneumococcal
strains from 1 person to another.
Protein-conjugated vaccines involve the covalent linking of each of the pneumococcal capsular
polysaccharides to a protein carrier, which results in enhancement of immunogenicity and increased
antibody levels in young infants and children. The immune response to protein Ags is T-cell dependent.
This induces T-helper cells to stimulate polysaccharide specific B-cells to develop either antibody-
producing plasma cells or memory cells, which primes the vaccinated individual for an anamnestic or
booster response. The coupling of a polysaccharide antigen to a protein carrier converts the
polysaccharide from a T-independent to a T-dependent antigen, so that robust antibody production and
immunological memory is induced in very young infants. These vaccines are effective in reducing
nasopharyngeal carriage of pneumococcal organisms and provide some protection against mucosal
infections.
The advantages and disadvantages of protein-conjugated and polysaccharide pneumococcal vaccines

are shown in the Table.
PREP Pearls
 T-cell dependent (TD) antigens (Ags) require B cells to have direct contact with T-helper cells in
order to form antibodies.
 T-cell independent (TI) antigens are classified as types 1 and 2. The TI-1 Ags, such as
lipopolysaccharides, are B cell mitogens that function by polyclonally activating most B cells
regardless of their antigenic specificity. The TI-2 Ags, such as polysaccharides, activate B cells by
linking the membrane-bound immunoglobulin expressed on the surface of the B cell.
 There are 2 different types of pneumococcal vaccines that are licensed for use: a polysaccharide
vaccine and a protein conjugated vaccine. The polysaccharide vaccine induces antibodies
primarily by a TI mechanism, while the protein-conjugated vaccine induces antibodies by a TD
mechanism.
 Differentiate T-cell independent from T-cell dependent antigens
 Know the advantages/disadvantages of protein-conjugated and polysaccharide pneumococcal

vaccines
Question: 7
An otherwise healthy 8-year-old girl has had purulent drainage from her left lower leg for the past 7
months, at the site of a gunshot wound sustained 1 month prior to the drainage. She is afebrile and has
mild to moderate pain and tenderness at the site, but has no systemic signs or symptoms of infection.
Plain radiographs of the area show extensive bony destruction and periosteal reaction. Culture of the
drainage reveals Acinetobacter baumannii, Enterococcus faecalis, Klebsiella oxytoca, Pseudomonas
aeruginosa, and Staphylococcus aureus. Her orthopedic surgeon requests antibiotic recommendations,
but you ask for a culture of bone prior to starting therapy.
Of the organisms grown from her wound culture, the one MOST likely to be present in the bone culture
as well is
A. Acinetobacter baumannii
B. Enterococcus faecalis
C. Klebsiella oxytoca
D. Pseudomonas aeruginosa
E. Staphylococcus aureus
Question: 7
An otherwise healthy 8-year-old girl has had purulent drainage from her left lower leg for the past 7
months, at the site of a gunshot wound sustained 1 month prior to the drainage. She is afebrile and has
mild to moderate pain and tenderness at the site, but has no systemic signs or symptoms of infection.
Plain radiographs of the area show extensive bony destruction and periosteal reaction. Culture of the
drainage reveals Acinetobacter baumannii, Enterococcus faecalis, Klebsiella oxytoca, Pseudomonas
aeruginosa, and Staphylococcus aureus. Her orthopedic surgeon requests antibiotic recommendations,
but you ask for a culture of bone prior to starting therapy.
Of the organisms grown from her wound culture, the one MOST likely to be present in the bone culture
as well is
B. Enterococcus faecalis
C. Klebsiella oxytoca
D. Pseudomonas aeruginosa
E. Staphylococcus aureus
Individuals with chronic osteomyelitis may develop chronic, draining fistulae, which
can become colonized with bacteria that may not reflect the underlying pathogens in
the bone itself. Therefore, optimal management would include culture of the affected
bone itself, preferably accessed via an incision that does not go through the fistula or
abnormal tissue.
Mackowiak and colleagues documented the discrepancies between sinus tract and bone cultures in 40
adults with chronic osteomyelitis and concluded that sinus tract cultures could be misleading. The one
exception was Staphylococcus aureus; of the 9 patients growing this organism from the sinus tract, 7
also grew from bone. This information was updated by Zuluaga et al, who reported results of bone and
nonbone cultures of 100 patients (mostly adults) with chronic osteomyelitis who had been off of
antibiotics for at least 48 hours prior to sampling. Again, S aureus was most likely to have concordance
between bone and nonbone cultures. However, statistical analysis suggested that this concordance was
no better than that expected by chance alone. Thus, the preferred response is S aureus, but from a
clinical decision standpoint, one should not rely on sinus tract or nonbone cultures to address the
etiology of chronic osteomyelitis. It should also be noted that the latter study excluded osteomyelitis
resulting from diabetic foot or decubitus ulcers.
Optimal treatment for chronic osteomyelitis is highly controversial, with little evidence to support
recommendations. It seems prudent to debride any necrotic material or sequestra and drain abscesses,
but the duration and route of antimicrobial therapy has not been subjected to critical study. Commonly,
treatment duration is much longer than with acute osteomyelitis, with a tendency for more prolonged
parenteral therapy. In a review of systemic antibiotic therapy for chronic osteomyelitis in adults,
Spellberg and Lipsky refer to a standard 6-week course of parenteral therapy, but state that the
preference for the parenteral route is based more on custom than evidence. Oral therapy with well-
absorbed antibiotics is likely equivalent. The role of topical therapy, such as local antibiotic infusion or
antibiotic beads or cement, is popular, but requires more definitive study.
The Infectious Diseases Society of America plans publication of a clinical practice guideline for
osteomyelitis and septic arthritis in children for fall 2015.
PREP Pearls
 Wound cultures may not predict the etiologic agents of underlying chronic osteomyelitis.
Culture of the affected bone should be obtained.
 Duration and route of antimicrobial therapy for chronic osteomyelitis are uncertain and based
largely on anecdotal reports or retrospective case series.
 Combined medical and surgical management is often indicated.
 Recognize the clinical features, and plan the diagnostic evaluation and management of a patient
with chronic osteomyelitis
Question: 8
A local pediatrician calls your office regarding placement of the tuberculin skin test (TST) test in a 13-
month-old boy who has returned from a 3-month stay in Africa. Two weeks ago, he received routine
vaccinations that included measles, mumps, and rubella.
Of the following, the MOST accurate statement regarding administration of the TST for this child is
A. control skin tests should be placed alongside the TST
B. placement of the TST is not indicated
C. placement of the TST should be delayed by 4 to 6 weeks
D. the TST can be placed any time after live virus vaccines are given
E. TST testing is required prior to the administration of live virus vaccines

Question: 8
A local pediatrician calls your office regarding placement of the tuberculin skin test (TST) test in a 13-
month-old boy who has returned from a 3-month stay in Africa. Two weeks ago, he received routine
vaccinations that included measles, mumps, and rubella.
Of the following, the MOST accurate statement regarding administration of the TST for this child is
A. control skin tests should be placed alongside the TST
B. placement of the TST is not indicated
C. placement of the TST should be delayed by 4 to 6 weeks
D. the TST can be placed any time after live virus vaccines are given
E. TST testing is required prior to the administration of live virus vaccines
The tuberculin skin test (TST) is not required before the administration of live virus
vaccines. Further, because the administration of measles vaccine may diminish
delayed type hypersensitivity, if a TST needs to be placed, it should either be placed at
the same time as the administration of measles vaccine; and if not, it should be
delayed for 4 to 6 weeks after the administration of this vaccine. It is not known
whether the other live virus vaccines (varicella, yellow fever, or live attenuated
influenza) have the same effect as measles vaccine, but in the absence of data, it is recommended that
the same algorithm be applied to the administration of these vaccines as that used for the measles
vaccine. In contrast to live virus vaccines, inactivated, polysaccharide, and subunit vaccines, as well as
toxoids, do not alter the immune response to the TST. Control skin tests to assess cutaneous anergy are
no longer recommended. The TST placement is recommended for infants, children, and adolescents
with travel histories to countries with endemic countries and substantial contact with indigenous people
from such countries.
Conditions that are responsible for a diminished TST response include very young age,
immunocompromised states such as those seen with HIV and AIDS, malignancy, or chronic steroid
administration, malnutrition, severe or over whelming sepsis, or severe infection such as miliary
tuberculosis (TB), as well as viral infections that include varicella, measles, or influenza. Recent TB
infection may also diminish the immune response to the TST. It is important to keep in mind that 10% to
40% of immunocompetent children with culture-confirmed TB do not react to the TST. In fact, a negative
TST does not exclude TB disease or latent TB infection.
Other factors that may cause a diminished or false negative response to the TST include those related to
the tuberculin itself. These include improper storage or dilution and contamination or chemical
denaturation. Factors related to administration include improperly given injections, delayed
administration after loading the syringe, or injection of inadequate amount of antigen. Lastly, improper
reading of the TST caused by an inexperienced reader or an error in recording may also account for a
false negative TST.
In situations where the index of suspicion for TB is high, a false negative TST should not deter the
clinician from making the diagnosis of TB. Other factors that should be considered in making the
diagnosis would be history and clinical examination, as well as the results of the chest radiograph or the
interferon γ release assays. In addition to the presence of any of the factors previously stated, in
particular disease states such as immunosuppression due to chemotherapy, chronic corticosteroid
therapy, HIV, or other viral infections, should be taken into consideration. Two-step TB skin testing is not
routinely recommended, except in special circumstances such as health care workers with a prior history
of Bacillus Calmette–Guérin vaccination or for regular monitoring in countries with an intermediate
burden of TB. These allow for the distinction between old versus recent infection.
PREP Pearls
 Diminution in delayed type hypersensitivity responses may be seen after measles virus vaccine.
 While it is not known that the same may happen after administration of other live virus
vaccines, which include varicella, yellow fever, and live attenuated influenza vaccines, the same
principles should apply.
 Severe overwhelming infection with tuberculosis infection itself may lead to false negative
hypersensitivity test results.
 A negative tuberculin skin test does not exclude tuberculosis (TB) disease or latent TB infection
 Know clinical settings when delayed hypersensitivity testing is transiently diminished

(corticosteroid use, measles, varicella)
 Know clinical settings where delayed hypersensitivity testing may be falsely negative and how to
evaluate this setting
April
Question: 1
You receive a call from one of your HIV-infected patients who states that he has noticed that his skin and
nails have been looking blue for the last several days. The patient is taking several different medications
which include darunavir, ritonavir, tenofovir, and emtricitabine for the treatment of his HIV infection. In
addition, he also takes dapsone and azithromycin for Pneumocystis jirovecii pneumonia and
Mycobacterium avium complex prophylaxis, respectively.
Of the following, the medication MOST likely to be responsible for the patient’s skin and nail
discoloration is
A. azithromycin
B. dapsone
C. darunavir
D. emtricitabine
E. tenofovir
Question: 1
You receive a call from one of your HIV-infected patients who states that he has noticed that his skin and
nails have been looking blue for the last several days. The patient is taking several different medications
which include darunavir, ritonavir, tenofovir, and emtricitabine for the treatment of his HIV infection. In
addition, he also takes dapsone and azithromycin for Pneumocystis jirovecii pneumonia and
Mycobacterium avium complex prophylaxis, respectively.
Of the following, the medication MOST likely to be responsible for the patient’s skin and nail
discoloration is
A. azithromycin
B. dapsone
C. darunavir
D. emtricitabine
E. tenofovir
The patient in the vignette has methemoglobinemia secondary to dapsone. The drug
is metabolized in the liver to hydroxylated compounds, which are taken up by
erythrocytes while they remain in the circulation. These metabolites, in particular
dapsone monohydroxylamine, are primarily responsible for the hematologic adverse
effects caused by dapsone such as methemoglobinemia and hemolytic anemia.
Hemolysis is more likely to occur in individuals with glucose-6-phosphate
dehydrogenase deficiency. The incidence of these dapsone-related hematologic adverse events has
been reported to be between 4% and 13%. Azithromycin, darunavir, emtricitabine, and tenofovir are not
associated with methemoglobinemia.
Other hematologic adverse effects seen with chronic dapsone use include neutropenia,
thrombocytopenia, aplastic anemia, and agranulocytosis. Nonhematologic adverse effects associated
with dapsone use include peripheral neuropathy, hepatitis, and eosinophilic pneumonia, while acute
events such as nausea, abdominal pain, and seizures have also been reported. A dapsone
hypersensitivity syndrome (DHS) has also been described, which presents with fever, eosinophilia, skin
eruption, as well as multiple organ involvement, which may include the hepatobiliary system, lungs,
kidneys, peripheral and central nervous system, and bone marrow. Severe cases may present with toxic
epidermal necrosis and Stevens–Johnson syndrome. Dapsone hypersensitivity syndrome has been
reported to occur in 0.5% to 3.6% of patients treated with dapsone with a mortality rate of 9.9%.
Genome-wide association analysis has shown that individuals with HLA-B*13:01 who are treated with
dapsone may develop DHS.
Dapsone was first introduced in the 1940s for the treatment of leprosy, and later in the 1980s was used
for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP). Despite the emergence of resistance, it
continues to be the drug of choice for the treatment of leprosy (both tuberculoid and lepromatous) as
part of a combination regimen with rifampin and clofazime. For the prophylaxis of PCP, its use is limited
primarily to patients who are unable to take trimethoprim-sulfamethoxazole.
Dapsone is a synthetic sulfone that inhibits the enzyme dihydropteroate synthetase, thus decreasing
folate synthesis. Due to its anti-inflammatory effects, primarily attributable to interference with
neutrophil chemotactic migration and adherence, dapsone has also been used for the treatment of
multiple dermatologic disorders such as dermatitis herpetiformis, acne vulgaris, cutaneous vasculitis,
pemphigus vulgaris, polyarteritis nodosa, and nodulocystic acne, to name a few. It has also been used
for the treatment of brown recluse spider bites.
PREP Pearls
 Dapsone remains an essential part of combination therapy in the treatment of both

lepromatous and tuberculoid leprosy.
 In individuals taking dapsone, the incidence of methemoglobinemia and hemolytic anemia has
been reported to be between 4% and 13%.
 Genome-wide association analysis has shown that individuals with HLA-B*13:01 who are treated
with dapsone may develop dapsone hypersensitivity syndrome.
 Other hematologic abnormalities such as agranulocytosis and neutropenia may also be seen.
 Know the clinical indications for the use of dapsone therapy
 Know the adverse effects of dapsone therapy

Question: 2
A 20-year-old patient presents with severe headache, cranial nerve seven palsy, nausea, vomiting,
generalized weakness, and somnolence. History reveals that he recently returned from a 1-month
mission trip to several South Pacific islands. During his trip, he participated in several local rituals and
food customs as a part of his cultural immersion experience. Cerebrospinal fluid (CSF) examination
reveals 500 white blood cells/high power field (50% eosinophils), glucose level of 70 mg/dL (3.9
mmol/L), and a protein level of 200 mg/dL. A positive result is found with performance of enzyme
immunoassay for Angiostrongylus cantonensis on CSF sent to the US Centers for Disease Control and
Prevention.
Of the following, the MOST likely ingestion exposure resulting in A cantonensis meningitis in this patient
is
A. contaminated water
B. soil contaminated with lamb feces
C. soil contaminated with raccoon feces
D. uncooked snails
E. undercooked pork
Question: 2
A 20-year-old patient presents with severe headache, cranial nerve seven palsy, nausea, vomiting,
generalized weakness, and somnolence. History reveals that he recently returned from a 1-month
mission trip to several South Pacific islands. During his trip, he participated in several local rituals and
food customs as a part of his cultural immersion experience. Cerebrospinal fluid (CSF) examination
reveals 500 white blood cells/high power field (50% eosinophils), glucose level of 70 mg/dL (3.9
mmol/L), and a protein level of 200 mg/dL. A positive result is found with performance of enzyme
immunoassay for Angiostrongylus cantonensis on CSF sent to the US Centers for Disease Control and
Prevention.
Of the following, the MOST likely ingestion exposure resulting in A cantonensis meningitis in this patient
is
A. contaminated water
B. soil contaminated with lamb feces
C. soil contaminated with raccoon feces
D. uncooked snails
E. undercooked pork
The patient in the above vignette has been diagnosed with eosinophilic meningitis
(EM) caused by Angiostrongylus cantonensis, which is also known as the rat
lungworm. Adult worms live in rat pulmonary arteries and lay eggs in the lung. The
larvae migrate from the alveoli to the trachea and are then ingested into the enteric
track and excreted in the feces. Many species of snails and slugs then serve as the
intermediate host in which the larvae develop into infectious third stage larvae. These
infectious larvae are then ingested by rats or sometimes humans and then migrate from the enteric
tract into the blood stream and then the central nervous system (CNS), which is characteristic of this
parasite’s life cycle. Therefore, the preferred response is uncooked snails. Ingestion of contaminated
water would more likely lead to cause infection with Paragonimus westermani or Fasciola hepatica
(Table). Accidental ingestion of soil contaminated by raccoon feces is the main risk factor for developing
infection with Baylisascaris procyonis, and accidental ingestion of soil contaminated by lamb feces is the
primary risk factor for Echinococcus granulosus. Finally, ingestion of undercooked pork is most often
associated with Trichinella spiralis.
Although all of these organisms are associated with EM, A cantonensis is the most common cause of EM
worldwide. A cantonensis is rare in the United States, but has occurred in a child who had no prior
history of travel who ate a raw snail on a dare. In addition to helminthes, the presence of eosinophils in
the cerebrospinal fluid (CSF) may suggest other etiologies such as fungi or noninfectious causes
including medications, CNS neoplasms, or as an allergic reaction to ventriculoperitoneal shunt material.
Accurate identification of eosinophils in the CSF is very important, as they can easily be mistaken for
neutrophils if the cell counts are only performed in an automatic cell counter. Further, eosinophils are
not readily discernable without Wright or Giemsa staining, and careful attention must be paid in the
microbiology laboratory, as cytologic cell features can be distorted or destroyed during processing.
Noninfectious causes of EM should be considered in patients in the appropriate clinical scenario.

Eosinophilic meningitis is an uncommon, but well described feature of certain types of leukemia,
lymphoma, and some other primary CNS tumors (Table). Additionally, medications, such as nonsteroidal
anti-inflammatory agents and certain antibiotics may also cause EM. Finally, hypersensitivity reactions
resulting from shunt material in the CNS and autoimmune disorders have resulted in EM.
PREP Pearls
 Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis worldwide.
 The differential diagnosis for eosinophilic meningitis is quite large and history should include
epidemiologic risk factors.
 Noninfectious causes of eosinophilic meningitis should be considered in the appropriate clinical

setting.
 Recognize the clinical and epidemiologic features needed to formulate the differential diagnosis
of a patient with eosinophilic meningitis
Question: 3
You are asked by the employee health department at your children’s hospital to offer recommendations
for a newly hired neonatal intensive care unit nurse. The nurse is healthy and has no contraindication to
receiving any vaccines. Review of her immunization records reveal that she was immunized with tetanus
toxoid and reduced diphtheria (Td) vaccine 1 year ago and has never been immunized with tetanus
toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. She has no history of varicella
and her serologic studies confirm that she is nonimmune to varicella.
Of the following, the MOST appropriate recommendation is for her to receive 2 doses of varicella
vaccine 4 to 8 weeks apart and
A. one dose of Tdap now
B. one dose of Tdap 2 years after receipt of her previous Td vaccine
C. one dose of Tdap 5 years after receipt of her previous Td vaccine
D. two doses of Tdap vaccine 4 to 8 weeks apart
E. two doses of Tdap vaccine 4 to 8 weeks apart, starting 2 years after receipt of previous Td vaccine
Question: 3
You are asked by the employee health department at your children’s hospital to offer recommendations
for a newly hired neonatal intensive care unit nurse. The nurse is healthy and has no contraindication to
receiving any vaccines. Review of her immunization records reveal that she was immunized with tetanus
toxoid and reduced diphtheria (Td) vaccine 1 year ago and has never been immunized with tetanus
toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. She has no history of varicella
and her serologic studies confirm that she is nonimmune to varicella.
Of the following, the MOST appropriate recommendation is for her to receive 2 doses of varicella
vaccine 4 to 8 weeks apart and
A. one dose of Tdap now
B. one dose of Tdap 2 years after receipt of her previous Td vaccine
C. one dose of Tdap 5 years after receipt of her previous Td vaccine
D. two doses of Tdap vaccine 4 to 8 weeks apart
E. two doses of Tdap vaccine 4 to 8 weeks apart, starting 2 years after receipt of previous Td
vaccine
The US Centers for Disease Control and Prevention (CDC) states that healthcare facilities should
maximize efforts to immunize all healthcare professionals (HCP) with tetanus toxoid, reduced diphtheria
toxoid, and acellular pertussis (Tdap) to prevent transmission of Bordetella pertussis. Therefore, HCP
should receive a single dose of Tdap vaccine as soon as feasible if they have not previously received
Tdap. Protection against pertussis is of paramount importance and the safety of Tdap following tetanus
toxoid and reduced diphtheria (Td) vaccine has been demonstrated, therefore Tdap can be administered
regardless of the time since the most recent Td vaccination. At the current time, Tdap is not licensed for
multiple vaccinations (but is routinely is being recommended for each pregnancy). Thus, for the nurse in
the vignette, a single dose of Tdap vaccine is indicated. The safety of Tdap vaccination in adults has been
documented both in pre- and postlicensure studies. The recommendation to vaccinate all healthcare
workers with a pertussis-containing vaccine is based on the fact that pertussis transmission can occur
from HCP to patients and from patients to HCP. The efficacy of vaccination with Tdap among adults in
prelicensure studies was estimated at 92%. Recent postlicensure studies have demonstrated vaccine
effectiveness to be 66% to 78%.
Recent outbreaks of pertussis that have occurred in the hospital setting have been costly and disruptive,
resulting in the need for medical evaluation, diagnostic testing, prophylactic antibiotics, and exclusion
from work. Estimates of cost savings from pertussis vaccine programs in health settings have
documented a cost saving of $2.38 for every dollar spent on the vaccination program. Tdap is not
currently licensed for multiple administrations, therefore HCP should receive Td vaccine for future
booster vaccinations against tetanus and diphtheria. Prevaccination serologic testing is not
recommended for HCP. Serologic correlates of protection for pertussis are not well established,
therefore immunity following Tdap vaccination cannot be demonstrated.
Tdap coverage among HCP is suboptimal (31% in 2012), and the duration of protection from one dose of
Tdap is unknown, therefore, vaccination should not influence the need for postexposure prophylaxis in
HCP who are exposed to pertussis; postexposure antimicrobial prophylaxis should be provided for those
HCP who have contact with patients at risk for severe disease.
It is important that healthcare institutions ensure that all HCP have evidence of immunity to varicella.
This information should be readily available and those without evidence of immunity should receive 2
doses of varicella vaccine given 4 to 8 weeks apart. Institutions should also establish protocols and
recommendations for screening and vaccinating HCP and for the management of HCP after exposures in
the work place. In healthcare settings, serologic testing before vaccination of personnel without
evidence of immunity is likely to be effective. The CDC defines evidence of immunity for HCP as any of
the following:
 Written documentation of vaccination with 2 doses of varicella vaccine
 Laboratory evidence of immunity or laboratory confirmation of disease
 Diagnosis or verification of a history of varicella disease by a HCP, or
 Diagnosis or verification of a history of herpes zoster by a HCP
Routine testing for varicella immunity after 2 doses of varicella is not recommended. This is based on
the fact that available commercial assays are not 100% sensitive, seroconversion does not always result
in full protection against disease, and the absence of antibodies does not necessarily mean
susceptibility. Thus, documentation of 2 doses of varicella vaccine should supercede results of
subsequent serologic testing.
Healthcare professionals who have received 2 doses of varicella vaccine and who are exposed to
varicella can be monitored daily during days 8 to 21 after exposure for signs of infection and excluded
immediately if symptoms occur. Healthcare professionals who have received 1 dose of vaccine and who
are exposed should receive the second dose of vaccine within 3 to 5 days after exposure. Unvaccinated
HCP who are susceptible to varicella and are exposed should be furloughed from days 8 to 21 after
exposure, but should receive varicella vaccine as soon as possible after exposure in hopes of modifying
the disease if infection occurs.
Healthcare professionals who develop a vaccine-related rash after varicella vaccination should avoid
contact with persons who are susceptible to varicella and who are at high risk for severe infection until
all lesions have resolved. Healthcare professionals who develop macules and papules (rather than
vesicular lesions) after vaccination should avoid contact with persons who are susceptible to varicella
until no new lesions appear or a 24-hour period.
PREP Pearls
 Healthcare professionals should receive a single dose of tetanus toxoid, reduced diphtheria
toxoid, and acellular pertussis (Tdap) vaccine as soon as feasible, if they have not previously
received Tdap and regardless of the time elapsed since tetanus toxoid and reduced diphtheria
(Td) vaccination.
 The Tdap vaccine is not currently licensed for multiple administrations (but is routinely is being
recommended for each pregnancy).
 Healthcare professionals who do not have evidence of immunity to varicella should receive 2
doses of varicella vaccine given 4 to 8 weeks apart.
 Make recommendations for immunization of hospital personnel with varicella vaccine
 Make recommendations for the adult Tdap vaccine for hospital personnel
April
Question: 4
An 18-year-old young man who just graduated high school is traveling to several countries in Southeast
Asia on a backpacking trip 6 weeks from now. He would like to receive appropriate vaccines for travel.
His relevant immunization record is shown in the Chart.
In addition to typhoid, Japanese encephalitis, rabies, and influenza vaccines, the MOST important
vaccine he needs before he begins his trip is
A. human papilloma virus vaccine (HPV)
B. inactivated polio vaccine (IPV)
C. meningococcal conjugate vaccine quadrivalent (MCV4)
D. tetanus, diphtheria (Td)
E. tetanus, diphtheria, and acellular pertussis vaccine (Tdap)

Question: 4
An 18-year-old young man who just graduated high school is traveling to several countries in Southeast
Asia on a backpacking trip 6 weeks from now. He would like to receive appropriate vaccines for travel.
His relevant immunization record is shown in the Chart.
In addition to typhoid, Japanese encephalitis, rabies, and influenza vaccines, the MOST important
vaccine he needs before he begins his trip is
A. human papilloma virus vaccine (HPV)
B. inactivated polio vaccine (IPV)
C. meningococcal conjugate vaccine quadrivalent (MCV4)
D. tetanus, diphtheria (Td)
E. tetanus, diphtheria, and acellular pertussis vaccine (Tdap)
A small risk of tetanus from soil-related exposures during recreational activities can be
anticipated for all persons while traveling abroad, so a traveler should be up to date
on tetanus vaccination. Since the patient received his last tetanus-containing vaccine
over 5 years ago, he should receive tetanus and diphtheria toxoids (Td) before he
begins his trip. He received meningococcal conjugate vaccine quadrivalent (MCV4) at
16 years of age, and does not need a booster at this time. He is up to date on pertussis vaccination,
having received Tdap at 11 years of age. He does not need an inactivated polio vaccine (IPV) booster
because no Southeast Asian countries are polio-infected or polio-exporting. Initiation of a human
papilloma virus vaccine (HPV) series is recommended, but could be deferred until his return.
The need to receive tetanus vaccine before a trip depends upon the child’s tetanus immunization status.
Young children should have received 3 doses of tetanus and diphtheria toxoid-containing vaccines by 6
months of age, 4 doses by 18 months of age, 5 doses by their seventh birthday, and 6 doses by 11 to 12
years of age. Travelers who need a primary series should try to complete as many doses as possible
before travel. The first 2 doses can be administered 4 weeks apart and the third dose 6 to 12 months
after the second. Unless there is contraindication to the use of pertussis vaccine, the tetanus-containing
vaccine should be DTaP up to the seventh birthday, and Tdap for a child older than 7 years (Td if the
child has received Tdap previously). For adolescents 11 years of age or older and adults who are
traveling abroad, a booster dose of a tetanus-containing vaccine should be administered if more than 5
years have elapsed since the last dose, followed by Td booster doses every 10 years after that. Tetanus
vaccine may be administered concurrently with other vaccines. The only contraindication to tetanus
vaccine is history of a moderate or serious reaction (including anaphylactic reaction or severe central
nervous system disorder) after receiving tetanus-containing vaccine.
The young man in the vignette has received a complete primary series of hepatitis B vaccine and is
considered immune. If a young adult is not up to date with hepatitis B vaccine, indications for
immunizing prior to travel would be: prolonged stay in any foreign country, frequent short stays in high-
risk areas with high (> 8%) prevalence of hepatitis B infection (all of Africa, all of Southeast Asia, the
Middle East except Israel, the southern and western Pacific islands, the interior Amazon River basin, and
parts of the Caribbean [Haiti and the Dominican Republic]), adventure travel, possibility of a new sexual
partner during the trip, potential to receive medical or dental care, tattooing, body piercing, or
acupuncture in local facilities, working as a healthcare worker, or having an underlying medical illness. If
an accelerated schedule is needed and the adolescent has not received hepatitis A vaccine, a
combination of hepatitis B (Engerix-B®, 20 μg) and hepatitis A (Havrix®, 720 enzyme-linked
immunosorbent assay units [ELU]) vaccine (Twinrix®) is licensed for use in people 18 years of age and
older in a 4-dose schedule at days 0, 7, and 21 to 30, followed by a booster dose at 12 months. In
addition, a 2-dose schedule, administered at 0 months and then 4 to 6 months later, is licensed for
adolescents 11 through 15 years of age using the adult formulation of Recombivax HB® (10 μg). A single
dose of hepatitis B vaccine has been shown to provide protective antibodies to 30% to 55% of healthy
adults, 2 doses to about 75%, and 3 doses to about 90%.
PREP Pearls
 Tetanus immunization should be maintained up to date for anyone who travels abroad
 Hepatitis B immunization should be maintained up to date for people who travel abroad
because of the numerous situations in which the risk of acquiring hepatitis B is high.
 Recommend tetanus immunization for a patient preparing for foreign travel based on past
history of immunization and nature of the patient's trip
 Know the indications for immunizing young adults against hepatitis B, including those traveling
to areas with high incidences of hepatitis B infection
Question: 5
You are evaluating a 11-year-old boy 12 days after he was running along the shore of a pond while at
summer camp and stepped on an old railroad spike that was buried in the mud. The spike was noted to
go through the sole of his tennis shoe with the tip coming out the top of his left foot. The patient pulled
the spike out and the wound was washed out with soap and water by the camp nurse several hours
after it happened. Over the past several days, his left foot has become very erythematous, swollen, and
painful to the point that he is unable to bear weight on the foot. The patient is healthy, except for some
exercise-induced asthma. His immunizations are up to date.
Physical examination is significant for marked swelling of his left foot and toes. There is a 1 cm puncture
wound on the plantar surface of his forefoot just below the level of the metatarsal heads. There is
marked erythema, induration, and tenderness surrounding the puncture wound with a seropurulent
discharge from the wound. There is a scab on the dorsum of his foot with erythema and tenderness
around the scab, but no discharge.
Plain radiograph of the foot demonstrates no foreign body, however, there is marked soft tissue edema
of the plantar surface of the foot with some periosteal reaction of the lateral surface of the shaft of the
third metatarsal and marked widening of the space between the second and third metatarsal bones
consistent with a large fluid collection.
Of the following, the risk factor that placed this patient at GREATEST risk for developing an infection of
his puncture wound is
A. depth of wound
B. elapsed time since the injury
C. footwear type
D. scene of the injury

E. underlying illness
Question: 5
You are evaluating a 11-year-old boy 12 days after he was running along the shore of a pond while at
summer camp and stepped on an old railroad spike that was buried in the mud. The spike was noted to
go through the sole of his tennis shoe with the tip coming out the top of his left foot. The patient pulled
the spike out and the wound was washed out with soap and water by the camp nurse several hours
after it happened. Over the past several days, his left foot has become very erythematous, swollen, and
painful to the point that he is unable to bear weight on the foot. The patient is healthy, except for some
exercise-induced asthma. His immunizations are up to date.
Physical examination is significant for marked swelling of his left foot and toes. There is a 1 cm puncture
wound on the plantar surface of his forefoot just below the level of the metatarsal heads. There is
marked erythema, induration, and tenderness surrounding the puncture wound with a seropurulent
discharge from the wound. There is a scab on the dorsum of his foot with erythema and tenderness
around the scab, but no discharge.
Plain radiograph of the foot demonstrates no foreign body, however, there is marked soft tissue edema
of the plantar surface of the foot with some periosteal reaction of the lateral surface of the shaft of the
third metatarsal and marked widening of the space between the second and third metatarsal bones
consistent with a large fluid collection.
Of the following, the risk factor that placed this patient at GREATEST risk for developing an infection of
his puncture wound is
A. depth of wound
B. elapsed time since the injury
C. footwear type
D. scene of the injury
E. underlying illness
The patient in the vignette has sustained a plantar puncture wound through the sole of his tennis shoe.
Of the choices listed, the depth of the wound is the risk factor that places the patient at greatest risk for
infection: the deeper the puncture wound, the higher the risk for infection. Elapsed time since the injury
of greater than 24 hours before obtaining medical care may also increase the risk for infection.
Footwear type and scene of the injury are helpful in determining the type of organisms to which the
patient would have been exposed and may help to guide empiric antibiotic therapy. Staphylococcus
aureus and group A streptococci are common causes of skin and soft tissue infections including puncture
wounds. Pseudomonas aeruginosa is commonly isolated in patients who sustain a plantar puncture
wound while wearing tennis shoes. Pseudomonas osteomyelitis has been reported after plantar
puncture wounds to bare feet, as well as through nonsneaker type shoes. Also, other Gram-negative
organisms may be the cause of this type of infection. Injury occurring in the vicinity of a pond or lake
should raise the possibility of Aeromonas species as the infecting organism, while injury in a farm setting
or in areas with a lot of animals exposes the patient to bowel flora from the animals; this should be
considered when choosing an antibiotic. When osteomyelitis arises from a puncture injury, underlying
illnesses can be helpful in determining the most likely common pathogens. S aureus or a polymicrobial
infection tends to be more common in diabetic patients, while P aeruginosa is seen more commonly in
nondiabetic patients. A history of asthma has no influence on the type of infecting pathogen for a
patient with a puncture wound.
Treatment of osteomyelitis depends on appropriate antibiotic therapy and may also require surgical
intervention. Indications for surgical drainage of osteomyelitis include:
1. a deep sequestered abscess or subperiosteal abscess(es)
2. the presence of avascular and necrotic tissue
3. failure to clinically improve despite appropriate intravenous antibiotic treatment for 48 hours
4. the presence of extensive chronic refractory osteomyelitis
5. the presence of a fistula, or
6. the presence of complicated pyogenic vertebral osteomyelitis with mechanical spinal instability,
epidural abscess formation, presence of neurologic deficits, or the presence of infected
hardware and other prosthetic material
Based on the findings of the plain radiograph of the patient in the vignette, this patient appears to have
an osteomyelitis of the lateral surface of his third left metatarsal and a deep abscess, making him a
prime candidate for surgical drainage. A shorter course antibiotic therapy of 7 to 14 days is sufficient for
the treatment of plantar puncture wound infections when accompanied by adequate surgical
debridement.
PREP Pearls
 Treatment of osteomyelitis may require surgical intervention, in addition to appropriate

antibiotic therapy.
 Indications for surgical drainage of osteomyelitis include: a deep sequestered abscess or

subperiosteal abscess, the presence of avascular and necrotic tissue, failure to clinically improve
despite 48 hours of appropriate intravenous antibiotic therapy, presence of extensive chronic
refractory osteomyelitis, presence of a fistula or the presence of complicated pyogenic vertebral
osteomyelitis with mechanical spinal instability, epidural abscess, neurologic deficits, or the
presence of infected hardware.
 Shorter course antibiotic therapy of 7 to 14 days is sufficient for the treatment of plantar
puncture wound infections when accompanied by adequate surgical debridement.
April
Question: 6
A primary care pediatrician asks you for advice regarding testing for Clostridium difficile colitis in a
previously healthy 10 week-old female infant who developed fever and bloody diarrhea yesterday. No
other family members are ill. Her mother has worked at a nursing home for 2 years, but she states that
she is not aware of any unusual diarrheal illness in the facility. The infant has a normal physical
examination.
Of the following, the BEST advice for C difficile stool testing in this child is
A. cell culture cytotoxicity neutralization assay
B. glutamate dehydrogenase and toxin enzyme immunoassay
C. no testing
D. nucleic acid amplification testing
E. toxigenic culture
Question: 6
A primary care pediatrician asks you for advice regarding testing for Clostridium difficile colitis in a
previously healthy 10 week-old female infant who developed fever and bloody diarrhea yesterday. No
other family members are ill. Her mother has worked at a nursing home for 2 years, but she states that
she is not aware of any unusual diarrheal illness in the facility. The infant has a normal physical
examination.
Of the following, the BEST advice for C difficile stool testing in this child is
A. cell culture cytotoxicity neutralization assay
B. glutamate dehydrogenase and toxin enzyme immunoassay
C. no testing
D. nucleic acid amplification testing
E. toxigenic culture
Clostridium difficile causes pseudomembranous colitis, characterized most commonly

by fever, bloody diarrhea, and abdominal pain. Asymptomatic carriage of toxin-
producing forms of the organism is common in young children, approaching
approximately one-third of those younger than 6 months of age. Thus, testing for C
difficile infection (CDI) should be avoided in children younger than 12 months of age,
unless they have a severe gastrointestinal motility disorder such as Hirschsprung disease or in an
outbreak situation. For children aged 12 to 36 months, asymptomatic carriage still occurs, so a positive C
difficile test must be interpreted within the clinical context. Beyond 3 years of age, a positive test in the
appropriate clinical setting indicates probable CDI. In addition to underlying bowel disease and outbreak
situations, additional risk factors for CDI include receipt of antibacterial or proton pump inhibitory
agents, renal insufficiency, and impaired humoral immunity.
A number of methods are available for diagnosing CDI. The gold standard is histologic evidence of
pseudomembranous colitis, but noninvasive testing of stool is utilized more commonly; most rely on
detection of C difficile toxins A or B. Both toxins can cause significant disease, although toxin B is a
considerably more potent cytotoxin. A culture of stool for toxigenic strains of C difficile (toxigenic
culture) is the most accurate stool testing method, but it is now used primarily for research purposes as
a gold standard comparison for other assays.
Of the various stool assays available, stool cell culture cytotoxicity neutralization assay (CCNA) was the
first toxin assay to be utilized widely. The neutralization step is primarily directed against toxin B, but
toxin A also is detected to a lesser extent. However, CCNA is tedious and has a slow turnaround time, in
addition to relatively poor sensitivity. It has been replaced by other methods, usually a 2-step algorithm
utilizing testing for C difficile glutamine dehydrogenase (GDH) presence, with confirmation of positive
results with a toxin A and B enzyme immunoassay (EIA) because GDH is not specific for toxin-producing
strains. Enzyme immunoassay has a high rate of false positive results and is therefore a poor choice to
use alone as a diagnostic test. Studies with nucleic acid amplification tests (NAAT) for C difficile toxins
are encouraging and are used in some pediatric hospitals as a confirmatory assay when GDH is positive,
but EIA is negative. However, studies in children are not sufficient to assess the exact role of NAAT in
management. It is also important to note that these tests persist positive in stool for many weeks after
clinical resolution and thus should not be used as a test of cure.
Several treatment options exist for CDI, but discontinuation of any antibacterial agents is likely the most
effective modality. However, for children in whom this is not possible, or for those who have moderate
disease, oral metronidazole is the drug of choice. For more severe disease, or for a second recurrence of
CDI, oral vancomycin with or without metronidazole is recommended. Vancomycin has been
administered rectally to patients with severe ileus associated with CDI. Other modalities utilized for
recurrences of CDI include tapered or pulsed regimens of oral vancomycin and fecal transplantation.
Fidaxomicin, a macrocyclic antibiotic, has been shown to be noninferior to oral vancomycin for CDI in
adults, and fidaxomicin recipients had a lower recurrence rate. Clinical trials of fidaxomicin in pediatric
CDI are ongoing.
PREP Pearls
 Clostridium difficile is commonly shed in stools of asymptomatic young children. Testing should
be avoided in children in the first year after birth.
 Stopping any antimicrobial agents is the first stage in treating Clostridium difficile colitis.
 Clostridium difficile assays normally remain positive after therapy for C difficile colitis and should
not be used as a test of cure.
 Understand the means of diagnosing Clostridium difficile colitis (cytoxin detection, antigen
detection, culture)
 Know that Clostridium difficile frequently colonizes in neonates and infants and toxin may be
present in the stool without associated disease in this age group
 Recognize the manifestations of Clostridium difficile colitis

 Plan the management of a patient with Clostridium difficile disease (discontinuing antibiotic,
drugs of choice, alternative drugs) and of a patient with relapsed Clostridium difficile colitis
Suggested Readings
 Burnham C-AD, Carroll KC. Diagnosis of Clostridium difficile infection: an ongoing conundrum for
clinicians and clinical laboratories. Clin Microbiol Rev. 2013;26(3):604-630. DOI:
10.1128/CMR.00016-13
 Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile
infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA)
and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol.
2010;31(5):431-455. DOI: 10.1086/651706
 Moore T, Rodriguez A, Bakken JS. Fecal microbiota transplantation: a practical update for the
infectious disease specialist. Clin Infect Dis. 2014;58(4):541-545. DOI: 10.1093/cid/cit950
 Planche TD, Davies KA, Coen PG, et al. Differences in outcome according to Clostridium difficile
testing method: a prospective multicentre diagnostic validation study of C difficile infection.
Lancet Infect Dis. 2013;13(11):936-945. DOI: 10.1016/S1473-3099(13)70200-7
 Schutze GE, Willoughby RE. Clostridium difficile infection in infants and children. Pediatrics.
2013;131(1):196-200. DOI: 10.1542/peds.2012-2992
Question: 7
You are consulted on a 17-year-old patient with sepsis in the pediatric intensive care unit (PICU). The
patient has underlying liver disease caused by perinatally acquired hepatitis C infection for which he is
currently not on any treatment. The PICU attending had started the patient empirically on cefotaxime
and gentamicin. The microbiology laboratory just called and is reporting the growth of a nonlactose
fermenting, Gram-negative, enteric bacillus.
Further history reveals that the patient began to complain of abdominal pain, diarrhea, and vomiting 4
to 5 days before admission. His symptoms progressed and he was seen by his primary care physician
who thought it was probably a viral infection and treated him symptomatically. However, the patient’s
symptoms continued to worsen and he was admitted to the hospital overnight and transferred to the
PICU because of hypotension and concern for sepsis. He is also noted to have purplish-red lesions on his
extremities. The patient is an 11th grade student and has spent the summer working on a pig and cattle
farm where his primary responsibilities have included cleaning the pig and cattle pens.
Of the following, the MOST likely organism responsible for the patient’s sepsis is
A. Citrobacter koseri
B. Enterobacter cloacae
C. Escherichia coli
D. Klebsiella oxytoca
E. Yersinia enterocolitica
Question: 7
You are consulted on a 17-year-old patient with sepsis in the pediatric intensive care unit (PICU). The
patient has underlying liver disease caused by perinatally acquired hepatitis C infection for which he is
currently not on any treatment. The PICU attending had started the patient empirically on cefotaxime
and gentamicin. The microbiology laboratory just called and is reporting the growth of a nonlactose
fermenting, Gram-negative, enteric bacillus.
Further history reveals that the patient began to complain of abdominal pain, diarrhea, and vomiting 4
to 5 days before admission. His symptoms progressed and he was seen by his primary care physician
who thought it was probably a viral infection and treated him symptomatically. However, the patient’s
symptoms continued to worsen and he was admitted to the hospital overnight and transferred to the
PICU because of hypotension and concern for sepsis. He is also noted to have purplish-red lesions on his
extremities. The patient is an 11th grade student and has spent the summer working on a pig and cattle
farm where his primary responsibilities have included cleaning the pig and cattle pens.
Of the following, the MOST likely organism responsible for the patient’s sepsis is
A. Citrobacter koseri
B. Enterobacter cloacae
C. Escherichia coli
D. Klebsiella oxytoca
E. Yersinia enterocolitica
All of the organisms listed are usually lactose fermenters, with the exception of
Yersinia enterocolitica. Therefore, response choice E is the preferred response.
Patients with chronic liver disease, particularly those with cirrhosis, are susceptible to
recurrent bacterial infections such as spontaneous bacterial peritonitis (SBP),
bacteremia, pneumonia, and urinary tract infections. Common causative organisms of
SBP include Streptococcus pneumoniae and Escherichia coli. They are also vulnerable
to infections caused by certain microorganisms that have the potential to cause severe disease in these
individuals. These organisms include Vibrio, Campylobacter, Pasteurella, Yersinia, Listeria, Enterococcus,
Plesiomonas, Aeromonas, and Capnocytophaga species. Of these, infections with Vibrio species are the
most well recognized in individuals with underlying liver disease and have been reported in association
with the consumption of raw or undercooked shellfish or following water-related injuries. Besides these
microorganisms, unusual bacteria such as Shewanella species have also been reported with increasing
frequency in patients with chronic liver disease. Shewanella are nonlactose fermenting, Gram-negative
rods with a worldwide distribution found primarily in bodies of warm sea water.
Several factors contribute to the pathophysiology of infections in patients with cirrhosis, which is known
to result in an acquired immune deficiency state. Low complement and opsonin levels, neutrophil and
reticuloendothelial dysfunction, which includes decreased chemotaxis, increased permeability of the gut
mucosa favoring bacterial translocation, as well as the availability of free iron or iron overload states
enable the growth of organisms such as Vibrio, Plesiomonas, Listeria, and Yersinia species. There is also
evidence that there is a marked up regulation of cytokine responses in patients with cirrhosis, leading to
a “cytokine storm,” which results in an inflammatory response that may be damaging rather than
protective and lead to further exacerbation of the sepsis syndrome in susceptible patients.
In addition to routine bacterial infections, clinicians need to recognize the possibility of infection with
unusual organisms when treating individuals with underlying chronic liver disease.
PREP Pearls
 Individuals with underlying chronic liver disease are susceptible to sepsis with several different
organisms including Vibrio, Campylobacter, Pasteurella, Yersinia, Listeria, Enterococcus,
Plesiomonas, Aeromonas and Capnocytophaga species.
 Another genus that has been reported with increasing frequency is Shewanella.
 Susceptibility to severe sepsis with these organisms is caused by an acquired immunodeficiency

state in these individuals.
 Identify the organisms to which patients with chronic liver disease are most susceptible
Suggested Readings
 Anderson M, Knudson M, Frieberg E, Petrescu M, Van Dyke R, Fortgang I. Fatal Vibrio vulnificus
sepsis in vertically acquired hepatitis C. J Pediatr Gastroenterol Nutr. 2013;56(5):e32-e33. DOI:
10.1097/MPG.0b013e31825089d3
 Brann OS. Infectious complications of cirrhosis. Curr Gasteroenterol Rep. 2001;3(4):285-292.
 Bunchorntavakul C, Chavalitdhamrong D. Bacterial infections other than spontaneous bacterial

peritonitis in cirrhosis. World J Hepatol. 2012;4(5):158-168. Available at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365435/
 Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology.
2009;50(6):2022-2033. DOI: 10.1002/hep.23264
 Otsuka T, Noda T, Noguchi A, Nakamura H, Ibaraki K, Yamaoka K. Shewanella infection in

decompensated liver disease: a septic case. J Gastroenterol. 2007;42(1):87-90. DOI:
10.1007/s00535-006-1957-0
Question: 8
An 8-year-old boy who has been previously healthy presents to the emergency room 2 days after onset
of an illness with intermittent fever (temperature maximum at 38.6°C), and moderate, constant
noncolicky abdominal pain mostly in the right lower quadrant. He has no nausea and has not vomited.
He has passed semi-soft stools without blood or mucus 3 to 5 times for 2 days. On examination, he is
nontoxic appearing, cooperative, and in moderate pain, but is able to walk comfortably. There is mild
tenderness on palpation over the right lower quadrant, but no rebound tenderness or pain on
percussion, and a negative Psoas sign. The only abnormality on his laboratory is a white blood cell count
of 15,500/µL (15.5 x 109/L), with a differential count of 40% polymorphonuclear leukocytes, 48%
lymphocytes, and 12% monocytes (no band forms or eosinophils).
Of the following, the MOST likely diagnosis in this boy with right lower quadrant pain and leukocytosis is
A. acute appendicitis
B. acute infectious colitis
C. Crohn disease
D. iliopsoas pyomyositis
E. mesenteric adenitis
Question: 8
An 8-year-old boy who has been previously healthy presents to the emergency room 2 days after onset
of an illness with intermittent fever (temperature maximum at 38.6°C), and moderate, constant
noncolicky abdominal pain mostly in the right lower quadrant. He has no nausea and has not vomited.
He has passed semi-soft stools without blood or mucus 3 to 5 times for 2 days. On examination, he is
nontoxic appearing, cooperative, and in moderate pain, but is able to walk comfortably. There is mild
tenderness on palpation over the right lower quadrant, but no rebound tenderness or pain on
percussion, and a negative Psoas sign. The only abnormality on his laboratory is a white blood cell count
of 15,500/µL (15.5 x 109/L), with a differential count of 40% polymorphonuclear leukocytes, 48%
lymphocytes, and 12% monocytes (no band forms or eosinophils).
Of the following, the MOST likely diagnosis in this boy with right lower quadrant pain and leukocytosis is
A. acute appendicitis
B. acute infectious colitis
C. Crohn disease
D. iliopsoas pyomyositis
E. mesenteric adenitis
Acute appendicitis is a prime diagnostic consideration in a child who has right lower
quadrant pain and leukocytosis. Acute appendicitis in children often presents with
features that vary from the classic presentation in adults, owing to their inability to
localize symptoms accurately, anatomic variations of the appendix location, and
because the first presentation can be as a ruptured appendix. Nausea is a very
common feature, and anorexia, vomiting, and colicky pain are usually present. The
pain and tenderness can be periumbilical, epigastric, or generalized, rather than in the right lower
quadrant. Helpful physical signs include McBurney point tenderness, Rovsing sign, Psoas sign and
Obturator sign (Table 1). A retrocecally located appendix inflames the iliopsoas muscle, in which the
child maintains a flexed and externally rotated right hip. A pelvically oriented appendix can present with
signs of rectal inflammation such as diarrhea. The diagnosis of appendicitis should generally be made
clinically, but ultrasonography or computed tomography (CT) can be helpful in patients without a classic
physical examination. For the boy in the vignette, the lack of nausea, vomiting, rebound tenderness or
pain on percussion, a negative Psoas sign, and a normal absolute neutrophil count indicates a lower
probability of acute appendicitis. The negative Psoas sign and his ability to walk without pain also make
streptococcal or staphylococcal pyomyositis of the iliopsoas or pelvic muscles unlikely. The lack of colic
and of blood and mucus in the stools makes acute infectious colitis caused by organisms that affect the
large bowel (Salmonella, Shigella, Campylobacter, and Yersinia species, enterohemorrhagic Escherichia
coli, Clostridium difficile) less likely. Although his symptoms could be the first presentation of Crohn
disease, his previously healthy state makes this unlikely. By exclusion, his most likely diagnosis is
mesenteric adenitis.
The clinical presentation of mesenteric adenitis can mimic acute appendicitis. Many children who are
initially suspected of having appendicitis but who improve rapidly without progression to classic signs, or
are found at laparotomy to not have an inflamed appendix, are presumed to have mesenteric adenitis.
The diagnosis is supported by findings of clusters of enlarged mesenteric lymph nodes and thickened
mesenteric folds on CT imaging, or by visualization at laparoscopy. The cause is presumed to be viral in
the majority of instances, but some cases are attributable to infection with Yersinia species (especially Y
enterocolitica). In the pseudoappendicitis presentation of acute yersiniosis, Yersinia is cultured from
inflamed nodes, and there is periappendiceal and terminal ileum inflammation, often with little or no
diarrhea. Bartonella and Streptococcus pyogenes are rare causes of mesenteric adenitis. Mesenteric
adenitis could also be part of another disease process such as inflammatory bowel disease or ileocecal
tuberculosis.
Pelvic inflammatory disease and tubo-ovarian abscess should be considered in the differential diagnosis
of right lower quadrant pain with leucocytosis in adolescent girls. Generally, adolescents with pelvic
inflammatory disease who are symptomatic present with poorly localized or generalized lower
abdominal pain. Diagnostic criteria from the US Centers of Disease Control and Prevention should be
consulted (Table 2). Ectopic pregnancy and ovarian torsion are other uncommon causes in young
women. Occasionally, acute pyelonephritis may present with right lower quadrant pain and leucocytosis
in younger children. Other diseases to consider are retroperitoneal abscess as a complication of
inflammatory bowel disease, gastrointestinal surgery or rupture of perirenal abscess, incarcerated
inguinal hernia, intussusception in children younger than 3 years of age, and testicular torsion in older
boys.
PREP Pearls
 The differential diagnosis of right lower quadrant pain with leucocytosis is broad and extends
beyond acute appendicitis.
 Mesenteric adenitis is a common diagnosis of exclusion in children with right lower quadrant
pain with leukocytosis.
 Pelvic inflammatory disease, ovarian torsion, and ectopic pregnancy can present with right
lower quadrant pain and leukocytosis.

 Formulate the differential diagnosis of a patient with right lower quadrant pain and leukocytosis
Suggested Readings
 Kharbanda AB, Taylor GA, Fishman SJ, Bachur RG. A clinical decision rule to identify children at
low risk for appendicitis. Pediatrics. 2005;116(3):709-716. DOI: 10.1542/peds.2005-0094
 Rao PM, Rhea JT, Novelline RA. CT diagnosis of mesenteric adenitis. Radiology. 1997;202(1):145-
149. DOI: 10.1148/radiology.202.1.8988204
 Ross A, LeLeiko NS. Acute abdominal pain. Pediatr Rev. 2010;31(4):135. DOI: 10.1542/pir.31-4-
135
Question: 1
A previously healthy, 15-year-old male patient is hospitalized with mild dehydration following 4 days of
fever to 39.4°C, severe nausea, and pain and tingling in his right shoulder. Other than signs of mild
dehydration, the patient’s physical examination is unremarkable, including the area of his shoulder
where his complaints are localized. On the second hospital day, his father mentions that his son now
seems very agitated and states that he is afraid to eat or drink anything. Later that day, the adolescent
experiences a 10-minute, generalized tonic-clonic seizure. Shortly after the seizure, he tells his father
that he knows that he is going to die. The patient is transferred to intensive care and a diagnostic
evaluation is initiated.
Of the following, the test MOST likely to confirm a diagnosis of rabies at this point in the illness is the
detection of
A. rabies-specific antigen in a punch biopsy of skin cells
B. rabies-specific immunoglobulin G from cerebrospinal fluid
C. rabies-specific immunoglobulin M from serum
D. rabies-specific nucleic acid in cerebrospinal fluid using polymerase chain reaction
E. rabies virus, by culture, from cerebrospinal fluid

Question: 1
A previously healthy, 15-year-old male patient is hospitalized with mild dehydration following 4 days of
fever to 39.4°C, severe nausea, and pain and tingling in his right shoulder. Other than signs of mild
dehydration, the patient’s physical examination is unremarkable, including the area of his shoulder
where his complaints are localized. On the second hospital day, his father mentions that his son now
seems very agitated and states that he is afraid to eat or drink anything. Later that day, the adolescent
experiences a 10-minute, generalized tonic-clonic seizure. Shortly after the seizure, he tells his father
that he knows that he is going to die. The patient is transferred to intensive care and a diagnostic
evaluation is initiated.
Of the following, the test MOST likely to confirm a diagnosis of rabies at this point in the illness is the
detection of
A. rabies-specific antigen in a punch biopsy of skin cells
B. rabies-specific immunoglobulin G from cerebrospinal fluid
C. rabies-specific immunoglobulin M from serum
D. rabies-specific nucleic acid in cerebrospinal fluid using polymerase chain reaction
E. rabies virus, by culture, from cerebrospinal fluid
There are many methods by which to establish the diagnosis of rabies. Direct
fluorescent antibody staining of corneal epithelial cells, obtained by doing corneal
impressions onto a glass slide, or skin from a punch biopsy at the nape of the neck are
the best tests to perform shortly after the patient’s symptoms begin. These results are
positive early because virus migrates from the brain along the richly innervated
cornea and hair follicles. The presence of rabies-specific nucleic acid using polymerase chain reaction
(PCR) can be used, but it has low sensitivity early in infection and a culture will not help the clinician in
the acute stage of the infection. The PCR may remain negative, even when the diagnosis is established
by staining the corneal epithelial cells or skin punch biopsies. The diagnosis can also be confirmed by
identifying the pathognomonic Negri bodies (cytoplasmic inclusions) in brain tissue (Figure).
The appearance of rabies-specific antibody (eg, immunoglobulin M or immunoglobulin G) responses are

delayed and have no role in the initial diagnostic evaluation, but because the development of a host-
neutralizing response may be a marker for survival, measuring anti-rabies antibody during treatment
may be of value. It is important to recognize that administration of rabies immune globulin or vaccine to
rabies-infected patients can further delay the host antibody response to the infection; therefore, current
protocols state that administration of rabies immune globulin or rabies vaccine are to be avoided in any
infected patient.
Rabies is an acute viral infection of the central nervous system (CNS) that is transmitted to humans from
other mammals. The infection is usually fatal, but early recognition and confirmation of the diagnosis
allows for the initiation of a unique series of interventions that, on rare occasions, have resulted in
patient survival. Details regarding outcomes from patients treated with evolving versions of the
Milwaukee protocol can be found at
http://www.mcw.edu/Pediatrics/InfectiousDiseases/PatientCare/Rabies.htm. All patients with
suspected or confirmed rabies infection should be managed in consultation with the US Centers for
Disease Control and Prevention.
Rabies is transmitted from mammals to human through bites, scratches, or aerosols. While dogs account
for most rabies cases outside of developed countries, skunks, raccoons, foxes, and bats remain
important sources of rabies exposure in North America. Patients who experience an event that could
transmit rabies, such as a bite from a wild mammal, should be evaluated for post-exposure prophylaxis,
which, when done properly, prevents rabies quite effectively. Unlike bites from raccoons, skunks, foxes,
and other medium-sized wild mammals, the bite from a bat, especially while sleeping, can go completely
unnoticed, offering the most probable explanation for why nearly all nonimported human cases of
rabies in developed countries are caused by bat strain viruses. In the vignette, no history of a known
exposure was offered because this is more often the case than not for cases in the United States. In such
cases, when the rabies virus is characterized, it is almost always a strain found in bats.
The earliest symptoms of rabies infection are often vague and insidious. Perhaps the most obvious
clinical clue may be pain or tingling at the site of the bite, such as that described by the patient in the
vignette. Together with fever and nausea, the inoculation site pain may last several days before overt
neurologic symptoms begin. As the infection progresses, patients exhibit extreme agitation,
hyperactivity, fluctuating levels of consciousness, aerophobia, hypersalivation, and hydrophobia. The
majority of patients with rabies will have meningismus, but cerebrospinal fluid (CSF) findings are
abnormal in a minority. When abnormal, the CSF shows a mild mononuclear cell pleocytosis. In cases
where the clinical presentation is less classic or the exposure history is unknown, additional causes of
severe meningoencephalitis should be included in the differential diagnosis and studies to investigate
them as possible etiologic agents added to the diagnostic evaluation. Herpes simplex should always be
considered. Other viruses that cause severe, even fatal meningoencephalitis include several of the
arboviruses such as Eastern Equine Encephalitis and La Crosse. Clues from the history may add
additional possibilities to the differential diagnosis. Herpes B, for example, would be considered if the
bite were known to come from a macaque, while CNS infection from free-living amoeba would be
considered if there was direct exposure to standing water.
Paralytic rabies is an unusual manifestation of infection that presents with acute flaccid paralysis. As
such, paralytic rabies may be confused with a polio-like illness (secondary to polio virus or to one of the
other neurovirulent enteroviruses), or Guillain-Barré syndrome.
PREP Pearls
 Serum antibody testing plays no role in the initial diagnostic evaluation for rabies other than to
establish a baseline titer.
 The most sensitive tests to detect rabies in an infected individual at the time of presentation are
direct fluorescent antibody staining of corneal epithelial cells, or of skin from a punch biopsy at
the nape of the neck.
 Absence of a known mammalian bite by history does not exclude rabies as a possibility as bat
bites, particularly during sleep, may go unnoticed.
 Recognize the clinical features of rabies
 Formulate a differential diagnosis in a patient in whom rabies is suspected
 Know the means to establish a laboratory diagnosis of rabies: detection of viral antigen in
tissues, demonstration of antibody in serum or CSF, isolation of virus, or detection of viral
nucleic acid from saliva
Suggested Readings
 Mani CS, Murray DL. Rabies. Pediatr Rev. 2006;27(4):129-136. DOI: 10.1542/pir.27-4-129
 Medical College of Wisconsin. Rabies. Medical College of Wisconsin website. 2015. Available at:
http://www.mcw.edu/Pediatrics/InfectiousDiseases/PatientCare/Rabies.htm
 Willoughby RE Jr, Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction
of coma. N Engl J Med. 2005;352(24):2508-2514. DOI: 10.1056/NEJMoa050382
Question: 2
You receive a call at 2 AM about a patient who was admitted to the pediatric intensive care unit (PICU)
earlier in the evening. In the PICU, the patient had a seizure and was noted to be unresponsive. The
PICU attending is about to take him down for an emergency head computed tomography and would like
your input regarding appropriate antimicrobials. He has already been started on ceftriaxone and
vancomycin. Further history reveals that the patient had been seen earlier that day in the emergency
room with a history of headache and vomiting and admitted to the pediatric floor for intravenous fluids.
During the course of the day, he continued to complain of worsening headache and nausea and was
noted to become sleepier. His blood pressure was also noted to be high with irregular respirations and
decreased heart rate. He was transferred to the PICU with concerns for meningoencephalitis.
His parents report that the family had been to visit a state park in the southeastern United States for a
brief summer vacation a few days before admission. He had been swimming and diving in the waterfall
at the park. His parents noted that he had not been his usual self for the last 2 to 3 days and had been
complaining of nausea and intermittent headache. He was seen by his primary care physician and
diagnosed with otitis media for which he had been given amoxicillin. His past history was completely
unremarkable and his immunizations were noted to be up to date.
Based on the history provided, you are MOST likely to recommend addition of the antimicrobial
A. amphotericin B
B. azithromycin
C. imipenem
D. rifampin
E. voriconazole
Question: 2
You receive a call at 2 AM about a patient who was admitted to the pediatric intensive care unit (PICU)
earlier in the evening. In the PICU, the patient had a seizure and was noted to be unresponsive. The
PICU attending is about to take him down for an emergency head computed tomography and would like
your input regarding appropriate antimicrobials. He has already been started on ceftriaxone and
vancomycin. Further history reveals that the patient had been seen earlier that day in the emergency
room with a history of headache and vomiting and admitted to the pediatric floor for intravenous fluids.
During the course of the day, he continued to complain of worsening headache and nausea and was
noted to become sleepier. His blood pressure was also noted to be high with irregular respirations and
decreased heart rate. He was transferred to the PICU with concerns for meningoencephalitis.
His parents report that the family had been to visit a state park in the southeastern United States for a
brief summer vacation a few days before admission. He had been swimming and diving in the waterfall
at the park. His parents noted that he had not been his usual self for the last 2 to 3 days and had been
complaining of nausea and intermittent headache. He was seen by his primary care physician and
diagnosed with otitis media for which he had been given amoxicillin. His past history was completely
unremarkable and his immunizations were noted to be up to date.
Based on the history provided, you are MOST likely to recommend addition of the antimicrobial
A. amphotericin B
B. azithromycin
C. imipenem
D. rifampin
E. voriconazole
Given the history of swimming and diving in southeastern United States during the
summer, as well as rapid development of symptoms suggestive of increased
intracranial pressure (hypertension, bradycardia, and irregular respirations [Cushing triad]), the patient
in the vignette most likely has primary amebic meningoencephalitis (PAM) secondary to the free living
amoeba Naegleria fowleri. The other free living amebae, Acanthamoeba species and Balamuthia
mandrillaris, generally cause a more insidious illness with symptoms that may progress slowly over
weeks to months after exposure.
Although an effective regimen for PAM has not been identified, amphotericin B has long been
considered the drug of choice. Treatment generally has been unsuccessful and, until recently, there
were only 4 cases of patients that had survived this devastating infection.
N fowleri is found in warm fresh water and soil. In the United States, infection occurs primarily in the
summer months along the southern states, from California to Florida, with the greatest numbers of
cases reported from Texas and Florida. Infection occurs in individuals swimming in warm fresh water
such as lakes, hot springs, and ponds and usually affects young children and adults. Males have
accounted for a greater number of cases as opposed to females primarily because they are more likely
to be involved in water sports such as diving, waterskiing, wakeboarding, tubing, or other water related
activities. It is believed that the rapid propulsion of water up the nose facilitates the spread of the
infection to the brain directly via the olfactory nerves and through the cribriform plate. However, the
overall risk of PAM for all individuals who swim in warm fresh waters is low and PAM remains a rare
disease. Most cases reported in the literature were in bodies of water that were either untreated or
poorly treated, resulting in increased bacterial growth, which would provide the ameba with fertile
grounds to feed and grow. Cases of PAM have also been associated with ritual nasal rinsing or ablution.
The incubation period for N fowleri is short, 3 to 7 days, and the infection usually progresses fairly
rapidly. Early symptoms of infection are nonspecific and include fever, headache, vomiting, and
sometimes disturbances of smell and taste. Later in the course of the infection, affected individuals
develop nuchal rigidity, altered mental status, and seizures. Death usually results from increased
intracranial pressure and herniation of the brain. On autopsy, most individuals are found to have acute
hemorrhagic necrosis of the olfactory bulbs and cerebral cortex (Figure 1).
Primary amebic meningoencephalitis is a rare disease and the key to early diagnosis is the history
because the clinical features do not distinguish this from any other types of meningoencephalitis. The
disease should be suspected in individuals who have a history of swimming or diving during the summer,
particularly in the southern United States, along with signs and symptoms consistent with a rapidly
progressing meningitis or meningoencephalitis.
Once the disease has been suspected, treatment should be initiated immediately without waiting for
confirmatory test results. There are several methods that may be used for diagnosis. These include the
classic evaluation of cerebrospinal fluid (CSF) by the hanging drop method, ie, microscopic
demonstration of motile trophozoites on a wet mount of centrifuged CSF
(http://www.cdc.gov/parasites/naegleria/naegleria-fowleri-images.html).
The CSF indices usually show a polymorphonuclear pleocytosis with increased protein and normal to low
glucose concentrations. The CSF smears should be stained with either Giemsa, Trichrome, or Wright
stains to be able to visualize the trophozoites because routine gram stains are not useful (Figure 2).
Laboratory personnel should be alerted to the clinical suspicion of PAM given that the trophozoites may
sometimes be mistaken for leukocytes and to maximize yield from microscopic examination. The
organism can also be cultured on 1.5% non-nutrient agar layered with enteric bacteria held in PAS
(Page’s ameba saline solution). Physicians with suspected cases of PAM should call the US Centers for
Disease Control and Prevention (CDC) for assistance with diagnosis at 1-800-CDC-INFO. This includes the
ability to get immunoflourescent stains for detection on biopsy material and detection of amoeba by
polymerase chain reaction from the CDC.
Amphotericin B has been used in combination with multiple medications including azoles such as
fluconazole, miconazole, voriconazole, and rifampin for the treatment of PAM. Both standard
amphotericin B, as well as liposomal amphotericin B, have been used and it is not clear that one has an
advantage over the other, except that higher doses of liposomal amphotericin may be used with less
concern for toxicity. Other drugs that have been used in different combinations, again mostly with
amphotericin, include azithromycin, which is also known to have both in vitro and in vivo efficacy, as
well as pentamidine, sulfadiazine, flucytosine, trimethoprim-sulfamethoxazole, and clarithromycin.
Carbapenems such as imipenem have not been used and do not have a role in the treatment of this
infection. Other supportive treatment modalities include the use of steroids to reduce cerebral edema,
which develops rapidly in patients with PAM caused by N fowleri in particular.
Most recently, an investigational drug miltefosine used for the treatment of leishmaniasis and breast
cancer was used in 2 individuals who survived PAM. It is available directly from the CDC under an
expanded access investigational new drug protocol. Guidance may be obtained by calling the CDC
Emergency Operations C enter at 770-488-7100 to consult with an expert regarding the use of this drug.
It is believed that earlier recognition and treatment, as well as adjunctive care such as hypothermia,
contributed to the survival of these patients.
PREP Pearls
 Primary amebic meningoencephalitis is a rare disease and the key to early diagnosis is the
history because the clinical features do not distinguish this from any other bacterial meningitis.
 The disease should be suspected in individuals who have a history of swimming or diving during
the summer, particularly in the southern United States, along with signs and symptoms
consistent with a rapidly progressing meningitis or meningoencephalitis.
 Contact the US Centers for Disease Control and Prevention for assistance with diagnosis, as well
as guidance regarding treatment.
 Understand the methods of diagnosis of Naegleria fowleri infestation (ie, hanging drop
examination of cerebrospinal fluid)
 Recognize the setting and clinical and CSF manifestations of Naegleria fowleri infestation
involving the brain, leading to fatal encephalitis
Suggested Readings
 Lopez C, Budge P, Chen J, et al. Primary amebic meningoencephalitis: a case report and
literature review. Pediatr Emerg Care. 2012;28(3):272-276. DOI:
10.1097/PEC.0b013e3182495589
 US Centers for Disease Control and Prevention. Investigational drug available directly from CDC
for the treatment of infections with free-living amebae. MMWR Morb Mortal Wkly Rep.
2013;62(33):666. Accessed 10/1/2014 at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6233a4.htm
 US Centers for Disease Control and Prevention. Primary amebic meningoencephalitis associated
with ritual nasal rinsing — St. Thomas, U.S. Virgin Islands, 2012. MMWR Morb Mortal Wkly Rep.
2013;62(45):903. Accessed 10/1/2014 at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6245a5.htm?s_cid=mm6245a5_w
Question: 3
You are seeing a 13-month-old boy in your clinic for an evaluation for recurrent infections and failure to
thrive. The parents state that the boy has had 3 episodes of serious bacterial infection requiring
hospitalization and intravenous antibiotics. These have included 2 bouts of sepsis caused by
Streptococcus pneumonia and 1 bout of cellulitis with an unknown organism. In addition, he has been
treated with several courses of oral antibiotics for recurrent otitis media, and has had chronic diarrhea.
His stools have been positive for Cryptosporidium on multiple occasions. The parents also report that he
has recurrent oral ulcers, which appear every 3 to 4 weeks, frequently accompanied by fever. On
physical examination, the child is below the fifth percentile for weight, generalized lymphadenopathy,
gingivitis, and hepatosplenomegaly.
The only available records that you have reveal that the child has had a negative HIV DNA polymerase
chain reaction.
Of the following, the finding MOST likely to be present in this child is
A. eosinophilia
B. hypergammaglobulinemia
C. neutropenia
D. normal responses to diphtheria and tetanus antigens
E. thrombocytopenia
Question: 3
You are seeing a 13-month-old boy in your clinic for an evaluation for recurrent infections and failure to
thrive. The parents state that the boy has had 3 episodes of serious bacterial infection requiring
hospitalization and intravenous antibiotics. These have included 2 bouts of sepsis caused by
Streptococcus pneumonia and 1 bout of cellulitis with an unknown organism. In addition, he has been
treated with several courses of oral antibiotics for recurrent otitis media, and has had chronic diarrhea.
His stools have been positive for Cryptosporidium on multiple occasions. The parents also report that he
has recurrent oral ulcers, which appear every 3 to 4 weeks, frequently accompanied by fever. On
physical examination, the child is below the fifth percentile for weight, generalized lymphadenopathy,
gingivitis, and hepatosplenomegaly.
The only available records that you have reveal that the child has had a negative HIV DNA polymerase
chain reaction.
Of the following, the finding MOST likely to be present in this child is
A. eosinophilia
B. hypergammaglobulinemia
C. neutropenia
D. normal responses to diphtheria and tetanus antigens
E. thrombocytopenia
The child in the vignette has failure to thrive, serious and recurrent infections,
including bacterial and chronic protozoal infection early in life, generalized
lymphadenopathy and hepatosplenomegaly, which are concerning for a combined B-
and T-cell immunodeficiency. Given that HIV has been excluded by testing, a
congenital combined B- and T-cell immunodeficiency is most likely. The additional
finding of recurrent oral ulcers and gingivitis are concerning for the presence of
chronic or cyclic neutropenia, which can occur in the presence of a primary B- and T-cell
immunodeficiency. Neutropenia has been well described in patients with severe combined
immunodeficiency (SCID), hyperimmunoglobulin M (HIGM) syndrome, X-linked agammaglobulinemia
(XLA), and common variable immunodeficiency (CVID). Patients with combined B- and T-cell
immunodeficiencies have hypo- rather than hypergammaglobulinemia, do not have normal responses to
protein antigens such as tetanus and diphtheria, and do not have eosinophilia. While some of these
disorders may be associated with thrombocytopenia or eosinophilia, these are much less frequent
findings than neutropenia.
Neutropenia is variably present in children who have combined B- and T-cell immunodeficiencies. For
example, neutropenia is reported to be present in about 60% of patients with HIGM syndrome and
often contributes to the early manifestations of this disorder, which includes oral aphthous ulcers,
gingivitis, and an increased susceptibility to bacterial infections. Bone marrow examination in these
patients may show a maturational arrest at the promyelocyte stage. Neutropenia has been reported in
about 20% to 30% of patients with XLA, contributes to the development of fungal infections in these
patients, and often resolves with the initiation of immunoglobulin therapy.
The mechanism of the neutropenia in patients with combined B- and T-cell immunodeficiency is not
clearly delineated. An autoimmune mechanism has been proposed for HIGM syndrome, CVID, and SCID.
The Bruton tyrosine kinase mutation in XLA may play a direct or indirect role in the maturation of
myeloid cells.
PREP Pearls
 Neutropenia is known to occur in patients with primary immunodeficiency syndromes.
 Neutropenia may contribute to the initial presentation of primary immunodeficiency

syndromes.
 Recognize that neutropenia can be a manifestation of primary immunodeficiency involving B

and T cells
Suggested Readings
 Aghamohammadi A, Parvaneh N, Rezaei N, et al. Clinical and laboratory findings in hyper-IgM

syndrome with novel CD40L and AICDA mutations. J Clin Immunol. 2009;29(6):769-776. DOI:
10.1007/s10875-009-9315-7
 Cham B, Bonilla MA, Winkelstein J. Neutropenia associated with primary immunodeficiency

syndrome. Semin Hematol. 2002;39(2):107-112. DOI: 10.1053/shem.2002.31916
 Rezaei N, Moazzami K, Aghamohammadi A, Klein C. Neutropenia and primary immunodeficiency

diseases. Int Rev Immunol. 2009;28(5):335-366. DOI: 10.1080/08830180902995645
Question: 4
The pediatric infectious diseases service is consulted for treatment of a scalp infection in both a 3-year-
old child (Figure 1 and Figure 2) and his 17-year-old mother. Both have patches of alopecia. The clinical
pharmacist is recommending treatment with griseofulvin for the child and his adolescent mother. Both
are healthy, except for the alopecia; neither has fever, takes medications, or has any drug allergies.
Of the following, the MOST appropriate screening test before starting griseofulvin for this 17-year-old
adolescent is
A. alanine aminotransferase
B. complete blood cell count
C. human chorionic gonadotropin
D. prothrombin time
E. urine porphobilinogen
Question: 4
The pediatric infectious diseases service is consulted for treatment of a scalp infection in both a 3-year-
old child (Figure 1 and Figure 2) and his 17-year-old mother. Both have patches of alopecia. The clinical
pharmacist is recommending treatment with griseofulvin for the child and his adolescent mother. Both
are healthy, except for the alopecia; neither has fever, takes medications, or has any drug allergies.
Of the following, the MOST appropriate screening test before starting griseofulvin for this 17-year-old
adolescent is
A. alanine aminotransferase
B. complete blood cell count
C. human chorionic gonadotropin
D. prothrombin time
E. urine porphobilinogen
This child has tinea capitis (ringworm of the scalp). Systemic antifungal therapy is
required to treat tinea capitis, and the standard treatment for tinea capitis is
griseofulvin. Griseofulvin is contraindicated in pregnancy, porphyria, and hepatic
disease. Therefore, the adolescent in this vignette should have a urine or serum
pregnancy test performed (human chorionic gonadotropin). A urine estimation of
porphobilinogen is a diagnostic test for porphyria, but is not indicated for the
adolescent in the vignette. Children or adolescents who have no history or clinical evidence of liver
disease are not required to have serum hepatic enzyme values tested either before or during a standard
course of therapy lasting 8 weeks. Therefore, an alanine aminotransferase is not recommended.
Prolonged therapy with griseofulvin may be associated with a greater risk of hepatotoxicity and enzyme
testing every 8 weeks during treatment is recommended. A rare complication of griseofulvin treatment
is leukocytopenia. However, a complete blood cell count is not recommended before initiating therapy.
Griseofulvin may reduce the effectiveness or decrease level of oral contraceptives, warfarin,
cyclosporine, and phenobarbital. A prothrombin time is used to monitor therapy with warfarin, but is
not recommended as routine screening. Cross-reactivity with griseofulvin may occur in penicillin-allergic
patients.
Griseofulvin is an antifungal agent first isolated from a Penicillium species in 1939. The compound is
insoluble in water. Ingestion with a heavy fatty meal and reduction in particle size (ie, ultra microsize
preparation) enhances the absorption of griseofulvin. Note that dosages differ depending on whether
microsize or ultra microsize preparations are used. Nearly 100% of the dose the ultramicrosize
griseofulvin is absorbed whereas absorption of microsize griseofulvin is variable, and may be between
25-70% of the oral dose. It is effective after oral ingestion, reaching the skin and hair, where it is
deposited in keratin precursor cells. The drug binds to tubulin, interfering with microtubule function,
thus inhibiting mitosis of the fungus.
Tinea capitis (Figure 1 and Figure 2), tinea corporis (Figure 3, Figure 4, and Figure 5), and pityriasis
versicolor (Figure 6) are common superficial fungal infections in the pediatric population. Tinea capitis is
a common dermatophyte infection worldwide, and is most common in children. In North America, the
cause is almost exclusively Trichophyton tonsurans (> 90%). Diagnosis of tinea capitis usually can be
made by clinical features alone; skin scrapings prepared with potassium hydroxide for microscopic
examination or a cotton swab for fungal culture are usually diagnostic. About 15% of the world
population has fungal infections of the feet (tinea pedis [Figure 7] or athlete's foot), the groin, and
upper thighs (tinea cruris). There are many clinical presentations of tinea pedis. It is most commonly
seen between the toes (interdigital) and on the soles, heels, and sides of the foot (plantar). Plantar tinea
pedis is known as moccasin foot. Once acquired, the infection can spread to other sites, including the
nails and onychomycosis (tinea unguium), which can be a source of re-infection.
Topical antifungal therapy is usually effective for tinea pedis, tinea cruris, tinea corporis, and pityriasis
versicolor. Oral therapy is usually reserved for chronic conditions or when topical treatment has failed.
Griseofulvin may be considered for systemic antifungal therapy. The standard treatment for tinea capitis
is griseofulvin. Terbinafine and griseofulvin are both effective against T tonsurans and are US Food and
Drug Administration (FDA)-approved for treatment of tinea capitis in children. For tinea capitis caused
by Microsporum species, griseofulvin is superior to terbinafine treatment. Adjunctive topical therapy for
the patient and household contacts decreases transmission of this infection.
Itraconazole and terbinafine have in large part replaced griseofulvin in the treatment of onychomycosis
(tinea unguium) and, in addition to fluconazole and ketoconazole, are evolving treatments for tinea
capitis. Small, open-label studies of itraconazole, terbinafine, and fluconazole have reported
encouraging results, suggesting that these drugs may be effective alternatives to griseofulvin; however,
in large controlled studies, griseofulvin continues to exhibit greater or equal efficacy. Ketoconazole
appears to be the least efficacious. All 5 drugs appear relatively safe; however, only griseofulvin has a
long track record of safety, is FDA-approved for the treatment of tinea capitis in children more than 2
years of age, and has the least known drug interactions. Terbinafine is FDA-approved for children older
than 4 years of age for tinea capitis. Fluconazole is FDA-approved for use in children older than 6 months
of age, but not for treatment of tinea capitis. Oral griseofulvin and terbinafine tablets are the least
expensive of the antifungal agents; griseofulvin suspension is, however, more expensive than
fluconazole suspension. For the combined reasons of efficacy, safety, cost, and a long track record of
use, oral griseofulvin is still the current treatment of choice for tinea capitis.
PREP Pearls
 Griseofulvin is contraindicated in pregnancy, porphyria, and hepatic disease.
 Children or adolescents who have no history or clinical evidence of liver disease are not required
to have serum hepatic enzyme values tested either before or during a standard course of
therapy of griseofulvin lasting 8 weeks.
 Terbinafine and griseofulvin are both effective against Trichophyton tonsurans (> 90% in North
America) and are US Food and Drug Administration (FDA)-approved for treatment of tinea
capitis in children. Terbinafine is FDA-approved for children older than 4 years of age and
griseofulvin is FDA-approved for children older than 2 years of age.
 For tinea capitis caused by Microsporum species, griseofulvin is superior to terbinafine

treatment.
 Know the appropriate use of griseofulvin
 Know the important drug interactions for and adverse effects of griseofulvin
Suggested Readings
 American Academy of Pediatrics. Recommended doses of parenteral and oral antifungal drugs.
In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, ed. Red Book: 2012 Report of the Committee
on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
 Bell-Syer SE, Khan SM, Torgerson DJ. Oral treatments for fungal infections of the skin of the foot.
Cochrane Database Syst Rev. 2012. DOI: 10.1002/14651858.CD003584.pub2
 Bennett ML, Fleischer AB, Loveless JW, Feldman SR. Oral griseofulvin remains the treatment of
choice for tinea capitis in children. Pediatr Dermatol. 2000;17(4):304-309. DOI: 10.1046/j.1525-
1470.2000.01784.x
 Gupta AK, Drummond-Main C. Meta-analysis of randomized, controlled trials comparing

particular doses of griseofulvin and terbinafine for the treatment of tinea capitis. Pediatr
Dermatol. 2013;30(1):1-6. DOI: 10.1111/j.1525-1470.2012.01866.x
 Kelly BP. Superficial fungal infections. Pediatrics In Review. 2012;33(4):e22-e37. DOI:

10.1542/pir.33-4-e22
Question: 5
You are consulted to see a previously healthy 15-year-old female adolescent who presented to the
emergency department in mid-April with a 5-day history of fever to 39.4°C, headache, and abdominal
pain with new onset vomiting and diarrhea. She also reports severe myalgias, making it difficult for
her to walk. Her vital signs show a heart rate of 120 beats/min, blood pressure of 90/60 mm Hg, and
respiratory rate of 22 breaths/min after 2 L of isotonic saline. Physical examination reveals
tachycardia, clear but shallow breath sounds, and a slightly distended abdomen. Injected sclera are
noted and her skin has a diffuse erythematous rash without necrosis that is tender to palpation
(Figure 1a, Figure 1b, Figure 1c). Laboratory evaluation shows:
 White blood cell count, 2,500/µL (2.5 x 109/L) (90% segmented neutrophils) (normal 4,500-
10,000/µL)
 Hemoglobin, 8 g/dL (80 g/L) (normal 12-15 g/dL)
 Platelets, 95 X 103/μL (95 x 109/L) (normal 150-450 x 103/μL)
 Sodium, 133 mEq/L (133 mmol/L) (normal 135-145 mEq/L)
 Potassium, 4 mEq/L (4 mmol/L) (normal 3.5-5.2 mEq/L)
 Chloride, 110 mEq/L (110 mmol/L) (normal 95-107 mEq/L)
 Blood urea nitrogen, 50 mg/dL (17.9 mmol/L) (normal 7-20 mg/dL)
 Creatinine, 1.2 mg/dL (106.1 µmol/L) (normal 0.5-1 mg/dL)
 Aspartate aminotransferase, 200 U/L (3.3 µkat/L) (normal < 50 U/L)
 Alanine aminotransferase, 150 U/L (2.5 µkat/L) (normal < 50 U/L)
 Total bilirubin, 5 mg/dL (85.5 µmol/L) (normal 0.1-1.2 mg/dL)
 Direct bilirubin, 4 mg/dL (68.4 µmol/L) (normal 0-0.3 mg/dL)
 Albumin, 2 g/dL (20 g/L) (normal 2.5-5 g/dL)
 Creatinine phosphokinase, 5,000 IU/L (8-150 IU/L)
Of the following, the MOST appropriate combination of empiric therapy for this patient is
A. cefepime, clindamycin, and rifampin

B. ceftriaxone, metronidazole, and gentamicin
C. ceftriaxone, metronidazole, and vancomycin
D. oxacillin, clindamycin, and gentamicin
E. vancomycin, clindamycin, and oxacillin
Question: 5
You are consulted to see a previously healthy 15-year-old female adolescent who presented to the
emergency department in mid-April with a 5-day history of fever to 39.4°C, headache, and abdominal
pain with new onset vomiting and diarrhea. She also reports severe myalgias, making it difficult for her
to walk. Her vital signs show a heart rate of 120 beats/min, blood pressure of 90/60 mm Hg, and
respiratory rate of 22 breaths/min after 2 L of isotonic saline. Physical examination reveals tachycardia,
clear but shallow breath sounds, and a slightly distended abdomen. Injected sclera are noted and her
skin has a diffuse erythematous rash without necrosis that is tender to palpation (Figure 1a, Figure 1b,
Figure 1c). Laboratory evaluation shows:
 White blood cell count, 2,500/µL (2.5 x 109/L) (90% segmented neutrophils) (normal 4,500-
10,000/µL)
 Hemoglobin, 8 g/dL (80 g/L) (normal 12-15 g/dL)
 Platelets, 95 X 103/μL (95 x 109/L) (normal 150-450 x 103/μL)
 Sodium, 133 mEq/L (133 mmol/L) (normal 135-145 mEq/L)
 Potassium, 4 mEq/L (4 mmol/L) (normal 3.5-5.2 mEq/L)
 Chloride, 110 mEq/L (110 mmol/L) (normal 95-107 mEq/L)
 Blood urea nitrogen, 50 mg/dL (17.9 mmol/L) (normal 7-20 mg/dL)
 Creatinine, 1.2 mg/dL (106.1 µmol/L) (normal 0.5-1 mg/dL)
 Aspartate aminotransferase, 200 U/L (3.3 µkat/L) (normal < 50 U/L)
 Alanine aminotransferase, 150 U/L (2.5 µkat/L) (normal < 50 U/L)
 Total bilirubin, 5 mg/dL (85.5 µmol/L) (normal 0.1-1.2 mg/dL)
 Direct bilirubin, 4 mg/dL (68.4 µmol/L) (normal 0-0.3 mg/dL)
 Albumin, 2 g/dL (20 g/L) (normal 2.5-5 g/dL)
 Creatinine phosphokinase, 5,000 IU/L (8-150 IU/L)

Of the following, the MOST appropriate combination of empiric therapy for this patient is
A. cefepime, clindamycin, and rifampin
B. ceftriaxone, metronidazole, and gentamicin
C. ceftriaxone, metronidazole, and vancomycin
D. oxacillin, clindamycin, and gentamicin
E. vancomycin, clindamycin, and oxacillin
The patient in the vignette has a diagnosis of shock with tachycardia and hypotension,
despite significant fluid resuscitation, likely related to sepsis. Her examination findings
of injected sclera and erythroderma are concerning for toxic shock syndrome (TSS).
The clinical examination and laboratory evaluation provide further evidence of TSS
with mucous membrane hyperemia, gastrointestinal symptoms, and hematologic,
renal, hepatic, and muscular involvement (Table 1). Both Staphylococcus aureus and Streptococcus
pyogenes can cause TSS and are clinically indistinguishable, although erythroderma is not a required
feature of streptococcal TSS (Table 2, Figure 1d, Figure 1e, Figure 1f). When there is high suspicion of
TSS, empiric therapy with vancomycin is prudent to provide coverage for methicillin-resistant
Staphylococcus aureus (MRSA), in addition to clindamycin to downregulate toxin production and an
antistaphylococcal penicillin (eg, oxacillin or nafcillin) for rapid bactericidal effect. Cefepime provides
broad spectrum coverage, including methicillin-susceptible Staphylococcus aureus (MSSA) and
Pseudomonas aeruginosa coverage, which is an important part of empiric therapy in immune
compromised patients, especially those with ecthyma gangrenosum, but is not typically necessary in a
healthy host. In addition, rifampin is indicated in certain clinical settings of endocarditis (eg, prosthetic
valve endocarditis) or refractory S aureus bacteremia, but is not routinely recommended in the setting
of TSS. Therefore, cefepime, clindamycin, and rifampin is an unlikely choice for the patient in the
vignette. Ceftriaxone, metronidazole, and gentamicin would likely be considered when there is a high
index of suspicion of intestinal perforation with intra-abdominal sepsis. Although the patient presented
with abdominal pain, nausea, and vomiting, intra-abdominal sepsis does not generally present with
severe myalgias and erythroderma, making this an incorrect answer. Similarly, ceftriaxone,
metronidazole, and vancomycin is incorrect as intra-abdominal sepsis is unlikely, as stated previously,
and vancomycin provides only slow bactericidal activity against S aureus and Streptococcus pyogenes,
which is not ideal in the setting of shock or TSS. Oxacillin provides rapid bactericidal activity against
MSSA and S pyogenes, but has no MRSA coverage. Clindamycin provides MRSA coverage and serves to
downregulate protein production, thus decreasing toxin production, but has variable susceptibility to
MRSA, depending on the local antibiogram, and should not be used as the sole agent in the setting of
sepsis when MRSA is in the differential diagnosis. Finally, gentamicin is indicated as an adjunctive agent
in the setting of intra-abdominal sepsis and in patients with endocarditis in the presence of a prosthetic
valve or certain pathogens (eg, Enterococcus faecalis).
A multitude of toxins produced by both Staphylococcus aureus and Streptococcus pyogenes contribute
to the virulence of the bacteria and the dermatologic manifestations seen across a spectrum of disease
with these organisms. Streptococcus pyrogenic exotoxins (SPE) are the primary cause of the
scarlatiniform rash of scarlet fever (Figure 2a), as well as the more severe manifestations of
streptococcal TSS and necrotizing fasciitis (Table 3, Figure 3c, Figure 3d). Toxic shock syndrome toxin-1
(TSST-1) is most commonly involved (75%) in staphylococcal TSS. However, enterotoxins B and C make
up approximately 25% of the rest of the cases of staphylococcal TSS and share homology with the SPE
toxins. Exfoliative toxins A and B are responsible for the dermatologic manifestations of bullous
impetigo (Figure 4) and staphylococcal scalded skin syndrome (SSSS) (Figure 5), causing skin disruption
and peeling in the stratum granulosum layer of the epidermis. γ leucocidin is thought to be involved in
dermonecrosis in the setting of necrotizing Staphylococcus aureus infection.
Ecthyma gangrenosum (EG) is a necrotizing dermatologic manifestation of infection characterized by

hemorrhagic lesions that evolve into necrotic ulcers with a tender erythematous border (Figure 6). The
pathophysiology consists of organism invasion of small arteries and veins in the dermis and
subcutaneous tissues causing a necrotizing vasculitis, which interrupts blood supply to these tissues
resulting in necrosis. Contrary to necrotizing infection caused by Staphylococcus aureus and
Streptococcus pyogenes, which are often seen in the healthy host, EG is seen almost exclusively in
patients who have immune comprising conditions (eg, leukemia). Classically, EG is associated with
Pseudomonas aeruginosa, but several other organisms have been associated with EG. This phenomenon
has been coined EG-like disease and includes other Gram-negative bacteria (eg, Escherichia coli), fungi
(eg, Aspergillus fumigatus), and herpes simplex virus. Both Streptococcus pyogenes and Staphylococcus
aureus have also been associated with EG-like disease.
Various medications and infectious etiologies are capable of producing a spectrum of skin
manifestations including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which
have overlapping characteristics with SSSS and TSS. However, SJS and TEN are characterized by
apoptotic keratinocyte cell death in the epidermis with dermal-epidermal separation, resulting in deeper
bullae formation (Figure 7a, Figure 7b, Figure 8a, Figure 8b). Stevens-Johnson syndrome and TEN are
often distinguished by percent of affected body surface area (BSA), with SJS estimated at less than 10%,
an overlapping syndrome between 10% to 20% of affected BSA, and greater than 30% in TEN. The
pathophysiology differs from SSSS and TSS in that the skin manifestations are not caused by bacterial
toxin production, but rather host activation of various proteins (eg, perforin and granzyme B) from
cytotoxic T lymphocytes (CTLs), cytokines (interferon-γ, and tumor necrosis factor-α) from macrophages
and T cells, secretion of granulysin from CTLs, and natural killer cells. Up to 50% of SJS is considered to
be idiopathic, however, recent respiratory infection (eg, Mycoplasma) is a common preceding factor in
children, whereas medications are the primary precipitating factor associated with TEN, including
antibiotics (eg, sulfonamides), anticonvulsants (eg, valproic acid), nonsteroidal anti-inflammatory agents
(eg, ibuprofen), and anti-retroviral agents (eg, nevirapine and abacavir).
PREP Pearls
 Streptococcal pyrogenic toxins produce a spectrum of dermatologic manifestations from scarlet

fever to streptococcal toxic shock syndrome.
 Staphylococcal toxic shock syndrome is typically caused by toxic shock syndrome toxin-1, but
25% are caused by enterotoxins.
 Ecthyma gangrenosum is generally caused by Pseudomonas aeruginosa and occurs exclusively in

the immune compromised patient.
 Recognize the dermatologic manifestations (eg, epidermal necrolysis, erythroderma, ecthyma

gangrenosum, scarlatiniform exanthems) of bacterial toxins
Suggested Readings
 American Academy of Pediatrics. Group A streptococcal infections. In: Pickering LK, Baker CJ,
Kimberlin DW, Long SS, ed. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th
ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012:668-680.
 American Academy of Pediatrics. Staphylococcal infections. In: Pickering LK, Baker CJ, Kimberlin
DW, Long SS, ed. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk
Grove Village, IL: American Academy of Pediatrics; 2012:653-368.
 Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy,
and management of complications: a statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery
and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of
America. Circulation. 2005;111(23):e394-e434. DOI: 10.1161/CIRCULATIONAHA.105.165564
 Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society
of America for the treatment of methicillin-resistant staphylococcus aureus infections in adults
and children. Clin Infect Dis. 2011;52(3):e18–e55. DOI: 10.1093/cid/ciq146
Question: 6
You are participating in a joint infectious diseases and neonatology conference, and the case
presentation by the fellow concerns a preterm newborn cared for in the neonatal intensive care unit
who subsequently developed chronic lung disease.
Of the following, the organism with the STRONGEST association with chronic lung disease in preterm
newborns is
A. group A streptococcus
B. herpes simplex
C. Mycoplasma hominis
D. Neisseria gonorrhoeae
E. Ureaplasma urealyticum
Question: 6
You are participating in a joint infectious diseases and neonatology conference, and the case
presentation by the fellow concerns a preterm newborn cared for in the neonatal intensive care unit
who subsequently developed chronic lung disease.
Of the following, the organism with the STRONGEST association with chronic lung disease in preterm
newborns is
A. group A streptococcus
B. herpes simplex
C. Mycoplasma hominis
E. Ureaplasma urealyticum
Ureaplasma urealyticum (UU) has been associated with chronic lung disease among
preterm newborns. In a meta-analysis of 23 studies examining the possible
relationship between Ureaplasma colonization and neonatal bronchopulmonary
dysplasia, Ureaplasma colonization was associated with chronic lung infection
manifesting as long-term oxygen requirements and radiographic changes typical of
bronchopulmonary dysplasia. However, the studies included in this meta-analysis
were small. Ureaplasma urealyticum has also been associated with non-gonococcal urethritis in men,
and reproductive morbidity (chorioamnionitis, spontaneous abortion, stillbirth, preterm birth, and
postpartum endometritis) in women. Mother-to-child transmission occurs in approximately 50% of
colonized mothers. Colonization of newborns is more likely with longer duration of ruptured
membranes and lower birth weight. Newborn colonization occurs (with decreasing order of likelihood)
in the vagina, nasopharynx and throat, rectum, and conjunctiva. Neonatal colonization acquired
peripartum gradually disappears after birth.
U urealyticum is usually susceptible to agents that interfere with protein synthesis, such as tetracyclines
and macrolides, and is resistant to cell wall-active drugs, like β-lactam-containing agents. For neonates
with infections caused by Ureaplasma species, erythromycin has been used most commonly. However,
given the association of erythromycin with pyloric stenosis, azithromycin or clarithromycin may be
better choices for neonates with disease caused by Ureaplasma species outside of the central nervous
system. Due to its toxicity, doxycycline is not an alternative unless UU is isolated from cerebrospinal
fluid. Treatment of neonates colonized with UU does not improve outcomes.
In general, isolation of Mycoplasma hominis from the neonatal respiratory or urinary tract is not
associated with clinical illness. However, isolation of M hominis from normally sterile sites of neonates is
associated with adverse clinical outcomes. In the neonate, septicemia, meningitis, ventriculitis, brain
abscess, pneumonia, pericarditis, wound infection, submandibular adenitis, and subcutaneous abscess
have been described. Septicemia, ventriculitis, and pleural effusion have also been reported in infants
and young children. M hominis may colonize the lower genitourinary tract of otherwise healthy adults.
Isolating M hominis is more likely in women with cervicitis, urethritis, or bacterial vaginosis.
Reproductive morbidity associated with M hominis includes amnionitis and postpartum fever.
In general, M hominis is susceptible to clindamycin, fluoroquinolones, and tetracyclines, but up to 20%

of M hominis isolates are resistant to tetracycline and doxycycline. M hominis is almost always resistant
to erythromycin and azithromycin. Treatment of M hominis infections in neonates is particularly
challenging since doxycycline and fluoroquinolones are generally avoided due to concerns about
toxicities. Clindamycin is the best treatment option because it has activity in vitro, and has been
reported to be successful in the treatment of neonatal infections due to M hominis.
None of the other pathogens listed is associated with chronic lung disease in preterm newborns. Group
A streptococcus is associated with impetigo neonatorum and other invasive infections. Herpes simplex
virus is associated with 3 types of neonatal infections: skin, eye, or mouth; central nervous systems; and
disseminated. Neisseria gonorhoeae is associated with ophthalmia neonatorum, as well as invasive
disease in the neonate.
PREP Pearls
 Isolation of Mycoplasma hominis from the neonatal respiratory or urinary tract is generally not
associated with adverse clinical outcomes.
 Ureaplasma urealyticum has been associated with chronic lung disease in preterm infants.
 Recognize the possible association of Ureaplasma urealyticum and M. hominis with

genitourinary tract infections, urethritis, and reproductive morbidity
 Plan the management of a patient with Ureaplasma urealyticum and Mycoplasma hominis
infections
Suggested Readings
 Kester LM, Burstein GR, Blythe MJ. Sexually transmitted infection syndromes. In: Long SS,
Pickering LK, Prober CG, ed. Principles and Practice of Pediatric Infectious Diseases. 4th ed. New
York, NY: Saunders Elsevier; 2012:345-349.
 Shah SS. Other Mycoplasma species. In: Long SS, Pickering LK, Prober CG, ed. Principles and
Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier; 2012:998-999.
 Shah SS. Ureaplasma urealyticum. In: Long SS, Pickering LK, Prober CG, ed. Principles and
Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier; 2012:1000-
1002.
 Viscardi RM. Ureaplasma species: role in neonatal morbidities and outcomes. Arch Dis Child
Fetal Neontal Ed. 2014;99(1):F87-F92. DOI: 10.1136/archdischild-2012-303351
Question: 7
A previously healthy 5-month-old female infant is admitted to the hospital because of low-grade fever,
cough, decreased feeding, and increased work of breathing. Three days prior to admission, she had clear
rhinorrhea and a mild cough. On physical examination, her temperature is 38.4°C, respiratory rate of 70
breaths/min, pulse of 140 beats/min, and blood pressure is 80/40 mm Hg. She has nasal congestion, a
wet cough, bilateral wheezing, and subcostal retractions. Her pulse oximetry level is 88% on room air.
Of the following, the MOST appropriate plan of management for this infant should include
A. antibacterial therapy
B. chest physiotherapy
C. corticosteroids
D. albuterol
E. supplemental oxygen
Question: 7
A previously healthy 5-month-old female infant is admitted to the hospital because of low-grade fever,
cough, decreased feeding, and increased work of breathing. Three days prior to admission, she had clear
rhinorrhea and a mild cough. On physical examination, her temperature is 38.4°C, respiratory rate of 70
breaths/min, pulse of 140 beats/min, and blood pressure is 80/40 mm Hg. She has nasal congestion, a
wet cough, bilateral wheezing, and subcostal retractions. Her pulse oximetry level is 88% on room air.
Of the following, the MOST appropriate plan of management for this infant should include
A. antibacterial therapy
B. chest physiotherapy
C. corticosteroids
D. albuterol
E. supplemental oxygen
Bronchiolitis, inflammation of the lower respiratory tract, occurs most commonly in

young infants and children, and is caused by seasonal respiratory viruses such as
respiratory syncytial virus. These infections are characterized by edema, increased
mucus production, necrosis, and regeneration of the epithelial cells lining the
bronchioles. The clinical presentation of bronchiolitis can vary widely from mild
tachypnea to respiratory failure, and often includes rhinorrhea, cough, tachypnea,
increased work of breathing, hypoxia, and variable wheezes and crackles on examination. The American
Academy of Pediatrics (AAP) has recently published an updated clinical practice guideline, which offers
recommendations for the diagnosis, testing, and management of bronchiolitis based on the available
evidence.
The diagnosis of bronchiolitis is made on the basis of the classic history and physical examination.
Routine laboratory and radiologic testing, including chest radiographs and viral studies, are not
recommended for typical presentations. Management strategies for bronchiolitis emphasize the
importance of supportive care, including hydration and oxygenation. Thus, for the infant in the vignette,
assessment of the oxygenation status of the infant along with the infant’s hydration status, are the
primary therapeutic interventions. Measurement of oxygen saturation may detect transient fluctuations
in oxygenation; supplemental oxygen is recommended when oxyhemoglobin saturation persistently falls
below 90% in a previously healthy infant, such as the infant in the vignette. The updated guidelines note
that clinicians may choose not to provide supplemental oxygen to infants with bronchiolitis who have
oxyhemoglobin saturations over 90%, based on the premise that saturations over 90% are adequate to
oxygenate tissues and pose a minimal risk of hypoxemia. Infants with bronchiolitis who cannot maintain
hydration orally should be given intravenous fluids or nasogastric feeding. Although several therapeutic
interventions, such as antibacterial therapy, corticosteroids, bronchodilators, and physiotherapy, are
often considered for infants with bronchiolitis, none have been demonstrated to have a significant
impact on the clinical course, duration of illness, or subsequent clinical outcome.
Antibacterial agents have no impact on viral bronchiolitis and are not recommended, unless there is a
concurrent or strongly suspected bacterial infection. Although antibiotic therapy continues to be
overused for young infants because of concern for undetected serious bacterial infection, infants with
distinct viral syndrome, including bronchiolitis, are at a very low risk of serious bacterial infection and
meningitis.
Chest physiotherapy should not be used in the management of bronchiolitis, based on the fact that
multiple studies examining the use of vibration, percussion, or passive expiratory techniques have failed
to show clinical benefit.
A recent comprehensive systematic review and large multi-center randomized trials provide evidence
that corticosteroids do not provide significant benefit to children with bronchiolitis. Additionally, the use
of corticosteroids has been associated with prolonged viral shedding in patients with bronchiolitis.
Therefore, corticosteroids are not recommended to treat bronchiolitis.
The updated AAP guidelines state that bronchodilators, such as albuterol or salbutamol, should not be
used in infants and children who are diagnosed with bronchodilators. Although studies have shown that
bronchodilators may improve clinical symptom scores, they do not affect disease resolution, need for
hospitalization, or length of stay.
Many studies examining the benefit of nebulized hypertonic saline in infants with acute viral
bronchiolitis have found 3% nebulized saline to be safe and effective at improving symptoms of mild to
moderate bronchiolitis after 24 hours of use and reducing length of stay in settings in which the length
of stay exceeds 3 days. Hypertonic saline has not been shown to be effective in emergency settings or
when the length of usage is brief. Thus, the updated guidelines state that clinicians may administer
nebulized saline to infants and children hospitalized with bronchiolitis, but not to infants in the
emergency department setting.
PREP Pearls
 Supportive care, including assessment and attention to hydration status and adequate
oxygenation, are of paramount importance in the management of bronchiolitis
 Interventions such as corticosteroids, chest physiotherapy, antibacterial agents, and

bronchodilators are not recommended for the management of bronchiolitis
 Nebulized hypertonic saline may be effective in reducing symptoms for infants and children with
mild to moderate bronchiolitis in the inpatient setting.
 Plan the management of a patient with bronchiolitis
Question: 8
You are consulted regarding diagnostic studies on a 12-year-old, previously healthy boy admitted to the
pediatric intensive care unit who has a clinical and echocardiographic diagnosis of myocarditis. The boy
had fever and mild constitutional symptoms for 2 to 3 days, resolving 10 days prior to admission. Today,
he presented with chest pain and shortness of breath.
On physical examination, he is listless, though nontoxic, alert, and responsive, and has no rash. Serum
troponin and B-type natriuretic peptide levels are elevated. The diagnostic tests ordered so far include a
panel of viral serologic studies and cultures. You review epidemiologic data on the prevalence of viruses
in acute myocarditis for the critical care team, and though it is not commonly performed at your
institution, bring up the role of endomyocardial biopsy (EMB) in specific etiologic diagnosis.
Of the following, the viral agent detected MOST frequently on endomyocardial specimens is
A. adenovirus
B. coxsackie B virus
C. hepatitis C virus
D. human herpes virus 6
E. parvovirus B19
Question: 8
You are consulted regarding diagnostic studies on a 12-year-old, previously healthy boy admitted to the
pediatric intensive care unit who has a clinical and echocardiographic diagnosis of myocarditis. The boy
had fever and mild constitutional symptoms for 2 to 3 days, resolving 10 days prior to admission. Today,
he presented with chest pain and shortness of breath.
On physical examination, he is listless, though nontoxic, alert, and responsive, and has no rash. Serum
troponin and B-type natriuretic peptide levels are elevated. The diagnostic tests ordered so far include a
panel of viral serologic studies and cultures. You review epidemiologic data on the prevalence of viruses
in acute myocarditis for the critical care team, and though it is not commonly performed at your
institution, bring up the role of endomyocardial biopsy (EMB) in specific etiologic diagnosis.
Of the following, the viral agent detected MOST frequently on endomyocardial specimens is
A. adenovirus
B. coxsackie B virus
C. hepatitis C virus
D. human herpes virus 6
E. parvovirus B19
Several infectious and noninfectious triggers of myocarditis are described. Of the

infectious agents associated with acute myocarditis, viral infections are the most
frequently implicated. Accurate epidemiologic data on the viral etiology of myocarditis are scant as
biopsy; viral genome assays and serology are rarely done in most regions of the world. Based on studies
published in the last 2 decades or so, parvovirus B19 is the most likely viral agent to be detected on
endomyocardial biopsy (EMB) by nucleic acid assay. Enteroviruses, especially coxsackie group B viruses,
were the most commonly implicated viruses in seroepidemiological studies in the 1950s and 1960s. In
the 1990’s adenoviruses began to be implicated more often. Subsequently, polymerase chain reaction
and other molecular detection techniques on myocardial biopsy specimens in Europe and North America
revealed that parvovirus B19 and human herpes virus 6 are more frequent, with parvovirus B19
detected most commonly. Hepatitis C virus was linked to myocarditis and dilated cardiomyopathy in
Japan and in the United States largely based on serologic data. Adenoviruses were detected
uncommonly on EMB in recent studies. Cytomegalovirus, Epstein-Barr virus, human immunodeficiency
virus, and influenza viruses also are associated with myocarditis. Whether identification of nucleic acids
on myocardial biopsy specimens constitutes an “innocent bystander” phenomenon or a true infection is
controversial.
In patients with human immunodeficiency virus infection, myocarditis was observed in more than 50%
of autopsies. Eosinophilic-lymphocytic myocarditis is reported after smallpox vaccination. Most cases of
myocarditis are the consequence of a postviral, immune-mediated response. Children more often than
adults have a fulminant presentation, and myocarditis is an important cause of sudden death in children.
Importantly, over 20% of patients develop dilated cardiomyopathy, leading to disability and the need for
cardiac transplantation.
PREP Pearls
 Common viral agents have been associated with myocarditis
 Be aware of the limitation of diagnostic assays in identification of specific etiology of myocarditis
 Parvovirus B19 and human herpes virus 6 are now frequently implicated in myocarditis based
solely upon detection in biopsy specimens
 Know the epidemiologic features and microbial etiologies of viral myocarditis
Suggested Readings
 Cooper LT Jr. Myocarditis. N Engl J Med. 2009;360(15):1526-1538. DOI:

10.1056/NEJMra0800028
 Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol.

2012;59(9):779-792. DOI: 10.1016/j.jacc.2011.09.074
 Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated
cardiomyopathy in children. JAMA. 2006;296(15):1867-1876. DOI: 10.1001/jama.296.15.1867
 Yilmaz A, Klingel K, Kandolf R, Sechtem U. A geographical mystery: do cardiotropic viruses

respect national borders. J Am Coll Cardiol. 2008;52(1):82-83. DOI: 10.1016/j.jacc.2008.01.072
June
Question: 1
You are evaluating a 10-year-old girl for a 3-day history of painful, erythematous “bumps” that have
developed on her shins and thighs. By history, she was ill with low grade fever to 38.3°C, malaise, and
nonproductive cough 2 weeks ago that has since resolved. Her immunizations are up to date. Physical
examination is significant for a tired-appearing girl with shotty bilateral cervical adenopathy. There are
several 2 cm erythematous, warm, tender raised plaques on her bilateral shins and thighs.
Laboratory tests show a peripheral white blood cell count of 14,000/µL (14 x 109/L), hemoglobin of 12
g/dL (12 g/L), and platelet count of 210 x 103/µL (210 x 109/L) with a differential of S55L40M5
(segmented neutrophils 55, lymphocytes 40 and monocytes 5). Her erythrocyte sedimentation rate is 60
mm/h and C-reactive protein is 4.0 mg/L (38.1 nmol/L).
Of the following, the MOST accurate statement about this patient’s condition is
A. it involves the dermal layer of the skin
B. it is associated with a type iv delayed hypersensitivity response
C. it is more commonly seen in boys than girls
D. Mycobacterium tuberculosis is the most common associated infectious agent
E. scarring and ulceration of the affected area is common

Question: 1
You are evaluating a 10-year-old girl for a 3-day history of painful, erythematous “bumps” that have
developed on her shins and thighs. By history, she was ill with low grade fever to 38.3°C, malaise, and
nonproductive cough 2 weeks ago that has since resolved. Her immunizations are up to date. Physical
examination is significant for a tired-appearing girl with shotty bilateral cervical adenopathy. There are
several 2 cm erythematous, warm, tender raised plaques on her bilateral shins and thighs.
Laboratory tests show a peripheral white blood cell count of 14,000/µL (14 x 109/L), hemoglobin of 12
g/dL (12 g/L), and platelet count of 210 x 103/µL (210 x 109/L) with a differential of S55L40M5
(segmented neutrophils 55, lymphocytes 40 and monocytes 5). Her erythrocyte sedimentation rate is 60
mm/h and C-reactive protein is 4.0 mg/L (38.1 nmol/L).
Of the following, the MOST accurate statement about this patient’s condition is
A. it involves the dermal layer of the skin
B. it is associated with a type iv delayed hypersensitivity response
C. it is more commonly seen in boys than girls
D. Mycobacterium tuberculosis is the most common associated infectious agent
E. scarring and ulceration of the affected area is common

The patient in the vignette has erythema nodosum (EN). Erythema nodosum is a
painful disorder of the subcutaneous fat and is the most common type of panniculitis.
Erythema nodosum represents a nonspecific inflammatory process involving the septa
between subcutaneous fat lobules. Histologically, what is seen is a neutrophilic
infiltrate around proliferating capillaries, which results in septal thickening in early
lesions that may be associated with hemorrhage (Figure). Actinic (Miescher) radial
granulomas (small, well-defined nodular aggregates of tiny histiocytes around a central stellate cleft) are
a characteristic finding. Erythema nodosum may occur in response to numerous antigens, with most
evidence supporting the involvement of a type IV delayed hypersensitivity response. Overall, EN occurs
in approximately 1 to 5 per 100,000 people. In adults, it is more common among women, with a male-
to-female ratio of 1:6, while in children, the ratio is 1:1. The peak incidence of disease occurs in persons
between 20 and 30 years of age, although EN can occur at any age.
Erythema nodosum typically presents acutely as painful, symmetric, warm, erythematous nodules and
raised plaques that vary from 1 to 10 cm in diameter and are poorly demarcated. The pretibial area is
the most common site of involvement, although the extensor surfaces of the forearm, the thighs,
ankles, neck, trunk, and the face may also be affected. Initially, the nodules can be firm, but may
become more fluctuant during the clinical evolution. Individual nodules may last for 2 weeks and new
lesions may continue to arise for up to 6 weeks. The nodules often take approximately 1 to 2 months to
heal completely and may develop a bruise-like appearance as they fade. They do not tend to ulcerate
and usually resolve without atrophy or scarring. A less common variant of EN in children and young
adults is characterized by lesions involving only the palms of the hands and soles of the feet and is
frequently the process is unilateral. Regardless of etiology, a prodrome commonly occurs 1 to 3 weeks
before the onset of EN. Symptoms may include weight loss, malaise, low-grade fever, cough, and
arthralgia with or without arthritis. Less frequent findings include lymphadenopathy, hepatomegaly,
splenomegaly, and pleuritis. Abnormal laboratory findings may include leukocytosis (> 10,000 per mm3)
and elevated erythrocyte sedimentation rate and C-reactive protein levels.
Erythema nodosum is usually idiopathic, accounting for up to 55% of cases, however, as shown in the
Table, there are a wide variety of infectious and noninfectious etiologic factors that may cause EN. The
most common causes of EN include:
1) Infections with group A β-hemolytic streptococcus (Streptococcus pyogenes), which is the most
frequent etiologic factor associated with the development of EN, accounting for up to 44% of cases in
adults and 48% of cases in children. Erythema nodosum eruptions may appear 2 to 3 weeks after an
episode of streptococcal pharyngitis.
2) Mycobacterium tuberculosis, which is also a bacterium that is commonly linked with EN. Erythema
nodosum may occur with primary tuberculosis, as well as, with Bacillus Calmette-Guérin (BCG)
vaccination and placement of a tuberculin skin test. Several different atypical mycobacteria have also
been associated with EN.
3) Sarcoidosis, which causes up to 25% of EN cases. Bilateral hilar adenopathy is often seen in patients
with EN caused by sarcoidosis.
4) Hypersensitivity reactions to medications have been recognized as a cause of up to 10% of EN cases
with oral contraceptives (eg, combination estrogen and progesterone agents, hormone therapy) and
numerous antibiotics being the most commonly associated agents.
5) Erythema nodosum is seen in up to 5% of women who are pregnant, possibly as a result of estrogen
production or relative levels of estrogen and progesterone.

6) Enteropathies (eg, ulcerative colitis, Crohn disease, regional enteropathy) account for up to 4% of all
cases of EN.
Erythema nodosum is usually self-limited, with the most common approach to treatment being
supportive. Diagnosis and treatment should be directed toward any underlying disorders. Supportive
therapy includes bed rest, avoidance of contact irritation of the affected areas, and pain management
with nonsteroidal anti-inflammatory drugs. Other treatment options include oral potassium iodide
prepared as a supersaturated solution in a dosage of 400 to 900 mg per day for 1 month, which provides
symptomatic relief early in the onset of EN. The mechanism of action of potassium iodide in EN is not
well understood, but it appears that it causes heparin release from mast cells, and heparin acts to
suppress delayed hypersensitivity reactions. Systemic steroids are also a relatively safe therapeutic
option. Oral prednisone at a dose of 1 mg/kg of body weight per day is the standard dosage. Some
patients may respond to a course of colchicine, 0.6 to 1.2 mg twice a day, or hydroxychloroquine, 200
mg twice a day.
PREP Pearls
 Erythema nodosum is a nonspecific inflammatory process involving the septa between

subcutaneous fat lobules and is the most common form of panniculitis.
 Erythema nodosum presents acutely as painful, symmetric, warm, erythematous nodules and
raised plaques that are poorly demarcated. The pretibial area is the most common site of
involvement, although the extensor surfaces of the forearm, the thighs, ankles, neck, trunk, and
the face may also be affected.
 Infections caused by Streptococcus pyogenes are the most frequent etiologic factor associated
with the development of erythema nodosum.
 Erythema nodosum may develop in response to a wide variety of infectious and noninfectious
conditions.
 Recognize the clinical manifestations and etiologic agents (infectious and noninfectious) of
erythema nodosum
Suggested Readings
 Kakourou T, Drosatou P, Psychou F, et al. Erythema nodosum in children: a prospective study. J

Am Acad Dermatol. 2001;44(1):17-21.
 Requena L, Yus ES. Erythema nodosum. Dermatol Clin. 2008;26(4):425-438. DOI:

10.1016/j.det.2008.05.014
 Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician.
2007;75(5):695-700.
Question: 2
You are evaluating a 1-day-old newborn whose blood culture is growing Gram-negative bacilli. The blood
culture was obtained at 6 hours of age when the newborn developed respiratory distress and
temperature instability. The newborn was treated empirically with ampicillin and gentamicin, and is
currently doing well. The newborn was born at term to a 24-year-old mother who had good prenatal
care and who had no prenatal risk factors for infection. On physical examination, the newborn’s vital
signs are stable and the examination is nonfocal. Growth parameters and head circumference are
normal.
Of the following, the MOST sensitive laboratory measure correlating with bacterial infection in this
newborn is
A. elevated absolute immature neutrophil (band) count
B. elevated absolute neutrophil count
C. elevated immature neutrophil (band) to neutrophil ratio
D. elevated total white blood cell count
E. thrombocytopenia
Question: 2
You are evaluating a 1-day-old newborn whose blood culture is growing Gram-negative bacilli. The blood
culture was obtained at 6 hours of age when the newborn developed respiratory distress and
temperature instability. The newborn was treated empirically with ampicillin and gentamicin, and is
currently doing well. The newborn was born at term to a 24-year-old mother who had good prenatal
care and who had no prenatal risk factors for infection. On physical examination, the newborn’s vital
signs are stable and the examination is nonfocal. Growth parameters and head circumference are
normal.
Of the following, the MOST sensitive laboratory measure correlating with bacterial infection in this
newborn is
A. elevated absolute immature neutrophil (band) count
B. elevated absolute neutrophil count
C. elevated immature neutrophil (band) to neutrophil ratio
D. elevated total white blood cell count
E. thrombocytopenia
The utility of the peripheral white blood cell count and differential count in predicting
bacterial infection has been studied extensively in neonates being evaluated for early-
onset bacterial infection. These studies have examined the utility of the total white
blood cell count, the absolute neutrophil count, absolute band count, and ratio of
immature (bands) to total neutrophils (I/T). Although the sensitivity of the I/T ratio in
neonatal bacterial infections has ranged in various studies from 30% to 90%, it
appears to have the best sensitivity of any of the neutrophil indices. None of the neutrophil indices have
good positive predictive value for bacterial infection. However, a normal I/T ratio (< 0.2) is associated
with very high negative predictive value (99%). Thus, neutrophil indices have proven most useful in
identifying neonates without infection rather than neonates with infection. Like the neutrophil indices,
thrombocytopenia is not a sensitive marker for bacterial infection in the newborn, especially early in the
course of infection. Many of the studies examining the association between neutrophil indices and
bacterial infection have stressed the importance of timing of the white blood cell count and differential;
counts obtained 6 to 12 hours after birth are more likely to be abnormal than those obtained at birth
and thus more reliable. Furthermore, neutropenia has been found to be a more specific marker for
sepsis than neutrophilia or an elevated I/T ratio.
The normal maturation of the neutrophil series in the bone marrow progresses from myeloblasts to
promyelocytes to myelocytes to metamyelocytes to band forms to mature neutrophils. Only band forms
and mature neutrophils are normally present in the peripheral smear. An increased number of the
neutrophilic band forms and less mature neutrophils in the peripheral blood smear is referred to as a
“left shift,” and is most often associated with acute bacterial infection and acute inflammatory
conditions. Although the presence of a left shift is commonly associated with acute bacterial infection,
the diagnostic accuracy of a left shift in predicting a bacterial infection is not high enough to generally
allow management decisions to be based solely on this finding. Various viral infections in children, such
as adenovirus, influenza A, and disseminated herpes simplex, have been associated with increased left
shift on a peripheral smear and can mimic bacterial infection. Often, overwhelming bacterial sepsis is
associated with depletion of the bone marrow’s storage pool, resulting in neutropenia rather than
neutrophilia and a leftward shift in neutrophils.
PREP Pearls
 A left shift in the peripheral white blood cell count, while nonspecific, is generally associated
with acute bacterial infection and acute inflammatory conditions.
 The immature neutrophil (band) to neutrophil ratio has a very high negative predictive value for
the presence of bacterial infection in neonates.
 Viral infections in children may also cause a left shift in the peripheral white blood cell count.
 Recognize the significance of a leftward shift of PMNs on blood smear

Question: 3
An adolescent boy who was born and raised in the United States is referred to you because he was
recently diagnosed with hepatitis C virus (HCV) infection. You order viral genotyping.
Of the following, the MOST likely genotype for this patient’s HCV is
A. genotype 1
B. genotype 3
C. genotype 4
D. genotype 5
E. genotype 6
Question: 3
An adolescent boy who was born and raised in the United States is referred to you because he was
recently diagnosed with hepatitis C virus (HCV) infection. You order viral genotyping.
Of the following, the MOST likely genotype for this patient’s HCV is
A. genotype 1
B. genotype 3
C. genotype 4
D. genotype 5
E. genotype 6
Hepatitis C virus (HCV) is a single-stranded RNA virus with an envelope and belongs to
the Hepacivirus genus in the Flaviviridae family. Once HCV infection has been
diagnosed, genotyping of HCV is recommended in order to predict the response to
and to determine the duration of therapy. There are at least 6 genotypes of HCV
(genotypes 1-6). The prevalence of the 6 genotypes of HCV varies according to
geographic location. Genotype 1 is responsible for most of the infections in the United
States and Europe, genotype 3 is most commonly encountered in India and Australia, genotype 4 is
found in Africa and the Middle East, genotype 5 is associated with southern Africa, and genotype 6 is
found in southeast Asia and Australia. Treatment recommendations for HCV are rapidly evolving, but it
has been suggested that therapy for HCV genotypes 1 and 4 be generally twice as long as therapy for
HCV genotypes 2 and 3. Therapy for HCV genotypes 2 and 3 is more likely to be successful.
Although the proportion of adults infected with HCV is higher than in the pediatric population, HCV
infection can occur in pediatric patients. Approximately 1.6% of the US population is chronically infected
with HCV, with less than 5% of all HCV infections in the United States among individuals younger than 20
years of age. Among the pediatric population, the prevalence of HCV infection is estimated to range
from 0.2% (children aged 6 to 11 years) to 0.4% (individuals aged 12 to 19 years).
Hepatitis C virus is transmitted through direct percutaneous exposure to blood. Transmission can also
occur with mucous membrane exposures to blood, but is less efficient. Although HCV can be detected in
other body fluids (saliva, semen, breast milk), these fluids are not efficient means of transmission.
Among pediatric patients, mother-to-child transmission represents the most common mode of
acquisition of HCV infection. Older children and adolescents may acquire infection through injection
drug use or sexual transmission. Previously (before 1992, when more advanced HCV screening was
implemented), receipt of a blood or blood product transfusion or receipt of a solid organ transplant was
associated with acquisition of HCV infection.
PREP Pearls
 Once hepatitis C virus (HCV) infection is confirmed, genotyping of HCV is important in order to
predict the response to and duration of therapy.
 Hepatitis C virus is a single-stranded RNA virus with an envelope, and belongs to the Hepacivirus
genus in the Flaviviridae family.
 The prevalence of the 6 genotypes of HCV varies according to geographic location, with
genotype 1 being responsible for most of the infections in the United States and Europe.
 Know that hepatitis C virus is a flavivirus
 Understand the utility of genotyping in hepatitis C infection
Suggested Readings
 Tohme RA, Holtzman D, Holmberg SD. Hepatitis C virus. In: Long SS, Pickering LK, Prober CG, ed.
Principles and Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier;
2012:1102-1112.
 World Health Organization. Guidelines for the screening, care, and treatment of persons with
hepatitis C infection. World Health Organization website. 2015. Available at:
http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1&ua=1
Question: 4
A 12-year-old boy with a history of hypoplastic right heart syndrome, pulmonary atresia, and a
hypoplastic tricuspid valve was admitted with syncope and fever to the pediatric intensive care unit
(PICU). Prior to admission, he had 12 days of fever, first to a temperature of 37.8°C and in the past 3
days to 38.3°C, malaise, chills, and poor appetite. On the day of admission, he had 2 episodes of syncope
after climbing several flights of steps. He also was noticed to have several episodes when his lips were
blue and his fingers were blue up to his knuckles. His past cardiac surgery included a pulmonary
valvotomy and insertion of a Blalock-Taussig shunt, a bidirectional Glenn shunt, and a pulmonary valve
replacement with pericardial bioprosthetic valve, and a bovine pericardial patch angioplasty of the main
pulmonary artery at the pulmonary valve insertion site.
Upon admission to the PICU, he had blood cultures obtained. His admission chest film is shown in Figure
1, which is no different from his recent chest films. He was started on intravenous vancomycin,
gentamicin, and heparin; the pediatric infectious diseases service is consulted. A computed tomography
of the brain was unremarkable. Laboratory values at admission are in Table 1.
A magnetic resonance angiography was performed with gadolinium contrast that revealed a lack of
enhancement of the pulmonary artery lumen (Figure 2).
Of the following, the next MOST important management option is

A. change gentamicin to cefepime
B. heart catheterization
C. surgical consultation
D. trans-esophageal echocardiogram
E. ventilation perfusion scan
Question: 4
A 12-year-old boy with a history of hypoplastic right heart syndrome, pulmonary atresia, and a
hypoplastic tricuspid valve was admitted with syncope and fever to the pediatric intensive care unit
(PICU). Prior to admission, he had 12 days of fever, first to a temperature of 37.8°C and in the past 3
days to 38.3°C, malaise, chills, and poor appetite. On the day of admission, he had 2 episodes of syncope
after climbing several flights of steps. He also was noticed to have several episodes when his lips were
blue and his fingers were blue up to his knuckles. His past cardiac surgery included a pulmonary
valvotomy and insertion of a Blalock-Taussig shunt, a bidirectional Glenn shunt, and a pulmonary valve
replacement with pericardial bioprosthetic valve, and a bovine pericardial patch angioplasty of the main
pulmonary artery at the pulmonary valve insertion site.
Upon admission to the PICU, he had blood cultures obtained. His admission chest film is shown in Figure
1,which is no different from his recent chest films. He was started on intravenous vancomycin,
gentamicin, and heparin; the pediatric infectious diseases service is consulted. A computed tomography
of the brain was unremarkable. Laboratory values at admission are in Table 1.
A magnetic resonance angiography was performed with gadolinium contrast that revealed a lack of
enhancement of the pulmonary artery lumen (Figure 2).
Of the following, the next MOST important management option is
A. change gentamicin to cefepime
B. heart catheterization
C. surgical consultation
D. trans-esophageal echocardiogram
E. ventilation perfusion scan
The patient in this vignette has infective endocarditis (IE) with a large vegetation
originating from the pulmonary valve, involving the majority of the main pulmonary
artery, and extending to the lobar branches of the left pulmonary artery (Figure 3 ).
This patient requires urgent pediatric cardiothoracic consultation for evaluation and
surgical removal of this large mass. There is no advantage to changing the antibiotic
coverage from gentamicin to cefepime. A ventilation perfusion scan, a trans-
esophageal echocardiogram, nor a heart catheterization will provide any additional information than
what the magnetic resonance angiography (MRA) provided.
Surgery can be a valuable adjunct to medical therapy in the management of IE. The generally accepted
indications for surgical intervention during active endocarditis are summarized in Table 2. Factors that
may predispose a child to develop high risk complications from IE include prosthetic valves, left-sided IE,
Staphylococcus aureus IE, fungal IE, previous IE, prolonged clinical symptoms (> 3 months), cyanotic
congenital heart disease, patients with systemic-to-pulmonary shunts, and poor clinical response to
antimicrobial therapy. Congestive heart failure (CHF) may occur acutely or insidiously; urgent surgery in
patients with moderate to severe heart failure improves the likelihood of preservation of heart function
and survival. Despite a higher operative mortality rate in patients with CHF than in those without CHF,
patients with IE who have CHF and undergo valve surgery have a substantially reduced mortality rate
compared to those treated with medical therapy alone. The incidence of reinfection of newly implanted
valves in patients with active IE is 2% to 3% and is far less than the mortality rate for IE and CHF without
surgical therapy, which approaches 51%. The highest rates of embolization are associated with mitral
valve vegetations (25%) than aortic vegetations (10%), and highest rates of embolization have been
observed in patients with mitral vegetations attached to the anterior rather than the posterior mitral
leaflet. This may be related to the fact that the mitral valve (as compared to the aortic valve) undergoes
2 excursions per cardiac cycle, which may contribute to the propensity of a vegetation to fragment and
embolize.
PREP Pearls
 Surgical intervention in infective endocarditis (IE) include: refractory congestive heart failure,
uncontrolled infection, persistent bacteremia, > 2 serious embolic episodes, fungal endocarditis,
most prosthetic-valve endocarditis, and local supperative complications, including perivalvular
or myocardial abscess with conduction system abnormalities.
 The highest rates of embolization are associated with mitral valve vegetations (25%) and are
more common than aortic vegetations (10%), and highest rates of embolization have been
observed in patients with mitral vegetations attached to the anterior rather than the posterior
mitral leaflet.
 Despite a higher operative mortality rate in patients with congestive heart failure (CHF) than in
those without CHF, patients with IE who have CHF and undergo valve surgery have a
substantially reduced mortality rate compared to those treated with medical therapy alone.
 Recognize the indications for surgery in the management of endocarditis
Suggested Readings
 Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy,
and management of complications: a statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery
and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of
America. . Circulation. 2005;111(23):e394-434. DOI: 10.1161/CIRCULATIONAHA.105.165564
 Bayer AS, Bolger AF, Taubert KA, et al. Diagnosis and management of infective endocarditis and
its complications. Circulation. 1998;98(25):2936-2948. DOI: 10.1161/01.CIR.98.25.2936
 Ferrieri P, Gewitz MH, Gerber MA, et al. Unique features of infective endocarditis in childhood.
Circulation. 2002;105(17):2115-2126. DOI: 10.1161/01.CIR.0000013073.22415.90
Question: 5
A 3-week-old neonate was hospitalized with a fever to 40°C. He was born at 40 weeks gestation after an
uncomplicated pregnancy. Maternal screening for group B streptococcus was negative. The neonate was
exclusively breastfed. He received 1 dose of hepatitis B vaccine in the newborn nursery and was
discharged home at 36 hours after birth in good health. He was seen once in the primary care office for
a weight check at 1 week of age and was doing well. He is uncircumcised. No sick household contacts
were identified. On physical examination, he was well nourished and well hydrated. There was no focus
for his fever. Laboratory investigation showed a white blood count of 28,000/µL (28 x 109/L) with 92%
neutrophils and 8% lymphocytes. Cerebrospinal fluid results were all within normal limits. A urinalysis
showed trace proteinuria, 100 white blood cells/high power field, presence of leukocyte esterase and
nitrates, and 4+ Gram-negative rods on an unspun urine Gram stain. Empiric therapy was initiated with
cefotaxime. A renal ultrasonography demonstrated a dilated collecting system on the left side. Twenty-
four hours later, the patient was already improving when the laboratory reported that the urine culture
obtained on admission was growing "mixed urogenital flora."
Of the following, the MOST likely explanation for this urine culture result is that the
A. neonate does not have a urinary tract infection
B. neonate has a polymicrobial urinary tract infection
C. urine sample was centrifuged before it was inoculated onto the culture media
D. urine sample was collected in a urine bag
E. urine sample was refrigerated overnight in the laboratory
Question: 5
A 3-week-old neonate was hospitalized with a fever to 40°C. He was born at 40 weeks gestation after an
uncomplicated pregnancy. Maternal screening for group B streptococcus was negative. The neonate was
exclusively breastfed. He received 1 dose of hepatitis B vaccine in the newborn nursery and was
discharged home at 36 hours after birth in good health. He was seen once in the primary care office for
a weight check at 1 week of age and was doing well. He is uncircumcised. No sick household contacts
were identified. On physical examination, he was well nourished and well hydrated. There was no focus
for his fever. Laboratory investigation showed a white blood count of 28,000/µL (28 x 109/L)with 92%
neutrophils and 8% lymphocytes. Cerebrospinal fluid results were all within normal limits. A urinalysis
showed trace proteinuria, 100 white blood cells/high power field, presence of leukocyte esterase and
nitrates, and 4+ Gram-negative rods on an unspun urine Gram stain. Empiric therapy was initiated with
cefotaxime. A renal ultrasonography demonstrated a dilated collecting system on the left side. Twenty-
four hours later, the patient was already improving when the laboratory reported that the urine culture
obtained on admission was growing "mixed urogenital flora."
Of the following, the MOST likely explanation for this urine culture result is that the
A. neonate does not have a urinary tract infection
B. neonate has a polymicrobial urinary tract infection

C. urine sample was centrifuged before it was inoculated onto the culture media
D. urine sample was collected in a urine bag
E. urine sample was refrigerated overnight in the laboratory
The case presented is typical for pyelonephritis in a neonate. The patient is

uncircumcised (a known risk factor for infant urinary tract infection) and has evidence
both on enhanced urinalysis and on renal ultrasonography indicating that his left
kidney is infected. The report from the laboratory stating that the urine culture is
growing “mixed urogenital flora” is unexpected. Polymicrobial pyelonephritis is quite
uncommon, proving to be a convincing diagnosis only in patients with complicated
urinary tact anatomy or chronic obstruction. Urine cultures are performed in a standardized manner so
that the results yield a quantitative result. Unspun urine is plated onto solid media using a sterile
calibrated loop, so that colony forming unit estimates can be made from counting the colonies present
on the solid media. Centrifugation is not part of this process, although spun urine sediment is examined
separately as part of the urinalysis. Finally, urine samples that are collected for the purpose of culture
should always be refrigerated after collection and prior to processing so that any bacteria that are
present do not continue to replicate during the transport and processing period.
The most likely reason that the urine culture for this patient was reported as “mixed urogenital flora” is
that the sample itself was not collected or stored properly prior to reaching the laboratory.
There are several appropriate techniques to obtain urine for culture. The most common technique used
in older children and adults is the collection of clean-voided midstream urine. Females should be
instructed to clean with soap and water, rinse with water, hold their labia apart, and begin voiding
directly into the toilet. After several mL of urine have been expelled, a midstream sample is collected
into the container. Males should be instructed to clean the glans with soap and water, rinse with water,
retract the foreskin, and begin voiding directly into the toilet. After several mL are expelled, a midstream
sample is collected into the container. In infants, younger children, and in those who are not able to
control timing of voiding, a straight catheter urine sample is preferred. After cleaning and rinsing the
area surrounding the urethral opening, the catheter is inserted so that urine is introduced into the
sterile container directly. If the catheterization proves technically difficult such as in boys with phimosis,
or in girls where the urethra is not immediately identified, contamination of the catheter can lead to
contamination of the urine sample. The practice of obtaining urine for culture from young infants using
a bag urine collection where a plastic adhesive bag is applied over the genitals until urine is produced is
strongly discouraged. Such samples will typically yield culture results with more than 1 type of bacteria.
After urine is collected for culture, it should always be refrigerated. Specimens obtained from catheters
should be transported to the laboratory at 4°C within 2 hours of collection. Midstream samples should
be maintained at 4°C and transported to the laboratory within 24 hours. Failure to refrigerate urine or
transport the sample to the laboratory in a timely fashion increases the possibility of a falsely positive
culture result, as urine is an excellent culture medium for bacteria.
It is appropriate for the laboratory to reject biologic samples submitted for culture when the transport
or storage of that sample would be expected to compromise the interpretation of the microbiologic
findings. Some of the reasons for which a specimen may be rejected include instances where the
information on the sample container does not match the information on the requisition, if the sample
was transported at an incorrect temperature or delivered in an improper container, if the container was
leaking, or if an insufficient quantity of the sample is available for the test requested. The laboratory
personnel should know to contact the ordering provider so that an appropriate sample can be resent
when feasible.
When the laboratory receives a biologic sample for testing and the test is not performed immediately,
the sample must be stored. Depending on the sample type, the transport medium used, and the
infectious agents suspected, storage and handling differ in an attempt to optimize the validity of the
final result. For example, specimens that are submitted for anaerobic culture should never be
refrigerated, while cerebrospinal fluid should always be maintained at 37°C. Urine and stool specimens
submitted for virus culture, cervical specimens for chlamydia or ureaplasma testing, sputa, and foreign
devices such as medical plastics should be stored at 4°C. Serum submitted for serologic testing may be
frozen for a week (sometimes longer) at -20°C, and tissue or serum for long-term storage should be
maintained at -70°C or colder.
PREP Pearls
 Careful attention to specimen collection and handling is essential to optimize the validity of the
reported results.
 Urine cultures reported to be growing more than one type of bacteria are likely to have been
collected or handled improperly, and if possible, should be repeated.
 Refrigeration is appropriate during transport of most specimen types, but cerebrospinal fluid
and samples where anaerobic cultures are requested should not be kept cold.
 Understand importance of collection method and transport time for culture of urine
 Know for which clinical specimens refrigeration is appropriate (urine, stool for C.difficile toxin,
cervical secretions in transport medium for Chlamydia and Ureaplasma, stool in transport
solution for ova and parasites)
Suggested Readings
 Tille PM. Specimen management. Bailey & Scott’s Diagnostic Microbiology. 13th ed. St. Louis,
MO: Mosby Elsevier; 2013:53-67.
Question: 6
A 6-year-old boy with sickle cell disease presents with a 1-week history of fever and limp. He recently
returned from a 2-week summer trip with his family to Acapulco, Mexico, where he visited the local
beaches and ate local foods. He experienced a short, self-limited diarrheal illness while in Mexico.
Physical examination shows a thin boy with a temperature of 37.8°C. His left lower leg is slightly swollen,
erythematous, and indurated with reproducible point tenderness over the midshaft of the left tibia.
Plain radiographs of the lower leg were unremakrable. Magnetic resonance imaging of the left lower leg
shows signal changes in bone marrow and several small abscesses in the left tibia and fibula. Aspiration
of the left lower leg abscesses grew a Gram-negative rod.
Of the following, the organism that is MOST likely the cause of this child’s condition is
B. Escherichia coli
C. Salmonella enterica
D. Shigella sonnei
E. Vibrio vulnificus
Question: 6
A 6-year-old boy with sickle cell disease presents with a 1-week history of fever and limp. He recently
returned from a 2-week summer trip with his family to Acapulco, Mexico, where he visited the local
beaches and ate local foods. He experienced a short, self-limited diarrheal illness while in Mexico.
Physical examination shows a thin boy with a temperature of 37.8°C. His left lower leg is slightly swollen,
erythematous, and indurated with reproducible point tenderness over the midshaft of the left tibia.
Plain radiographs of the lower leg were unremakrable. Magnetic resonance imaging of the left lower leg
shows signal changes in bone marrow and several small abscesses in the left tibia and fibula. Aspiration
of the left lower leg abscesses grew a Gram-negative rod.
Of the following, the organism that is MOST likely the cause of this child’s condition is
B. Escherichia coli
C. Salmonella enterica
D. Shigella sonnei
E. Vibrio vulnificus
This child has osteomyelitis, most likely caused by Salmonella enterica serotype
enterica, a gram-negative bacillus that is one of the most commonly reported human
isolates of Salmonella in the United States. Salmonella organisms may cause
gastroenteritis, bacteremia, and focal invasive infections, including meningitis and
osteomyelitis. Osteomyelitis is a common and serious infection in children with
hemoglobinopathies, including hemoglobin SS or sickle-cell disease (SCD), hemoglobin
S-thal, hemoglobin SC, or hemoglobin SO Arab. Organisms associated with osteomyelitis in children with
hemoglobinopathies include Gram-positive organisms, such as Staphylococcus aureus. However,
patients with SCD have a significantly higher frequency of osteomyelitis caused by aerobic gram-
negative organisms, most commonly Salmonella species. Other aerobic Gram-negative rods such as
Shigella sonnei, Escherichia coli, Pseudomonas aeruginosa, and Serratia marcescens have also been
isolated from children with SCD and osteomyelitis. The factors that contribute to the increased
incidence of osteomyelitis caused by Salmonella species in patients with SCD include intestinal mucosa
injuries from thrombotic crises that may facilitate entry of Salmonella into the blood stream. When
blood stream infections occur, splenic dysfunction and impaired opsonic activity in these patients may
allow a prolonged or greater magnitude bacteremia. Furthermore, bacteria may also lodge in infarcted
bone of these patients.
In addition to hemoglobinopathies, osteomyelitis, and other extra-intestinal infections caused by

Salmonella species, such as meningitis, may be seen in special hosts with disorders of their intestinal
tract that alter gastric pH or decrease intestinal motility, or who have primary or acquired immune
deficiency disorders or metabolic disorders. Neonates and infants younger than 3 months of age are also
at higher risk for invasive infections with Salmonella (Table).
Acinetobacter baumannii is a Gram-negative, aerobic bacillus, or coccobacillus. It is a major cause of

health-care associated infections and an emerging cause of community-acquired infections. It most
commonly causes infections in patients with a severe, underlying, immune compromising illness, who
also have had invasive instrumentation, such as indwelling catheters or endotracheal intubation. It is not
a cause of focal osteomyelitis in patients with SCD.
Vibrio vulnificus is a nontoxigenic, facultatively-anaerobic, motile Gram-negative bacillus that naturally

inhabits marine environments. It typically causes septicemia and severe, life-threatening wound
infections. Even though this patient has a history of exposure to salt water beaches, the lack of severe
illness or signs of hemorrhagic bullous or necrotic skin lesions makes this organism unlikely.
PREP Pearls
 Salmonella may cause extra intestinal infections in immune compromised hosts.
 Salmonella may cause extra intestinal infections in hosts with Hemoglobinopathies.
 Recognize association of Salmonella osteomyelitis and other extraintestinal infections in certain

hosts (sickle cell disease, galactosemia, iron overload states)
 Know the genetic immunodeficiencies that predispose to severe or disseminated Salmonella

infection
Suggested Readings
 American Academy of Pediatrics. Salmonella infections. In: Pickering LK, Baker CJ, Kimberlin DW,
Long SS, ed. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2012:635-640.
 Ochoa T, Santiseban-Ponce J. Salmonella. In: Cherry JD, Harrison GJ, Kaplan SL, Steinbach W,
Hotez P, ed. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia,
PA: Saunders Elsevier; 2014:1491-1509.
 Sommet J, Missud F, Holvoet L, et al. Morbidity among child travelers with sickle-cell disease
visiting tropical areas: an observational study in a tertiary care center. Arch Dis Child.
2013;98(7):533-536. DOI: 10.1136/archdischild_2012-302500
Question: 7
A 4-year-old girl has recently moved to the area and her mother seeks advice regarding treatment for an
infected cervical lymph node. Approximately 1 year ago, she developed swelling with mild tenderness
just below the angle of her right jaw. After the swelling persisted for about a week, her pediatrician
treated her with a series of unknown antibiotics, totaling about 6 weeks. The swelling gradually
increased in size, and she was referred to an otolaryngologist who removed the node surgically and
treated her with additional unknown antibiotics. Her mother has a pathology report stating that the
excised node showed caseating granulomas.
The mother is concerned because, when her daughter attempts to smile, her right lower lip is higher
than the left lower lip. Otherwise, the girl is healthy. On examination, she has normal movement of her
eyelids, forehead, and mid-face, plus a well-healed, nontender surgical scar on the right neck. When
asked to smile, the only abnormality is a failure of her right lower lip to move downward. The remainder
of her examination is unremarkable.
Of the following, the MOST likely cause of the asymmetric smile is
A. linezolid-associated peripheral neuropathy

B. Mycobacterium avium abscess compressing the facial nerve
C. quinolone-associated tendon rupture
D. staphylococcal abscess compressing the facial nerve
E. surgical damage to facial nerve
Question: 7
A 4-year-old girl has recently moved to the area and her mother seeks advice regarding treatment for an
infected cervical lymph node. Approximately 1 year ago, she developed swelling with mild tenderness
just below the angle of her right jaw. After the swelling persisted for about a week, her pediatrician
treated her with a series of unknown antibiotics, totaling about 6 weeks. The swelling gradually
increased in size, and she was referred to an otolaryngologist who removed the node surgically and
treated her with additional unknown antibiotics. Her mother has a pathology report stating that the
excised node showed caseating granulomas.
The mother is concerned because, when her daughter attempts to smile, her right lower lip is higher
than the left lower lip. Otherwise, the girl is healthy. On examination, she has normal movement of her
eyelids, forehead, and mid-face, plus a well-healed, nontender surgical scar on the right neck. When
asked to smile, the only abnormality is a failure of her right lower lip to move downward. The remainder
of her examination is unremarkable.
Of the following, the MOST likely cause of the asymmetric smile is
A. linezolid-associated peripheral neuropathy
B. Mycobacterium avium abscess compressing the facial nerve

C. quinolone-associated tendon rupture
D. staphylococcal abscess compressing the facial nerve
E. surgical damage to facial nerve
This child has a clinical examination consistent with paralysis of the marginal
mandibular branch of the facial nerve. This branch supplies the muscles of the lower
lip and chin and perhaps is more prone to surgical damage due to its long course,
small diameter, and paucity of anastomoses to other nerve branches. It is the most
common neurologic injury related to surgical treatment for cervical lymphadenitis.
Linezolid has been reported as a rare cause of peripheral neuropathy, and quinolone-
associated tendon rupture does occur although primarily in older adults. Neither is a likely cause in this
case. The child’s age (between 1 and 5 years) and slow progression of disease with no apparent
response to antibiotic therapy, plus histologic features of the excised node, strongly point to
nontuberculous mycobacterial infection as the etiology. However, Staphylococcus aureus is another
common cause of cervical adenitis. Abscess formation from any etiology rarely can compress facial
nerve branches. However, this child does not have signs or symptoms of ongoing infection, so it is
unlikely this would explain her current findings.
The overall prognosis of pediatric lymphadenitis and lymphangitis is excellent, unless treatment is
delayed. Complications seem to be more related to the extent of disease rather than particular patient
ages or type of organism. More indolent infections, such as nontuberculous mycobacteria, seem to be
most associated with complications. Chronic draining fistulae can be problematic with incomplete
treatment of nontuberculous lymphadenitis, due either to the lack of medical or surgical treatment,
needle aspiration without follow-up medical or surgical treatment, or incomplete surgical excision with
or without follow-up treatment. In the published literature, complications from nontuberculous
mycobacterial lymphadenitis are most commonly the result of excision of an infected node. Transient
facial nerve paresis may occur in up to 30% of children undergoing cervical node excision; this
complication is less likely when curettage rather than total excision is performed. Permanent facial
nerve paralysis is much less common. Wound infection caused by a different organism (eg, S aureus) has
been reported to occur in up to 14% of these children, leading some otolaryngologists to prescribe
routine post-operative anti-staphylococcal therapy. Recurrence also is somewhat common (5%-10%),
due either to incomplete excision of a nontuberculous node or to new abscess formation with S aureus.
Clearly, surgical therapy should be avoided if possible, but debate continues on whether medical
therapy alone for nontuberculous adenitis (following diagnosis by fine needle aspiration) achieves
equivalent outcomes. In terms of children with more acute, purulent infections, one retrospective study
suggested that those who presented with fluctuance or had prior emergency department visits were
more likely to receive surgical drainage.
Serious suppurative complications, such as sepsis, mycotic aneurysm, or septic embolus, are very
uncommon.
PREP Pearls
 Complications of lymphadenitis/lymphangitis are related to location of infection, extent of

involvement, and surgical interventions needed.
 Recognize the complications and sequelae of lymphadenitis/lymphangitis according to age,

clinical manifestations, and organisms (eg, fistulae, facial nerve palsy, postoperative)
Suggested Readings
 Healy CM, Baker CJ. Cervical lymphadenitis. In: Cherry JD, Harrison GJ, Kaplan SL, Steinbach WJ,
Hotez PJ, ed. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia,
 Lindeboom JA, Kuijper EJ, van Coppenraet ESB, Lindeboom R, Prins JM. Surgical excision versus
antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a
multicenter, randomized, controlled trial. Clin Infect Dis. 2007;44(8):1057-1064. DOI:
10.1086.512675.
 Lindeboom JA. Surgical treatment for nontuberculous mycobacterial (NTM) cervicofacial

lymphadenitis in children. J Oral Maxillofac Surg. 2012;70(2):345-348. DOI:
10.1016/j.joms.2011.02.034
 Parker NP, Scott AR, Finkelstein M, et al. Predicting surgical outcomes in pediatric cervicofacial
nontuberculous mycobacterial lymphadenitis. Ann Otol Rhinol Laryngol. 2012;121(7):478-484.
Question: 8
A physician from the university health center calls to discuss an outbreak of conjunctivitis among
students. The health center staff has evaluated 10 students with complaints of itching and burning
beneath the eye lid and photophobia. On physical examination of these students, the most common
findings have been large oval follicles within the conjunctiva (Figure 1). There is minimal exudate and
vision does not appear to be affected.
Of the following, the MOST likely cause of conjunctivitis is:
A. Adenovirus
B. Haemophilus influenzae
C. Enterovirus
D. Herpes simplex virus
E. Streptococcus pneumonia
Question: 8
A physician from the university health center calls to discuss an outbreak of conjunctivitis among
students. The health center staff has evaluated 10 students with complaints of itching and burning
beneath the eye lid and photophobia. On physical examination of these students, the most common
findings have been large oval follicles within the conjunctiva (Figure 1). There is minimal exudate and
vision does not appear to be affected.
Of the following, the MOST likely cause of conjunctivitis is:
A. Adenovirus
C. Enterovirus
D. Herpes simplex virus

E. Streptococcus pneumoniae
Epidemic keratoconjunctivitis is a rapidly developing follicular conjunctivitis with little

exudate. Follicular keratoconjunctivitis usually indicates infection with a viral or
intracellular agent (e.g., Chlamydia trachomatis) or less commonly, a drug reaction.
The most common cause of epidemic keratoconjunctivitis is adenovirus, serotype 8.
Patients complain of a itching and burning behind the eyelid, similar to the discomfort
associated with a foreign body. Edema and photophobia are present as well as large
oval follicles within the conjunctiva. Preauricular adenopathy and corneal pseudomembrane formation
may also be present. Children are more likely to have symptoms of a concomitant upper respiratory
infection and/or pharyngitis and have corneal complications as compared to adults. No specific medical
therapy decreases the symptoms or shortens the duration of disease but patients need to understand
that the eye can be affected for 2-3 weeks, and sometimes longer.
In any outbreak of conjunctivitis, direct inoculation from infected hands is the most important
mechanism of spread, whether in the healthcare setting (especially newborn intensive care units and
ophthalmology and optometry offices, but also nursing homes, other critical care units, and other
venues) or elsewhere. A study of the incidence of epidemic keratoconjunctivitis in Korea before, during,
and after the H1N1 pandemic noted a 44.9% decrease in cases of epidemic keratoconjunctivitis during
the H1N1 pandemic compared to the 5 previous years (mean number of cases annually pre-pandemic
was 54,711). Strikingly, this decrease was largest among those aged 10 years to 19 years (62%,
compared to 29% to 44% in all other age groups). The authors propose that aggressive hand hygiene
education promoted and adopted during the H1N1 pandemic resulted in decreased spread of
adenovirus. Contact with an infected person is a recognized risk factor for college and university
pneumococcal epidemic conjunctivitis (as are contact lens use, belonging to a sports team, and living in
or attending parties at a fraternity or sorority house), as well. Similarly, outbreaks of conjunctivitis
among soldiers (including one involving 6,378 affected personnel) emphasize the importance of close
contact in the spread of these infections.
The most important risk factor for healthcare-associated epidemic keratoconjunctivitis is exposure to an
infected individual. However, exposure to contaminated fomites, such as the retractors used to spread
the eyelids of neonates during ophthalmologic examination or treatment, as a cause of epidemic
conjunctivitis is well-recognized. Also, drops instilled into eyes may become contaminated and spread
infection. Finally, ophthalmologic procedures and use of equipment are recognized sources of infection.
Outbreaks have been associated with examinations, tonometry, optical coherence tomography, excimer
laser photorefractive surgery, and laser photocoagulation, among others. The importance of appropriate
infection–prevention and sterilization techniques cannot be overemphasized. However, hand hygiene
remains the mainstay of prevention of epidemic keratoconjunctivitis.
Among the bacterial causes of epidemic conjunctivitis, Streptococcus pneumoniae and Haemophilus
influenzae are the most common. The clinical presentation with either of these agents is characterized
by conjunctival hyperemia, edema, mucopurulent exudate and eye lids that stick together after sleeping
(Figure 2). Gram stain and culture of the exudate are helpful establishing the diagnosis and
differentiating the causative agent. Conjunctivitis due to bacterial agents usually responds to warm
compresses and the application of topical antimicrobial agents. In addition to S pneumoniae and H
influenzae, rare case reports describe nursery outbreaks of conjunctivitis due to Staphylococcus aureus,
Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa. A published report of
epidemic keratoconjunctivitis showed methicillin-resistant S aureus among neonates, infants, and young
children in the hospital setting. Further, a series has been reported of cases of microsporidial
conjunctivitis, caused by Vittaforma corneae, in bathers in hot springs.
Conjunctivitis due to Herpes simplex virus (HSV) is most associated with blepharitis and tender
preauricular lymphadenopathy. While the conjunctiva may appear edematous, there is rarely a
purulent discharge. Vesicular lesions may be found on the lid margins and/or on the periorbital skin.
This may occur in a primary or recurrent infection of HSV. HSV conjunctivitis can be missed without slit
lap examination and the use of fluorescein stain (Figure 3). Care should be taken with dealing with HSV
ocular infections and consultation with an ophthalmologist is usually warranted. Treatment depends on
the presence or absence of corneal involvement and which layer of the cornea is involved. Oral
antivirals (e.g., acyclovir) with one of a number of topical antiviral agents (e.g., 1% trifluridine, 0.1%
iododeoxyuridine, 3% vidarabine) are usually used. Topical corticosteroids by themselves are
contraindicated but may be used in conjunction with antiviral agents by an ophthalmologist.
Epidemics of hemorrhagic conjunctivitis caused by enteroviruses may occur (e.g., enterovirus 70,
cosackievirus A24). The explosive epidemics occur mainly via eye-hand-fomite-eye transmission. A
sudden onset of severe eye pain with photophobia, blurred vision, lacrimation, conjunctival erythema,
lid edema, preauricular adenopathy and in some cases subconjunctival hemorrhages and superficial
punctate keratitis (Figure 4). Eye discharge can become purulent due to secondary bacterial infections.
Treatment is supportive.
PREP Pearls
 Hand hygiene is the most important measure to prevent epidemic conjunctivitis.
 The most common causes of epidemic keratoconjunctivitis is adenovirus serotype 8.
 Outbreaks of epidemic keratoconjunctivitis are most frequently spread by contaminated hands,

fomites, and ophthalmologic tools and equipment.
 Recognize which viral and bacterial pathogens and situations are associated with epidemics of
conjunctivitis (eg, adenoviral infections, nosocomial transmission by contaminated eye devices,
S. pneumoniae)
Suggested Readings
 Fan NW, Wu CC, Chen TL, et al. Microsporidial keratitis in patients with hot springs exposure. J
Clin Microbiol. 2012;50(2):414-418. DOI: 10.1128./JCM.05007-11
 Kim HS, Choi HC, Cho B, Lee JY, Kwon MJ. Effect of the H1N1 influenza pandemic on the
incidence of epidemic keratoconjunctivitis and on hygiene behavior: a cross-sectional study.
PLoS ONE. 2011;6(8):e23444. DOI: 10.1371/journal.pone.0023444
 Richards A, Guzman-Cottrill JA. Conjunctivitis. Pediatrics in Review. 2010;31(5):196-208. DOI:

10.1542/pir.31-5-196
July
Search
Question: 1
The director of a long-term care facility, housing mostly children with severe neurodevelopmental
disabilities, is uncertain of infectious disease risks associated with use of medical devices in such
settings.
Of the following, the MOST common cause of medical device-associated infection in such facilities is
A. bloodstream infection
B. cytomegalovirus
C. hepatitis A virus
D. hepatitis B virus
E. urinary tract infection
Question: 1
The director of a long-term care facility, housing mostly children with severe neurodevelopmental
disabilities, is uncertain of infectious disease risks associated with use of medical devices in such
settings.
Of the following, the MOST common cause of medical device-associated infection in such facilities is
A. bloodstream infection
B. cytomegalovirus
C. hepatitis A virus
D. hepatitis B virus
E. urinary tract infection

Very little information is known about the prevalence of infectious diseases in children who reside
in facilities with special needs. In fact, the American Board of Pediatrics Infectious Diseases Exam
Content Specifications suggests that hepatitis A and B, diarrhea, and cytomegalovirus infections are
acquired in excess of the general population, but this statement is not supported by current evidence.
Harris cites data from an otherwise unpublished abstract showing that device-associated infections are
common, with the frequency and type of infection correlated with the number of devices used per
patient, as well as the type of long term care facility. Otherwise, most available information about
infectious disease risk in such facilities is found in studies of nursing homes for the elderly, which have
many differences from facilities for children. According to a 2006 report by Harris, urinary tract
infection is the most common device-related nosocomial infection in children, followed by catheter-
related bloodstream infection and ventilator-associated lower respiratory tract infection. However,
these data sources included patients in typical pediatric intensive care unit settings, so they may not
accurately reflect extended care facility infection rates.
In the past, hepatitis B and other infections may have been more prevalent in such pediatric facilities,
but no evidence currently supports this. Documented infection outbreaks in pediatric long term care
facilities are similar to those seen in acute care hospitals: influenza, adenovirus, and human
metapneumovirus are examples of infectious disease outbreaks in pediatric long term care facilities in
the past decade.
Little guidance exists for infection control practices in pediatric long term care facilities. Guzman-
Cottrill et al published pediatric specific guidelines, but they pertain more to residential facilities (eg,
Ronald MacDonald House) than to facilities for the handicapped. The Society for Healthcare
Epidemiology of America (see Smith et al in the Suggested Reading) publishes guidelines that deal
primarily with adult facilities, although the document states they are applicable to pediatric facilities as
well. A clear need exists for better evidence to support infection prevention and control in pediatric
long term care facilities for those with special needs.
PREP Pearls
 Specific infection risks for children in facilities for those with special needs is largely unknown.
 These risks likely vary widely based on patient population served.
 Society for Healthcare Epidemiology of America guidelines for infection control in long term
care facilities and in family-centered pediatric residential facilities can help mitigate infection
risk.
 Know what diseases children in facilities for the handicapped acquire in excess of the general
population (eg, hepatitis A and B, diarrhea, CMV)
Suggested Readings
 Guzman-Cottrill JA, Ravin KA, Bryant KA, Zerr DM, Kociolek L, Siegel JD. Infection prevention
and control in residential facilities for pediatric patients and their families. Infect Control Hosp
Epidemiol. 2013;34(10):1003-1041. DOI: 10.1086/673141
 Harris JS. Infection control in pediatric extended care facilities. Infect Control Hosp Epidemiol.
2006;27(6):598-603. DOI: 10.1086/504937
 Johnston J, Loeb M. Epidemiology and prevention of infections in residents of long-term care
facilities. In: Mayhall CG, ed. Hospital Epidemiology and Infection Control. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2012:1452-1461.
 Smith PW, Bennett G, Bradley S, et al. SHEA/APIC guideline: infection prevention and control
in the long-term care facility. Am J Infect Control. 2008;36(7):504-35. DOI:
10.1016/j.ajic.2008.06.001
Question: 2
An 8-year-old girl, who emigrated with her family from Central America, presents with seizures. An
imaging study of the brain is performed and shown in the Figure. You plan treatment for this child.
Of the following, the MOST appropriate drug for treatment of this infection is
A. mebendazole
B. nitazoxanide
C. paromomycin
D. praziquantel
E. triclabendazole
Question: 2
An 8-year-old girl, who emigrated with her family from Central America, presents with seizures. An
imaging study of the brain is performed and shown in the Figure. You plan treatment for this child.
Of the following, the MOST appropriate drug for treatment of this infection is
A. mebendazole
B. nitazoxanide
C. paromomycin
D. praziquantel
E. triclabendazole
Correct
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Average Percent Correct:50.35%
e40f3ffd-08fe-4701-b407-51443ec1822d
Praziquantel or albendazole are used to treat central nervous system disease caused by
cysticercosis. Albendazole is preferred over praziquantel because of fewer interactions with
anticonvulsant agents and dosing for praziquantel is based on data for treatment of other helminthic
infections for children older than 4 years of age. Praziquantel is an antihelminthic drug used to treat
various diseases caused by flatworms, including: hydatid disease (caused by tapeworms of the genus
Echinococcus), cysticercosis (pork tapeworm, Taenia solium), schistosomasis (trematodes of the
genus Schistosoma), clonorchiasis (Chinese live fluke, Clonorchis sinensis), paragonimiasis (lung
flukes, most of the species Paragonimus westermani), and fasciolopsiasis (intestinal fluke, Fasciolopsis
buski). Praziquantel does not kill developing worms. Therefore, treatment administered within 4 to 8
weeks of exposure should be repeated 4 to 8 weeks later. Praziquantel should be taken with liquids
during a meal. Adverse events experienced by patients treated with praziquantel usually include
manifestations of the release of the parasites as they are killed and the host‘s immune response. The
adverse events become more frequent and severe when the parasite burden is greater. Adverse
events experienced by patients receiving praziquantel include those localized to:
· Gastrointestinal tract (abdominal pain or cramps, with or without nausea and vomiting, diarrhea
[sometimes bloody])
· Liver (transient increases in liver enzymes [alanine aminotransferase, aspartate aminotransferase],
but not liver failure)
· Skin (rash, urticaria, pruritus)
· Blood (eosinophilia)
· Central nervous system (dizziness, headache, somnolence, vertigo, worsening of pre-existing
neurological problems, seizures, meningismus)
Other reported adverse events include myalgia, arthralgia, fever, hypotension, and cardiac
arrhythmias. In patients with multiple lesions, pretreatment with steroids and anticonvulsants is
recommended. Treatment is controversial for patients with only a single lesion.
Mebendazole is used to treat angiostrongyliasis, eosinophilic colitis due to Ancylostoma caninum,

pinworms (Enterobius vermicularis), trichinellosis (Trichinella spiralis), and Trichuris trichiura.
Nitazoxanide is used to treat cryptosporidiosis and giardiasis. Paromomycin is used to treat
asymptomatic carriers of Entamoeba histolytica, and is used for treatment of dientamebiasis.

Triclabendazole is used for treatment of the sheep liver fluke(Fasciola hepatica).

PREP Pearls
 Praziquantel is an antihelminthic drug used to treat neurocysticercosis, schistosomiasis,

hydatid disease, and other worm infestations.
 Adverse events experienced by patients treated with praziquantel usually are manifestations of
the release of the parasites as they are killed and the host‘s immune response.
 Know the indications for the use of praziquantel (eg, neurocysticercosis, fluke infestation,
schistosomiasis, tapeworm infestation)
Suggested Readings
 American Academy of Pediatrics. Drugs for parasitic infections. In: Pickering LK, Baker CJ,
Kimberlin DW, Long SS, ed. Red Book: 2012 Report of the Committee on Infectious Diseases.
29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012:848-868.
 Bradley JS, Nelson JD, Kimberlin DW, et al. Alphabetic listing of antimicrobials. Nelson’s
Pediatric Antimicrobial Therapy, 19th ed. Elk Grove Village, IL: American Academy of
Pediatrics; 2012:135-163.
 Cappello M, Schantz PM, White AC Jr. Taenia solium, Teania asiatica, and Taenia Satinate
(taeniasis and cystercercosis). In: Long SS, Pickering LK, Prober CG, ed. Principles and
Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier;
2012:1350-1356.
Question: 3
A 3-year-old child is admitted to the pediatric intensive care unit (PICU) with fever. His past medical
history is significant for prematurity and short gut syndrome as a result of necrotizing enterocolitis in
the neonatal period. He receives total parenteral nutrition at home by broviac catheter. Upon
admission to the PICU, the child is not responsive except to painful stimuli. On physical examination
he is mottled, with capillary refill of more than 5 seconds. His blood work reveals a peripheral white
blood cell count of 1500/µL (1.5 x 109/L) with 15% bands, 45% polymorphonuclear leukocytes, 20%
monocytes, and 20% lymphocytes, hemoglobin is 9.8 g/dL (98 g/L), and platelet count of 25 × 103/µL
(25 x 109/L). His systolic blood pressure is less than 50 mm Hg. Within 3 hours, the microbiology
laboratory calls to say that the admission blood culture is growing a Gram negative rod. The pediatric
infectious disease team is consulted to assist in the management of this child.
Of the following, the finding MOST likely to also be present in this patient is
A. elevated mean arterial pressure
B. hyperactive bowel sounds
C. hyperlactemia
D. hypochloremic metabolic alkalosis
E. hypoglycemia
Question: 3
A 3-year-old child is admitted to the pediatric intensive care unit (PICU) with fever. His past medical
history is significant for prematurity and short gut syndrome as a result of necrotizing enterocolitis in
the neonatal period. He receives total parenteral nutrition at home by broviac catheter. Upon
admission to the PICU, the child is not responsive except to painful stimuli. On physical examination
he is mottled, with capillary refill of more than 5 seconds. His blood work reveals a peripheral white
blood cell count of 1500/µL (1.5 x 109/L) with 15% bands, 45% polymorphonuclear leukocytes, 20%
monocytes, and 20% lymphocytes, hemoglobin is 9.8 g/dL (98 g/L), and platelet count of 25 × 103/µL
(25 x 109/L). His systolic blood pressure is less than 50 mm Hg. Within 3 hours, the microbiology
laboratory calls to say that the admission blood culture is growing a Gram negative rod. The pediatric
infectious disease team is consulted to assist in the management of this child.
Of the following, the finding MOST likely to also be present in this patient is
A. elevated mean arterial pressure
B. hyperactive bowel sounds
C. hyperlactemia
D. hypochloremic metabolic alkalosis
E. hypoglycemia
Correct
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8c26c73b-e2c8-4286-9662-1d3601eaf074
The child is this vignette has Gram negative septic shock, likely from catheter-related infection.
Expected findings in a child with septic shock include an elevated lactic acid level (hyperlactemia with
a level > 1 mmol/L), hyperglycemia (a serum glucose of > 140 mg/dL [7.8 mmol/L] in the absence of
diabetes), metabolic acidosis, arterial hypotension with a mean arterial pressure (MAP) of less than 70
mm Hg, absent bowel sounds (ie, ileus), and, without a history of significant vomiting or electrotype
loses, a normal serum chloride level. The preferred response for the child in the vignette is C,
hyperlactemia. Hypoglycemia is mostly to occur in a neonate with sepsis or shock.
The pathophysiology of septic shock is highly complex and is related to actions of endogenous
mediators as a result of systemic inflammatory response to infection (Table 1) and the metabolic
derangements are numerous. Septic shock results in a cascade of events that is intertwining, with
production of 1 cytokine stimulating the synthesis of others; synergistic in that some cytokine activity
acts in concert with another; and sometimes antagonistic, with the production of inhibiting or
competing cytokines. Cytokines modulate the balance between humoral and cell-based immune
responses, they regulate the maturation, growth, and responsiveness of particular cell populations,
and some cytokines enhance or inhibit the action of other cytokines. The same cytokines that are
meant to protect the host, at high levels, result in systemic vasodilation (hypotension), diminished
myocardial contractility, widespread endothelial injury and activation, cause systemic leukocyte
adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, and
culminate in disseminated intravascular coagulation (DIC). The hypoperfusion resulting from the
combined effects of widespread vasodilation, myocardial pump failure, and DIC lead to multi-organ
system failure that affects the liver, kidneys, and central nervous system, among others. Unless the
underlying infection is rapidly brought under control, the patient usually dies.
Cytokines include chemokines, interferons, interleukins, lymphokines, tumor necrosis factor, and are
produced by macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells,
fibroblasts, and various stromal cells. A given cytokine may be produced by more than 1 type of cell
and often act through toll-like receptors. Toll-like receptors (TLRs) are a class of proteins that play a
key role in the innate immune system by recognizing molecules that are broadly shared by pathogens,
collectively referred to as pathogen-associated molecular patterns, but distinguishable from host
molecules. Once microbes breach physical barriers such as the skin, mucous membranes, and
respiratory or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell
responses, including cytokines. There are over 10 known TLRs in humans and each receptor has a
specific molecular activation trigger. Tumor-necrosis factor (TNF) or cachectin, a polypeptide hormone,
appears to be 1 of the key cytokines mediating septic shock; it is stimulated by lipopolysaccharides,
C5a, viruses, and enterotoxins, among other agents and is synthesized by a wide variety of cells such
as monocytes, macrophages, natural killer cells, microglial cells, and hepatic Kuffer cells. The TNF
stimulates the production of mediators: interleukin-1, interleukin-6, eicosanoids, and platelet-
activating factor, which lead to a cascade of events causing tissue and endothelial cell injury.
Bacteremia may be caused by a wide variety of Gram positive and Gram negative microorganisms,
and may or may not be associated with a specific focus of infection, such as meningitis or pneumonia.
In otherwise healthy children beyond the newborn age, Streptococcus pneumonia, Haemophilus
influenzae type b (in unimmunized children), Staphylococcus aureus, group A Streptococcus, Neisseria
meningitidis, and Salmonella species are the most common microorganisms. Children hospitalized, as
well as those with underlying illnesses that depress the immune system and host response to
infection, may develop infection with these same microorganisms, as well as infections from
Enterobacteriaceae, coagulase-negative staphylococci, and fungi. Indwelling vascular catheters,
endotracheal tubes, and urinary catheters, as well as other foreign material, may further predispose
children to infection. Children with severe immunosuppression from HIV/AIDS are also at increased
risk for bacterial infection and bacteremia caused by Gram negative bacilli, especially Pseudomonas
aeruginosa. Therefore, the initial selection of antibiotics for administration to a child with suspected
bacteremia is based upon the clinical situation (Table 2). A recent study questioned the use
aminoglycoside therapy for Gram negative bacteremia in pediatric patients and found that the use of
β-lactam monotherapy reduced subsequent nephrotoxicity without compromising survival. Other
therapies for shock include intensive care monitoring, ventilator and inotropic support, fluid and
electrolyte management, in addition to antimicrobial therapy. A recent meta-analysis found that the
fluid bolus may be harmful compared to no bolus in children with septic shock. Further studies are
needed to assist providers determining who could potentially be harmed by the provision of bolus
fluids and who will benefit. Corticosteroids, insulin, and immunoglobulin may play a role in the
management of certain patients.
PREP Pearls
 The pathophysiology of septic shock is highly complex and is related to actions of endogenous
mediators as a result of systemic inflammatory response to infection.
 The initial selection of antibiotics for administration to a child with suspected bacteremia is
based upon the clinical situation.
 Know the metabolic derangements associated with shock

 Plan the anti-infective and supportive therapies of shock
Suggested Readings
 Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines
for management of severe sepsis and septic shock, 2012. Intensive Care Med.
2013;39(2):165-228. DOI: 10.1007/s00134-012-2769-8
 Ford N, Hargreaves S, Shanks L. Mortality after fluid bolus in children with shock due to sepsis
or severe infection: a systematic review and meta-analysis. PLoS One. 2012;7(8):e43953.
DOI: 10.1371/journal.pone.0043953
 Menon K, McNally D, Choong K, Sampson M. A systematic review and meta-analysis on the
effect of steroids in pediatric shock. Pediatr Crit Care Med. 2013;14(5):474-480. DOI:
10.1097/PCC.0b013e31828a8125
 Tamma PD, Turnbull AE, Harris AD, Milstone AM, Hsu AJ, Cosgrove SE. Less is more:
combination antibiotic therapy for the treatment of gram-negative bacteremia in pediatric
patients. JAMA Pediatr. 2013;167(10):903-910. DOI: 10.1001/jamapediatrics.2013.196
Question: 4
You are asked to see a 6-year-old boy because he will be traveling with his father next month on a trip
to a polio endemic country. The child‘s father is aware that there have been recent cases of paralytic
polio in the region they plan to visit, and was given an inactivated polio vaccine (IPV) booster
yesterday by his internist. He is now seeking immunization advice from you regarding his son. The
child‘s immunization records indicate that he received doses of IPV at 2 months, 4 months, 14
months, and 5 years of age. The last dose was administered 9 months ago.
Of the following, the MOST appropriate advice to give to the father about the polio vaccination status
of his son is that he has
A. completed the standard IPV series and needs no further doses prior to travel
B. completed the standard IPV series, but should receive a booster dose prior to travel
C. completed the standard IPV series, but should receive 2 booster doses 4 weeks apart prior
to travel
D. not yet completed the standard IPV series and should receive a booster dose prior to travel
E. not yet completed the standard IPV series and should receive 2 booster doses 4 weeks apart
prior to travel
Question: 4
You are asked to see a 6-year-old boy because he will be traveling with his father next month on a trip
to a polio endemic country. The child‘s father is aware that there have been recent cases of paralytic
polio in the region they plan to visit, and was given an inactivated polio vaccine (IPV) booster
yesterday by his internist. He is now seeking immunization advice from you regarding his son. The
child‘s immunization records indicate that he received doses of IPV at 2 months, 4 months, 14
months, and 5 years of age. The last dose was administered 9 months ago.
Of the following, the MOST appropriate advice to give to the father about the polio vaccination status
of his son is that he has
A. completed the standard IPV series and needs no further doses prior to travel
B. completed the standard IPV series, but should receive a booster dose prior to travel
C. completed the standard IPV series, but should receive 2 booster doses 4 weeks apart prior
to travel
D. not yet completed the standard IPV series and should receive a booster dose prior to travel
E. not yet completed the standard IPV series and should receive 2 booster doses 4 weeks apart
prior to travel
Correct
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Individuals at greatest risk for polio infection are those who are unvaccinated. The US Universal
Child And Adolescent Immunization Schedule includes inactivated polio vaccine (IPV) for all infants
and children as part of their routine childhood immunization series. Before traveling to any area with
known wild poliovirus transmission, all travelers should have completed their age-appropriate polio
vaccine series and receive a booster if necessary.
The routine polio vaccination schedule for infants and children in the United States is 4 doses of IPV at
at ages 2 months, 4 months, 6 through 18 months, and 4 to 6 years of age. The final dose should be
given at least 6 months after the previous dose, and after 4 years of age. Infants and children
traveling to areas where wild poliovirus has circulated in the last 12 months should be vaccinated
according to this routine schedule. If travel plans will not allow the standard dosing schedule, an
accelerated immunization schedule can be administered. The first dose of IPV is given any time at or
after 6 weeks of age. Dose 2 can be given 4 weeks after dose 1, and dose 3 given 4 weeks after dose
2. The minimum interval between the third and fourth dose is 6 months. If the schedule is to be
continued outside of the United States, in an affected country, the polio vaccine formulation that is
available on site can be used (either IPV or oral polio vaccine [OPV]). For children traveling for 4
weeks or longer to areas where polio has been identified in the last 12 months, a provisional
recommendation is to give them an extra dose of IPV if their previous dose of vaccine was more than
1 year ago.
Adults who have completed a routine series of polio vaccine are considered to have lifelong immunity,
but evidence-based data to support this assumption are lacking. As a precaution, individuals 18 years
of age and older are recommended to receive a booster IPV dose if they are traveling to a region
where polio has been identified within the past 12 months. Available data do not indicate the need for
more than a single booster dose in the patient‘s lifetime.
Two formulations of polio vaccine are used globally, inactivated polio vaccine (IPV), and live
attenuated polio vaccine (OPV). In the United States, OPV was widely used until 1997, when expanded
use of IPV was first recommended. After a brief transition period that lasted until 2000, IPV became
the only polio vaccine used in the United States.
A trivalent inactivated polio vaccine, IPV is made by harvesting and purifying the viruses from cell
culture supernatants, then inactivating them with formalin. Each polio type (1, 2, and 3) is grown,
harvested, and purified separately, and after tests for residual infectivity, lots from each of the 3 polio
types are combined. Concentrations of the 3 vaccine types are adjusted based on the poliovirus D
antigen, for a final product containing 40 antigen units of polio type 1, 8 of type 2, and 32 of type 3.
Like other inactivated vaccines, a patient‘s individual immune response depends on the antigen
concentration, the number of doses received, and the interval between doses. Inactivated polio
vaccine is highly immunogenic for each of the 3 polio types. In US-based infant clinical vaccine trials,
nearly all infants are seropositive after the second dose. Early clinical vaccine trials have also shown
IPV to be highly effective at preventing polio infection. The original large scale trial in France
demonstrated 80% to 90% efficacy in the prevention of paralytic polio. Later studies in the United
States estimated efficacy at 96% through 2 polio seasons in Houston, TX. Trials in Africa indicate that
single dose efficacy is approximately 36% and 2-dose efficacy is approximately 89%. Neutralizing
antibody levels above the 1:8 dilution are the accepted standard when evaluating immunogenicity
results as a surrogate for protection. Inactivated polio vaccine, unlike OPV, is given by intramuscular
injection. While this route of delivery is highly effective at inducing systemic immunity, injected
vaccine bypasses the gastrointestinal mucosa and the missed opportunity to achieve high level
mucosal immunity.
Oral polio vaccine is a trivalent live attenuated vaccine that also contains vaccine strains of poliovirus
1, 2, and 3. In early studies when monovalent attenuated vaccines were delivered, seroconversion
was found in 80% to 100% of recipients. When the 3 polio vaccine types were combined into a
trivalent preparation, virus replication and subsequent antibody production was consistently lower
than when each was administered separately. When equal amounts of each virus were used in the
early vaccine, poliovirus type 2 showed higher levels of excretion, commensurate with higher serum
antibody levels than serotypes 1 or 3. In the United States, prior to the discontinuation of OPV
altogether in 2000, trivalent OPV contained approximately one log higher virus concentration of types
1 and 3 compared to serotype 2. It has been reasoned that immunity induced by OPV is lifelong
because the attenuated viruses contained in OPV formulations induce humoral immune responses that
are similar to wild type polio, and because wild type polio is believed to induce lifelong immunity. An
advantage of using OPV in areas of the world where wild type polio remains a threat is its ability to
induce local gastrointestinal mucosal immunity, thereby preventing those who are immunized from
carrying, shedding, and transmitting wild type polio.
The most obvious example of OPV effectiveness is its use in the successes of the global polio
eradication campaign, including the entire Western Hemisphere, the Western Pacific, and European
regions, which were certified polio-free in 1994, 2000, and 2002, respectively. Clinical trial efficacy
studies are sparse, but 1 study published in 1991 demonstrated a 3-dose OPV series to be 90%
effective at preventing paralytic polio during an outbreak in Oman.
The rationale for replacing OPV with a complete IPV schedule in the United States was to eliminate the
risk for the development of vaccine-associated paralytic polio (VAPP). Of the 61 cases of VAPP
reported in the United States between 1990 and 2003, 27 occurred in immunologically normal vaccine
recipients, 10 occurred in healthy contacts of immunologically normal vaccine recipients, and 16
occurred in immunodeficient vaccinees or in immune deficient contacts of an immunologically normal
vaccinee.
The global polio eradication initiative has achieved great strides toward global eradication, but wild
poliovirus circulation in Afghanistan, Nigeria, and Pakistan has never been interrupted. Over the last
decade, at least 40 polio-free countries have been affected by polio cases through international travel.
In 2014, at least 10 countries reported active polio transmission, and 4 of those countries (Cameroon,
Equatorial Guinea, Pakistan, and Syria) exported infection to other countries (Figure).
By June of 2014, the US Centers for Disease Control and Prevention (CDC) issued a health alert
providing guidance on new World Health Organization (WHO) polio vaccine requirements for travel by
residents of and long term visitors to countries with active poliovirus transmission.
While only 3 countries remain endemic for polio (Afghanistan, Nigeria, and Pakistan), countries where
wild poliovirus has circulated within the last 12 months have been identified by the WHO and CDC as
potentially high risk for polio exposure, explaining why vaccine recommendations for travelers to these
areas have evolved. Since polio infections and polio outbreaks are an ongoing problem, the specific
countries and areas involved at a given time can shift. For some regions, exit requirements for proof
of polio vaccination at airports and borders exist in an effort to eliminate further exportation. By the
end of 2014, areas identified as high risk because of either polio outbreaks or environmental evidence
of active poliovirus circulation included Cameroon, Ethiopia, Equatorial Guinea, Iraq, Israel, Somalia,
and Syria. Travelers working in health care settings, refugee camps, or other aid settings in these and
neighboring countries might be at risk for exposure to wild type polio and therefore need to have their
immunization status verified and updated as necessary.
Errata: Content revised to fix typographical error. 9/2015

Question: 5
You are consulted on a 6-year-old child admitted to the hospital overnight with high fever up to 39°C,
severe otalgia, and otorrhea. The mother reported that the latter symptoms had been present for
more than 10 days, however, the fever had just started a day prior to admission and she had noted
that the child‘s face looked asymmetric and that there was some drooling. On physical examination,
the child has right-sided peripheral facial palsy. The ear examination is significant for purulent
otorrhea with a swollen tender external auditory canal. It was difficult to visualize the tympanic
membrane, however, the otolaryngology attending was able to clean the canal and reported that the
tympanic membrane looked intact. The history is also significant for juvenile diabetes mellitus
diagnosed 2 years ago, which has not been under good control with an average hemoglobin A1C level
of 9.
Based on the information provided the MOST likely diagnosis in this patient is
A. acute otitis media
B. acute recurrent otitis media
C. chronic suppurative otitis media
D. malignant otitis externa
E. otitis externa
Question: 5
You are consulted on a 6-year-old child admitted to the hospital overnight with high fever up to 39°C,
severe otalgia, and otorrhea. The mother reported that the latter symptoms had been present for
more than 10 days, however, the fever had just started a day prior to admission and she had noted
that the child‘s face looked asymmetric and that there was some drooling. On physical examination,
the child has right-sided peripheral facial palsy. The ear examination is significant for purulent
otorrhea with a swollen tender external auditory canal. It was difficult to visualize the tympanic
membrane, however, the otolaryngology attending was able to clean the canal and reported that the
tympanic membrane looked intact. The history is also significant for juvenile diabetes mellitus
diagnosed 2 years ago, which has not been under good control with an average hemoglobin A1C level
of 9.
Based on the information provided the MOST likely diagnosis in this patient is
A. acute otitis media
B. acute recurrent otitis media
C. chronic suppurative otitis media
D. malignant otitis externa
E. otitis externa
Correct
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4023361d-9239-4129-b905-9855d58f5017
The lack of a history of recurrent ear infections, as well as the appearance of the tympanic
membrane, makes the diagnosis of otitis media, recurrent otitis media, and chronic suppurative otitis
media (CSOM) unlikely. The constellation of high fever, severe otalgia and otorrhea, as well as
involvement of the facial nerve, suggests that the child has more than just a simple otitis externa
(OE). Therefore, malignant otitis externa (MOE) is the most likely diagnosis in this child. The fact that
the child is diabetic further lends support to the diagnosis because diabetes mellitus is by far the most
common predisposing factor, although the disease is more common in adults than in children.
The distinguishing features of OE, MOE, and CSOM are described in the Table. Malignant otitis externa
or necrotizing OE is a result of invasive infection of the bone and cartilage of the external ear canal.
Infection begins in the external auditory canal and extends to the base of the skull through the
fissures of Santorini, which are small perforations in the cartilaginous portion of the canal. A more
accurate description of MOE would be osteomyelitis of the base of the skull following severe OE. The
bones of the skull base become replaced with granulation tissue as the infection spreads. This leads to
bony destruction, often with involvement of the mastoid. The term malignant often used to describe
this entity refers specifically to the severity of the disease. Malignant otitis externa is seen more
frequently in adults than in children, often with predisposing factors (Table). Occasionally, it may be
seen in individuals without any underlying conditions.
Interpretation of the results of external ear cultures requires knowledge of the normal commensal
bacteria of the external ear, as well as the method by which the cultures were obtained (ie, superficial
ear swabs versus cultures obtained after curettage in the otolaryngologist‘s office) so that the
infection can be managed appropriately. The normal flora of the external ear includes coagulase-
negative staphylococci, Micrococcus, α-hemolytic Streptococcus, and Corynebacterium species.
Pseudomonas aeruginosa is usually the causative organism seen in individuals with persistent otorrhea
associated with tympanostomy tubes or with OE associated with swimming. Staphylococcus may also
be seen in these individuals. Both S aureus and Streptococcus pyogenes are usually associated with
the extension of a focal infection. Anaerobic bacteria may be isolated in about a quarter of patients,
therefore both anaerobic and aerobic cultures should be obtained particularly in patients that do not
respond to treatment as expected and in those with chronic or recurrent infections.
Otomycosis may be seen with prolonged use of antibiotics although in general fungi are uncommon
causes of OE. When fungi are the cause of OE, Aspergillus and Candida species are the predominant
fungi seen.
Interpretation of ear swab cultures done in cases of OE should be done with caution, particularly when
the culture results are consistent with normal commensal bacteria of the external auditory canal
(Table). Ideally, cultures of the external ear should be reserved for cases where there is no response
to appropriate topical treatment after more than 2 weeks, when MOE is suspected, after ear surgery,
or when the OE is severe or recurrent.
PREP Pearls
 High fever, otalgia, and otorrhea in a child with any underlying condition such as diabetes,
malignancy, malnutrition, or immune dysfunction should raise the suspicion for malignant or
necrotizing otitis externa.
 This disease entity involves osteomyelitis of the base of the skull and infection of the adjoining
tissues, which is severe.
 The most common causative organism is Pseudomonas aeruginosa, followed by
Staphylococcus aureus.
 Differentiate the clinical manifestations of uncomplicated otitis externa from those of chronic
suppurative otitis media and malignant otitis externa
 Interpret culture results obtained from drainage from the external ear
Suggested Readings
 Adams A, Offiah C. Central skull base osteomyelitis as a complication of necrotizing otitis

externa: imaging findings, complications and challenges of diagnosis. Clin Radiol.
2012;67(10):e7-e16. DOI: 10.1016/j.crad.2012.02.004
 Boyce TG. Otitis externa and necrotizing otitis externa. In: Long SS, Pickering LK, Prober CG,
ed. Principles and Practice of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: Saunders
Elsevier; 2012:220-222.
 Hobson CE, Moy JD, Byers KE, Raz Y, Hirsch BE, McCall AA. Malignant otitis externa: evolving
pathogens and implications for diagnosis and treatment. Otolaryngol Head Neck Surg.
2014;151(1):112-116. DOI: 10.1177/0194599814528301
 Llor C, McNulty CAM, Butler C. Ordering and interpreting ear swabs in otitis externa. BMJ.
2014;g5259:349. DOI: 10.1136/bmj.g5259
Question: 6
While on infectious disease rounds in the pediatric intensive care unit (PICU), a discussion ensues
about the clinical utility of nonculture fungal assays for the diagnosis of invasive fungal infections.
If a pretest likelihood of invasive candidiasis is 3% in the PICU and the nonculture fungal assay test
has a sensitivity of 80% and a specificity of 70%, the positive predictive value of the assay is
A. 8%
B. 23%
C. 55%
D. 80%
E. 99%
Question: 6
While on infectious disease rounds in the pediatric intensive care unit (PICU), a discussion ensues
about the clinical utility of nonculture fungal assays for the diagnosis of invasive fungal infections.
If a pretest likelihood of invasive candidiasis is 3% in the PICU and the nonculture fungal assay test
has a sensitivity of 80% and a specificity of 70%, the positive predictive value of the assay is
A. 8%
B. 23%
C. 55%
D. 80%
E. 99%
Correct
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The positive predictive value (PPV) is 8%.
Nonculture diagnosis may identify invasive fungal disease currently unrecognized or missed by
conventional testing, as well as eliminate overtreatment; nonculture assays also may expand our
understanding of disease spectrum. The clinical utility of nonculture diagnostic tests is determined by
the pretest likelihood of invasive disease in a typical intensive care unit and the sensitivity and
specificity of that assay. The positive predictive value, which is the probability that a patient with a
positive test truly has the disease, and negative predictive value, which is the probability that a
patient with a negative test does not have the disease, can then be determined.
Use the following 2 x 2 tables, you can easily calculate the positive predictive value and negative
predictive value of this assay because you are given in the vignette the sensitivity, specificity, and
pretest likelihood of disease. Table 1 shows this calculation.
Table 1.
Disease present Disease absent

Test + A B
Test - C D
Sensitivity = A ÷ (A + C), which is the percentage of all with disease present who have a positive test.
Specificity = D ÷ (B + D), which is the percentage of all with a negative test who also have disease
absent.
Positive predictive value = A ÷ (A + B)
Negative predictive value = D ÷ (C + D)
The pretest likelihood of invasive fungal disease in the vignette is 3%. Therefore, out of 1,000
patients, 30 patients will have invasive candidiasis; this is the number of patients with disease
present. The number of patients with disease absent is 1,000 minus 30 or 970, as shown in Table 2.
Table 2.

N=30 N=970
Test + A B
Test - C D
Knowing that the sensitivity of the assay is 80% allows for the calculation of A to be determined. A is
the number of patients with both a positive test and disease present. The calculation is: A= 80% of
the disease present. In other words, A= .80 x 30, which equals 24 (A is a true positive). C is the
number with a negative test and disease present; C= 30 minus A, or C=6 (C is a false negative). This
is shown in Table 3.
Table 3.

N=30 N=970
Test + A=24 B
Test - C=6 D
Knowing that the specificity is 70%, B and D can likewise be calculated. D is the number with a
negative test and disease absent; D = 70% times the number with disease absent. In other words, D
= .70 x 970, or D equals 679 (D is a true negative). B is the number with a positive test and disease
absent; B= 970 minus D, or B= 291 (B is a false positive) (Table 4).
Table 4.

N=30 N=970
Test + A=24 B=291
Test - C=6 D=679
Now the calculation of the PPV and the negative predictive value (NPV) can be obtained:
Positive predictive value = A ÷ (A + B) = 24 ÷ (24+291) = 24 ÷ 315 = 8%.

Positive predictive value is the probability that subjects with a positive screening test truly have the
disease.
Negative predictive value = D ÷ (C + D) = 679 ÷ (6 + 679) = 679 ÷ 685 = 99%. Negative predictive
value is the probability that subjects with a negative screening test truly don't have the disease.
If the pretest likelihood increases to 10%, the PPV and NPV can be calculated. Again, the 2 x 2 table
can be used to calculate these values, with 1,000 patients (Table 5).
Table 5.

N=100 N=900
Test + A=80 B=270
Test - C=20 D=630
Positive predictive value = A ÷ (A + B) = 80 ÷ (80 +270) = 80 ÷ 350 = 23%.
Negative predictive value = D ÷ (C + D) = 630 ÷ (20 + 630) = 630 ÷ 650 = 97%.
The PPV improves to 23% whereas the NPV remains 97%. The low PPV results would therefore limit
this nonculture test as a definitive diagnostic invasive fungal infection assay and limit its ability to be
used to make anti-fungal therapy recommendations solely on test results. Thus, a positive assay
result must be interpreted judiciously.
Invasive fungal infections (IFIs) constitute a serious threat to an ever-growing population of

immunocompromised individuals and other individuals at risk. Invasive aspergillosis (IA) occurs in 8%
to 15% of patients undergoing allogenic stem cell transplantation and in 5% to 15% of patients
undergoing stem cell transplantation. Despite advances in therapy, IA is associated with significant
morbidity and mortality, ranging from 30% to 70% in transplant recipients. The diagnosis of IFIs,
including IA is challenging, because clinical and radiographic signs are nonspecific or very insensitive,
and traditional methods like culture, histopathology, and radiology that are still considered the gold
standards, have low sensitivity. Attempts have also been made to predict susceptibility to fungal
disease in high risk patients with limited success. Biopsy with histopathologic analysis is often not
possible in patients suspected of pulmonary aspergillosis because of the increased bleeding risk, and
blood cultures for invasive candidiasis (IC), IA, or other IFIs are limited by poor sensitivity and slow
turnaround time. Radiographic testing is often used to predict IFIs, but suffers from an inability to
differentiate pathogens and does not generally provide certainty of an IFI diagnosis. Early diagnosis of
IFIs is desired because it would lead to prompt institution of appropriate therapy and improved patient
outcomes.
The desire for early and certain diagnosis of IFIs underscores the need for novel means of detecting
fungal infectious agents, and has led to the development of the nonculture fungal assays. Nonculture
fungal assays include mannan antigen/anti-mannan immunoglobulin G testing for invasive candidiasis,
polymerase chain reaction (PCR), galactomannan, and 1-3-D-β- glucan assays (Table 6). All are
intended as detection tests, but may also be employed as biomarkers to assess a patient‘s risk of IC,
IA, or IFIs when considering anti-fungal prophylaxis.
The nonculture fungal assays represent tools with promise, but are fraught with variable sensitivity
and specificity for the rapid diagnosis of IFIs (Table 7); better standardization of these methods is
still required for their routine clinical use. Likely reasons for the differences in sensitivity and
specificity between studies are that different thresholds were considered positive, different assays
were used, patient populations varied, and study design was not uniform. Despite the substantial
heterogeneity among different studies, the 1-3-β-D-glucan assay has good accuracy for distinguishing
patients with proven or probable invasive fungal infections from patients without invasive fungal
infection. Polymerase chain reaction is a very appealing technology for the detection of human
pathogens, but the detection of fungal pathogens is particularly challenging. Fungi have cell walls that
impede the efficient lysis of organisms and liberation of DNA, which can lead to false negative PCR
results. Conversely, some human pathogens are also ubiquitous environmental saprophytes that can
contaminate PCR reagents and cause false positive results. Each test must be considered in the
context of the pretest likelihood that a disease is present in the patient being tested. Therefore, the
PPV is useful in helping to interpret test results. Perhaps the most helpful alternative use of the
nonculture assays is employment of the NPV to rule out invasive fungal infection and justify stopping
unnecessary prophylactic or empiric antifungal therapy.
Additional assays are needed and there are many considerations that must be taken into account
when developing a non-culture fungal assay (Table 8). Newer assays are in study, and early results
demonstrate that fluorescence in situ hybridization (FISH) procedures for the direct identification of
invasive fungal infections in blood cultures and cerebrospinal fluid (CSF) samples may be a valuable
tool for the identification of invasive mycoses in the future. Polymerase chain reaction and other
molecular approaches, such as matrix-assisted laser desorption ionization (MALDI) have proved
promising in clinical trials, but still need to undergo standardization before their clinical use can
become widespread.
PREP Pearls
 Nonculture fungal assays include mannan antigen/anti-mannan immunoglobulin G testing for

invasive candidiasis, polymerase chain reaction, galactomannan, and 1-3-D-ß- glucan assays.
All are intended as detection tests, but may also be employed as biomarkers to assess a
patient‘s risk of invasive candidiasis, invasive aspergillosis, and invasive fungal infection when
considering anti-fungal prophylaxis.
 The nonculture fungal assays represent tools with promise, but are fraught with variable
sensitivity and specificity for the rapid diagnosis of invasive fungal infections; better
standardization of these methods is still required for their routine clinical use.
 A helpful use of the nonculture fungal assays is employment of the negative predictive value
to rule out invasive fungal infection and justify stopping unnecessary prophylactic or empiric
antifungal therapy.
 Know the sensitivity and specificity of methods other than culture to identify fungus (PCR,
galactomannan, antigen testing)
Suggested Readings
 Clancy CJ, Nguyen MH. Finding the "missing 50%" of invasive candidiasis: how nonculture
diagnostics will improve understanding of disease spectrum and transform patient care. Clin
Infect Dis. 2013;56(9):1284-1292. DOI: 10.1093/cid/cit006
 He S, Hang JP, Zhang L, Wang F, Zhang DC, Gong FH. A systematic review and meta-analysis
of diagnostic accuracy of serum 1,3-Beta-d-glucan for invasive fungal infection: focus on
cutoff levels. J Microbiol Immunol Infect. 2014. DOI: 10.1016/j.jmii.2014.06.009
 Lamoth F, Cruciani M, Mengoli C, et al. Beta-Glucan antigenemia assay for the diagnosis of
invasive fungal infections in patients with hematological malignancies: a systematic review
and meta-analysis of cohort studies from the Third European Conference on Infections in
Leukemia (ECIL-3). Clin Infect Dis. 2012;54(5):633-643. DOI: 10.1093/cid/cir897
 Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum 1,3-ß-D-glucan for
pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic
review and meta-analysis. J Clin Microbiol. 2012;50(1):7-15. DOI: 10.1128/JCM.05267-11
 Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan
assay: a meta-analysis. Clin Infect Dis. 2006;42(10):1417-1727. DOI: 10.1086/503427
 Rex JH. Galactomannan and the diagnosis of invasive aspergillosis. Infect Dis.
2006;42(10):1428-1430.
Question: 7
A pediatrician from the Midwest calls you in September about an unusually high number of infants
with respiratory illness that their practice has seen in the last 2 weeks. The clinical presentation
includes copious rhinorrhea, nasal congestion, cough, wheezing, and tachypnea. Patients typically
manifest fever over 38.5°C for the first 48 hours. She believes that there may be an ongoing
community outbreak and wants to know which virus is the most likely cause.
Of the following, the MOST likely viral etiology in these patients is
A. adenovirus
B. coronavirus
C. parainfluenza
D. respiratory syncytial virus
E. rhinovirus
Question: 7
A pediatrician from the Midwest calls you in September about an unusually high number of infants
with respiratory illness that their practice has seen in the last 2 weeks. The clinical presentation
includes copious rhinorrhea, nasal congestion, cough, wheezing, and tachypnea. Patients typically
manifest fever over 38.5°C for the first 48 hours. She believes that there may be an ongoing
community outbreak and wants to know which virus is the most likely cause.
Of the following, the MOST likely viral etiology in these patients is
A. adenovirus
B. coronavirus
C. parainfluenza
D. respiratory syncytial virus
E. rhinovirus
Correct
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83ad90ad-16e2-48b0-9945-7d2403c1260c
The patients described in the vignette have viral bronchiolitis and based on the time of year (ie,
early fall), parainfluenza is the most likely etiology. Though many viruses cause bronchiolitis (Table
1), parainfluenza has the ability to cause epidemics in the early spring and fall, and type 3 is
associated with bronchiolitis in infants and young children. Although adenovirus circulates throughout
the year without a distinct seasonal peak, it is an uncommon cause of bronchiolitis. Human
coronavirus (HCoV) is a common cause of upper respiratory infection in young children, and is a less
frequent cause of bronchiolitis, croup, and pneumonia in infants, and immunocompromised children
and adults. A self-limited illness that peaks on day 3 to 4, HCoV occurs annually in the winter and
early spring in temperate climates.
Rhinovirus is the most frequent cause of rhinosinusitis and can be associated with pharyngitis, acute
otitis media, and lower respiratory tract infections including bronchiolitis and pneumonia. Transmission
occurs throughout the year and peaks in autumn and spring. Rhinovirus is detected in half of all
children with asthma who present with an exacerbation during the peak seasons. Although rhinovirus
is a known cause of bronchiolitis, it is not the most likely cause in the setting of an outbreak.
Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants and young
children overall. Annual epidemics occur in the winter and early spring months in temperate climates.
Therefore, RSV would not be the most likely cause of a bronchiolitis outbreak in the fall.
Most children become infected with RSV during the first year of life and infection is universally
expected by 2 years of age. The majority of disease occurs in the upper respiratory tract, and
approximately 20% to 30% of patients develop lower tract disease including bronchiolitis or
pneumonia. Common presenting symptoms include tachypnea, wheezing, and cough. Physical
examination findings often include nasal flaring, crackles on auscultation, and use of accessory
muscles. Imaging may show hyperinflation, atelectasis, or peribronchial thickening, and right upper
lobe collapse. Most previously healthy infants and children do not require hospitalization, but
approximately 1% to 3% are hospitalized annually. When hospitalization does occur, it is typically less
than 5 days in duration.
There are a few noninfectious disease processes that may mimic bronchiolitis (Table 2). Congenital
diaphragmatic hernia has presented with cough and wheezing, leading to initial misdiagnosis.
Additionally, foreign body aspiration may present with cough, wheeze, and hyperinflation (typically
unilateral) on chest radiograph. Certain anatomic abnormalities may also lend themselves to an initial
appearance of bronchiolitis. Neonates with an anomalous coronary artery may present with
diaphoresis, irritability, and evidence of congestive heart failure, while infants may have poor feeding,
dyspnea, wheezing, and pallor. Other vascular anomalies include vascular rings. Patients with vascular
rings may present with symptoms of airway obstruction (eg, stridor) and swallowing difficulty in older
infants and children who are taking in solid foods. Finally, congenital pulmonary airway malformation
(CPAM) is caused by malformation of the bronchopulmonary foregut. The diagnosis is commonly made
during antenatal ultrasonography, but may not be made until the infant presents with progressive
respiratory distress.
PREP Pearls
 While the most common cause of bronchiolitis overall is respiratory syncytial virus,
parainfluenza type 3 is a more common cause in the autumn.
 Several congenital malformations can mimic bronchiolitis in infants, including vascular rings,
congenital diaphragmatic hernia, and an anomalous coronary artery.
 Identify the most likely etiologic agents in a patient in whom bronchiolitis is suspected, based
on age and season
 Formulate a differential diagnosis in a patient in whom bronchiolitis is suspected, including
infectious and noninfectious entities
Suggested Readings
 American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, Baker CJ,
Kimberlin DW, Long SS, ed. Red Book: 2012 Report of the Committee on Infectious Diseases.
 Angelini P. Coronary artery anomalies; an entity in search of an identity. Circulation.
2007;115(10):1296-1305. DOI: 10.1161/CIRCULATIONAHA.106.618082
 Martin ET, Kuypers J, Wald A, Englund JA. Multiple versus single virus respiratory infections:
viral load and clinical disease severity in hospitalized children. Influenza Other Respir Viruses.
2012;6(1):71-77. DOI: 10.1111/j.1750-2659.2011.00265.x
 Meissner HC. Bronchiolitis. In: Long SS, Pickering LK, Prober CG, ed. Principles and Practice of
Pediatric Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone Elsevier; 2013:231-
234.
Question: 8
You are caring for a 1-year-old boy with Escherichia coli urosepsis. Antibiotics have been initiated and
include gentamicin at a dose of 7.5 mg/kg per day (2.5 mg/kg per dose every 8 hours). A trough level
checked prior to the fourth dose is reported as 3.0 micrograms/mL.
Of the following, the MOST appropriate next step regarding gentamicin dosing is
A. administer a higher dose, but maintain the same dosing schedule
B. administer a lower dose, but maintain the same dosing schedule
C. administer the same dose and the same dosing schedule
D. administer the same dose, but change the dosing schedule to be every 12 hours
E. administer the same dose, but change the dosing schedule to be every 24 hours
Question: 8
You are caring for a 1-year-old boy with Escherichia coli urosepsis. Antibiotics have been initiated and
include gentamicin at a dose of 7.5 mg/kg per day (2.5 mg/kg per dose every 8 hours). A trough level
checked prior to the fourth dose is reported as 3.0 micrograms/mL.
Of the following, the MOST appropriate next step regarding gentamicin dosing is
A. administer a higher dose, but maintain the same dosing schedule
B. administer a lower dose, but maintain the same dosing schedule
C. administer the same dose and the same dosing schedule
D. administer the same dose, but change the dosing schedule to be every 12 hours
E. administer the same dose, but change the dosing schedule to be every 24 hours
Correct
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c2a654c6-b75f-4590-a8c6-db7b2563d881
Aminoglycoside antibiotics such as gentamicin are generally initiated at a dose of 7.5 mg/kg per
day (2.5 mg/kg per dose every 8 hours). A trough serum concentration checked prior to the fourth
dose is used to assess for possible drug accumulation and related toxicity. Elevated trough
concentrations (> 2 micrograms/mL for gentamicin and tobramycin, > 10 micrograms/mL for
amikacin) are suggestive of drug accumulation; the interval between doses of the aminoglycoside is
generally increased in response (eg, maintaining the same dose of the drug but increasing the interval
between doses, such that the total daily dose is decreased). With the patient in the vignette, the
dosing of gentamicin was initiated at 2.5 mg/kg per dose every 8 hours for a total daily dose of 7.5
mg/kg per day. In response to a serum trough concentration greater than 2.0 mg/mL, the dosing
schedule of gentamicin could be decreased to every 12 hours (with the original dose of 2.5 mg/kg per
dose) to result in a lower total daily dose (5.0 mg/kg per day). In general, decreasing the dose but
maintaining the dosing schedule is not implemented in response to a high serum trough concentration.
Also, decreasing the dosing schedule from every 8 hours to every 12 hours is generally utilized (and
the serum trough concentration is rechecked) before increasing the dosing interval to every 24 hours.
Maintaining or increasing the total daily dose (eg, by administering the same dose at the same dosing
level or by administering a higher dose but maintaining the same dosing schedule) would not be an
appropriate response to the elevated serum trough concentration. If the serum trough concentration is
low, a reasonable response would be to increase the dose by 10% (while maintaining the same dosing
interval), and to recheck the serum trough concentration. The peak serum concentration is generally
checked half an hour to 1 hour after the third dose to ensure that this concentration is in a therapeutic
and safe range. If the peak serum concentration is low, the dosage generally is increased and the
peak serum concentration is rechecked after the third dose of the new dosing regimen.
Nephrotoxicity and ototoxicity are the major toxicities associated with aminoglycoside therapy. With
regard to the potential for nephrotoxicity, blood urea nitrogen and creatinine measurements should be
obtained regularly during therapy, in addition to serum peak and trough aminoglycoside
concentrations. Nephrotoxicity is dose dependent. Ototoxicity may manifest itself as cochlear damage
(tinnitus or high frequency hearing loss) or vestibular toxicity (vertigo, nystagmus, and ataxia).
Damage may be unilateral or bilateral. The ototoxicity may be reversible or permanent. Factors
associated with an increased risk of ototoxicity include longer courses of aminoglycoside therapy and
impaired renal function. Ototoxicity is primarily associated with elevated trough concentrations.
PREP Pearls
 Once aminoglycoside antibiotics such as gentamicin are initiated, a trough serum

concentration is checked prior to the third dose and is used to assess for possible drug
accumulation and related toxicity.
 Nephrotoxicity and ototoxicity are the major toxicities associated with aminoglycoside therapy.
 Plan dosage adjustment of aminoglycoside for a patient for given peak and trough serum
concentrations
 Recognize the toxicities of aminoglycoside therapy (ototoxicity, nephrotoxicity)
Suggested Readings
 American Academy of Pediatrics. Adverse reactions to antimicrobial agents. In: Bradley JS,
Nelson JD, Kimberlin DW, et al, ed. 2012-2013 Nelson’s Pediatric Antimicrobial Therapy. 19th
ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012:183.
 Bradley JS, Long SS. Principles of anti-infective therapy. In: Long SS, Pickering LK, Prober CG,
ed. Principles and Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders
Elsevier; 2012:1412-1421.
August
Question: 1
You are seeing a previously healthy, but unimmunized, 4-month-old infant with a 3-day history of
fever, vomiting, and watery diarrhea. There are no sick contacts in the household, but the infant
attends daycare 3 days each week where the other children often have minor illnesses. You explain to
the mother that her infant most likely has rotavirus infection given the lack of immunization.
Of the following, the MOST appropriate diagnostic test to confirm your clinical suspicion of rotavirus
gastroenteritis is
A. serum anti-rotavirus immunoglobulin A titer
B. serum anti-rotavirus immunoglobulin G titer
C. serum anti-rotavirus immunoglobulin M titer
D. stool rotavirus antigen test
E. stool viral culture
Question: 1
You are seeing a previously healthy, but unimmunized, 4-month-old infant with a 3-day history of
fever, vomiting, and watery diarrhea. There are no sick contacts in the household, but the infant
attends daycare 3 days each week where the other children often have minor illnesses. You explain to
the mother that her infant most likely has rotavirus infection given the lack of immunization.
Of the following, the MOST appropriate diagnostic test to confirm your clinical suspicion of rotavirus
gastroenteritis is
A. serum anti-rotavirus immunoglobulin A titer
B. serum anti-rotavirus immunoglobulin G titer
C. serum anti-rotavirus immunoglobulin M titer
D. stool rotavirus antigen test
E. stool viral culture
Correct
View Peer Results
34d5c19a-3c84-4452-9b67-f4b9ccd1d75f
The clinical triad of fever, vomiting, and watery diarrhea in an unimmunized 4-month-old infant
is characteristic of, but not specific for, rotavirus infection. In early epidemiologic studies, electron
microscopy was used to confirm the diagnosis because the virus has a characteristic appearance and
is shed in very high numbers. In the clinical virology laboratory, this labor-intensive technique has
been replaced by various rotavirus antigen detection assays. Rotavirus infection can also be diagnosed
serologically, but results are difficult to interpret in infants because of the presence of maternally
derived anti-rotavirus immunoglobulin G (IgG). Serologic testing for rotavirus-specific IgG can be very
helpful in epidemiologic studies on seroprevelance.
The sensitivity of rotavirus-specific immunoglobulin M (IgM) and immunoglobulin A (IgA) assays are
also quite good. The IgA detection assays were widely used during clinical vaccine trials to document
seroconversion to live attenuated rotavirus vaccines, but rotavirus-specific IgA or IgM testing has
never been widely used as a diagnostic study. Techniques to isolate rotavirus from stool samples using
tissue culture methods have been established, but most clinical virology laboratories do not attempt to
do so, relying instead on rapid turnaround, easy-to-perform antigen detection methods.
At the present time, enzyme-linked immunosorbent assay (ELISA) is the only rapid antigen test
available for the diagnosis of rotavirus infection. For rotavirus, rapid assays have excellent sensitivity
and specificity, especially the commercial kits that utilize monoclonal antibody for detection. One
problem that has been recognized when newborn stool is tested is false positivity with some ELISA
kits.
Antigen detection methods are available for many viruses. Their primary advantage is that they are
quite rapid compared to traditional cell culture methods. Antigen tests are also available for viruses
that are difficult, impractical, or impossible to cultivate in the laboratory (such as rotavirus).
Generally, for cultivatable viruses, antigen detection tests are less sensitive than optimized culture,
but do have very high specificity. In the clinical laboratory, viral antigen testing may be done using
direct immunofluorescence (DFA), indirect immunofluorescence (IFA), or ELISA.
The Figure shows 3 examples of solid phase ELISA test results. In each case, a biologic sample
obtained from the patient (such as stool or respiratory secretions) is added to a solid phase membrane
impregnated with antibody specific for an antigen of interest. The top image demonstrates a positive
test result for rotavirus from a stool sample. Rotavirus-specific antibody in the membrane ―captures‖
the rotavirus antigen from the patient‘s stool sample, and because of the presence of a colorimetric
indicator, the antigen-antibody complex is seen as a pink line. Every solid phase ELISA also requires
an internal control to be sure each of the reagents is working as expected. In the top panel, the blue
line represents that control.
The middle panel, left side shows solid phase ELISA results obtained from a respiratory sample. In this
test, the solid phase of the ELISA has been separated into 2 wells. The top well contains a membrane
impregnated with influenza A-specific antibody, and the bottom well contains a membrane
impregnated with influenza B-specific antibody. Here the patient‘s sample can be tested
simultaneously for the presence of antigen against both major influenza types. The small dot at the
center of each of the wells in this case represents the internal control. The test shown on the left side
is therefore read as negative. In contrast, the influenza ELISA shown on the right side shows
triangular shaped results in both the top and bottom wells indicating the presence of both influenza A
and influenza B specific antigen. This sample is read as positive for both influenza A and influenza B.
The bottom panel shows a positive ELISA test for respiratory syncytial virus (RSV) antigen. Here, a
plus sign indicates a positive test result for RSV. The horizontal bar of the plus sign represents the
control, while the vertical bar of the plus sign is only visible if RSV antigen is present in the test
sample. The presence of both horizontal and vertical bars are visualized as a ―plus sign‖ and the test is
read as positive for detection of RSV antigen. A negative test result would show only the horizontal
line, as if indicating a ―minus, or negative‖ sign. In that case, the test result would be negative.
Direct fluorescent antibody testing uses virus-specific monoclonal antibody labeled with fluorescein
dye to detect the presence of a viral antigen. The staining procedure is often completed in 30 min. For
indirect immunofluorescence tests, unlabeled antibody is used first. Unbound antibody is washed away
before a labeled secondary (indirect) antibody is added. The incubations, washes, and microscopic
evaluation take 2 to 3 hours before a result is available. The DFA was first used in the clinical virology
laboratory to detect herpes simplex virus (HSV), and remains a sensitive and specific diagnostic assay
today in that context. Similarly, DFA remains an excellent tool for detecting varicella zoster virus
(VZV), a virus that is much more difficult than HSV to culture. Antigen testing for the detection of
cytomegalovirus (CMV) also remains available, including tests to determine CMV antigenemia.
The DFA, IFA, and ELISA are also available for the detection of common respiratory viral pathogens
such as RSV and influenza virus, however, the recent availability and widespread use of nucleic acid
amplification tests with very high sensitivity and specificity for the detection of more than a dozen
respiratory viruses simultaneously, often with a turnaround time of less than 2 hours, has reduced
enthusiasm for the use of antigen assays in large clinical virology laboratories. Antigen detection
assays to confirm RSV or influenza are, however, still widely used in primary care offices, particularly
when confirmation of a suspected viral diagnosis could impact patient care. For example, the rapid
point-of-care confirmation of influenza infection may help to reduce the need for additional diagnostic
testing in a febrile child, may assist in a decision to prescribe antiviral medication, or may influence
decisions regarding antiviral prophylaxis in household exposures. Antigen tests are less expensive and
require little training to perform accurately when compared with the nucleic acid-based testing.
Latex agglutination (LA) has been used primarily for the detection of rotavirus, although similar assays
are available for HSV and adenovirus. For the detection of rotavirus, LA has lower sensitivity than
ELISA.
Most clinical virology laboratories have transitioned from antigen-based testing to nucleic acid
amplification testing methods for respiratory virus diagnostics. Similar amplification tests that can
detect nucleic acid from a battery of potential stool pathogens (including rotavirus) are emerging, but
have not yet replaced the more traditional rapid ELISA (antigen) tests for the diagnosis of rotavirus
gastroenteritis.
PREP Pearls
 Antigen-based testing for the diagnosis of rotavirus infection remains the gold standard.
 The etiology of a respiratory viral infection can often be confirmed with rapid antigen testing,
but in large diagnostic laboratories, antigen testing is being replaced by the more sensitive
nucleic acid based amplification tests.
 Know the advantages (eg, speed, less concern for specimen handling, cost) and disadvantages
of rapid antigen detection of virus (eg, false positive and false negative results)
 Know the suspected diagnoses for which antigen detection of virus is the preferred laboratory
test (eg, rotavirus diarrhea, respiratory syncytial virus bronchiolitis/pneumonia)
Suggested Readings
 Gautam R, Lyde F, Esona MD, Quaye O, Bowen MD. Comparison of Premier™ Rotaclone®,
ProSpecT™, and RIDASCREEN® rotavirus enzyme immunoassay kits for detection of rotavirus
antigen in stool specimens. J Clin Virol. 2013;58(1):292-294. doi:10.1016/j.jcv.2013.06.022
 Humphries RM, Miller MJ. Viral laboratory diagnosis. In: Cherry J, Demmler-Harrison GJ,
Kaplan SL, Steinbach WJ, Hotez P, eds. Feigin and Cherry‘s Textbook of Pediatric Infectious
Diseases. 7th ed. Philadelphia, PA: Saunders Elsevier; 2014:3600-3620 .
 Liu J, Kabir F, Manneh J, et al. Development and assessment of molecular diagnostic tests for
15 enteropathogens causing childhood diarrhoea: a multicentre study. Lancet Infect Dis.
2014;14(8):716-724. doi:10.1016/S1473-3099(14)70808-4
Question: 2
You evaluate a 6-month-old, otherwise healthy female infant who is departing in 4 weeks for an
extended stay in a developing country with her parents who will be doing missionary work. The infant
has received immunizations through 4 months of age, but no other medications since birth. At the
visit, you plan to give her routine 6 month immunizations, in addition to measles-mumps-rubella
(MMR) vaccine, and meningococcal conjugate vaccine. Immune prophylaxis with intramuscular
immune globulin (IG) for hepatitis A is also discussed.
Of the following, the MOST accurate statement regarding the relative contraindication to MMR vaccine
in conjunction with IG is
A. administer IG and MMR vaccine at the same time
B. defer IG for 1 week following MMR vaccine
C. defer IG for 2 weeks following MMR vaccine
D. defer MMR vaccine for 3 months following IG
E. defer MMR vaccine for 5 months following IG

Question: 2
You evaluate a 6-month-old, otherwise healthy female infant who is departing in 4 weeks for an
extended stay in a developing country with her parents who will be doing missionary work. The infant
has received immunizations through 4 months of age, but no other medications since birth. At the
visit, you plan to give her routine 6 month immunizations, in addition to measles-mumps-rubella
(MMR) vaccine, and meningococcal conjugate vaccine. Immune prophylaxis with intramuscular
immune globulin (IG) for hepatitis A is also discussed.
Of the following, the MOST accurate statement regarding the relative contraindication to MMR vaccine
in conjunction with IG is
A. administer IG and MMR vaccine at the same time
B. defer IG for 1 week following MMR vaccine
C. defer IG for 2 weeks following MMR vaccine
D. defer MMR vaccine for 3 months following IG
E. defer MMR vaccine for 5 months following IG
Correct
View Peer Results
2620902b-40a5-4b44-8337-1be8ea46ea23
The infant in the vignette is traveling to a developing country that can be presumed to pose high
risk for measles and hepatitis A acquisition. Measles vaccine is recommended for any child 6 months
of age or older who will be traveling internationally and a second dose is recommended for children
older than 12 months of age who have received the first dose, provided 28 days have passed. While
hepatitis A typically causes subclinical disease in infants and young children, these children serve as a
reservoir, spreading infection to their adult caretakers. Thus, it is also important to consider hepatitis
A prophylaxis with immune globulin (IG) in an infant who is too young to be immunized. The timing of
measles-mumps-rubella (MMR) vaccine and hepatitis A prophylaxis is an important consideration
during visits for pre-travel counseling. The MMR vaccine should be given at least 2 weeks prior to IG
to elicit an adequate immune response. Antibodies to MMR are likely present in IG preparations, and
thus providing IG too soon after MMR vaccine will potentially decrease the host‘s ability to elicit the
appropriate immune response. Alternatively, if a child has received recent IG for a diagnosis requiring
IG (eg, Kawasaki disease) a longer period of time should elapse prior to MMR vaccination (Table 1).
Further, if a child has received IG related to hepatitis A exposure or previous international travel, 3
months should elapse before MMR vaccine is provided. While the corresponding answer choice (D) is a
correct statement, it does not apply to the infant in the vignette, as this infant has no prior travel
history and has not received IG in the past. Additionally, the MMR vaccine should not be given
simultaneously with IG and MMR should be preferentially given over IG for any infant who is 6 months
of age and will be traveling internationally, even if the date of departure is less than 2 weeks away,
preventing provision of IG.
There are several other contraindications, relative contraindications, and precautions for the MMR
vaccine (Table 2). Some true contraindications to MMR vaccine include: anaphylaxis from a previous
dose of measles vaccine in a patient with a positive skin test result to measles vaccine or known
measles immunity, known T-cell lymphocyte or mixed T- and B-cell lymphocyte deficiencies, severe
immune suppression, current treatment for malignancy, immune suppression following solid organ or
bone marrow transplant, or immune suppression for a rheumatologic diagnosis. Temporary
contraindications include high dose (2 mg/kg) corticosteroid use for 14 days or longer in the last
month, current serious illness, pregnancy, and current or recent IG therapy. There are a few
precautions related to MMR vaccine, including significant thrombocytopenia related to a previous dose
of MMR vaccine and previous anaphylaxis to gelatin or topical neomycin. For the latter, consultation
with an allergist should occur and vaccine should be provided in a controlled setting. Finally, situations
arise in which concern is present regarding whether MMR vaccine should be provided, but no
contraindication exists. These situations include children with mild to moderate illness, siblings or
parents of a child with a high risk condition (eg, HIV or leukemia), history of seizures, and allergies to
eggs, chickens, or feathers.
PREP Pearls
 True contraindications to measles-mumps-rubella (MMR) vaccine include: anaphylaxis from a

previous dose of measles vaccine in a patient with a positive skin test result to measles
vaccine or known measles immunity, known T-cell lymphocyte or mixed T- and B-cell
lymphocyte deficiencies, severe immune suppression related to HIV infection, current
treatment for malignancy, immune suppression following solid organ or bone marrow
transplant, or immune suppression for a rheumatologic diagnosis.
 Temporary contraindications include high dose (2 mg/kg) corticosteroid use for 14 days or
more in the last month, current serious illness, pregnancy, and current or recent immune
globulin therapy.
 The MMR vaccine is not contraindicated in children with mild to moderate illness, siblings or
parents of a child with a high risk condition (eg, HIV or leukemia), history of seizures, and
allergies to eggs, chickens, or feathers.
 Know the contraindications and precautions for measles immunization, including

administration during concurrent illness
Suggested Readings
 American Academy of Pediatrics. Active Immunization. In: Kimberlin DW, Brady MT, Jackson
MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed.
Elk Grove Village, IL: American Academy of Pediatrics; 2015:39. American Academy of
Pediatrics. Active Immunization. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red
Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL:
American Academy of Pediatrics; 2015:39.
http://redbook.solutions.aap.org/chapter.aspx?sectionid=88186980&bookid=1484
 US Centers for Disease Control and Prevention. General recommendations on immunizations:
epidemiology and prevention of vaccine-preventable diseases. US Centers for Disease Control
and Prevention website. http://www.cdc.gov/vaccines/pubs/pinkbook/genrec.html
Question: 3
The Department of Pediatrics at your hospital hosts a quarterly joint fellow conference with the
Divisions of Infectious Diseases, Hematology/Oncology, and Allergy/Immunology. The next conference
topic involves the role white blood cells play in normal and abnormal immune response to disease. In
preparation for the conference, you divide up the pediatric fellows into 5 teams. Each team is to
prepare a short presentation about their assigned white blood cell (WBC)'s function, and choose a
team name that best exemplifies their WBC's function. One group of fellows is named "The Activation
Team."
Of the following, the WBC MOST likely requiring activation to function is the
A. basophil
B. eosinophil
C. macrophage
D. natural killer cell
E. neutrophil
Question: 3
The Department of Pediatrics at your hospital hosts a quarterly joint fellow conference with the
Divisions of Infectious Diseases, Hematology/Oncology, and Allergy/Immunology. The next conference
topic involves the role white blood cells play in normal and abnormal immune response to disease. In
preparation for the conference, you divide up the pediatric fellows into 5 teams. Each team is to
prepare a short presentation about their assigned white blood cell (WBC)'s function, and choose a
team name that best exemplifies their WBC's function. One group of fellows is named "The Activation
Team."
Of the following, the WBC MOST likely requiring activation to function is the
A. basophil
B. eosinophil
C. macrophage
D. natural killer cell
E. neutrophil
Correct
View Peer Results
046324fe-6999-4a24-b748-357487c0fc60
Macrophages are classified into 2 groups, designated M1 and M2 macrophages, and require
activation to function (Figure 1). None of the other white blood cells, basophils, eosinophils,
neutrophils, or lymphocytes, require activation in order to function. Macrophage activation function
significantly influences the quality, duration, and magnitude of most inflammatory reactions.
Traditionally, macrophages have been described as antigen-presenting phagocytes that secrete pro-
inflammatory and antimicrobial mediators. Macrophages also possess the unique ability to metabolize
the amino acid arginine to result in inflammation and tissue destruction (by using arginine to produce
nitric oxide, or wound healing and anti-inflammation (by using arginine to produce the repair
molecule, ornithine.It is now better understood that multiple macrophage phenotypes carry out
different functions. M1 classically activated macrophages exhibit a T helper 1 (Th1)-like phenotype,
promoting inflammation, extracellular matrix (ECM) destruction, and apoptosis, while M2 alternatively
activated macrophages display a T helper 2 (Th2)-like phenotype, promoting ECM construction, cell
proliferation, and angiogenesis. Although both phenotypes are important components of the innate
and adaptive immune systems, the M1 macrophage tends to elicit chronic inflammation and tissue
injury, whereas the M2 macrophage tends to resolve inflammation and facilitate wound healing
(Table).
Macrophages are white blood cells produced by the differentiation of monocytes in tissues. Monocytes
originate in the bone marrow from a common hematopoietic stem cell. They undergo differentiation
steps during which they commit to the myeloid and then to the monocyte lineage. In response to
macrophage colony-stimulating factor, they divide and differentiate into monoblasts and then
promonocytes before becoming monocytes, which exit the bone marrow and enter the bloodstream.
The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue.
Monocytes migrate to different tissues, where they replenish tissue-specific macrophages (Figure 2).
The macrophage's basic role is to phagocytize bacteria and damaged tissue, as well as to debride
damaged tissue through the release of proteases.
Macrophages derive their name from the Greek words makros (large) and phagein (to eat); they are
found in essentially all tissues, where they search for potential pathogens and play a critical role in
digesting cellular debris, foreign substances, microbes, and cancer cells in the process called
phagocytosis. As prodigious phagocytic cells, macrophages clear approximately 2 × 10 11 erythrocytes
each day; this equates to almost 3 kg of iron and hemoglobin per year. This clearance process is a
vital metabolic contribution without which the host would not survive. Macrophages are also involved
in the removal of cellular debris that is generated during tissue remodeling, and rapidly and efficiently
clear cells that have undergone apoptosis. The primary role of macrophages is not to function as an
elite immune effector cell, but instead as a common janitorial cell, the main function of which is to
clear the interstitial environment of extraneous cellular material. Necrosis that results from trauma or
stress also generates cellular debris that must be cleared by macrophages. The debris from necrosis is
loaded with endogenous danger signals, such as heat-shock proteins, nuclear proteins, histones, DNA
and other nucleotides, and components of the ECM that are cleaved by cellular proteases, usually
resulting in no harm to the host.
The M1 macrophage is interferon-γ (IFN-γ)-dependent for activation; this Th1-type response to

infection with intracellular pathogens is a well-established feature of cellular immunity. Differentiation
of M1 classically activated macrophages requires a priming signal; when the primed macrophage
subsequently encounters an appropriate stimulus, such as bacterial lipopolysaccharide, it becomes
classically activated. Pathogens and pathogen components are subsequently taken up by phagocytosis
and delivered to lysosomes where they are exposed to a variety of degradation enzymes. M1
macrophage activation depends on the products of specifically activated Th1-type lymphocytes and
natural killer (NK) cells, in particular IFN-γ, and a cytokine network involving interleukin-12 (IL-12)
and IL-18, which are produced by antigen-presenting cells. Release of these molecules is important for
host defense and direction of the adaptive immune system.
Differentiation of M2 alternatively activated macrophages does not require priming; M2 macrophage

activation occurs from stimuli of the Th2-type cytokines, mediated by IL-4 and IL-13, acting through a
common receptor chain, IL-4 Rα. Similar to the M1 macrophage, the M2 macrophage changes its
cellular morphology and secretory pattern as a result of appropriate stimulation. During cell injury,
sources of innate IL-4 production include basophils, mast cells, and granulocytes; these cells can also
produce IL-4 in response to chitin, a structural biopolymer that is found in some fungi and parasites.
Within 2 days at a wound site, neutrophils are replaced by monocytes that mature, along with IL-4,
into M2 macrophages programmed to promote wound healing. By the third to fourth day, M2
macrophages begin to secrete growth factors and other cytokines to attract cells involved in the
proliferation stage of healing to the area; M2 macrophages are also further stimulated by IL-4 to
convert arginine to ornithine, a precursor of polyamines and collagen, thereby contributing to the
production of the ECM. M2 macrophages contribute to fibrin dissolution and the removal of dead tissue
while simultaneously producing factors that induce and speed angiogenesis, regulate fibroblast
recruitment and connective-tissue remodeling, stimulate cells to re-epithelialize the wound, create
granulation tissue, and lay down a new ECM. These Th2-type immune responses are primarily induced
in response to disturbances at mucosal surfaces, particularly important in the lung and intestines; they
can also occur in nonmucosal tissues, especially in response to helminth infections.
In their role as a phagocytic immune cell, macrophages are responsible for engulfing pathogens to
destroy them. Some pathogens subvert this process by disrupting or redirecting IFN-γ signaling or by
inhibiting phagosome–lysosome fusion in macrophages; this disruption allows organisms to live and
replicate inside the macrophage, staying hidden from the immune system. Examples of pathogens
that can evade phagocytosis and remain latent within the macrophage include Mycobacterium
tuberculosis, Leishmania species, chikungunyavirus, adenovirus, and Brucella species. Tuberculosis,
leishmaniasis, and brucellosis are examples of diseases well known for the latency of infection. Local
joint inflammation during and after the acute phase of chikungunya virus infection is felt to be due to
the ability of the virus to evade phagocytosis within macrophages. Adenovirus can remain latent in
host macrophages of the eye, leading to continued viral shedding 6 to 18 months after initial infection
in a patient with epidemic keratoconjunctivitis.
In addition to its beneficial activities, the macrophage has been implicated as a key mediator in the
pathogenesis of disease. By eliciting massive leukocyte infiltration and flooding the surrounding tissue
with inflammatory mediators, pro-apoptotic factors, and matrix degrading proteases, the macrophage
is capable of inflicting serious injury to tissues. Tissue destruction perpetrated by chronic inflammation
has been associated with the development of tumors, autoimmune diseases, including rheumatoid
arthritis and inflammatory bowel disease, glomerulonephritis, promotion of allergy and asthma, as
well as tissue fibrosis that occurs during chronic schistosomiasis from the uncontrolled activation of
wound-healing macrophages. Macrophages are present, and are occasionally abundant, in a range of
tumors; further studies are required to isolate tumor-associated macrophages, to characterize them
phenotypically, and to establish whether they contribute to tumor progression and metastasis.
Question: 4
Increasing blood culture contamination rates at your hospital have prompted the institution of several
quality control measures. One of these measures has been a system-wide educational intervention for
the nurses, phlebotomy teams, and the resident staff.
Of the following, the statement that BEST describes the current state of knowledge regarding blood
culture contamination is
A. alcohol-based chlorhexidine gluconate has been associated with lower contamination rates
compared to povidone-iodine preparations
B. as many as 40% of skin-associated bacteria survive disinfection because they are located in
the deeper layers of the skin
C. povidone-iodine preparations require 30 seconds, whereas iodine tincture requires 1.5 to 2

min of contact time to produce maximal antiseptic effect
D. studies have shown an increase in the rate of contamination with the use of the two-needle
as opposed to the single-needle technique
E. use of dedicated phlebotomy teams increases blood culture contamination rates as opposed
to those collected by nursing staff
Question: 4
Increasing blood culture contamination rates at your hospital have prompted the institution of several
quality control measures. One of these measures has been a system-wide educational intervention for
the nurses, phlebotomy teams, and the resident staff.
Of the following, the statement that BEST describes the current state of knowledge regarding blood
culture contamination is
A. alcohol-based chlorhexidine gluconate has been associated with lower contamination rates
compared to povidone-iodine preparations
B. as many as 40% of skin-associated bacteria survive disinfection because they are located in
the deeper layers of the skin
C. povidone-iodine preparations require 30 seconds, whereas iodine tincture requires 1.5 to 2

min of contact time to produce maximal antiseptic effect
D. studies have shown an increase in the rate of contamination with the use of the two-needle
as opposed to the single-needle technique
E. use of dedicated phlebotomy teams increases blood culture contamination rates as opposed
to those collected by nursing staff
Correct
View Peer Results
a570d227-1d73-4ec6-a465-723836254b23
Blood culture contamination continues to be a vexing problem. The accepted benchmark for
blood culture contamination rates in the hospital setting is between 2% to 3%. However, published
studies show that rates of contamination depend on the methods used for selection, as well as the
site. Rates vary between institutions and have been reported to be up to 6%, while contamination
rates in emergency departments have been reported as high as 11%. Blood culture contamination is
an even bigger challenge in the pediatric population where adequate volumes, as well as multiple
blood cultures, may be difficult to obtain.
There are multiple reasons attributable for blood culture contamination and different methods have
been employed to reduce contamination rates. As many as 20% of skin bacteria are located in the
deeper layers of the skin where antiseptics used for preparation of venipuncture sites cannot
penetrate. Time of contact to provide maximal antiseptic effect also seems to play a role in decreasing
contamination rates. Povidone-iodine (PI) preparations require 1.5 to 2 min of contact time, whereas
iodine tincture (alcoholic solution of elemental iodine and potassium iodide) requires approximately 30
seconds. Use of dedicated phlebotomy teams, as well as the 2-needle technique, have been shown to
result in decreased contamination rates. The 2-needle technique has fallen out of favor due to
concerns for accidental needle stick injuries. Several different antiseptic products have been used and,
in general, evidence does suggest less contamination with alcohol-based products.
The most commonly used substances for skin antisepsis are: alcohols (ethanol, isopropanol and n-
propanol), chlorhexidine (available commonly as chlorhexidine gluconate [CHG]), and PI, which is an
organic iodine compound. Alcohols are microbiologically more active, but have no appreciable residual
activity. Chlorhexidine gluconate and PI are less effective, but have more residual activity on the skin,
which is greater for CHG than PI. Chlorhexidine gluconate and PI are available as aqueous solutions
where they are the sole active ingredients. They can be combined with alcohols, creating a solution
with 2 active agents.
Different commercially available products have been compared to each other. In 1 study of PI, tincture
of iodine, isopropyl alcohol, and PI with alcohol were compared. While a significant difference between
the 4 antiseptics was not found, there was evidence to suggest less contamination with alcohol-based
antiseptics. Another study looked at a solution of 0.5% CHG in 67% isopropyl alcohol and found this
to be superior to PI in preventing blood culture contamination. Again, the suggestion was that this was
because of the alcohol component of the chlorhexidine solution rather than the chlorhexidine itself.
Recent meta-analysis of different CHG products alone and in combination with alcohol shows that
there is good evidence that CHG alcohol products are superior to PI alone.
Apart from antiseptics, other measures employed to reduce blood culture contamination include the
use of fully sterile procedures with the use of standardized gloves, large volume chlorhexidine skin
antisepsis, and fenestrated sterile drapes, as opposed to nonsterile procedures to collect blood
cultures. Using sterile blood culture collection kits, separate venipuncture sites for blood culture
collection and intravenous catheterization, and trained phlebotomy teams are other techniques that
have been shown to reduce contamination rates and result in significant cost savings.
Difficulty also arises in the interpretation of multiple isolates from a single blood culture. There are
different tools that have been used for interpreting the significance of isolates from positive blood
cultures. Depending on the site (peripheral versus intravascular lines) and technique (as discussed),
other factors to consider when determining the significance of isolates include the identity of the
microorganism itself. This can be particularly challenging, as in the case of coagulase-negative
staphylococci (CoNS), which is one of the most frequent blood culture isolates. Assessment of the time
to positivity, use of other markers such as the C-reactive protein, quantity of growth, species, and
strain identification, as well as the clinical status of the patient, have all been employed to determine
the significance of multiple isolates in a single positive blood culture. Communication with the
microbiology laboratory may be helpful in these situations.
Most isolates from cultures obtained from an indwelling line in a patient who is showing signs and
symptoms of illness such as fever, elevated white blood cell count, or a host who is
immunocompromised would be considered significant. Growth of skin flora such as CoNS,
Corynebacterium species, Bacillus species other than B anthracis, and Propionibacterium acnes from
single peripheral blood cultures in normal healthy hosts rarely represent true bacteremia. However,
isolation from patients with vascular and other prosthetic devices needs to be interpreted with caution.
Therefore, the clinical significance of these as well as other microorganisms such as viridans group
streptococci cannot be judged solely on the basis of their identity. Growth of Staphylococcusaureus,
Streptococcus pneumoniae, Neisseria meningitidis, and other members of the Enterobacteriaceae
family from the same blood culture would generally be considered significant. However, once again,
the results of the blood culture must be interpreted in the context of the patient and other clinical
findings. Therefore, distinguishing pathogenic from nonpathogenic isolates from single blood cultures
remains problematic.
PREP Pearls
 Chlorhexidine products in combination with alcohol seem to be superior antiseptic agents as

compared to povidone-iodine.
 Combined with other techniques such as sterile blood culture collection methods, sterile
collection kits, and trained phlebotomy teams results in decreased blood culture contamination
rates.
 Isolation of microorganisms from single blood cultures is dependent on multiple interpretations
and often cannot be judged solely on the basis of their identity.
 Know how to disinfect the skin when obtaining blood for culture (effective agents, ineffective
agents, technique)
 Interpret multiple isolates from one blood culture (significant and insignificant situations)
Suggested Readings
 Maiwald M, Chan ESY. The forgotten role of alcohol: a systematic review and meta-analysis of
the clinical efficacy and perceived role of chlorhexidine in skin antisepsis. PloS One.
2012;7(9):e44277. doi: 10.1371/journal.pone.0044277
 Marlowe L, Mistry RD, Coffin S, et al. Blood culture contamination rates after skin antisepsis
with chlorhexidine gluconate versus povidone-iodine in a pediatric emergency department.
Infect Control Hosp Epidemiol. 2010;31(2):171-176. doi:10.1086/650201
 Self WH, Mickanin J, Grijalva CG, et al. Reducing blood culture contamination in community
hospital emergency departments: a multicenter evaluation of a quality improvement
intervention. Acad Emerg Med. 2014;21(3):274-282. doi:10.1111/acem.12337
Question: 5
You are seeing a 13-year-old adolescent who is preparing to travel to northern Nicaragua on a mission
trip. She has come for pre-travel counseling, immunizations, and necessary medications. Her activities
include staying with a host family in a remote village, helping to dig wells to provide clean water to
local villagers, and a few days at the beach. She recently started doxycycline for moderate acne. You
inform her that doxycycline is an effective agent for malaria prophylaxis in Central America and you
provide further education regarding this medication.
Of the following, the MOST common adverse effect of doxycycline use that should be discussed with
this patient is
A. enamel discoloration
B. enamel hypoplasia
C. esophageal ulcers
D. hepatotoxicity
E. photosensitivity
Question: 5
You are seeing a 13-year-old adolescent who is preparing to travel to northern Nicaragua on a mission
trip. She has come for pre-travel counseling, immunizations, and necessary medications. Her activities
include staying with a host family in a remote village, helping to dig wells to provide clean water to
local villagers, and a few days at the beach. She recently started doxycycline for moderate acne. You
inform her that doxycycline is an effective agent for malaria prophylaxis in Central America and you
provide further education regarding this medication.
Of the following, the MOST common adverse effect of doxycycline use that should be discussed with
this patient is
A. enamel discoloration
B. enamel hypoplasia
C. esophageal ulcers
D. hepatotoxicity
E. photosensitivity
Correct
View Peer Results
35a76608-d966-49f8-a967-ce9e1e3b29c7
The patient in the vignette is most at risk for photosensitivity. Development of a photosensitivity
rash is common in sun-exposed patients taking tetracyclines, and is a result of phototoxic drug
accumulation in the skin caused by inhibition of cellular incorporation of thymidine. The rash may
develop within minutes or after several hours of sun exposure and can persist for a few days after the
drug is discontinued. Edema, papules, vesiculation, and onycholysis may develop in severe cases. Sun
screen may not provide adequate protection, thus skin should remain covered.
Enamel hypoplasia and subsequent discoloration occurs in fetuses who are exposed in utero and in
children younger than 8 years of age with repeated drug exposure. Despite this, doxycycline is the
drug of choice in young children for certain tick borne illnesses. Enamel discoloration may also occur in
adults taking minocycline for prolonged periods of time, but does not occur with doxycycline in older
children and adults. The exact mechanism of enamel discoloration with chronic minocycline is
unknown, but is thought to be different than the mechanism causing enamel hypoplasia and
subsequent discoloration in young children.
While gastrointestinal adverse effects are the most common adverse event associated with
tetracycline use overall, esophageal ulcers occur uncommonly in the setting of tetracycline and
doxycyline use. Minocycline is a rare cause of esophageal ulcers. Pill esophagitis and esophageal ulcer
are typically associated with use of the pill form of medication without adequate intake of water.
Patients should be counseled to take the medication with plenty of water and to stay upright for at
least 90 seconds after swallowing the medication. Hepatotoxicity is a rare adverse event, mostly
occurring in pregnant women and in those with chronic renal dysfunction. Hepatotoxicity also occurs in
patients who receive high dose tetracyclines. Table 1 provides organ-specific detail regarding adverse
reactions with use of tetracyclines.
Tetracyclines are broad spectrum antibiotics. Tigecycline, a glycylcycline, has added Gram-positive,
Gram-negative, and anaerobic coverage not included in earlier tetracyclines. The primary indications
for use of tetracyclines include tickborne and zoonotic illnesses, Table 2 lists the spectrum of activity
and indications for use in young children.
PREP Pearls
 Gastrointestinal adverse effects are the most commonly occurring adverse event with
tetracycline use overall, but photosensitivity is also common.
 There are limited indications for tetracyclines in young children (eg, tickborne illnesses).
 Tetracycline agents possess a broad spectrum of activity.
 Know the indications for use of tetracyclines (Brucella, Chlamydia, Ehrlichia, Borrelia
burgdorferi, MRSA, Mycoplasma, Rickettsia, vibrios), including those in young children
 Know the toxicity of tetracyclines (skin photosensitivity, enamel discoloration and hypoplasia,
esophageal ulcers, hepatotoxicity)
Suggested Readings
 Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in children treated with
doxycycline for suspected rocky mountain spotted fever. J Pediatr. 2015.
doi:10.1016/j.jpeds.2015.02.015
 Zhanel GG, Homenuik K, Nichol K, et al. The glycylcyclines: a comparative review with the
tetracyclines. Drugs. 2004;64(1):63-88 .
Question: 6
You are talking to a group of medical students about the macrolide antibiotics. You tell them that, as
opposed to erythromycin and clarithromycin, azithromycin has demonstrated minimal drug-drug
interactions.
Of the following, the reason that BEST explains the lack of drug interactions as compared to the other
macrolides is that azithromycin
A. alters drug binding sites on the ribosome by methylation
B. has better tissue penetration than the other macrolides
C. has lower serum levels as compared to the other macrolides
D. is an azalide as opposed to the other macrolides
E. is not metabolized by the hepatic cytochrome p450 system

Question: 6
You are talking to a group of medical students about the macrolide antibiotics. You tell them that, as
opposed to erythromycin and clarithromycin, azithromycin has demonstrated minimal drug-drug
interactions.
Of the following, the reason that BEST explains the lack of drug interactions as compared to the other
macrolides is that azithromycin
A. alters drug binding sites on the ribosome by methylation
B. has better tissue penetration than the other macrolides
C. has lower serum levels as compared to the other macrolides
D. is an azalide as opposed to the other macrolides
E. is not metabolized by the hepatic cytochrome p450 system
Correct
View Peer Results
b3daf40b-d57c-49b0-aafb-593279889c83
Azithromycin is an erythromycin derivative with a broad spectrum of antimicrobial activity. The

substitution of nitrogen in place of the carbonyl group in the 15-member lactone ring structurally
changes the drug from a macrolide to an azalide. This renders the compound more acid stable and
results in a longer serum half-life, increased tissue penetration, and greater activity against Gram-
negative organisms as compared with the parent compound erythromycin, as well as clarithromycin.
Azithromycin elimination occurs primarily in the feces as unchanged drug and urinary excretion is
minimal. Unlike the other 2 macrolides, azithromycin does not interact with the cytochrome P450
system, making drug-drug interactions minimal. In patients with mild-to-moderate hepatic
impairment, dosage adjustments do not seem to be necessary.
Like other macrolide antibiotics, azithromycin is bacteriostatic. It binds reversibly to the 50S subunit of
the bacterial ribosome inhibiting RNA-dependent protein synthesis. Mechanisms of resistance involve
alteration of the drug-binding site on the ribosome by methylation or by active drug efflux pumps.
Azithromycin is lipophilic and is extensively distributed in body fluids and tissues. It is relatively stable
in the acid pH of the stomach, and after a single 500 mg oral dose, the bioavailability is approximately
37%. However, oral absorption of azithromycin is 5-fold lower than that of the other macrolides, but
tissue concentrations are considerably higher. Azithromycin has a large volume of distribution and has
a tissue half-life of approximately 3 days, which allows for the convenient once a day dosing for
shorter treatment periods.
Mean tissue concentrations are 10- to 100-fold greater than serum concentrations and do not peak
until 48 hours after administration of the drug. In addition, high levels persist for several days
afterwards. Thus, azithromycin pharmacokinetics permits a 5-day, single daily dose regimen for
respiratory tract and soft tissue infections that allow a therapeutic tissue concentration of
approximately 10 days. The high tissue concentrations are thought to be due to the presence of 2
basic tertiary amine groups that give azithromycin amphiphilic properties, which allow the drug to
concentrate in lysosomes and host defense cells.
High concentrations of the drug are found in tissues such as lung, prostate, liver, and lymph nodes
with relatively lower concentrations in fat and muscle (Table). In clinical studies, 24 hours after the
last dose of drug has been administered, concentrations of azithromycin in lung epithelial cell lining
exceeded serum concentrations by 20-fold. For the same time interval, levels in alveolar macrophages
were 800 times their respective serum concentrations. Azithromycin also distributes well into the
middle ear fluid, tonsils, and adenoid tissue, and persists in therapeutic concentrations at these sites.
In published studies, tissue concentrations have been 1- to 2-fold higher than serum concentrations.
Most of the data on the pharmacokinetics of azithromycin have been from adult studies because
studies in children are limited.
Azithromycin is active against a wide array of Gram-positive and Gram-negative pathogens, which
include Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Mycoplasma
pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, Bordetella
pertussis, as well as enteric pathogens including Escherichia coli, Salmonella species, Yersinia
enterocolitica, and Shigella species. It is also active against Campylobacter jejuni as well as against
genital pathogens, which include Neisseria gonorrhoeae, Haemophilus ducreyi, Ureaplasma
urealyticum, and Mycoplasma hominis. Azithromycin is inactive against methicillin-resistant
Staphylococcus aureus.
Clinical indications for use include upper and lower respiratory tract infections, including otitis media,
sinusitis, pharyngitis, and community acquired pneumonia. While surveillance studies in the United
States show that 28% to 35% of Streptococcus pneumoniae isolates are resistant to macrolides,
azithromycin remains a popular choice for the treatment of these infections because of ease of
administration (once daily dosing), short treatment duration, and good tolerability. Single daily dose
therapy with azithromycin for otitis media has been evaluated for short 1-, 3-, and 5-day treatment
courses, which have been found to be similar for clinical and microbiologic outcomes to 10-day
courses of comparable β-lactam antibiotics in acute uncomplicated otitis media. Short treatment
course (3 to 5 day) for sinusitis and community acquired pneumonia (5-day) have also been
evaluated. A short course treatment regimen for streptococcal pharyngitis (dose of 12 mg/kg per day)
has also been studied. While these shorter treatment regimens have been evaluated, the data were
insufficient to recommend their use. Azithromycin is also the preferred drug for infants younger than 1
month of age with pertussis despite some concerns for hypertrophic pyloric stenosis. It is also being
increasingly utilized for the treatment of pertussis in older children and adults, and has largely
replaced erythromycin for this purpose in clinical practice.
Other indications for the use of azithromycin in children include treatment of skin and soft tissue
infections, particularly for those with allergies to penicillin or cephalosporin antibiotics. It is also the
only antibiotic that has been evaluated prospectively for the treatment of cat scratch lymphadenitis
caused by Bartonella henselae and is widely used for the treatment of this infection.
Another major indication for the use of azithromycin is for the treatment of sexually transmitted
infections. Single dose (1 g) azithromycin has demonstrated excellent clinical efficacy in the therapy of
chlamydial urethritis and cervicitis, due to the high and prolonged tissue levels of the antibiotic,
enabling such a regimen to be effective. Infections caused by Chlamydia trachomatis, nongonococcal
urethritis, as well as genital ulcer disease caused by Haemophilus ducreyi may all be treated with the
1 g dose regimen.
Azithromycin has also been used for the treatment of infections such as those caused by multi-drug
resistant Salmonella Typhi,trachoma, and traveler‘s diarrhea. Azithromycin is also indicated for the
treatment of Mycobacterium avium complex (MAC) in immunocompromised patients, particularly
those with HIV/AIDS, and is also used for the once weekly prophylaxis of MAC infections in these
patients.
In addition to antibacterial activity, azithromycin, like the other macrolide antibiotics, is also well
known for its anti-inflammatory and immunomodulatory properties, and has been used for this
purpose in patients with a wide variety of chronic inflammatory diseases such as post-transplant
bronchiolitis, panbronchiolitis, and rosacea, and for its effect on modulation of host immune responses
in patients with cystic fibrosis, noncystic chronic bronchiectasis, as well as in exacerbations of chronic
obstructive pulmonary disease.
Like other macrolides, gastrointestinal intolerance is the main adverse effect associated with the use
of azithromycin, although it occurs at a significantly reduced rate as compared to the other agents in
its class. Most common patient complaints include diarrhea, nausea, abdominal pain, and headache or
dizziness. Laboratory abnormalities include minor increases in transaminases in 1.5% of patients. Pain
at the injection site and inflammation have been reported with use of the intravenous formulation of
azithromycin.
In 2013, the US Food and Drug Administration issued a safety announcement warning the public that
azithromycin may cause abnormal changes in the electrical activity of the heart leading to potentially
fatal arrhythmias. Patients at increased risk for this would be those with underlying heart disease or
arrhythmias, those who take other medications that may potentiate this effect, or those with
preexisting prolonged QTc interval or history of torsade de pointes.
PREP Pearls
 Substitution of nitrogen in the 15-member lactone ring structurally changes azithromycin from
a macrolide to an azalide making it more acid stable, resulting in a longer serum half-life,
increased tissue penetration, and greater activity against Gram-negative organisms.
 Unlike macrolides, lack of interaction with the cytochrome P450 system means that there are
minimal drug-drug interactions with azithromycin.
 Azithromycin use is associated with minimal gastrointestinal adverse effects.
 Know the spectrum of activity, pharmacologic properties, indications, and adverse effects of
azithromycin
Suggested Readings
 Abo-Salem E, Fowler JC, Attari M, et al. Antibiotic-induced cardiac arrhythmias. Cardiovasc

Ther. 2014;32(1):19-25. doi:10.1111/1755-5922.12054
 Bradley JS, Sauberan JB. Antimicrobial agents. In: Long SS, Pickering LK, Prober CG, eds.
Principles and Practice of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: Saunders
Elsevier; 2012:1453-1484 .
 Zuckerman JM, Qamar F, Bono BR. Macrolides, ketolides, and glycylcyclines: azithromycin,
clarithromycin, telithromycin, tigecycline. Infect Dis Clin North Am. 2009;23(4):997-1026.
doi:10.1016/j.idc.2009.06.013
Question: 7
You are asked to evaluate a 10-year-old boy with explosive, watery diarrhea. He also has nausea,
vomiting, abdominal cramping, and fever. Analysis of stool specimens reveals Vibrio
parahaemolyticus.
Of the following, the MOST accurate statement about Vibrio parahaemolyticus infections occurs
A. following ingestion of contaminated finfish is more common than that of oysters or clams
B. in those with pre-existing liver disease predisposes these individuals to septicemia and
death
C. is most common during the winter months
D. is most common in New England states
E. predominately in wounds rather than the gastrointestinal tract

Question: 7
You are asked to evaluate a 10-year-old boy with explosive, watery diarrhea. He also has nausea,
vomiting, abdominal cramping, and fever. Analysis of stool specimens reveals Vibrio
parahaemolyticus.
Of the following, the MOST accurate statement about Vibrio parahaemolyticus infections occurs
A. following ingestion of contaminated finfish is more common than that of oysters or clams
B. in those with pre-existing liver disease predisposes these individuals to septicemia and
death
C. is most common during the winter months
D. is most common in New England states
E. predominately in wounds rather than the gastrointestinal tract
Correct
View Peer Results
6ff82c7a-4732-49be-aab4-6906248083a8
The most common clinical manifestation of Vibrio parahaemolyticus infection is gastroenteritis. V

parahaemolyticus gastroenteritis is typically a self-limited disease not requiring antibiotic treatment.
Clinical manifestations of V parahaemolyticus gastroenteritis range from mild gastroenteritis to
dysentery-like disease. Diarrhea (watery and explosive) and abdominal pain occur in almost all (95%-
96%) of cases. Other symptoms include nausea, vomiting, and headache (40%-70%). Fever and chills
occur less frequently (20%). The incubation period usually ranges from 15 to 24 hours. Resolution of
symptoms usually occurs within 3 days, but may vary widely (eg, from a few hours to more than 10
days). In addition to gastroenteritis, V parahaemolyticus may cause wound infections (after bacterial
contamination of skin lacerations). Bacteremia may develop after either gastroenteritis or wound
infections caused by V parahaemolyticus, and immunocompromised patients (eg, with pre-existing
liver disease or leukemia) are at risk for septicemia and death. A V parahaemolyticus carrier state is
rare.
Outbreaks are typically concentrated along coastal areas, especially the Gulf Coast, during the spring,
summer, and autumn, with higher sea water temperatures associated with higher concentrations of
bacteria in the water. Both finfish and shellfish may be involved in the transmission of V
parahaemolyticus, but the risk of acquisition of infection is higher with molluscan shellfish (because of
the ability to concentrate bacteria by filter feeding). For example, the concentration of V
parahaemolyticus in oysters may be 100 times higher than that of the surrounding water.
A presumptive diagnosis of V parahaemolyticus may be made based on the clinical presentation and
known risk factors (eg, geographic region, ingestion of raw or undercooked seafood). Leukocytosis
and the presence of fecal leukocytes are compatible with the diagnosis. Confirmation of the diagnosis
of V parahaemolyticus (and V vulnificus) depends upon a positive stool culture on selective media (eg,
thiosulfate-citrate-bilesalts-sucrose [TCBS] agar). If a delay in processing the sample is expected, a
transport medium (eg, Cary-Blair) is necessary.
PREP Pearls
 The most common clinical manifestation of Vibrio parahaemolyticus infection is gastroenteritis.

 V parahaemolyticus gastroenteritis is typically a self-limited disease not requiring antibiotic
treatment. In addition to gastroenteritis, V parahaemolyticus may cause wound infections
(after bacterial contamination of skin lacerations).
 Outbreaks are typically concentrated along coastal areas, especially the Gulf Coast, during the
spring, summer, and autumn.
 Both finfish and shellfish may be involved in the transmission of V parahaemolyticus, but the
risk of acquisition of infection is higher with molluscan shellfish.
 Bacteremia may develop after either gastroenteritis or wound infections caused by V
parahaemolyticus, and immunocompromised patients (eg, with pre-existing liver disease or
leukemia) are at risk for septicemia and death.
 Know that need for selective media is the method of diagnosis of Vibrio parahaemolyticus and
Vibrio vulnificus infection
 Recognize the characteristics of disease due to Vibrio parahaemolyticus (geography,
self-limited, antibiotics of little benefit, raw seafood, salt water, carrier state rare)
Suggested Readings
 Cartwright EJ, Griffin PM. Other Vibrio species. In: Long SS, Pickering LK, Prober CG, eds.
Principles and Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders
Elsevier; 2012:854-855 .
 Fisher RG. Vibrio vulnificus. In: Cherry J, Demller-Harrison GJ, Kaplan SL, Steinbach J, Hotez
P, eds. Feigin and Cherry‘s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia, PA:
Saunders Elsevier; 2013:1560-1562.
 Hyun DY. Vibrio parahaemolyticus. In: Cherry J, Demller-Harrison GJ, Kaplan SL, Steinbach J,
Hotez P, eds. Feigin and Cherry‘s Textbook of Pediatric Infectious Diseases. 7th ed.
Philadelphia, PA: Saunders Elsevier; 2013:1556-1559 .
 Pickering LK, Shane AL, Lopman BA, et al. Gastrointestinal tract infections and intoxications.
In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious
Diseases. 4th ed. New York, NY: Saunders Elsevier; 2012:372-399.
Question: 8
You are asked by one of your general pediatric colleagues for advice regarding options of antimicrobial
therapy for a 17-year-old pregnant adolescent who has been diagnosed with a urinary tract infection
in the first trimester of pregnancy. In your discussion, you point out that trimethoprim would be a
drug to avoid in the early stages of pregnancy.
Of the following, the BEST rationale for the effects of this agent on the fetus is that it inhibits
A. dihydrofolate reductase
B. DNA-dependent RNA polymerase
C. DNA gyrase
D. DNA topoisomerase IV
E. mycolic acid
Question: 8
You are asked by one of your general pediatric colleagues for advice regarding options of antimicrobial
therapy for a 17-year-old pregnant adolescent who has been diagnosed with a urinary tract infection
in the first trimester of pregnancy. In your discussion, you point out that trimethoprim would be a
drug to avoid in the early stages of pregnancy.
Of the following, the BEST rationale for the effects of this agent on the fetus is that it inhibits
A. dihydrofolate reductase
B. DNA-dependent RNA polymerase
C. DNA gyrase
D. DNA topoisomerase IV
E. mycolic acid
Correct
View Peer Results
714594c3-0034-4fb7-aada-2c2beb956219
Trimethoprim (TMP) is an antibiotic that crosses the placenta and acts as a folate antagonist by
inhibiting dihydrofolate reductase and thus the synthesis of folate, which is required for the synthesis
and repair of DNA. Since trophoblasts are very sensitive to changes in the folate cycle, folate cycle
interference can induce miscarriage and congenital malformation. Trimethoprim has been shown to
decrease folate levels for up to 50 days after exposure and shown to be teratogenic when used in the
first trimester.
A nationwide register-based cohort study in Denmark showed a doubling of the risk of miscarriage and
an increased risk of congenital defects when pregnant women were exposed to TMP in the first
trimester. The overall risk of congenital defects was 10% in exposed children versus 5.2% in
unexposed children. The main defects noted in the exposed fetuses included heart, limb, neural tube
defects, and orofacial clefts.
Despite the fact that TMP is contraindicated during pregnancy, trimethoprim-sulfamethoxazole is

recommended by the US Centers of Disease Control and Prevention (CDC) for the prophylaxis or
treatment of Pneumocystis jirovecii pneumonia, prophylaxis of Toxoplasma gondii encephalitis, and for
the acute and chronic treatment of Q fever in pregnancy because the benefits outweigh the risks and
there are few alternatives. Use of TMP-containing products in the first trimester should be avoided
because safer options are available for other infections in pregnant women.
DNA gyrase and DNA topoisomerase IV are the targets for the action of the fluoroquinolones, while
mycolic acid is the target of isoniazid. Rifampin is an antimicrobial whose mechanism of action
involves the inhibition of DNA-dependent RNA polymerase, which also inhibits DNA synthesis and may
potentially have an adverse effect on the fetus. In animal studies, rifampin exposure during
organogenesis has been shown to cause congenital malformations, such as spina bifida, cleft palate,
and osteogenesis imperfecta. There have not been adequate well controlled studies in pregnant
women, although 1 study of 442 women taking rifampin during 446 pregnancies, including 109
exposed in the first trimester, did not show excess of birth defects. No excess of birth defects has
been noted in babies of more than 2,000 pregnant mothers taking rifampin. Thus, rifampin is
generally considered safe for use during pregnancy when its use is indicated. One important use of
rifampin during pregnancy is for the treatment of active tuberculosis, where the risk of tuberculosis to
the fetus is significant. For this indication, the CDC continues to recommend the use of rifampin, as
part of a 3-drug regimen (with isoniazid and ethambutol) during pregnancy when the probability of
maternal disease is moderate or high. It is important to note that rifampin can cause a postnatal
hemorrhage in the mother and hemorrhagic disease of the newborn, for which vitamin K may be
indicated, when administered during the last few weeks in pregnancy.
PREP Pearls
 Trimethoprim use during pregnancy has been associated with increased risk of miscarriage
and congenital deformities.
 Trimethoprim inhibits dihydrofolate reductase activity, which can have adverse effects on
trophoblasts.
 Rifampin is generally safe for use in pregnancy and is indicated for the treatment of active
tuberculosis in pregnancy.
 Know that trimethoprim is contraindicated in pregnancy because of possible teratogenic effects

 Know that rifampin is contraindicated in pregnancy
Suggested Readings
 American Thoracic Study, US Centers of Disease Control and Prevention, Infectious Diseases
Society of America. Treatment of tuberculosis. MMWR Morbid Mortal Wkly Rep. 2003;52:RR-
11.
 Anderson JT, Petersen M, Jimenez-Solem E, et al. Trimethoprim use in early pregnancy and
the risk of miscarriage: a register-based nationwide cohort study. Epidemiol Infect.
2013;141(8):1749-1755. doi: 10.1017/S0950268812002178
 Anderson JT, Petersen M, Jimenez-Solem E, et al. Trimethoprim use prior to pregnancy and
the risk of congenital malformation: A register-based nationwide cohort study. Obstet Gyncol
Int. 2013;2013:364526. doi:10.1155/2013/364526
 Mathad JS, Gupta A. Tuberculosis in pregnant and postpartum women: epidemiology,
management, and research gaps. Clin Infect Dis. 2012;55(11):1532-1549.
doi:10.1093/cid/cis732
September
Question: 1
A 16-year-old adolescent presents to the emergency department with a deep hand and first digit
laceration that occurred while attempting to repair a lawnmower blade. He is admitted to the hospital
for surgical repair of a nearly severed first digit on the left hand. During his admission, antibiotic
prophylaxis is provided for 72 hours with piperacillin-tazobactam to provide protection against
organisms from the soil. His immunization status is reviewed and he is found to be completely
unimmunized.
Of the following, the MOST appropriate treatment to prevent development of tetanus in this patient is
A. DTaP and tetanus immune globulin
B. Td vaccine and immune globulin
C. Td vaccine alone
D. Tdap vaccine and tetanus immune globulin
E. tetanus immune globulin alone

Question: 1
A 16-year-old adolescent presents to the emergency department with a deep hand and first digit
laceration that occurred while attempting to repair a lawnmower blade. He is admitted to the hospital
for surgical repair of a nearly severed first digit on the left hand. During his admission, antibiotic
prophylaxis is provided for 72 hours with piperacillin-tazobactam to provide protection against
organisms from the soil. His immunization status is reviewed and he is found to be completely
unimmunized.
Of the following, the MOST appropriate treatment to prevent development of tetanus in this patient is
A. DTaP and tetanus immune globulin
B. Td vaccine and immune globulin
C. Td vaccine alone
D. Tdap vaccine and tetanus immune globulin
E. tetanus immune globulin alone
Correct
View Peer Results
46f18687-43af-4b9d-a4fc-741fce036f55
The patient in the vignette has sustained a tetanus-prone wound caused by contamination with
soil from the lawnmower blade, and assessment of tetanus immunization status should occur during
the presentation for the acute injury in order to provide prompt tetanus prophylaxis. Thorough wound
cleaning with debridement of necrotic tissue is prudent, in addition to approximating the wound with
sutures, in the setting of a wound less than a few hours old or with bandaging for wounds that
occurred more than 12 hours prior. The patient in the vignette is previously unimmunized and thus
should receive tetanus immune globulin (TIG) in addition to a tetanus containing vaccine. While all the
tetanus vaccines provide equal tetanus protection, the recommended vaccine in this patient is Tdap,
which will provide some pertussis protection, in addition to tetanus and diphtheria immunity. The
DTaP vaccine is approved for use from 6 weeks through 6 years of age and is part of the routine
immunization schedule in infants and young children, but would not be recommended in a 16-year-old
patient. Tetanus toxoid (Td) vaccine would be recommended in a child who is 7 to 10 years of age and
has previously received the complete childhood DTaP series, and has not received a tetanus-
containing vaccine for 5 or more years. Tdap should be given to children 7 years of age and older who
have not yet received this vaccine and are 5 or more years beyond their last tetanus-containing
vaccine (Table).
There are 3 products available for tetanus prophylaxis: human tetanus immune globulin (TIG),
immunoglobulin intravenous (IGIV), and equine antitoxin. The preferred treatment is TIG, but IGIV is
an alternative when TIG is not available. However, its use has not been licensed by the US Food and
Drug Administration for this indication, and tetanus antibody levels are not routinely checked in IGIV.
Equine antitoxin for tetanus is not available in the United States. For patients outside of the United
States in which equine antitoxin is being considered, skin testing should be performed to evaluate for
animal sera sensitivity, and if the scratch test is negative, an intradermal test should be performed
prior to receipt. Tetanus immunoglobulin is given as a single dose of 250 units (regardless of age or
weight) as an intramuscular injection. Simultaneous administration of TIG with a tetanus-containing
vaccine does not substantially impair development of tetanus immunity.
PREP Pearls
 Tdap should be given to children 7 years of age and older in the setting of a tetanus-prone
wound and a history of receipt of less than 3 previous tetanus vaccines.
 Tdap should be given to adolescents and adults who have a tetanus-prone wound and have
never received Tdap in the past.
 Tetanus immune globulin should be given in the setting of a dirty or contaminated wound if
the patient has had less than 3 doses of tetanus-containing vaccine.
 Know the special products used for passive immunoprophylaxis for tetanus
 Know the indications and timing for passive immunoprophylaxis for tetanus in wound
management in combination with active immunization
Suggested Readings
 American Academy of Pediatrics. Tetanus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS,
eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove
 Brook I. Clostridium tetani (tetanus). In: Long S, Pickering LK, Prober CG, eds. Principles and
Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone Elsevier;
2012:966-970.
Question: 2
A 12-month-old boy is referred to you because of recurrent upper and lower respiratory tract
infections. Most recently he was treated for Pneumocystis jirovecii pneumonia. The child is HIV-
uninfected. Based on his clinical history and subsequent laboratory results, you suspect the child has a
hyperimmunoglobulin M (HIGM) syndrome.
Of the following, the laboratory result that is MOST consistent with HIGM syndrome is
A. decreased numbers of T cells
B. elevated levels of immunoglobulin A
C. elevated levels of immunoglobulin E
D. normal levels of immunoglobulin G
E. normal numbers of B cells

Question: 2
A 12-month-old boy is referred to you because of recurrent upper and lower respiratory tract
infections. Most recently he was treated for Pneumocystis jirovecii pneumonia. The child is HIV-
uninfected. Based on his clinical history and subsequent laboratory results, you suspect the child has a
hyperimmunoglobulin M (HIGM) syndrome.
Of the following, the laboratory result that is MOST consistent with HIGM syndrome is
A. decreased numbers of T cells
B. elevated levels of immunoglobulin A
C. elevated levels of immunoglobulin E
D. normal levels of immunoglobulin G
E. normal numbers of B cells
Correct
View Peer Results
5d819b6a-6f61-4be6-9fcf-7731a77c803c
The hyperimmunoglobulin M (HIGM) syndromes are a group of rare, severe immunodeficiency

disorders that result from defects in the CD40 ligand/CD40 signal pathway, leading to impairment of
immunoglobulin isotype switching in B cells (from immunoglobulin M [IgM] to immunoglobulin G
[IgG], immunoglobulin A [IgA], or immunoglobulin E [IgE]). Despite the name of this group of
disorders, it is now known that IgM levels, although often elevated, can be normal or even low. The B-
and T-cell numbers are normal, but impairment of isotype switching lead to low levels of other
immunoglobulins (IgG, IgA, and IgE).
Most (approximately 70%) cases of HIGM are associated with X-linked inheritance, but other types of
HIGM syndromes exist (autosomal dominant and autosomal recessive types). With X-linked
inheritance, males have mutations of a gene on the X chromosome coding for a T-cell ligand (CD40
ligand) for a B-cell surface molecule (CD40). B-cell proliferation, isotype switching, and final
differentiation of B cells into antibody-producing plasma cells require interaction of CD40 with the
CD40 ligand.
Clinical manifestations of HIGM syndromes include recurrent pyogenic infections during the first
months of life as transplacentally-acquired maternal antibodies decrease in concentration. Respiratory
tract infections, failure to thrive, and chronic diarrhea occur commonly. Other manifestations include
septicemia and meningitis. Opportunistic infections including Pneumocystis jirovecii pneumonia are
relatively common. Approximately 50% of patients with HIGM syndromes have neutropenia, which can
be intermittent. Certain autoimmune conditions, including nephritis and arthritis, and malignancies
have been reported to occur more frequently in HIGM patients compared with other children.
Over 50% of patients are diagnosed in infancy and almost all are diagnosed by 4 years of age.
Definitive diagnosis requires flow cytometry or genetic analysis. Boys who are suspected to have a
HIGM syndrome should have flow cytometry performed to document absence of expression of CD40
ligand on activated T cells, along with absence of CD40 expression on B cells. Other forms of HIGM
syndromes can be diagnosed by demonstrating mutations of genes encoding CD40, CD40 ligand, or
enzyme activation-induced cytidine deaminase.
Treatment of patients with HIGM syndromes with immunoglobulin replacement therapy and antibiotic
prophylaxis, including anti-infectives to prevent pneumocystis, is generally associated with significant
clinical improvement. Those with neutropenia may require granulocyte colony-stimulating factor. Stem
cell transplantation can cure those with X-linked HIGM and HIGM due to CD40 deficiency, but requires
a human leukocyte antigen-matched healthy sibling or closely matched unrelated donor. Bone marrow
transplantation should be performed soon after diagnosis (before severe complications ensue).
Therapy with CD40 agonists is being evaluated in terms of helping to suppress infectious
complications while awaiting stem cell transplantation.
PREP Pearls
 The hyperimmunoglobulin M (HIGM) syndromes are a group of rare, severe immunodeficiency

disorders that result from defects in the CD40 ligand/CD40 signal pathway, leading to
impairment of immunoglobulin isotype switching in B cells (from immunoglobulin M to
immunoglobulin G, immunoglobulin A, or immunoglobulin E).
 Most (approximately 70%) cases of HIGM are associated with X-linked inheritance, but other
types of HIGM syndromes exist (autosomal dominant and autosomal recessive types).
 Stem cell transplantation can cure those with X-linked HIGM and HIGM caused by CD40
deficiency, but requires a human leukocyte antigen-matched sibling or closely matched
unrelated donor.

 Plan a diagnostic evaluation for a patient with suspected hyperimmunoglobulin M syndrome

 Plan specific long term preventive therapy for a patient with hyperimmunoglobulin M
syndrome, including stem cell transplantation
Suggested Readings
 Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol.
2010;149(2):167-180. DOI: http://dx.doi.org/10.1111/j.1365-2141.2010.08077.x
 Heinold A, Hanebeck B, Daniel V, et al. Pitfalls of ―hyper‖-IgM syndrome: a new CD40 ligand
mutation in the presence of low IgM levels: a case report and a critical review of the literature.
Infection. 2010;38(6):491-496. DOI: http://dx.doi.org/10.1007/s15010-010-0061-9
 Qamar N, Fuleihan RL. The hyper IgM syndromes. Clin Rev Allergy Immunol. 2014;46(2):120-
130. DOI:http://dx.doi.org/10.1007/s12016-013-8378-7
 Uygungil B, Bonilla F, Lederman H. Evaluation of a patient with hyper-IgM syndrome. J Allergy
Clin Immunol. 2012;129(6):1692-1693. DOI:http://dx.doi.org/10.1016/j.jaci.2012.03.043
Question: 3
You are asked to provide antibiotic recommendations for a previously healthy 3-year-old girl who is
hospitalized in the pediatric intensive care unit. The girl developed upper respiratory tract symptoms 1
week ago and appeared to be recovering without incident. Over the past 2 days, she developed high
fever, a progressively worsening cough, and increased work of breathing. She was brought to the
emergency department today, where she had a temperature of 40.1°C, pulse rate of 160 beats/min,
respiratory rate of 60 breaths/min, and oxygen saturation of 85% on room air. She was noted to have
significantly decreased breath sounds and dullness to percussion in the right chest. A chest radiograph
was obtained and is shown in the Figure. Ultrasonography of the right chest revealed a large complex
pleural effusion with loculations. The surgery team has performed a video-assisted thoracoscopic
surgery and the pleural fluid was found to be grossly purulent. Gram stain of the fluid reveals many
polymorphonuclear cells and Gram-positive cocci. The pediatric intensive care unit team asks you for
recommendations regarding antimicrobial therapy.
In addition to vancomycin, the BEST empiric antimicrobial regimen for this child is
A. azithromycin
B. ceftriaxone
C. levofloxacin
D. meropenem
E. piperacillin-tazobactam
Question: 3
You are asked to provide antibiotic recommendations for a previously healthy 3-year-old girl who is
hospitalized in the pediatric intensive care unit. The girl developed upper respiratory tract symptoms 1
week ago and appeared to be recovering without incident. Over the past 2 days, she developed high
fever, a progressively worsening cough, and increased work of breathing. She was brought to the
emergency department today, where she had a temperature of 40.1°C, pulse rate of 160 beats/min,
respiratory rate of 60 breaths/min, and oxygen saturation of 85% on room air. She was noted to have
significantly decreased breath sounds and dullness to percussion in the right chest. A chest radiograph
was obtained and is shown in the Figure. Ultrasonography of the right chest revealed a large complex
pleural effusion with loculations. The surgery team has performed a video-assisted thoracoscopic
surgery and the pleural fluid was found to be grossly purulent. Gram stain of the fluid reveals many
polymorphonuclear cells and Gram-positive cocci. The pediatric intensive care unit team asks you for
recommendations regarding antimicrobial therapy.
In addition to vancomycin, the BEST empiric antimicrobial regimen for this child is
A. azithromycin
B. ceftriaxone
C. levofloxacin
D. meropenem
E. piperacillin-tazobactam
Correct
View Peer Results
5693b46d-e642-45bc-aac5-c2353914ea38
Based on the history, clinical, radiographic and ultrasonographic findings, and pleural fluid
findings, the girl in the vignette has a bacterial pneumonia complicated by a parapneumonic
empyema. Parapneumonic effusion refers to collections of fluid in the pleural space adjacent to a
pneumonic process, while a parapneumonic empyema represents a purulent or seropurulent collection

adjacent to a pneumonic process. In previously healthy children, typical bacterial causes of
community-acquired pneumonia, such as Streptococcus pneumoniae, Staphylococcus aureus, and
Streptococcus pyogenes, are responsible for the majority of parapneumonic effusions and empyema.
Although S pneumoniae is the most commonly isolated pathogen in cases of parapneumonic effusion
and empyema, in most studies, community-associated methicillin-resistant Staphylococcus aureus
(CA-MRSA) has emerged as an important cause of complicated pneumonia, including empyema. Less
frequent causes of parapneumonic effusion include mycobacterial infections such as tuberculosis,
fungi, and mixed anaerobic pathogens. Parapneumonic effusion occurs in up to 20% of pneumonias
caused by Mycoplasma pneumoniae and in about 10% of viral pneumonias, but these agents usually
cause small, uncomplicated, and clinically insignificant effusions.
Antimicrobial therapy for parapneumonic effusion and empyema should be directed towards the most
likely etiologic agents. For the child in the vignette, the combination of vancomycin and ceftriaxone
provides the most appropriate coverage. A third-generation cephalosporin, such as ceftriaxone or
cefotaxime, provides excellent coverage against S pneumoniae, including most penicillin-resistant
strains, and is the empiric agent of choice for life-threatening complications of pneumonia, such as
empyema. Vancomycin (or clindamycin) is used empirically when CA-MRSA is suspected based on
regional epidemiologic factors or in severe, life-threatening situations, such as for the girl in the
vignette. Once results of blood and pleural fluid bacterial cultures and susceptibility testing are
available, the antimicrobial regimen can be altered accordingly. However, it is important to note that
the specific pathologic agent often is not isolated from the pleural fluid, which may reflect antibiotic
treatment prior to the collection of pleural fluid. Studies examining cases of empyema in children have
found that most cases of culture-negative empyema fluid are caused by S pneumoniae, and that
empyema caused by CA-MRSA is more likely to result in a positive pleural fluid culture result than
empyema caused by S pneumoniae. This may be helpful in determining whether to continue
vancomycin or clindamycin in cases of culture-negative empyema. Azithromycin is used for
community-acquired pneumonia caused by atypical bacterial such as M pneumoniae, and would not
provide adequate coverage for typical agents of community-acquired pneumonia and empyema.
Although levofloxacin, meropenem, and piperacillin-tazobactam provide coverage against S
pneumoniae, these agents should not be used routinely for community-acquired pneumonia and its
complications, given their very broad spectrum and availability of agents with less broad activity that
have been shown to be effective. The duration of antimicrobial therapy for parapneumonic effusion
and empyema depends on the adequacy of drainage and clinical response. In general, 2 to 4 weeks is
recommended.
Analysis of pleural fluid can help identify the nature of the infectious process. An empyema is defined
by the presence of gross pus, a positive bacterial culture or Gram stain, or a white blood cell count
(WBC) greater than 50,000/μL (50 x 109/L). A Gram stain and culture from pleural fluid should be
obtained whenever pleural fluid is obtained and, when positive, can be used to guide antimicrobial
therapy. Molecular testing of pleural fluid increases the yield for pathogens and may be helpful in
management. The use of biochemical tests, such as pH, pleural fluid to serum protein ratio, glucose,
and lactate dehydrogenase concentrations have traditionally been used to distinguish exudative from
transudative effusions The overwhelming majority of parapneumonic effusions in the pediatric
population are caused by infection, therefore these biochemical tests are rarely required to establish
the etiology of the effusion, do not alter management, and are not recommended according to recent
Pediatric Infectious Diseases Society and Infectious Diseases Society of America guidelines. The use of
the pleural fluid WBC count and differential may be used to differentiate bacterial from mycobacterial,
fungal, or malignancy etiologies.
The need for drainage of a parapneumonic effusion depends on the size of the effusion and the degree
of respiratory compromise. In general, small effusions that do not cause respiratory compromise do
not require drainage. Moderate effusions (> 10 mm rim of fluid, but opacities less than half of the
hemithorax) causing respiratory compromise, large effusions (opacities more than half of the
hemithorax), and purulent effusions generally should be drained. The choice of drainage procedure
should be based on local and regional expertise and experience. In general, the options for drainage of
nonloculated collections include chest tube drainage, chest tube drainage with the addition of
fibrinolytics (urokinase or tissue plasminogen activator), or video-assisted thoracoscopic surgery
(VATS). For loculated effusions, a VATS procedure can be performed initially, or can be performed if
the effusion persists despite 48 to 72 hours of chest tube drainage with fibrinolysis. The use of VATS
and chest tube drainage with fibrinolytics have been shown to result in faster resolution of infection
and decreased length of hospital stay, when compared to chest tube drainage and antibiotics alone.
PREP Pearls
 Typical bacterial causes of community-acquired pneumonia, such as Streptococcus

pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes, cause the majority of
parapneumonic effusions and empyema.
 Biochemical testing of pleural fluid, such as protein, lactate dehydrogenase, glucose
concentrations, and pH is not recommended for children with infectious parapneumonic
effusions.
 The need for drainage of a parapneumonic effusion depends on the size of the effusion and the
degree of respiratory compromise.
 Identify the most likely infectious causes of pleural fluid accumulations (empyema, effusion)
 Interpret results of pleural fluid analysis (eg, cell count, protein, glucose, LDH, pH, and Gram
stain)
 Plan the management of a patient with suspected or proven empyema or effusion (drugs,
duration, procedures)
Suggested Readings
 Alfaro C, Fergie J, Purcell K. Emergence of community-acquired methicillin-resistant

Staphylococcus aureus in complicated parapneumonic effusions. Pediatr Infect Dis J.
2005;24(3):274-276.
 Avansino JR, Goldman B, Sawin RS, Flum DR. Primary operative versus nonoperative therapy
for pediatric empyema: a meta-analysis. Pediatrics. 2005;115(6):1652-1659. DOI:
http://dx.doi.org/10.1542/peds.2004-1405
 Blaschke AJ, Heyrend C, Byington CL, et al. Molecular analysis improves pathogen
identification and epidemiologic study of pediatric parapneumonic empyema. Pediatr Infect Dis
J. 2011;30(4):289-294. DOI: http://dx.doi.org/10.1097/INF.0b013e3182002d14
 Bradley JS, Byington CL, Shah S, et al. The management of community-acquired pneumonia
in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric
Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis.
2011;53(7):e25-e76. DOI: http://dx.doi.org/10.1093/cid/cir531
 Islam S, Calkins CM, Goldin AB, et al. The diagnosis and management of empyema in
children: a comprehensive review from the APSA outcomes and clinical trials committee. J
Pediatr Surg. 2012;47(11):2102-2110. DOI:
http://dx.doi.org/10.1016/j.jpedsurg.2012.07.047
Question: 4
During a discussion after grand rounds you conducted on vaccine safety, several pediatricians report
they have at least 1 child in their practice with neurologic sequelae after an illness diagnosed as acute
encephalomyelitis. Most of these children had received a vaccine shortly before their illness. The
pediatricians would like specific information on the association of vaccines and encephalomyelitis. You
emphasize that, for most vaccines, a causal association is very unlikely, but you list a few vaccines for
which postvaccination encephalomyelitis is biologically plausible.
Of the following vaccines in current use, the one MOST likely to be associated with encephalomyelitis
is
A. human papillomavirus
B. influenza
C. measles
D. pertussis
E. rabies
Question: 4
During a discussion after grand rounds you conducted on vaccine safety, several pediatricians report
they have at least 1 child in their practice with neurologic sequelae after an illness diagnosed as acute
encephalomyelitis. Most of these children had received a vaccine shortly before their illness. The
pediatricians would like specific information on the association of vaccines and encephalomyelitis. You
emphasize that, for most vaccines, a causal association is very unlikely, but you list a few vaccines for
which postvaccination encephalomyelitis is biologically plausible.
Of the following vaccines in current use, the one MOST likely to be associated with encephalomyelitis
is
A. human papillomavirus
B. influenza
C. measles
D. pertussis
E. rabies
Correct
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Acute disseminated encephalomyelitis (ADEM) is an autoimmune condition that occurs in

genetically susceptible individuals after exposure to a variety of infectious pathogens or occasionally
vaccines. Reports of ADEM diagnosed after administration of a vaccine are common, but in most
cases, the association is temporal. Among the vaccines listed in the vignette, measles vaccine is the
one most likely to be associated with ADEM. The incidence of measles vaccination-associated ADEM is
reported to be 0.1 per 100,000, but this is much lower than the incidence in measles infection.
Influenza, human papillomavirus and pertussis vaccines are very unlikely to be triggers of
encephalomyelitis; the Institute of Medicine has found the evidence insufficient to accept or reject an
association with these vaccines, and several others. Historically, rabies and smallpox vaccines were
known to cause encephalomyelitis. The encephalomyelitis that followed administration of neural
tissue-derived rabies vaccines is a prototypic ADEM. It occurred in 50 to 200 per 100,000, or 1 per
2,000 to 8,000 vaccines, but modern cell culture derived vaccines have not been associated with
ADEM. When the smallpox vaccine was in use, encephalomyelitis occurred at a rate of 1 to 30 cases
per 100,000 vaccinations.
Acute disseminated encephalomyelitis is a demyelinating disorder of the central nervous system that
in the majority of cases follows a febrile illness in the preceding month. Acute disseminated
encephalomyelitis accounts for about 10% to 15% of cases of encephalitis in the United States. The
illness initially resembles an acute meningoencephalitis, with fever, headache, somnolence, and
meningeal signs being common at the onset, but altered mental status persists and is present by
definition. The clinical spectrum is variable and neurologic signs include long tract signs, acute
hemiparesis, cerebellar ataxia, cranial neuropathies, vision loss, aphasia, movement disorders, and
findings of spinal cord involvement: motor and sensory limb deficits, respiratory failure, constipation,
and urinary retention. Acute hemorrhagic leukoencephalitis is a variant presentation with rapid
progression, with magnetic resonance imaging (MRI) findings that could suggest herpes simplex
encephalitis. Multiphasic ADEM is uncommon in children and its occurrence suggests the diagnosis of
other chronic demyelinating diseases.
The pathogenesis of ADEM involves failure of normal nervous system immune system regulation and
surveillance mechanisms, which results in the activation of T cells reactive against myelin antigens.
The International Pediatric Multiple Sclerosis Society Study Group has developed clinical diagnostic
criteria, as there is no diagnostic test for ADEM, and recurrent forms of ADEM mimic multiple sclerosis
in children:
• A first polyfocal, clinical central nervous system event with presumed inflammatory demyelinating
cause
• Encephalopathy that cannot be explained by fever
• No new clinical and MRI findings emerge 3 months or more after the onset
• Brain MRI is abnormal during the acute (3 month) phase
• Typically on brain MRI:
• Diffuse, poorly demarcated, large (> 1–2 cm) lesions involving predominantly the cerebral white
matter
• T1 hypointense lesions in the white matter are rare
• Deep gray matter lesions (eg, thalamus or basal ganglia) can be present
The differential diagnosis of ADEM includes acute infectious causes of meningoencephalitis, which are
excluded by available diagnostic, microbiologic, and molecular assays. Characteristic MRI findings of
ADEM are demyelinating involvement of cortical white matter, appearing as hyperintense rounded
lesions with poorly defined margins on T2-weighted imaging, with an asymmetric distribution and
heterogeneous morphology. There is also some involvement of gray matter, especially the basal
ganglia and thalamus. In multiple sclerosis, which is rare in children, involvement of cortical gray
matter and deep nuclei is not common. Magnetic resonance images showing symmetric and confluent
lesions should suggest other diagnoses, such as leukodystrophies and inborn errors of metabolism.
Initial management of a child with suspected ADEM includes intravenous acyclovir and appropriate
antibiotics until an infectious etiology is excluded. There are no controlled trials available to guide the
management of ADEM. The primary modality of treatment is intravenous high dose corticosteroids,
either dexamethasone or methyl¬prednisolone followed by oral prednisone. Alternative modalities are
immunoglobulin intravenous for 2 to 5 days, and plasmapheresis, especially for patients who
deteriorate or fail to respond to the initial steroid doses. Other immunosuppressive agents such as
cyclophosphamide are considered in refractory cases, and for severe hemorrhagic variants, and
hemicraniectomy has been resorted to in severe cases with massive edema.
PREP Pearls
 Acute disseminated encephalomyelitis (ADEM) should be considered in a child who presents

with acute meningoencephalitis, but continues to experience an altered mental status.
 Clinical diagnostic criteria for ADEM have been published.
 The association of vaccination with ADEM is mostly temporal not causal, but certain vaccines
can trigger ADEM.
 The management of ADEM consists of immunosuppressive therapy, but good evidence from
clinical trials is lacking.
 Recognize the presentation and the diagnostic and management approach of acute
disseminated encephalomyelitis
Suggested Readings
 Dale RC, Branson JA. Acute disseminated encephalomyelitis or multiple sclerosis: can the
initial presentation help in establishing a correct diagnosis? Arch Dis Child. 2005;90(6):636-
639. DOI: http://dx.doi.org/10.1136/adc.2004.062935
 Holder L Jr, Lotze TE. Parainfectious and postinfectious demyelinating disorders of the central
nervous system: acute disseminated encephalomyelitis. In: Cherry J, Demmler-Harrison GJ,
Kaplan SL, Steinbach WJ, Hotez P, eds. Feigin and Cherry's Textbook of Pediatric Infectious
Diseases. 7th ed. Philadelphia, PA: Saunders Elsevier; 2013:513-519.
 Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group
criteria for pediatric multiple sclerosis and immune-mediated central nervous system
demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19(10):1261-
1267. DOI: http://dx.doi.org/10.1177/1352458513484547
 Maglione MA, Das L, Raaen L, et al. Safety of vaccines used for routine immunization of U.S.
children: a systematic review. Pediatrics. 2014;134(2):325-337. DOI:
Question: 5
A 2-month-old baby who was born at full term and had no underlying conditions presented with cough
without fever for a week and developed acute respiratory distress syndrome with severe pulmonary
hypertension. He was admitted to your hospital‘s intensive care unit and died within days, despite
being placed on antibiotics and extracorporeal membrane oxygenation. The final diagnosis was
pertussis, confirmed by polymerase chain reaction on nasopharyngeal swab specimen. This case has
resulted in heightened awareness of the resurgence of pertussis locally and you are invited to the
department‘s morbidity and mortality conference to educate the department on reasons for this
change in epidemiology. In your research, you learn that the problem is multifactorial, but you are
asked to identify the most important reason.
Of the following, the MOST important factor in the resurgence of pertussis in the United States is
A. genetic changes in Bordetella pertussis
B. improved awareness and reporting
C. use of polymerase chain reaction assays for diagnosis
D. vaccine refusal
E. waning vaccine immunity

Question: 5
A 2-month-old baby who was born at full term and had no underlying conditions presented with cough
without fever for a week and developed acute respiratory distress syndrome with severe pulmonary
hypertension. He was admitted to your hospital‘s intensive care unit and died within days, despite
being placed on antibiotics and extracorporeal membrane oxygenation. The final diagnosis was
pertussis, confirmed by polymerase chain reaction on nasopharyngeal swab specimen. This case has
resulted in heightened awareness of the resurgence of pertussis locally and you are invited to the
department‘s morbidity and mortality conference to educate the department on reasons for this
change in epidemiology. In your research, you learn that the problem is multifactorial, but you are
asked to identify the most important reason.
Of the following, the MOST important factor in the resurgence of pertussis in the United States is
A. genetic changes in Bordetella pertussis
B. improved awareness and reporting
C. use of polymerase chain reaction assays for diagnosis
D. vaccine refusal
E. waning vaccine immunity
Correct
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45aced2e-36f7-418d-9264-263e6bbe4c0b
After a steady decline in pertussis that followed introduction of whole cell pertussis vaccines to
an all-time low of 1,010 reported cases in 1976, an increase began in the 1980s, and the number of
cases continues to rise progressively. In 2014, 28,660 cases were reported. The highest incidence and
deaths are in infants younger than 1 year of age. Several factors contribute to this dramatic
resurgence. Of the reasons listed in the vignette, the strongest evidence is for lower efficacy of
acellular vaccines, as compared with whole cell vaccines. Age-related waning of immunity after
acellular pertussis vaccines is now recognized as a major contributing factor to the resurgence of
pertussis, with pertussis incidence correlated with increased length of time from the fifth dose of
diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The efficacy of multicomponent (3 or more
antigens) acellular vaccines is between 71% to 85%, depending on the definition used for confirmed
pertussis in trials. These acellular vaccines are more effective than low efficacy whole cell vaccines,
but may be less effective than the highest efficacy whole cell vaccines. In trials of acellular vaccines
that varied from 1 to 5 components, efficacy was correlated to the number of components in the
vaccine, but additional immunomodulatory components present in whole cell vaccines confer a longer
duration of protection, partly because of induction of T helper 1 immune memory cells. Immunity after
the booster DTaP dose at 4 to 6 years of age wanes, which results in a high incidence of pertussis in
children between 7 and 10 years of age. Immunity again begins to wane by 13 years of age, about 2
years after the recommended tetanus-diphtheria-acellular pertussis (Tdap) booster dose. Significantly,
children primed with even 1 dose of whole cell vaccine had lower pertussis attack rates after exposure
than those primed with only DTaP vaccines. Increased awareness and reporting accounts for some of
the resurgence, but this was a major reason primarily during the 1980s, when attention was focused
on the safety of whole cell vaccines. Sensitive polymerase chain reaction (PCR) assays have replaced
culture as the diagnostic test of choice, which leads to more cases being reported, but use of PCR is
not universal and the National Notifiable Diseases Surveillance System case definition is purely clinical.
Genetic changes in Bordetella pertussis by ―vaccine-driven adaptation‖ has been demonstrated in
Australia, Europe, and the United States. For example, increasing numbers of strains are found to be
deficient in pertactin, although evidence is lacking that these strains evade immune responses, and
thereby may not contribute to the resurgence. There are many pockets of populations with high rates
of vaccine refusal, but these alone do not account for the exponential increase in cases.
The only pertussis vaccines used until 1997 were whole cell (killed B pertussis) vaccines, formulated
as diphtheria-tetanus-pertussis (DTwP). The DTwP vaccine was replaced by purified acellular-
component pertussis vaccines because of common and, at times, severe local and systemic reactions.
―Acellular‖ pertussis (aP) signifies a vaccine that consists of 1 or more immunogens derived from the B
pertussis cell, which are adsorbed onto aluminum salts as adjuvant. These immunogens are
inactivated pertussis toxin, filamentous hemagglutinin, fimbrial proteins (agglutinogens) and pertactin
(an outer membrane 69-kd protein) (Table). All current aP vaccines in the United States are in DTaP
or in Tdap combination formulations. The lower case ―d‖ or ―p‖ signifies that the formulation has a
lower dose of that component, as compared with DTaP. Additionally, some DTaP vaccines have been
combined with one or more of inactivated poliovirus, hepatitis B, or Haemophilus influenzae type b
vaccines for convenience of administration, without loss of immunogenicity of the individual
immunogens. There are differences in the age range for which the various products are licensed
(Table), and DTaP is not licensed for individuals 7 years of age or older.
The following list summarizes recommendations of the Advisory Committee on Immunization Practices
for pertussis vaccine immunization of children and adolescents (Figure).
Acellular pertussis vaccines have an excellent safety profile. For DTaP, common local and systemic
reactions are short lived and include redness, swelling, induration, tenderness at the injection site,
and drowsiness; less common reactions include fretfulness, anorexia, vomiting, crying, and slight to
moderate fever. Bacterial or sterile abscess at the site of the injection is rare. Limb swelling of the
entire thigh or upper arm, which can be accompanied by erythema, pain, and fever, has been reported
in 2% to 3% of vaccines after administration of the fourth and fifth doses of an acellular pertussis
vaccine. There is a modestly increased risk of a similar reaction after the fifth dose. The frequency of
the following adverse events that were common with administration of DTwP is significantly lower with
DTaP: allergic reactions, seizures (which usually are febrile seizures), temperature of 40.5°C or
higher, and prolonged crying. For Tdap, fever is reported in 3% to 14%, headache in 40% to 44%,
and tiredness in 27% to 37% of recipients. Syncope can occur in adolescents and adults.
Contraindications to DTaP are:
1. History of a severe allergic reaction (anaphylaxis) after a previous dose of the vaccine or to a
vaccine component (unless the child has been desensitized)
2. Encephalopathy within 7 days after administration of DTwP, DTaP, or Tdap and not
attributable to another identifiable cause.
Precautions for administration of DTaPare:
1. Guillain-Barré syndrome within 6 weeks after a previous dose of tetanus toxoid-

containingvaccine, unless the child is in a community with a pertussis outbreak
2. Presence of a moderate or severe acute illness with or without a fever (applicable toall
vaccines).
For Tdap, in addition to the contraindications and precautions listed for DTaP, a history of severe
Arthus hypersensitivity reaction after a previous tetanus or diphtheria toxoid-containing vaccine
received within the past 10 years is a reason for deferral of Tdap (or Td) for 10 years after that
vaccine.
PREP Pearls
 The primary reason for the resurgence of pertussis is age-related waning of immunity caused
by reduced efficacy of acellular pertussis vaccines relative to most whole cell pertussis
vaccines.
 Use of different acellular pertussis vaccines should be according to age-specific US Food and
Drug Administration product licensure and age-specific Advisory Committee on Immunization
Practices recommendations.
 The safety profile of acellular pertussis vaccines is excellent and is much better than that of
whole cell vaccines.

 Know the composition of different pertussis vaccines, including major antigens, adjuvants, and
different product(s), (ie, whole-cell and acellular vaccines)
 Plan a routine schedule for pertussis immunization, including age of the patient, number of
doses and intervals and their reasons, and recommendation if schedule has been interrupted
 Know the clinical efficacy, safety, and appropriate use of acellular pertussis vaccines
Suggested Readings
 Cherry JD. Why do pertussis vaccines fail? Pediatrics. 2012;129(5):968-970. DOI:

 Jakinovich A, Sood SK. Pertussis: still a cause of death, seven decades into vaccination. Curr
Opin Pediatr. 2014;26(5):597-604. DOI: http://dx.doi.org/10.1097/MOP.0000000000000139
 Martin SW, Pawloski L, Williams M, et al. Pertactin-negative Bordetella pertussis strains:
evidence for a possible selective advantage. Clin Infect Dis. 2015;60(2):223-227. DOI:
http://dx.doi.org/10.1093/cid/ciu788
 McGirr A, Fisman DN. Duration of pertussis immunity after DTaP immunization: a meta-
analysis. Pediatrics. 2015;135(2):331-343. DOI: http://dx.doi.org/10.1542/peds.2014-1729
 Zhang L, Prietsch SO, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping
cough in children. Cochrane Database Syst Rev. 2014;9(1):CD001478. DOI:
http://dx.doi.org/10.1002/14651858.CD001478.pub6
Question: 6
You are asked to provide management recommendations for a 5-year-old boy hospitalized with fever
and bacteremia. He was born at 27 weeks gestational age. During his newborn hospitalization, he
underwent resection of a large portion of his small bowel after developing necrotizing enterocolitis. He
depends on the administration of total parenteral nutrition via a tunneled central venous catheter. The
boy‘s physical examination does not reveal a source for the fever. He has a temperature of 38.2°C.
There is no redness or discharge from the catheter exit site on his chest wall. During your evaluation,
you discover that his blood cultures are growing Staphylococcus aureus, susceptible to methicillin. He
is currently being treated with intravenous cefazolin.
Of the following, the MOST appropriate management of this infection is to
A. remove the catheter, add gentamicin to the antibiotic regimen
B. remove the catheter, continue cefazolin
C. remove the catheter, discontinue cefazolin
D. retain the catheter, but switch cefazolin to clindamycin
E. retain the catheter, but switch cefazolin to vancomycin

Question: 6
You are asked to provide management recommendations for a 5-year-old boy hospitalized with fever
and bacteremia. He was born at 27 weeks gestational age. During his newborn hospitalization, he
underwent resection of a large portion of his small bowel after developing necrotizing enterocolitis. He
depends on the administration of total parenteral nutrition via a tunneled central venous catheter. The
boy‘s physical examination does not reveal a source for the fever. He has a temperature of 38.2°C.
There is no redness or discharge from the catheter exit site on his chest wall. During your evaluation,
you discover that his blood cultures are growing Staphylococcus aureus, susceptible to methicillin. He
is currently being treated with intravenous cefazolin.
Of the following, the MOST appropriate management of this infection is to
A. remove the catheter, add gentamicin to the antibiotic regimen
B. remove the catheter, continue cefazolin
C. remove the catheter, discontinue cefazolin
D. retain the catheter, but switch cefazolin to clindamycin
E. retain the catheter, but switch cefazolin to vancomycin
Correct
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Staphylococcus aureus bacteremia related to the presence of intravenous catheters and

infections of prosthetic medical devices are not uncommon. The Children‘s Hospital Association Quality
Transformation Networks data show that, among all microbiologic causes of catheter-associated
infections in pediatric intensive care patients, 5% were due to Saureus. Approximately half of the
Saureus bacteremias in that report were caused by methicillin-resistant Saureus (MRSA).
Growing evidence supports the notion that most uncomplicated catheter-associated bloodstream
infections can be treated medically with antibiotics but without catheter removal. However, catheter
removal should be strongly considered when the microbiologic isolate is known to be difficult to clear
with anti-infectives alone, or the organism is known to have a proclivity for spread to distal sites. S
aureus, Pseudomonas aeruginosa, mycobacteria, and yeast are included in this group. Sterilization of
the catheter may be delayed or never achieved when these organisms are involved, increasing the
potential for systemic complications such as septic thrombophlebitis and spread of the bacteria to
distal sites through hematogenous seeding. Therefore, catheter removal is the preferred intervention.
Infected catheters should likewise be removed immediately in patients with severe sepsis, septic
thrombophlebitis, endocarditis, or signs of metastatic seeding of the infection. When any organism
persists for more than 72 hours in the blood obtained from the catheter despite antibiotic treatment,
the catheter should likewise be removed. Persistently positive blood cultures found after catheter
removal raises concern for the presence of a septic thrombus and metastatic infection.
S aureus is known to cause both sporadic infections and epidemics. It can be transmitted by contact
with an infected lesion, by contact with an individual who is an asymptomatic carrier, or by contact
with a contaminated environmental object. S aureus colonizes the skin and mucous membranes of
30% to 50% of healthy adults and children, with about half of the isolates found to be methicillin-
susceptible (MSSA), and the other half to be methicillin-resistant (MRSA). For children who develop
skin and soft tissue infections, colonization of the groin is even more common than colonization of the
nasal mucous membranes. Asymptomatic carriers represent a potential source of infection for both
themselves and for others. In efforts to reduce transmission of S aureus, detecting and reducing nasal
carriage has proven less important that hand washing. Health care personnel who are colonized, or
who have mild S aureus lesions such as paronychia, can also transmit S aureus to others via direct
contact. In most cases of S aureus infection, whether community or hospital acquired, transmission is
thought to be by direct human-to-human contact. S aureus is also widespread in the environment,
particularly in warm moist areas such as bathrooms where S aureus can often be cultured from
environmental surfaces, hairbrushes, razors, toothbrushes, and damp towels. In the hospital setting,
fomites represent potential sources of transmission of S aureus, but airborne transmission can also
occur, especially in areas with poor ventilation and high traffic. Newborn nurseries continue to have
documented spread of S aureus infections. During outbreaks, newborn colonization rates at hospital
discharge have been found to be as high as 70%. Colonized newborns who go on to develop infection
characteristically present between 1 and 4 weeks of age with a skin infection. Mother and infant pairs,
both with S aureus mastitis, are well described.
Factors that predispose to infection with S aureus include breaks in skin integrity for any reason such
as surgery, recent piercings or tattoos, burns, trauma, eczema, varicella infection, or the presence of
an intravenous catheter. Neutrophils represent the primary defense against S aureus once the
organism has breached the skin, therefore individuals with neutropenia or functional neutrophil defects
such as chronic granulomatous disease are also at increased risk for invasive infection. Clinical
evidence from patients with cellular immune deficiencies do not implicate S aureus as a primary
pathogen in this group. It is not possible to distinguish an MRSA infection from an MSSA infection on
clinical grounds. For this reason, it is important to be aware of local community epidemiology,
including the most common antibiotic susceptibility patterns for MRSA.
PREP Pearls
 The management of choice for central catheters infected with Staphylococcus aureus is to
remove the device and continue appropriate antibiotic therapy.
 The primary route of transmission of S aureus is person-to-person through direct contact.
 S aureus colonizes the skin and mucous membranes of 30% to 50% of healthy adults and
children.
 Know the epidemiology of Staphylococcus aureus, MSSA, and MRSA, including normal sites of
colonization, routes of transmission, and predisposing factors to infection
 Plan the management for a patient with catheter-related Staphylococcus aureus bloodstream
infection (removal, follow-up cultures)
Suggested Readings
 American Academy of Pediatrics. Staphylococcal infections. In: Pickering LK, Baker CJ,
Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases.
 Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and
management of intravascular catheter-related infection: 2009 update by the Infectious
Disease Society of America. Clin Infect Dis. 2009;49(1):1–45. DOI:
http://dx.doi.org/10.1086/599376
Question: 7
A 4-year-old girl with history of prior urinary tract infection and grade IV left vesicoureteral reflux on
daily trimethoprim-sulfamethoxazole prophylaxis developed fever and left flank pain 4 days ago. Blood
and urine cultures were obtained at initial evaluation, and she has already received 2 doses of
ceftriaxone. In reviewing her medical record, you find that the blood culture was negative, but the
urine culture grew greater than 100,000 colony-forming units/mL of Escherichia coli. The organism
was susceptible to cefotaxime, but resistant to ampicillin and trimethoprim-sulfamethoxazole. Her
antimicrobial therapy was changed to oral cefixime, but she persisted with high (40°C) fever and flank
pain. On examination today, her temperature is 39.6°C, and she has moderate left costovertebral
angle tenderness, but is otherwise normal.
Of the following, the BEST next step in the management of this patient is
A. blood culture
B. renal computerized tomographic scan
C. renal dimercaptosuccinic acid (DMSA) scan
D. renal sonogram
E. urine culture
Question: 7
A 4-year-old girl with history of prior urinary tract infection and grade IV left vesicoureteral reflux on
daily trimethoprim-sulfamethoxazole prophylaxis developed fever and left flank pain 4 days ago. Blood
and urine cultures were obtained at initial evaluation, and she has already received 2 doses of
ceftriaxone. In reviewing her medical record, you find that the blood culture was negative, but the
urine culture grew greater than 100,000 colony-forming units/mL of Escherichia coli. The organism
was susceptible to cefotaxime, but resistant to ampicillin and trimethoprim-sulfamethoxazole. Her
antimicrobial therapy was changed to oral cefixime, but she persisted with high (40°C) fever and flank
pain. On examination today, her temperature is 39.6°C, and she has moderate left costovertebral
angle tenderness, but is otherwise normal.
Of the following, the BEST next step in the management of this patient is
A. blood culture
B. renal computerized tomographic scan
C. renal dimercaptosuccinic acid (DMSA) scan
D. renal sonogram
E. urine culture
Correct
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118cb6bd-529c-4b8f-8ade-794c0bad1540
This child most likely has a renal or perinephric abscess causing her apparent lack of response to
therapy, and this should be visible with renal sonogram. It is also possible that she has developed an
obstructive process somewhere in her renal collecting system, but renal sonogram would be
suggestive in this instance as well. It is unlikely she developed sepsis while on therapy, especially
without evidence of toxic appearance. Renal dimercaptosuccinic acid (DMSA) scan is a highly sensitive
test for pyelonephritis, but less likely to be helpful for finding perinephric abscess. Renal computerized
tomographic scan would also reveal nephric or perinephric abscess, but involves radiation exposure,
therefore renal sonogram is preferred.
Renal and perinephric abscesses are very uncommon in children, so most case series are small. Most
are related to urinary tract infections, especially if associated with underlying structural anomalies,
and are due to Gram-negative bacilli that most commonly cause such infections. Rarely, renal abscess
may develop from a hematogenous source, including severe sepsis, endocarditis, catheter-associated
bloodstream infection, intravenous drug use, dental-associated infection, and other deep-seated
infections. In the setting of vascular-associated abscess, pyuria can be the clinical clue to focus on
seeding of the genitourinary tract, and Staphylococcus aureus is the most common cause. Adjacent
infections, such as ruptured appendix, can result in polymicrobial renal or perinephric abscess that
include anaerobic bacteria. Finally, these types of infections may develop in immunocompromised
hosts, resulting in a wider variety of etiologic agents depending on the degree of immune compromise.
No prospective randomized trials of treatment for perinephric or renal abscesses in children are
available. While it is likely that medical therapy alone would eventually cure most infections, it usually
is more efficient to combine antibiotic therapy with drainage of the abscess, preferably by the
percutaneous route if feasible. Thus, close coordination of care with an interventional radiologist (or
surgeon, if needed) is optimal. Duration of therapy is uncertain, but likely should be at least 2 weeks,
depending on clinical response and success of the drainage procedure itself.
PREP Pearls
 Renal or perinephric abscess should be considered in children with urinary tract infection and
poor response to therapy, particularly if underlying genitourinary anomalies are present.
 Pyuria can be a clue to underlying renal or perinephric abscess in children with hematogenous
or vascular infections.
 Drainage of renal or perinephric abscesses, when feasible, is likely to facilitate cure.
 Recognize the clinical manifestations and most likely infectious causes of renal or perinephric
abscess by clinical presentation
 Recognize the predisposing factors for renal/perinephric abscess, including endocarditis
Suggested Readings
 Angel C, Shu T, Green J, Orihuela E, Rodriguez G, Hendrick E. Renal and peri-renal abscesses
in children: proposed physio-pathologic mechanisms and treatment algorithm. Pediatr Surg
Int. 2003;19(1-2):35-39. .
 Cheng CH, Chai MH, Su LH, et al. Renal abscess in children: a ten-year clinical and
radiographic experience in a tertiary medical center. Pediatr Infect Dis J. 2008;27(11):1025-
1027. DOI: http://dx.doi.org/10.1097/INF.0b013e31817b617b
 Gonzalez ET Jr, Kaplan SL. Renal abscess. In: Cherry JD, Harrison GJ, Kaplan SL, Steinbach
WJ, eds. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia,
Question: 8
You are speaking to a group of residents about the major threat that antibiotic resistant organisms
pose to the effective treatment of serious infections that are seen both in the community and hospital
settings. You review the use of various antimicrobials for antibiotic resistant organisms.
Of the following, ertapenem is an effective treatment agent for infections caused by
A. AmpC-producing Enterobacter cloacae
B. extended β-lactamase-producing Burkholderia cepacia
C. extended β-lactamase-producing Pseudomonas aeruginosa
D. metallo-β-lactamase-producing Klebsiella pneumoniae
E. penicillin-resistant Streptococcus pneumoniae

Question: 8
You are speaking to a group of residents about the major threat that antibiotic resistant organisms
pose to the effective treatment of serious infections that are seen both in the community and hospital
settings. You review the use of various antimicrobials for antibiotic resistant organisms.
Of the following, ertapenem is an effective treatment agent for infections caused by
A. AmpC-producing Enterobacter cloacae
B. extended β-lactamase-producing Burkholderia cepacia
C. extended β-lactamase-producing Pseudomonas aeruginosa
D. metallo-β-lactamase-producing Klebsiella pneumoniae
E. penicillin-resistant Streptococcus pneumoniae
Correct
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84e2851e-5022-4a54-8ee1-e5f099a0744f
Ertapenem is a parenteral broad spectrum 1-β-methyl carbapenem antimicrobial agent that was
licensed in the United States in November 2001 and in Europe in April 2002. It is rapidly bactericidal
and derives its activity from binding to penicillin-binding proteins (PBPs). By doing so, ertapenem
interferes with the lengthening and strengthening of the peptidoglycan portion of the cell wall.
Compared to imipenem and meropenem, ertapenem has a focused spectrum of activity and is highly
active in vitro against many common aerobic and anaerobic Gram-positive and Gram-negative
bacteria that are generally associated with community-acquired infections. This includes methicillin-
susceptible Staphylococcus aureus and many Haemophilus species, streptococci (including penicillin-
susceptible and penicillin-intermediate strains of Streptococcus pneumoniae), Moraxella species,
anaerobes (with the exception of Clostridium difficile), Lactobacillus species, and Enterobacteriaceae
(including those carrying plasmid- or chromosomal-mediated β-lactamases, including AmpC- and
extended spectrum β-lactamases). It has limited activity against Pseudomonas aeruginosa,
Acinetobacter species, enterococci, methicillin-resistant S aureus, Stenotrophomonas maltophilia,
Burkholderia cepacia, metallo-β–lactamase-producing organisms, and Aeromonas species, therefore, it
is not suitable for treatment of infections caused by these organisms. It also has variable and
uncertain activity against penicillin-resistant Streptococcus pneumoniae, and is not indicated for use
against atypical bacteria, such as Legionella species, Mycoplasma species, and Chlamydia species
(Table). For the organisms listed in the vignette, ertapenem would only be effective for an infection
caused by AmpC-producing Enterobacter cloacae.
As a β-lactam agent, ertapenem exerts time-dependent killing so that optimal activity and increased
killing occurs when the drug concentration exceeds the minimal inhibitory concentration (MIC) for a
specified portion of the dosing interval. This duration, time (T)>MIC, necessary for optimum killing is
less for the carbapenem antibiotic class compared to other β-lactams. Carbapenems generally achieve
maximum killing when free drug concentrations exceed the MIC for 30% of the dosing interval. By
contrast, the T>MIC for cephalosporins to achieve maximum killing is 50%. For ertapenem, 24% to
43% of the drug concentration interval above the MIC is required for maximum killing.
Following a 1 g intravenous (IV) dose, maximum plasma concentrations of ertapenem average 150
mg/L. Ertapenem is highly protein-bound and total and unbound concentrations are proportional to
the administered dose. Drug concentrations are identical following intramuscular 1 g doses. Plasma
concentrations are slightly lower compared with intravenous doses; however, the area under the curve
remains unchanged. The T>MIC of the drug is slightly longer (18.1 hours versus 16.9 hours, for
intravenous administration). In individuals 13 years of age or older, this allows the drug to be dosed
once daily. Approximately 40% of the drug is excreted in the urine intact and an identical fraction is
excreted as an open β-lactam metabolite. Ertapenem is primarily metabolized by the kidney; dosage
reductions are recommended in patients with advanced renal insufficiency, including end stage renal
disease. Hepatic metabolism and excretion from the gastrointestinal tract play a very minor role in
elimination, with about 10% of an administered dose being eliminated by biliary and fecal excretion.
Penetration into tissue fluids, lung tissue, inflamed meningeal tissue, and epithelial lining fluid is good;
however, ertapenem penetration into alveolar cells is poor. In studies of experimental penicillin-
sensitive or resistant pneumococci performed in young New Zealand white rabbits, the penetration of
ertapenem reached 7.1% and 2.4% into inflamed and noninflamed meninges, respectively. The dose
of ertapenem used produced levels in the serum corresponding to one intravenous injection of 500 mg
in humans. In this model, ertapenem was very efficacious in sterilizing the cerebrospinal fluid of all
rabbits infected with penicillin-sensitive strains of pneumococci and in 80% of the rabbits infected with
a penicillin-resistant strain. However, there is very limited data on the use of ertapenem in the
treatment of meningitis in humans and there is currently no indication for its use in the treatment of
meningitis. In large, randomized clinical trials, ertapenem at 1 g once a day was as effective as
piperacillin-tazobactam at 3.375 g every 6 hours for the treatment of complicated intra-abdominal,
complicated skin and skin structure, and acute pelvic infections. Ertapenem is as effective as
ceftriaxone at 1 g once a day for the treatment of complicated urinary tract infections and community-
acquired pneumonia.
The recommended dosing of ertapenem is 1 g/day administered intravenously or intramuscularly for

patients 13 years of age or older. For patients 3 months to 12 years of age, the dosing is 15 mg/kg of
body weight twice daily (not to exceed 1 g/day). Given that ertapenem is a β-lactam antibiotic, its use
is contraindicated in patients with hypersensitivity to penicillins, cephalosporins, or other β-lactam
antibiotics.
The safety profile of ertapenem has been assessed in 5 phase IIa and 8 phase IIb/III clinical trials,
including both adult and pediatric patients. In these trials, ertapenem was generally well tolerated,
and most adverse experiences reported in these clinical studies were described as mild-to-moderate in
severity. The most common clinical adverse events associated with ertapenem were diarrhea (5%),
vein complications (5%-7%), nausea (6%-9%), vomiting (4%), and headache (6%-7%). C difficile-
associated diarrhea occurred in 0.3% of patients and 0.2% had seizures during therapy. The most
common laboratory abnormalities were transient increases in alanine aminotransferase levels (8%),
increased platelet count (4%-7%), and increased alkaline phosphatase levels (4%-7%). Adverse
events consistent with central nervous system toxicity, primarily seen in the elderly population,
patients with severe renal insufficiency, and those on dialysis, have been reported with the use of
ertapenem. These events include stroke-like symptoms, headache, mental status changes,
encephalopathy, hallucinations, myoclonus, and seizures.
October
Question: 1
On July 15, a pediatrician contacts you about a previously healthy 6-week-old male infant who began
having loose stools yesterday. A rapid rotavirus assay performed in her office is positive and she is
asking whether this is sufficient evidence to avoid further workup of this illness. The infant lives in a
city in the northeastern United States and is a previously healthy term baby who has not traveled
outside the area, nor come into contact with any other children or foreign visitors. He lives at home
with his parents, who are not ill. He does not attend childcare. His physical examination is
unremarkable. On further questioning, the pediatrician provides the following information from the
test kit package insert: sensitivity of the assay is 97.0%, specificity is 96.5%, positive predictive value
is 97.0%, and negative predictive value is 96.5%.
Of the following, the MOST likely probability for this infant to have rotavirus gastroenteritis is
A. 3%
B. 22%
C. 55%
D. 72%
E. 97%
Question: 1
On July 15, a pediatrician contacts you about a previously healthy 6-week-old male infant who began
having loose stools yesterday. A rapid rotavirus assay performed in her office is positive and she is
asking whether this is sufficient evidence to avoid further workup of this illness. The infant lives in a
city in the northeastern United States and is a previously healthy term baby who has not traveled
outside the area, nor come into contact with any other children or foreign visitors. He lives at home
with his parents, who are not ill. He does not attend childcare. His physical examination is
unremarkable. On further questioning, the pediatrician provides the following information from the
test kit package insert: sensitivity of the assay is 97.0%, specificity is 96.5%, positive predictive value
is 97.0%, and negative predictive value is 96.5%.
Of the following, the MOST likely probability for this infant to have rotavirus gastroenteritis is
A. 3%
B. 22%
C. 55%
D. 72%
E. 97%
Correct
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97cea891-dd80-439b-9422-2dd2a681c510
This is a tricky question, because while it appears to require extensive computations, in fact it
requires none. The key to the correct answer rests with knowing that predictive values are highly
dependent on the prevalence of disease, while sensitivity and specificity values are generally stable
regardless of disease prevalence. Thus, to use predictive values in clinical practice, a clinician would
need to know details of the population that was studied to arrive at those numbers. The prevalence of
rotavirus in the summer in the northeastern United States in a child who has not traveled to the
southern hemisphere is near zero. One should not order a rotavirus antigen test on a child with
virtually no chance of having the disease. A positive result still points to absence of rotavirus disease.
This is analogous to ordering a urine pregnancy test on a man with early morning vomiting; if the test
is positive, it is a false positive.
A sample of original data that illustrate the sensitivity, specificity, and predictive values in this case is
shown in Table 1.
It is useful to know how to calculate sensitivity (true positives divided by total patients with the
disease, or 129/133 in this case) and specificity (true negatives divided by total patients without the
disease, or 109/113 in this case). Knowing that no test is perfect for all situations, a highly sensitive
test is useful as a screening tool because false negatives will be low. For example, while screening for
HIV infection, one would want to avoid missing any truly infected individuals, so a highly sensitive
assay is preferred. The downside of a highly sensitive test is usually a high rate of false positive
results that need to be confirmed by a more specific test. A positive result on a highly specific test can
help cinch a diagnosis.
It is less useful to know how to calculate and use predictive values because of the dependence of the
results on disease prevalence. However, if one can make an appropriate 2 x 2 table, the calculation is
an easy one by looking at the rows (Table 2).
The positive predictive value (PPV) is the number of true test positives divided by the total number of
positive tests. Similarly, the negative predictive value (NPV) is the number of true test negatives
divided by the total number of negative tests. Predictive values generally do not equate to probability
of disease; they are the same only if your patient comes from a population with the same prevalence
of disease as the one from which the predictive values were obtained.
In the example rotavirus assay, if the disease prevalence is 0.1% of infants with diarrhea, the
probability of disease if the test is positive is only 3%. If the prevalence is 1%, the probability
increases to 22%, still a low number. With a prevalence of 54%, which is the case in our example
(129 of 246 children had rotavirus disease), the probability of disease is a near certainty at 97%. Note
that these calculations are usually performed with programmed calculators or nomograms.
Using a patient population of 1,000 for easier calculations, Table 3 is what Table 2 would look like if
the disease prevalence is 0.1%, with the same sensitivity and specificity.
The PPV now changes to 1/35, or 3%, and NPV to 965/965, or 100%.
One other caveat regarding diagnostic test accuracy should be noted. Implicit in these calculations is
that a ―gold standard‖ exists to assess a new test. However, especially with highly sensitive tests such
as polymerase chain reaction assays, the new test actually may be better than the prior gold
standard. In this circumstance, it is difficult to assess sensitivity and specificity, especially when
determining whether apparent false positives are in fact correct and the gold standard is guilty of false
negatives.
PREP Pearls
 Positive predictive values (PPV) and negative predictive values (NPV) vary significantly with
the disease prevalence in a population, and therefore must be used with care in different
circumstances.
 Diagnostic tests should not be utilized if the predictive values are poor for a given population.
 Predictive values are easily calculated by dividing the number of patients with true positive
results by the number of total positive results (PPV) or number of true negative results by
total negative results (NPV).
 Recognize the importance of an independent "gold standard" in evaluating a diagnostic test

 Calculate and interpret sensitivity and specificity
 Calculate and interpret positive and negative predictive values
 Understand how disease prevalence affects the positive and negative predictive value of a test
Suggested Readings
 Altman DG, Bland JM. Diagnostic tests 1: sensitivity and specificity. BMJ.
1994;308(6943):1552. DOI: http://dx.doi.org/10.1136/bmj.308.6943.1552
 Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ. 1994;309(6947):102. DOI:
http://dx.doi.org/10.1136/bmj.309.6947.102
 Casscells W, Schoenberger A, Graboys TB. Interpretation by physicians of clinical laboratory
results. N Engl J Med. 1978;299(18):999-1001. DOI:
http://dx.doi.org/10.1056/NEJM197811022991808
 Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ. 2004;329(7458):168-9. DOI:
http://dx.doi.org/10.1136/bmj.329.7458.168
 Leeflang MG, Rutjes AWS, Reitsma JB, Hooft L, Bossuyt PMM. Variation of a test‘s sensitivity
and specificity with disease prevalence. CMAJ. 2013;185(11):E537-E544. DOI:
http://dx.doi.org/10.1503/cmaj.121286
 Manrai AK, Bhatia G, Strymish J, Kohane IS, Jain SH. Medicine‘s uncomfortable relationship
with math: calculating positive predictive value. JAMA Intern Med. 2014;174(6):991-993.
DOI: http://dx.doi.org/10.1001/jamainternmed.2014.1059
Question: 2
Shortly after you evaluate a sick patient, you receive a call from the pharmacy at your hospital. They
received an order for atovaquone and azithromycin for your patient but are concerned that you
intended that atovaquone–proguanil be given. You assure them that the initial order was correct.
Of the following patients, atovaquone and azithromycin is the MOST appropriate therapy for
A. fever in a child recently returned from visiting family in Africa
B. fever in a school-age child with hemoglobin SS disease
C. new onset seizures in an adolescent who recently emigrated from Central America
D. proctitis in an adolescent with acquired immunodeficiency syndrome
E. retinitis in a hematopoietic stem cell transplant recipient

Question: 2
Shortly after you evaluate a sick patient, you receive a call from the pharmacy at your hospital. They
received an order for atovaquone and azithromycin for your patient but are concerned that you
intended that atovaquone–proguanil be given. You assure them that the initial order was correct.
Of the following patients, atovaquone and azithromycin is the MOST appropriate therapy for
A. fever in a child recently returned from visiting family in Africa
B. fever in a school-age child with hemoglobin SS disease
C. new onset seizures in an adolescent who recently emigrated from Central America
D. proctitis in an adolescent with acquired immunodeficiency syndrome
E. retinitis in a hematopoietic stem cell transplant recipient
Correct
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5539ed42-54d4-45a1-9e95-7bc5c376f4ff
The combination of atovaquone and azithromycin has become the treatment of choice for
babesiosis, following a study that demonstrated therapeutic equivalence to quinine and clindamycin
with significantly fewer adverse effects. Although Babesia are intraerythrocytic parasites causing a
malaria-like illness, they are not treated with typical antimalarial agents (such as chloroquine), except
for quinine in combination with clindamycin (or atovaquone with azithromycin instead of proguanil). In
severe cases (eg, with high parasitemia), exchange transfusion or transfusion support may be an
adjunct to antibiotic treatment. Asplenia, as seen in older children with hemoglobin SS disease, is the
most significant immunodeficiency to predispose humans for severe babesiosis. Of the individuals
described in the response choices, the asplenic child is the one with disease most consistent with
babesiosis, and the one with the most likely predisposition to Babesia infection. Babesiosis is not a
disease of returning travelers, particularly those from Africa. Furthermore, new onset seizures,
proctitis, and retinitis would not likely result from Babesia infection or be treated with a combination
atovaquone and azithromycin.
Symptomatic babesiosis is a malaria-like illness resulting from infection by intraerythrocytic protozoan

parasites of the genus Babesia. In the northeastern and upper Midwestern United States, B microti is
the most common cause of babesiosis. B duncani rarely has been reported in the western United
States. The areas of endemicity in the United States as of 2013 are shown in Figure 1.
Figure 1 shows incidence of reported cases of 1762 cases of babesiosis, by county of residence, in 27
states. Of these, 95% were reported by the seven main B microti-endemic states. County-level
incidence rates ranged from 0 to >100 cases per 100,000 persons.
B divergens is the organism causing babesiosis in Europe, and B divergens-like organisms have been
identified in Kentucky, Missouri, and Washington in the United States. In Europe, it is much more
commonly seen among asplenic individuals with occupational exposure and a much more fulminant
infection, with mortality rates of 42% documented.
The primary vector for Babesia in the United States is Ixodes scapularis (Figures 2-4), which is also
the vector for Lyme disease and anaplasmosis. Reservoirs include the white-footed mouse (Figure 5)
for the tick. Larvae and nymphs and white-tailed deer (Figure 6) and other large mammals for the
adult ticks. The life cycle for Babesia is shown (Figure 7).
Most of those with babesiosis are asymptomatic. Symptomatic disease due to infection by B microti
may resemble a mild malaria-like illness, with fever, malaise, and evidence of hemolysis. Often, those
who are symptomatic note many (average, 9) different symptoms, lasting up to 10 weeks, including
fever (87%), fatigue (82%), chills (68%), sweats (57%), headache (50%), emotional lability (50%),
neck stiffness (48%), myalgia (46%), anorexia (38%), sore throat (31%), cough (29%), arthralgia
(26%), nausea (24%), vomiting (20%), joint swelling (11%), and conjunctivitis (11%). Fever is the
most common physical finding, although jaundice, pallor, hepatosplenomegaly, and/or dark-colored
urine may be identified. General laboratory findings are seldom helpful, but evidence of hemolysis,
relative thrombocytopenia, or elevated serum hepatic transaminases may be present.
The diagnosis of babesiosis rests on identification of the organism on thin blood smear (Figure 8) or
by polymerase chain reaction testing of whole blood.
Serology can be an adjunct, to confirm a positive blood smear, for example, but should not serve as
the basis for deciding to treat the infection.
Treatment should be offered to symptomatic individuals who have a positive thin blood smear or
polymerase chain reaction assay. A 7- to 10-day course is usually sufficient for the otherwise healthy
individual. For severe infection, treatment with quinine and clindamycin may prove beneficial.
Supportive measures, such as exchange transfusion, may be necessary. Duration of therapy in the
compromised host should be for at least 6 weeks or until thin blood smears are negative for at least 2
weeks (whichever is longer).
PREP Pearls
 Most infections with babesia are asymptomatic.

 Asplenic patients can develop life-threatening infection with babesia.
 The treatment of choice for babesiosis is atovaquone plus azithromycin.
 Know the vector, reservoir, geographic occurrence, clinical manifestations, (including dangers
of babesiosis in an asplenic individual and diagnostic tests for Babesia microti (babesiosis)
 Plan the management of a patient with severe babesiosis (atovaquone and azithromycin;
chloroquine ineffective)
Suggested Readings
 American Academy of Pediatrics. Babesiosis. In: Kimberlin DW, Brady MT, Jackson MA, Long
SS, eds. Red Book: 2015 Report of the Committee on Infectious Disease. 30th ed. Elk Grove
 Tolan RW Jr. Babesia species (babesiosis). In: Long SS, Pickering LK, Prober CG, eds.
Principles and Practice of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: Saunders
Elsevier; 2012:1261-1265.
 US Centers for Disease Control and Prevention (CDC). Babesiosis surveillance—18 states,
2011. MMWR Morb Mortal Wkly Rep. 2012;61(27):505-509.
 Vannier E, Krause PJ. Human babesiosis. N Engl J Med. 2012;366(25):2397-2407. DOI:
Question: 3
You are talking about the basic mechanisms of defense against microbes with a group of medical
students. These include both the innate and the adaptive immune systems. Innate or natural
immunity provides the first line of defense against microbes. WHICH of the following are true
statements regarding the functioning of the innate immune system:
1. Consists of cellular and biochemical defense mechanisms that are primed to respond even
before infections occur
2. Components of the humoral innate system include trimeric or hexameric proteins such as
pentraxins, ficolins and the complement system
3. Opsonization of ‗foreign particles‘ by complement proteins and recognition molecules promotes
phagocytosis
4. Mannose binding lectin, and pulmonary surfactant proteins SP-A and SP-D make up some of
the biochemical components of the innate immune system
5. Soluble recognition and effector molecules present in the plasma and blood, act as opsonins
enhancing the ability of phagocytes to kill microbes.
A. 1 and 2
B. 2 and 3
C. 1, 2 and 4
D. 1, 2, 3 and 4
E. All of the above

Question: 3
You are talking about the basic mechanisms of defense against microbes with a group of medical
students. These include both the innate and the adaptive immune systems. Innate or natural
immunity provides the first line of defense against microbes. WHICH of the following are true
statements regarding the functioning of the innate immune system:
1. Consists of cellular and biochemical defense mechanisms that are primed to respond even
before infections occur
2. Components of the humoral innate system include trimeric or hexameric proteins such as
pentraxins, ficolins and the complement system
3. Opsonization of ‗foreign particles‘ by complement proteins and recognition molecules promotes
phagocytosis
4. Mannose binding lectin, and pulmonary surfactant proteins SP-A and SP-D make up some of
the biochemical components of the innate immune system
5. Soluble recognition and effector molecules present in the plasma and blood, act as opsonins
enhancing the ability of phagocytes to kill microbes.
A. 1 and 2
B. 2 and 3
C. 1, 2 and 4
D. 1, 2, 3 and 4
E. All of the above
Correct
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Innate immunity also called natural or native immunity provides early or the first line of defense
against microbes (Figure). It consists of both cellular and biochemical defense mechanisms that exist
long before the human body is exposed to any foreign agent. These defenses are primed to respond
repeatedly to foreign insults thus proving protecting before any adaptive responses can even begin to
develop.
The principal components of innate immunity include a) physical and chemical barriers such as the
epithelial surfaces; b) phagocytic cells such as neutrophils and macrophages as well as dendritic and
natural killer cells; c) blood proteins- such as the complement system and other mediators of
inflammation (pentraxins, ficolins, collectins); and d) cytokines.
Different innate immune mechanisms work at different stages of infection and often simultaneously
and seamlessly to protect the host from infection. Epithelial barriers impair microbial entry, resident
and recruited phagocytes in epithelial and other tissues provide protection if barriers are breached and
plasma proteins and circulating phagocytes provide protection if microbes reach the blood stream.
Further, soluble recognition and effector molecules often sometimes called the ‗humoral‘ branch of
innate immunity (analogous to the humoral branch of adaptive immunity mediated by antibodies)
provide protection and an early line of defense against pathogens that are present outside host cells at
some part of their life cycle.
These soluble recognition and effector molecules provide protection in two ways. They bind to
microbes and act as ‗opsonins‘ thus enhancing the ability of macrophages, neutrophils and dendritic
cells to phagocytose microbes. The process of coating particles to promote phagocytosis is called
opsonization and substances that perform this function including antibodies and complement proteins
are called opsonins. Phagocytic cells express membrane receptors specific for these opsonins which
enhances the ability to bind the microbe. After binding to the microbe, soluble mediators of innate
immunity promote further inflammatory responses that bring more phagocytes to the site of infection
and also directly kill microbes.
The major components of the humoral innate immune system include natural antibodies, the
complement system, collectins, pentraxins, and ficolins. Examples of natural antibodies include those
such as the anti- ABO blood group antibodies expressed on the surface of many cell types including
blood cells. The complement system consists of several plasma proteins that work together to
opsonize microbes via different pathways (classical, alternate, lectin) and is discussed in detail in
other sections.
Pentraxins include several plasma proteins that belong to a group of pentameric proteins i.e. they are
formed by five identical subunits. Prominent members of this group include C-reactive protein (CRP),
serum amyloid protein (SAP) and the long pentraxin PTX3. Both CRP and SAP bind to several different
species of bacteria and fungi. PTX3 recognizes various molecules on fungi, selected gram- negative
and gram-positive bacteria and viruses. CRP, SAP and PTX3 all activate complement by binding C1q
and initiating the classical pathway. Plasma concentrations of CRP are low in healthy individuals but
can increase up to 1000-fold during infectious or inflammatory conditions and are due to increased
synthesis by the liver as a result of induction by cytokines IL-6 and IL-1. These cytokines are in turn
produced by phagocytes as part of the innate immune response. Induction of several other plasma
proteins including SAP is mediated by these cytokines hence as a group these plasma proteins are
referred to as acute phase reactants.
Once acute phase reactants are formed, they provide the host with several proteins with the functional
properties of antibodies which are able to bind to a broad range of pathogens. However, it is important
to recognize that acute phase reactants differ from antibodies in that they have no structural diversity
, they are not specifically induced and targeted and are made in response to any stimulus that triggers
the release of TNF-alpha, IL-1 and IL-6.
Collectins are a specific group of trimeric or hexameric proteins that contain an amino-terminal
collagen like domain and a carboxy-terminal C-typelectindomain. Three members of this family serve
as soluble effector molecules in the innate immune system: mannose binding lectin (MBL) and
pulmonary surfactant proteins SP-A and SP-D. The importance of this group of proteins is that the
lectin pathway serves one of the alternate trigger pathways for the complement system. MBL
functions as an opsonin by binding to and enhancing phagocytosis of microbes. It also acts an an
acute phase reactant. Low MBL levels are associated with increased susceptibility to a variety of
infections especially in combination with other immunodeficiency states. SP-A and SP-D are found in
the lung alveoli and are thought to play a major role in innate immune responses in the lung, acting
as opsonins and facilitating ingestion by alveolar macrophages. They may also inhibit bacterial growth
directly and activate macrophages.
Ficolins are plasma proteins that are structurally similar to collectins, bind to several species of
bacteria, opsonize them and activate complement in a manner similar to MBL. The molecular ligands
of the ficolins are structurally similar to the cell walls of gram positive bacteria. Ficolins and collectins
interact intimately with proteins of the complement system during an inflammatory response
triggering the system via the lectin pathway as mentioned above.
In conclusion, all the various components of the innate immune system i.e. the epithelial barriers,
cells, pathogen recognition receptors, soluble recognition and effector molecules work together by
inducing inflammation (of which opsonization and phagocytosis are an integral part), inducing
defensive mechanisms and stimulating adaptive immunity.
PREP Pearls
 Understand that innate immunity consists of a series of complex cellular and biochemical
mechanisms primed to respond before infections occur.
 Protein systems such as complement, C-reactive protein, mannose binding lectin, serum
amyloid protein all interact together to induce inflammation, act as opsonins and to facilitate
the process of phagocytosis.
 Most of these responses are not antigen specific and occur in response to a wide variety of
pathogens.
 Recognize that opsonization may be mediated by mannose-binding lectin and C-reactive

protein
 Recognize humoral factors that are important in opsonization
Suggested Readings
 Innate Immunity. Chapter 4, 55-88. Cellular and Molecular Immunology. Abbas AK, Lichtman
AH, Pillai S, eds. 7th Edition. Elsevier Saunders, 2012.
 Innate Immunity: The First Lines of Defense. Chapter 2. Pages 37-73. Janesway‘s
Immunobiology. Kenneth Murphy, ed. 8th edition 2012, Garland Science, Taylor & Francis
Group, LLC.
 Innate Immunity: The First Lines of Defense. Chapter 2. Pages 37-73. Janesway‘s
Immunobiology. Kenneth Murphy, ed. 8th edition 2012, Garland Science, Taylor & Francis
Group, LLC.
 Properties and Overview of Immune responses. Chapter 1, 1-14. Cellular and Molecular
Immunology. Abbas AK, Lichtman AH, Pillai S, eds. 7th Edition. Elsevier Saunders, 2012.
Question: 4
You are asked to evaluate a 12-year-old patient who developed interstitial pneumonia after
undergoing a stem cell transplant to treat myelodysplastic syndrome. The transplant team diagnosed
cytomegalovirus as the etiology of the pneumonia 3 days earlier and began treatment with ganciclovir,
but would like to discuss alternatives because of that medication‘s known myelosuppressive effects.
After reviewing the adverse effect profiles of ganciclovir, foscarnet, and cidofovir with the team, a
decision is made to switch therapy from ganciclovir to cidofovir. You explain that cidofovir has a broad
spectrum of antiviral activity, with its most specific and potent activity against cytomegalovirus.
The antiviral properties of cidofovir are BEST explained by the ability of the drug to inhibit viral
A. DNA polymerase
B. helicase
C. kinase
D. reverse transcriptase
E. RNA polymerase
Question: 4
You are asked to evaluate a 12-year-old patient who developed interstitial pneumonia after
undergoing a stem cell transplant to treat myelodysplastic syndrome. The transplant team diagnosed
cytomegalovirus as the etiology of the pneumonia 3 days earlier and began treatment with ganciclovir,
but would like to discuss alternatives because of that medication‘s known myelosuppressive effects.
After reviewing the adverse effect profiles of ganciclovir, foscarnet, and cidofovir with the team, a
decision is made to switch therapy from ganciclovir to cidofovir. You explain that cidofovir has a broad
spectrum of antiviral activity, with its most specific and potent activity against cytomegalovirus.
The antiviral properties of cidofovir are BEST explained by the ability of the drug to inhibit viral
A. DNA polymerase
B. helicase
C. kinase
D. reverse transcriptase
E. RNA polymerase
Correct
View Peer Results
0411341c-d262-4e3f-8024-fe28a321c447
Cidofovir is a monophosphate nucleotide analogue that inhibits viral replication by selectively

inhibiting viral DNA polymerases. After undergoing cellular phosphorylation to its diphosphate form, it
competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA by viral DNA
polymerase. Incorporation of the drug disrupts chain elongation. Unlike nucleoside analogues such as
acyclovir or ganciclovir, cidofovir is not phosphorylated by a viral kinase, so kinase mutant viruses do
not develop resistance to cidofovir.
Cidofovir demonstrates in vitro activity against a number of DNA viruses, including the herpesviruses,
adenoviruses, polyomaviruses, human papillomaviruses (HPV), and poxviruses. It is approved for use
in the treatment of cytomegalovirus (CMV) retinitis in adults with AIDS. While there are no specific
pediatric indications for its use, cidofovir has shown efficacy in the treatment of acyclovir-resistant
HSV and ganciclovir-resistant CMV infections. It also inhibits varicella zoster virus and human herpes
virus-6 replication in vitro, but no clinical trials to test efficacy in those contexts have been done to
date.
Cidofovir retains activity against thymidine kinase-negative herpes simplex virus (HSV) and UL97
phosphotransferase-negative CMV, which are mutant viruses resistant to acyclovir and ganciclovir.
Antiviral resistance testing of clinical isolates of CMV and HSV can help guide therapy, particularly in
patients who have limited clinical response to other antiviral therapy or who are experiencing
moderate-to-severe adverse effects from other medications.
Few antiviral agents have in vivo activity against adenoviruses, and no randomized, placebo-controlled
study of antiviral drug therapy for adenoviral infection has been performed. Available data suggest
that cidofovir could be used as preemptive antiviral therapy of adenoviral disease in selected high risk
patients. A reduction of DNA load has been shown with cidofovir, but the evidence of its efficacy in
preventing mortality in high risk (transplant) patients is inconsistent. Cidofovir has also been
investigated as a treatment for progressive multifocal leukoencephalopathy with successful case
reports of its use, but disappointing results in controlled studies. Cidofovir has modest in vitro activity
against smallpox and monkeypox, and might be considered on a limited basis in the event of a
bioterrorism incident with smallpox or a zoonotic outbreak of monkeypox. Brincidofovir, a lipodated
oral cidofovir derivative with much higher activity against smallpox, has also been developed.
Cidofovir shows anti-BK virus activity in a subgroup of renal transplant recipients, and is being
investigated as a complementary intralesional therapy against laryngeal papillomatosis caused by
HPV. It should be noted that clinical efficacy of cidofovir has been demonstrated rigorously only
against CMV. Its clinical utility in infections caused by the other DNA viral pathogens remains to be
determined.
Renal toxicity, the primary dose-limiting adverse effect of cidofovir can be reduced by co-
administration with probenecid and by maintaining excellent hydration. Other common adverse effects
include nausea, vomiting, neutropenia, hair loss, weakness, headache, chills, decreased intraocular
pressure, uveitis, and iritis. The renal toxicity of cidofovir is characteristically exacerbated by
concomitant use of other known nephrotoxic medications such as amphotericin B, foscarnet,
aminoglycosides, pentamidine, vancomycin, tacrolimus, and nonsteroid anti-inflammatory drugs.
When possible, the administration of such agents should be avoided when cidovofir therapy is being
administered.
PREP Pearls
 Cidofovir is a monophosphate nucleotide analogue that inhibits viral replication by selectively

inhibiting viral DNA polymerases. The in vitro antiviral activity of cidofovir includes
herpesviruses, adenoviruses, polyomaviruses, papillomaviruses, and poxviruses.
 Adequate hydration and administration of probenecid can reduce renal toxicity during
treatment with cidofovir.
 Understand the mechanism of action, adverse effects, and toxicity of cidofovir

 Know the possible indications for cidofovir therapy
Suggested Readings
 Bhadri VA, Lee-Horn L, Shaw PJ. Safety and tolerability of cidofovir in high-risk pediatric
patients. Transpl Infect Dis. 2009;11(4):373-379. DOI: http://dx.doi.org/10.1111/j.1399-
3062.2009.00391.x
 Engelmann G, Heim A, Greil J, et al. Adenovirus infection and treatment with cidofovir in
children after liver transplantation. Pediatr Transplant. 2009;13(4):421-428. DOI:
http://dx.doi.org/10.1111/j.1399-3046.2008.01014.x
Question: 5
You are consulted regarding treatment for a 10-year-old boy. The work-up confirms the diagnosis of
intracerebral Echinococcus granulosus (cystic echinococcosis). The cyst is small and there is minimal
adventitial reaction. You anticipate treatment with albendazole will be successful.
Of the following, the MOST common adverse event after treatment with albendazole is initiated is
A. alopecia
B. anemia
C. leukopenia
D. rash
E. renal toxicity
Question: 5
You are consulted regarding treatment for a 10-year-old boy. The work-up confirms the diagnosis of
intracerebral Echinococcus granulosus (cystic echinococcosis). The cyst is small and there is minimal
adventitial reaction. You anticipate treatment with albendazole will be successful.
Of the following, the MOST common adverse event after treatment with albendazole is initiated is
A. alopecia
B. anemia
C. leukopenia
D. rash
E. renal toxicity
Correct
View Peer Results
ff8b64d8-1305-412a-ac4c-64f662057ab1
Adverse events associated with albendazole therapy, generally reversible upon cessation of
treatment, include occasional abdominal pain, alopecia, and increased transaminases. Leukopenia,
rash, and renal toxicity are observed rarely. Anemia is not associated with albendazole therapy.
Albendazole is a benzimidazole anti-parasitic drug. It has broad-spectrum activity against cestodes,

nematodes, and protozoa. Albendazole is used to treat various infections, including echinococcal
infections and neurocysticercosis.
When possible, surgical removal of intact hydatid cysts remains the intervention with the best chance
of achieving a complete cure in cases of echinococcal infection. Surgery is preferred when cysts are
located in certain organs (ie, brain, kidney, lung), are relatively large (eg, more than 10 cm in
diameter), or are secondarily infected. However, surgery is contraindicated in certain circumstances:
pregnancy; pre-existing medical conditions that place the patient at increased risk of adverse
outcomes; or multiple cysts not easily accessible. Spilling of the contents of echinococcal cysts during
surgery may result in anaphylaxis, with potentially fatal consequences. Medical treatment of
echinococcal infections has an approximately 33% cure rate (complete, permanent disappearance of
cysts), with an additional 30% to 50% of patients having significant decreases in the size of cysts and
clinical improvement. The rate of success of medical treatment of echinococcal infections is enhanced
if there are fewer and smaller cysts, with minimal adventitial reaction. Complicated cysts, ie, those
with multiple compartments or those with thick, calcified surrounding adventitial reactions, do not
respond well to medical therapy. Both albendazole and mebendazole are efficacious for the treatment
of echinococcosis, but the results have been superior for albendazole.
Among patients with parenchymal neurocysticercosis, anti-parasitic therapy with albendazole is

recommended for those with vesicular cysts and those with degenerating (colloidal) cysts that are
single lesions or that represent moderate infections. Anti-parasitic therapy is not indicated for calcified
single or multiple lesions. Albendazole is indicated for certain manifestations of subarachnoid
neurocysticercosis (giant cyst, basal subarachnoid). Ventricular cysts are managed surgically, or with
a ventricular shunt plus albendazole. Hydrocephalus is managed with a ventricular shunt, but without
anti-parasitic therapy. Spinal and ocular cysts are managed surgically. However, with spinal cysts,
albendazole with corticosteroids may be utilized.
PREP Pearls
 Adverse events associated with albendazole therapy, generally reversible upon cessation of
treatment, include occasional abdominal pain, alopecia, and increased transaminases.
 Albendazole is used to treat various infections, including echinococcal infections and
neurocysticercosis.
 Medical treatment of echinococcal infections has an approximately 33% cure rate (complete,
permanent disappearance of cysts), with an additional 30% to 50% of patients having
significant decreases in the size of cysts and clinical improvement.
 Know the role of albendazole in the treatment of echinococcal infection and neurocysticercosis
Suggested Readings
 Cappello M, Schantz PM, White AC Jr. Taenia solium, Taenia asiatic, and Taenia saginata
(taeniasis and cysticercosis). In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice
of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier; 2012:1350-1356.
 Moro PL, Schantz PM. Echinococcus species (agents of cystic, alveolar, and polycystic
echninococcosis). In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of
Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier; 2012:1356-1361.
Question: 6
While in HIV/AIDS clinic, options for initiating antiretroviral therapy are discussed. The pharmacist
leading the discussion suggests that the clinic develop a protocol making sure that all patients are
screened to see if they possess a specific allele at the human leukocyte antigen B locus, HLA-B*57:01,
before considering use of nucleoside and nucleotide analogue reverse transcriptase inhibitors.
The nucleoside/nucleotide analogue reverse transcriptase inhibitor drug MOST likely to cause safety
concerns in patients who test positive for the HLA-B*57:01 allele is
A. abacavir
B. didanosine
C. emtricitabine
D. lamivudine
E. tenofovir
Question: 6
While in HIV/AIDS clinic, options for initiating antiretroviral therapy are discussed. The pharmacist
leading the discussion suggests that the clinic develop a protocol making sure that all patients are
screened to see if they possess a specific allele at the human leukocyte antigen B locus, HLA-B*57:01,
before considering use of nucleoside and nucleotide analogue reverse transcriptase inhibitors.
The nucleoside/nucleotide analogue reverse transcriptase inhibitor drug MOST likely to cause safety
concerns in patients who test positive for the HLA-B*57:01 allele is
A. abacavir
B. didanosine
C. emtricitabine
D. lamivudine
E. tenofovir
Correct
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bb237cf9-22a5-405d-9b42-08868be77d98
Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) used in combination with other
antiretroviral therapies for the treatment of HIV/AIDS. Hypersensitivity to abacavir has been observed
in approximately 5% of abacavir-treated adults and children and is strongly associated with a specific
allele at the human leukocyte antigen B locus, HLA-B*57:01. Patients positive for the HLA-B*57:01
allele should never be given abacavir. The US Food and Drug Administration (FDA) released an alert
concerning abacavir and abacavir-containing medications on July 24, 2008, and the FDA-approved
drug label for abacavir recommends pretherapy screening for the HLA-B*57:01 allele. None of the
other nucleoside and nucleotide analogue reverse transcriptase inhibitors, didanosine (ddI),
emtricitabine, lamivudine (3TC), stavudine, tenofovir, or zidovudine are associated with this HLA-
B*57:01 allele risk.
Hypersensitivity reactions (HSRs) can be fatal. Abacavir-associated HSR generally occur in the first 6
weeks of therapy, but has also been reported after a single dose. Symptoms may include fever,
nausea, vomiting, malaise or fatigue, loss of appetite, diarrhea, and respiratory symptoms (eg, cough
and shortness of breath); some patients may also develop a skin rash. Laboratory and radiologic
abnormalities include elevated liver function tests, elevated creatine phosphokinase, elevated
creatinine, lymphopenia, and pulmonary infiltrates. Lactic acidosis and severe hepatomegaly with
steatosis, including fatal cases, have also been reported. Pancreatitis can occur. Symptoms of
abacavir-associated HSR may be confused with symptoms of HIV, immune reconstitution disease,
hypersensitivity syndromes associated with other drugs, or infection.
The development of suspected HSRs to abacavir requires immediate and permanent discontinuation of
abacavir therapy in all patients, including patients who do not possess the HLA-B*57:01 allele, and
patients should never be rechallenged. Patients with no prior HLA-B*57:01 testing who are tolerating
abacavir do not need to be tested.
The mechanism underlying abacavir-associated HSR is related to the change in the HLA-B*57:01
protein product. Abacavir binds with high specificity to the HLA-B*57:01 protein, changing the shape
and chemistry of the antigen-binding cleft. This results in a change in immunological tolerance and the
subsequent activation of abacavir-specific cytotoxic T cells. The prevalence of the allele is estimated to
be 3.4% to 5.8% in populations of European ancestry, 17.6% in Indian Americans, 3.0% in Hispanic
Americans, and 1.2% in Chinese Americans. There is significant variability in the prevalence of HLA-
B*57:01 among African populations.
Abacavir should always be used in combination with other antiretroviral agents. Abacavir should not
be added as a single agent when antiretroviral regimens are changed due to loss of virologic response.
It is available as a tablet and oral solution or in the combination formulations: abacavir, zidovudine,
and lamivudine (Trizivir®), and abacavir and lamivudine (Epzicom®). Other adverse effects and
toxicities of abacavir are outlined in the Table.

PREP Pearls
 Hypersensitivity to abacavir is strongly associated with a specific allele at the human leukocyte
antigen B locus, HLA-B*57:01.
 Patients positive for the HLA-B*57:01 allele should never be given abacavir.
 The prevalence of the allele is estimated to be 3.4% to 5.8% in populations of European
ancestry, 17.6% in Indian Americans, 3.0% in Hispanic Americans, and 1.2% in Chinese
Americans. There is significant variability in the prevalence of HLA-B*5701 among African
populations.
 Alcohol increases abacavir levels by 41%.
 Understand the mechanism of action of abacavir

 Recognize the adverse effects and toxicity of abacavir
 Know the possible indications for abacavir therapy
Suggested Readings
 US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and
Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. US Department of Health and Human Services website.
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
 US Department of Health and Human Services Panel on Antiretroviral Therapy and Medical
Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in
pediatric HIV infection. US Department of Health and Human Services website.
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf
Question: 7
You are seeing a 14-year-old adolescent for evaluation of fever, progressively worsening cough,
headache, sore throat, and increased work of breathing for the last 4 days. By history, he spent the
last month working on his grandfather's turkey farm cleaning and repairing the turkey pens and
feeding the turkeys. His immunizations are up to date.
On physical examination, he is tired appearing and is coughing throughout the examination. He has a
temperature of 38.9°C and a respiratory rate of 28 breaths/min. He has pharyngeal erythema with no
exudate, diffuse coarse breath sounds with scattered rales in his left lung base, and his liver is down 3
cm below the right costal margin. The rest of his physical examination is within normal limits.
Of the following, the antibiotic class of choice for the treatment of this patient's illness is
A. cephalosporins
B. fluoroquinolones
C. macrolides
D. penicillins
E. tetracyclines
Question: 7
You are seeing a 14-year-old adolescent for evaluation of fever, progressively worsening cough,
headache, sore throat, and increased work of breathing for the last 4 days. By history, he spent the
last month working on his grandfather's turkey farm cleaning and repairing the turkey pens and
feeding the turkeys. His immunizations are up to date.
On physical examination, he is tired appearing and is coughing throughout the examination. He has a
temperature of 38.9°C and a respiratory rate of 28 breaths/min. He has pharyngeal erythema with no
exudate, diffuse coarse breath sounds with scattered rales in his left lung base, and his liver is down 3
cm below the right costal margin. The rest of his physical examination is within normal limits.
Of the following, the antibiotic class of choice for the treatment of this patient's illness is
A. cephalosporins
B. fluoroquinolones
C. macrolides
D. penicillins
E. tetracyclines
Correct
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0f32f576-0174-4ad8-af13-3ce421e864af
The patient in the vignette has psittacosis, which he contracted from the turkeys on his
grandfather's farm. The antibiotic class of choice for the treatment of psittacosis are the tetracyclines.
Oral doxycycline 100 mg twice per day or oral tetracycline hydrochloride 500 mg 4 times per day for
10 to 21 days is the recommended course of therapy. Minocycline is probably equivalent to
doxycycline in its efficacy, but clinical data are limited. In fulminant cases, where oral administration is
not possible or where absorption is in question, intravenous doxycycline or intravenous tetracycline
can be used. Macrolides such as azithromycin, clarithromycin, and erythromycin have good in vitro
activity and are alternative agents that may be used in pregnancy and in children. Fluoroquinolones,
especially levofloxacin and moxifloxacin, have good in vitro activity against Chlamydophilapsittaci,
however, clinical experience with these agents is lacking and the role of fluroquinolones as therapy for
psittacosis is not yet established. Penicillins and cephalosporins are not effective against this organism
and have no role in treatment. The optimal treatment for C psittaci endocarditis is not well defined,
but in the small number of reported cases, a successful outcome involves a combination of surgery
and antibiotic therapy. Tetracyclines (especially doxycycline) are the most effective agents for
treatment, and an extended course is indicated, especially in the absence of valve replacement. There
are no clear guidelines regarding the duration of therapy. However, most experts emphasis the need
for valve replacement or very prolonged antibiotic therapy (ie, years or a lifetime) for ultimate
disease-free survival. Without treatment, the fatality rate is approximately 20%; this drops to 1% with
treatment.
Psittacosis (also known as parrot fever or ornithosis) is a systemic zoonosis caused by infection with C
psittaci. C psittaci are Gram-negative, obligate intracellular bacteria belonging to the Chlamydiales
order. Birds are the major zoonotic reservoir for the organism and exposure to birds is the major risk
factor for psittacosis. However, 25% of patients have no history of any avian exposure. Most
commonly, infected birds are asymptomatic, however, they may develop a clinical illness consisting of
ruffled feathers, respiratory symptoms, conjunctivitis, or diarrhea. Transmission occurs either by
inhalation of aerosolized organisms in dried feces or respiratory tract secretions, or by direct bird
contact (this includes domesticated, exotic, and wild and feral birds). In the United States, birds of the
parrot family (macaws, cockatoos, parakeets, budgerigars), pigeons, and turkeys are common sources
of infection. Other important sources include finches (canaries, bullfinches, goldfinches, sparrows),
poultry (hens, ducks, geese, turkeys), pheasants, egrets, seagulls, and puffins. Individuals at greatest
risk for acquiring the disease are those with leisure or occupational exposure to birds, including pet
bird owners, veterinarians, pet shop employees, and poultry-processing plant employees. Handling of
plumage and mouth-to-beak contact are the most frequently described modes of exposure; however,
transmission has been reported through exposure to aviaries, bird exhibits, and lawn mowing.
Psittacosis can affect people of all ages, however, the peak incidence of disease is usually in middle
age, between 35 and 55 years of age. Children rarely present with a significant clinical illness. The
incubation period is usually 5 to 21 days after exposure. Symptom onset is usually abrupt and
symptoms tend to be nonspecific. The most common presenting symptoms and signs are shown in
Table 1.
The infection may be subclinical or may present as several clinical syndromes, as shown in Table 2.
Specific end organ involvement with psittacosis reflects the systemic nature of the disease, as shown
in Table 3.
PREP Pearls
 Psittacosis is a systemic zoonosis caused by infection with Chlamydophila psittaci, a Gram-

negative, obligate intracellular bacteria belonging to the Chlamydiales order.
 Birds are the major zoonotic reservoir for the organism and exposure to birds is the major risk
factor for psittacosis.
 The antibiotic class of choice for the treatment of psittacosis are tetracyclines, especially
doxycycline.
 Recognize the clinical manifestations of psittacosis

 Plan therapy for a patient with psittacosis
Suggested Readings
 American Academy of Pediatrics. Chlamydophila (formerly Chlamydia) psittaci (Psittacosis,

Ornithosis, Parrot Fever). In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book:
2015 Report of the Committee on Infectious Disease. 30th ed. Elk Grove Village, IL: American
Academy of Pediatrics; 2015:286-288.
 Cunha BA. The atypical pneumonias: clinical diagnosis and importance. Clin Microbiol Infect.
2006;12 Suppl 3:12-24.
 Johnston WB, Eidson M, Smith KA, et al. Compendium of measures to control Chlamycia
psittaci infections among humans (psittacosis) and pet birds (avian chlamydiosis). MMWR
Recomm Rep. 2000;49(RR08):3-18.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4908a1.htm
 Schlossberg D. Psittacosis (due to Chlamycia psittaci). In: Bennett JE, Dolin R, Blaser MJ, eds.
Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed.
Philadelphia, PA: Saunders Elsevier; 2015:2171-2173.
 Stewardson AJ, Grayson ML. Psittacosis. Infect Dis Clin N Am. 2010;24(1):7-25. DOI:
http://dx.doi.org/10.1016/j.idc.2009.10.003
Question: 8
You are consulted on a 16-year-old female patient admitted to the pediatric intensive care unit (PICU)
with meningococcal meningitis. The patient attended a 3-day family reunion over the past weekend
where she was in contact with multiple family members. As you try to determine close contacts of the
patients, you find out that the patient is on the equestrian team and volunteers on a regular basis in
the church daycare. Some of her school friends who have been visiting her in the hospital report that
she had not been feeling well for a few days before she got hospitalized. They report sharing some
classes with her.
You discuss with the clinical team the individuals who would be the best candidates for
chemoprophylaxis. Of the following, the BEST candidates are
A. classmates, household, and childcare contacts
B. family reunion members, household contacts, classmates
C. family reunion members, household and childcare contacts
D. family reunion members, household contacts, equestrian team
E. household and childcare contacts, equestrian team

Question: 8
You are consulted on a 16-year-old female patient admitted to the pediatric intensive care unit (PICU)
with meningococcal meningitis. The patient attended a 3-day family reunion over the past weekend
where she was in contact with multiple family members. As you try to determine close contacts of the
patients, you find out that the patient is on the equestrian team and volunteers on a regular basis in
the church daycare. Some of her school friends who have been visiting her in the hospital report that
she had not been feeling well for a few days before she got hospitalized. They report sharing some
classes with her.
You discuss with the clinical team the individuals who would be the best candidates for
chemoprophylaxis. Of the following, the BEST candidates are
A. classmates, household, and childcare contacts
B. family reunion members, household contacts, classmates
C. family reunion members, household and childcare contacts
D. family reunion members, household contacts, equestrian team
E. household and childcare contacts, equestrian team
Correct
View Peer Results

df778853-cb02-4bb7-bbf0-a9aab6dc3f46
Close contacts of cases of invasive meningococcal disease are at high risk of contracting disease
and should receive chemoprophylaxis regardless of whether or not they have received vaccination.
The secondary attack rate in households with an index case is approximately 1,000 times the attack
rate in the general population. In sporadic cases of disease, 1% to 3% of households have one or
more secondary cases of disease within 30 days of onset of the index case, if there is no intervention.
Household crowding and young age are recognized risk factors that increase the secondary attack
rate. The mode of transmission is via respiratory droplets or secretions. Therefore, household contacts
and daycare attendees are at highest risk and should always be candidates for chemoprophylaxis. Any
other individuals with close personal contact with the oral secretions of the index case should also be
considered for prophylaxis (Table 1).
Current vaccines do not provide 100% protection, therefore, regardless of vaccination status, close
contacts and those at high risk should be offered chemoprophylaxis. Throat and nasopharyngeal
cultures are not recommended because they are of no value in determining who should receive
chemoprophylaxis. Ideally, chemoprophylaxis should be initiated within 24 hours and within 7 days of
contact with the index case. Initiation of prophylaxis after 2 weeks of exposure has little value.
Infants and pregnant women are particularly vulnerable and should receive chemoprophylaxis,
although neither rifampin nor ciprofloxacin is recommended for use in pregnant women among whom
ceftriaxone is the preferred agent. The drug of choice for most infants and children is rifampin. A
complete listing of recommended antibiotics with doses is given in Table 2.
Chemoprophylaxis of the index case is not indicated if third-generation cephalosporins are used for the
treatment of meningococcal disease. However, where drugs other than third-generation
cephalosporins are used for treatment, as in the case of severe drug allergy, the child should receive
chemoprophylaxis to eradicate nasopharyngeal carriage of Neisseriameningitidis.
Ciprofloxacin may be administered in a single oral dose to eliminate nasopharyngeal colonization in

adults. However, it should not be used in parts of the United States where ciprofloxacin-resistant
strains of N meningitidis have been detected. In such cases, or where drug resistance is suspected,
azithromycin as a single oral dose may be used instead.
Meningococcal vaccine should be used as an adjunct to chemoprophylaxis since secondary cases can
occur several weeks after disease onset in the index case. Licensed vaccines against serogroups A, C,
Y and W-135, as well as serogroup B, are now available in the United States. Meningococcal vaccines
are also recommended for routine use in certain high risk groups of individuals such those including
infants with complement deficiencies (C3, C5-9, properdin, factors D and H), in individuals with
functional or anatomical asplenia including sickle cell disease, and those traveling to or residing in
endemic areas.
It is also important to emphasize that, despite the use of chemoprophylaxis, education of contacts for
signs and symptoms of disease remains crucial because no prophylactic strategy is 100% effective. Ill
contacts should be evaluated and a high index of suspicion for meningococcal disease maintained in
the appropriate clinical setting.
PREP Pearls
 Household and close personal contacts, including childcare and nursery school contacts of
cases of meningococcal meningitis, are at significantly high risk for meningococcal disease and
should receive appropriate chemoprophylaxis.
 Any other individuals with contact with the secretions of the patient should also receive
chemoprophylaxis.
 Rifampin, ceftriaxone, and ciprofloxacin may all be used for chemoprophylaxis, although
neither rifampin nor ciprofloxacin is recommended for use in pregnant women.
 Understand the rationale behind the assessment of risk to healthy and potentially immune
compromised patients (including neonates and pregnant women) following exposure to a
patient with a meningococcal infection and plan appropriate chemoprophylaxis
Suggested Readings
 American Academy of Pediatrics. Meningococcal infections. In: Kimberlin DW, Brady MT,
Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Disease.
 Pollard AJ, Finn A. Neisseria menigitidis. In: Long SS, Pickering LK, Prober CG, eds. Principles
and Practice of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: Saunders Elsevier;
2012:730-741.
November
Question: 1
A 13-year-old adolescent presents in April with a 2-week history of fever above 38.5°C, chills,
headache, weakness, nonproductive cough, anorexia, and left-sided chest pain on inspiration. His vital
signs reveal a temperature of 38.9°C, respiratory rate of 40 breaths/min, and heart rate of 120
beats/min. On examination, you note that he is in moderate respiratory distress with intercostal
retractions, and inspiratory rales are heard in the left upper lung field. Aside from tachycardia, the
remainder of his examination is unremarkable. Chest radiograph reveals a rounded segmental
infiltrate of the left upper lobe. Social history reveals that he lives with his family on a wheat farm and
also raises goats. They have an outdoor cat, 2 dogs, and a dozen chickens. He helped deliver several
goats 4 weeks ago for the first time.
Of the following, the BEST method to diagnose the infection in this patient is
A. direct fluorescent antibody of nasal secretions
B. paired serum antibody titers
C. polymerase chain reaction of blood
D. rapid antigen test of nasal secretion
E. routine blood culture

Question: 1
A 13-year-old adolescent presents in April with a 2-week history of fever above 38.5°C, chills,
headache, weakness, nonproductive cough, anorexia, and left-sided chest pain on inspiration. His vital
signs reveal a temperature of 38.9°C, respiratory rate of 40 breaths/min, and heart rate of 120
beats/min. On examination, you note that he is in moderate respiratory distress with intercostal
retractions, and inspiratory rales are heard in the left upper lung field. Aside from tachycardia, the
remainder of his examination is unremarkable. Chest radiograph reveals a rounded segmental
infiltrate of the left upper lobe. Social history reveals that he lives with his family on a wheat farm and
also raises goats. They have an outdoor cat, 2 dogs, and a dozen chickens. He helped deliver several
goats 4 weeks ago for the first time.
Of the following, the BEST method to diagnose the infection in this patient is
A. direct fluorescent antibody of nasal secretions
B. paired serum antibody titers
C. polymerase chain reaction of blood
D. rapid antigen test of nasal secretion
E. routine blood culture
The patient in the vignette has Q fever caused by Coxiella burnetii. The most likely source of his
exposure and subsequent infection is helping to birth goats on the farm. The most common
manifestation of acute Q fever is asymptomatic illness, which occurs in approximately 50% of those
infected. Pneumonia is another common manifestation and other acute and chronic infectious illnesses
also occur (Table). The optimal way to diagnose this infection is with paired acute and convalescent
serum antibody titers using indirect fluorescent antibody testing. A 4-fold increase of phase II
immunoglobulin G (IgG) 2 to 4 weeks apart confirms the diagnosis. Additionally, an initial phase II IgG
titer of greater than 1:128 is considered to be a probable infection. C burnetii undergoes changes in
its lipopolysaccharide during the course of the infection, causing antigenic shift. This phase variation in
antibody production causes antibodies to phase II antigens to predominate with higher titers than
what is seen for phase I antibodies in the setting of acute infection. However, in the setting of chronic
infection, phase I antibodies predominate. While direct fluorescent antibody testing is available for
some respiratory infections (eg, influenza), there is no available test for Q fever. Similarly, rapid
antigen tests, which are widely used for common respiratory conditions (eg, streptococcal
pharyngitis), are also not available for testing of suspected Q fever. Although polymerase chain
reaction (PCR) tests have been developed for Q fever and are US Food and Drug Administration-
approved, the highest yield for detection of C burnetii in the blood is during the first week of illness,
decreasing rapidly after that time. Therefore, a negative PCR test does not exclude disease. The
patient in this vignette has had symptoms for 2 weeks, decreasing the utility of PCR from the blood.
However, PCR testing of tissues (eg, heart valves) is useful in the setting of chronic disease. Routine
blood cultures will not identify C burnetii. Further, attempts to culture the organism should occur only
at laboratories who have received biosafety approval for selected agents.
Q fever was first recognized as a cause of human disease in Australia in 1935 and in the United States
in 1940. Domestic farm animals, including cows, sheep, and goats, are commonly infected.
Transmission is highest in the spring months, coinciding with domestic animal birthing season. The
organism becomes aerosolized during the birthing process and is inhaled by those attending the
delivery (Figure 1). C burnetii can remain viable for long periods of time in the environment and can
be spread in dust particles. C burnetii has a worldwide distribution, with sporadic cases and occasional
outbreaks occurring. The risk of seroconversion appears to be increased in US military personnel who
served in the Middle East in the first decade of the 2000s. Q fever is likely an underrecognized disease
within the United States as well, as 3% of the adult US population and up to 20% of those who are at
high risk (eg, farmers, veterinarians) have been found to be seropositive. Varying incidence is
reported within the United States, and the infection is not notifiable in all states (Figure 2). The risk
of infection increases with advancing age, with the peak between 60 to 64 years of age, but occurs at
all ages.
PREP Pearls
 Q fever most often occurs in the spring months, coinciding with domestic animal birthing
season.
 Diagnosis of Coxiella burnetii is typically made by acute and convalescent serology.
 C burnetti has worldwide distribution, and infection is often times asymptomatic.

 Recognize the setting, vector, and clinical manifestations of Q fever (Coxiella burnetii)
 Plan appropriate diagnostic testing for a patient in whom Q fever is suspected
 Suggested Readings
 American Academy of Pediatrics. Q fever. Coxiella burnetii infection. In: Kimberlin DW, Brady
MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious
Disease. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:656-658.
 Jaton K, Peter O, Raoult D, et al. Development of a high throughput PCR to detect Coxiella
burnetii and its application in a diagnostic laboratory over a 7 year period. New Microbe New
Infect. 2013;1(1):6-12. DOI: http://dx.doi.org/10.1002/2052-2975.8
November
Question: 2
A 12-year-old boy who is a competitive ice hockey player sustained a ruptured spleen and underwent
an emergency splenectomy. You educate the family about the risk of rapid onset and fulminant course
of postsplenectomy bacterial sepsis, counseling them to seek immediate medical attention for febrile
illnesses. In addition, you make them aware of potentially severe consequences of microorganisms
that could be acquired by bites of various types.
In an asplenic person, the HIGHEST risk of fatal infection after a bite is from
A. Babesia microti
B. Capnocytophaga canimorsus
C. Eikenella corrodens
D. Plasmodium falciparum
E. Salmonella species
Question: 2
A 12-year-old boy who is a competitive ice hockey player sustained a ruptured spleen and underwent
an emergency splenectomy. You educate the family about the risk of rapid onset and fulminant course
of postsplenectomy bacterial sepsis, counseling them to seek immediate medical attention for febrile
illnesses. In addition, you make them aware of potentially severe consequences of microorganisms
that could be acquired by bites of various types.
In an asplenic person, the HIGHEST risk of fatal infection after a bite is from
A. Babesia microti
B. Capnocytophaga canimorsus
C. Eikenella corrodens
D. Plasmodium falciparum
E. Salmonella species
Individuals with congenital or surgical asplenia or with functional hyposplenism, such as those
with sickle cell anemia, untreated HIV infection, or graft-versus-host disease after stem cell
transplantation, are at risk for life-threatening consequences of certain infections. The spleen plays a
pivotal role in clearance of microorganisms from the bloodstream. Spleen macrophages clear bacteria
opsonized with immunoglobulin G, as well as encapsulated bacteria not opsonized by antibodies or
complement. The spleen is also an important organ in the humoral immune system because its
memory B cells generate immunoglobulin M antibodies to polysaccharide antigens of encapsulated
bacteria, so its absence is associated with impaired responses to polysaccharide vaccines.
Several microorganisms are identified in clinical practice as causing infections in asplenic persons
(Table). The most frequent cause is bacteremic Streptococcus pneumoniae, which has a sudden onset
and can progress rapidly to fulminant infection. Postsplenectomy sepsis is associated with a high
mortality rate, even in the modern era. Infections are currently rare with another encapsulated
organism, Haemophilus influenzae type b (Hib), owing to the success of routine Hib immunization. In
addition to education about the risks of infection with encapsulated bacteria, it is important to make
patients aware of the risk of severe infections from other sources, especially animal and arthropod
bites. Of the choices in the vignette, the highest risk of fatality is presented by Capnocytophaga
canimorsus or C cynodegmi causing septicemia with or without cellulitis from dog bites and less
commonly from cat bites. There are rare reports of infection from exposure to saliva on unbroken
skin. The exact mechanism of susceptibility is unknown. Most tick or mosquito-borne organisms are
much less likely to cause fatal infection. However, Babesia infections are more severe and are
associated with a higher mortality rate in asplenic than in eusplenic persons, with Bdivergens-like
species responsible for a more severe illness than B microti. In fact, reports of B divergens-like illness
have been almost exclusively in asplenic patients. The increased severity is presumably because an
intact spleen clears infected erythrocytes from the bloodstream. Additionally, the spleen generates a
B-cell antibody response shown to be critical in immunity to B microti. The role of the spleen in
filtering out infected red blood cells that have reduced deformability may explain the increased level of
parasitemia in some patients with Plasmodium falciparum infection, but an increased fatality rate has
not been established. A human bite would entail the risk of Eikenella wound infection, but the
organism does not disseminate. Reptiles are carriers of Salmonella species, but disseminated
Salmonella infection, common in individuals with sickle cell disease, is rarely acquired by reptile bites.
Among other organisms known to cause infections in asplenic individuals, two-thirds of patients with
Bordetella holmesii bacteremia, an infection reported primarily in young adults, have functional or
anatomic asplenia. For some organisms (Neisseria meningitidis, Staphylococcus aureus, and Gram-
negative bacilli), evidence is lacking for asplenia as a true risk factor. Despite this, meningococcal
vaccination is recommended for asplenic individuals. The observed association with S aureus and
Gram-negative bacilli may be due to prevalence of these infections in asplenic patients with additional
risk factors, such as use of intravascular catheters.
PREP Pearls
 Postsplenectomy sepsis, most commonly caused by Streptococcus pneumoniae, causes

mortality even in the modern era.
 Asplenic persons are at risk for fulminant sepsis from Capnocytophaga infection following a
dog bite.
 Asplenic persons are at risk for severe and occasionally fatal sepsis from Babesia infection.

 Identify the usual microorganisms infecting patients with asplenia/hyposplenia
Suggested Readings
 Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who
have undergone splenectomy. Clin Microbiol Rev. 2010;23(4):740-780. DOI:
http://dx.doi.org/10.1128/CMR.00048-09
 Rubin LG, Schaffner W. Clinical practice: care of the asplenic patient. N Engl J Med.
2014;371(4):349-536. DOI: http://dx.doi.org/10.1056/NEJMcp1314291
November
Question: 3
You are speaking to a group of medical students about the different mechanisms that bacteria have
developed to evade host defenses and cause disease.
Of the following, the organism that is considered to be an intracellular pathogen is
A. Bacillus anthracis
C. Legionella pneumophila
D. Mycoplasma pneumoniae
E. Vibrio cholerae
Question: 3
You are speaking to a group of medical students about the different mechanisms that bacteria have
developed to evade host defenses and cause disease.
Of the following, the organism that is considered to be an intracellular pathogen is
A. Bacillus anthracis
C. Legionella pneumophila
D. Mycoplasma pneumoniae
E. Vibrio cholerae
Pathogenic bacteria can be grouped into different categories based on their invasive properties
for host cells. Intracellular bacterial invade host cells and survive within the cells, while extracellular
bacterial pathogens proliferate in the extracellular environment and do not invade host cells. Of the
organisms listed in the vignette, Legionella pneumophila is the only one that lives in the intracellular
environment.
Upon encountering a human host, a bacterial pathogen may illicit several host responses and use a
variety of mechanisms to evade the host defense. Bacteria have developed a number of mechanisms
for pathogenicity. The bacterial components that interact with the host are shown in the Table.
Host phagocytic cells possess mechanisms to counteract bacterial pathogenicity mechanisms and
destroy ingested bacteria. These killing mechanisms include: the production of reactive oxidative
intermediates, the lowing of pH of bacteria-containing vacuoles, and the activation of degradative
proteases. However, once adhered to a host cell surface, some pathogens invade the host cell and are
able to evade host mechanisms that destroy bacteria. This invasion may be either extracellular or
intracellular. Extracellular invasion occurs when a bacterial pathogen breaks down the barriers of a
tissue to disseminate in the host while remaining outside of the host cells. Intracellular invasion occurs
when a microbe actually penetrates the cells of a host tissue and survives within this environment.
Several bacterial pathogens have evolved to survive and replicate within host cells after invasion. The
range of host cell types in which pathogens can survive include nonphagocytic cells (ie, epithelial and
endothelial) and phagocytes (ie, macrophages and neutrophils). There are 3 general intracellular
niches in which intracellular pathogens reside:
1. Within an acidic, hydrolytically competent phagolysosomal vacuole. Coxiella burnetii is an

example of a pathogen that is able to reside in this toxic environment. It has adapted to this
environment by requiring low pH to initiate its intracellular replication.
2. Inside a vacuole that has not fused with a lysosome. Mycobacterium species, Salmonella
species, Legionella pneumophila, and Chlamydia trachomatis are bacteria that reside in
nonlysosomal vacuoles. The vacuoles that these pathogens occupy are referred to as
―specialized‖ or ―remodeled,‖ and are morphologically different than other cellular vacuoles
and contain a characteristic combination of surface markers.
3. In the host cell cytosol. Shigella flexneri, Listeria monocytogenes, and Rickettsia rickettsii are
pathogens that reside in the host cell cytosol. These bacteria share a common strategy of
enzymatically degrading the surrounding vacuole and spreading intracellularly via use of the
host cell cytoskeleton.
In recent years, genes that allow pathogens to invade host nonphagocytic cells have been identified.
These invasion genes encode an evolutionarily related type III protein secretion pathway that serves
to inject signaling proteins from the microbe into the host cell. The injected proteins than activate host
cell signaling pathways that cause the host cell to internalize the microbe. A common outcome of type
III secretion signaling is the rearrangement of host cell actin such that the cytoskeleton is recruited to
engulf the invading microbe. This entry mechanism is well characterized in Salmonella species and
Shigella species.
Bacteria that survive intracellularly may replicate and spread to other cells in the local area of
infection or migrate to other areas of the body. Chlamydia and Rickettsia lyse the host cell membrane,
releasing infectious bacteria that attach to and invade adjacent cells. Listeria uses a pathway of cell-
to-cell spread that involves extension of the infected cell into an adjacent cell. Invagination occurs
where the infected cell has protruded into the adjacent cell, followed by membrane fusion and
formation of a bacteria-containing vacuole in the adjacent cell. Bacteria residing in macrophages and
neutrophils may use these cells as vehicles to spread systemically via the blood or lymphatic
circulatory systems. Salmonella Typhi, Yersinia species, and Brucella species are thought to move
between tissues in this manner.
PREP Pearls
 Intracellular invasion occurs when a microbe actually penetrates the cells of a host tissue and
survives within this environment, evading host mechanisms that destroy bacteria.
 There are 3 general intracellular niches in which intracellular pathogens reside: 1) within an
acidic, hydrolytically competent phagolysosomal vacuole; 2) inside a vacuole that has not
fused with a lysosome; and 3) in the host cell cytosol.
 Coxiella burnetii, Mycobacterium species, Salmonella species, Legionella pneumophila,
Chlamydia trachomatis, Shigella flexneri, Listeria monocytogenes, and Rickettsia rickettsia are
examples of bacteria that are intracellular pathogens.
 Recognize intracellular bacteria (Brucella, Pasteurella, Listeria, mycobacteria), and how they
resist elimination by the host
Suggested Readings
 Boneca IG, Dussurget O, Cabanes D, et al. A critical role for peptidoglycan N-deacetylation in
Listeria evasion for the host innate immune system. Proc Natl Acad Sci USA.
2007;104(3):997-1002. DOI: http://dx.doi.org/10.1073/pnas.0609672104
 Divangahi M, Chen M, Gan H, et al. Mycoplasma tuberculosis evades macrophage defenses by
inhibiting plasma membrane repair. Nat Immunol. 2009;10(8):899-906. DOI:
http://dx.doi.org/10.1038/ni.1758
 Dornand J, Gross A, Lafont V, Liautard J, Oilaro J, Liautard JP. The innate immune response
against Brucella in humans. Vet Microbiol. 2002;90(1-4):383-394. DOI:
http://dx.doi.org/10.1016/S0378-1135(02)00223-7
 Huang J, Brumell JH. Autophagy in immunity against intracellular bacteria. Curr Top Microbiol
Immunol. 2009;335:189-215. DOI: http://dx.doi.org/10.1007/978-3-642-00302-8_9
 Norrby-Teglund A, Johansson L. Beyond the traditional immune response: bacterial interaction
with phagocytic cells. Inter J Antimicrob Agents. 2013;42 Suppl:S13-S16. DOI:
http://dx.doi.org/10.1016/j.ijantimicag.2013.04.005
 Sibley LD. Invasion and intracellular survival by protozoan parasites. Immunol Rev.
2011;240(1):72-91. DOI: http://dx.doi.org/10.1111/j.1600-065X.2010.00990.x
 Wilson BA, Ho M. Pasteurella multocida: from zoonosis to cellular microbiology. Clin Microbiol
Rev. 2013;26(3):631-655. DOI: http://dx.doi.org/10.1128/CMR.00024-13
 Wilson J, Schurr M, LeBlanc CL, Ramamurthy R, Buchanan K, Nickerson C. Mechanisms of

bacterial pathogenicity. Postgrad Med J. 2002;78(918):216-224. DOI:
http://dx.doi.org/10.1136/pmj.78.918.216
Question: 4
You are asked to see a 26-day-old newborn who is admitted to the pediatric intensive care unit for
apnea and ―brief resolved unexplained events‖ (previously known as apparent life-threatening
events). In speaking with the parents, they inform you that, for the past few days, their baby has a
history of severe episodes of coughing, gagging, and choking that occur without relation to feeding.
The newborn often turns blue and seems to stop breathing for up to a minute during these episodes.
While you are speaking with the parents, he experiences an episode consisting of sudden onset of
coughing spells, gagging, choking, and a 45-second apneic episode requiring vigorous stimulation by
the nursing staff. The newborn has been afebrile and, in between these episodes, appears well.
Several family members, including the mother and two school aged siblings, have had a cough for the
past 3 weeks, consisting of severe paroxysms of cough and posttussive emesis. The mother does not
recall receiving any immunizations during pregnancy. You examine the baby after the severe episode
of coughing and note no abnormalities. A complete blood cell count reveals a white blood cell count of
45,000/μL (45 x 109/L) with 80% lymphocytes and a platelet count of 550 x 103/μL (550 x 109/L).
Of the following, the MOST appropriate anti-microbial treatment for this newborn is
A. azithromycin
B. cephalexin
C. clarithromycin
D. erythromycin
E. trimethoprim-sulfamethoxazole
Question: 4
You are asked to see a 26-day-old newborn who is admitted to the pediatric intensive care unit for
apnea and ―brief resolved unexplained events‖ (previously known as apparent life-threatening
events). In speaking with the parents, they inform you that, for the past few days, their baby has a
history of severe episodes of coughing, gagging, and choking that occur without relation to feeding.
The newborn often turns blue and seems to stop breathing for up to a minute during these episodes.
While you are speaking with the parents, he experiences an episode consisting of sudden onset of
coughing spells, gagging, choking, and a 45-second apneic episode requiring vigorous stimulation by
the nursing staff. The newborn has been afebrile and, in between these episodes, appears well.
Several family members, including the mother and two school aged siblings, have had a cough for the
past 3 weeks, consisting of severe paroxysms of cough and posttussive emesis. The mother does not
recall receiving any immunizations during pregnancy. You examine the baby after the severe episode
of coughing and note no abnormalities. A complete blood cell count reveals a white blood cell count of
45,000/μL (45 x 109/L) with 80% lymphocytes and a platelet count of 550 x 103/μL (550 x 109/L).
Of the following, the MOST appropriate anti-microbial treatment for this newborn is
A. azithromycin
B. cephalexin
C. clarithromycin
D. erythromycin
E. trimethoprim-sulfamethoxazole
This newborn likely has pertussis based on the clinical and laboratory features. Unlike older
infants and children, neonates with pertussis often present with nonspecific signs of infection and
without the classically delineated catarrhal and paroxysmal phases. A paroxysmal cough and whoop
may be absent in neonates, who often present with gagging, choking, apnea, cyanosis, and ―brief
resolved unexplained events‖ (previously known as apparent life-threatening events), such as the
baby in the vignette. The marked leukocytosis and lymphocytosis, which correlate with disease
severity, are characteristic of pertussis.
Supportive care is critical in the management of pertussis infections. Hospitalization is indicated for
most infants younger than 6 months to assess for life-threatening events such as apnea, bradycardia,
and hypoxia. Hospitalization also provides the opportunity for continuous cardiorespiratory monitoring,
vigilant suctioning of the nasopharynx, oxygen therapy (if needed), careful attention to feeding and
hydration, and monitoring for complications such as pneumonia and seizures.
Antimicrobial therapy should be initiated for infants suspected of having pertussis. When started early
in the course of infection, antimicrobial therapy may decrease the duration and severity of symptoms.
Often, however, infants with pertussis present to medical attention well into their illness and the
clinical benefit for these infants is less clear. Nevertheless, antimicrobial therapy is indicated to
prevent spread of the infection. Azithromycin, clarithromycin, and erythromycin are appropriate
options for the treatment of pertussis (Table). Azithromycin is the preferred agent for infants younger
than 1 month of age, based on the fact that infantile hypertrophic pyloric stenosis (IHPS) has been
associated with oral erythromycin therapy. Recent data suggest that azithromycin has also been
associated with IHPS. Azithromycin remains the antibiotic of choice for treating pertussis in infants
younger than 1 month of age, where the risk of therapy is far outweighed by the potential benefit of
azithromycin in preventing life-threatening complication of pertussis. Although clarithromycin is an
alternative agent for treating pertussis in infants older than 1 month of age, this agent is not
recommended for infants younger than one month because of the lack of experience with this agent
and because this agent is generally not as well tolerated as azithromycin. Trimethoprim-
sulfamethoxazole (TMP-SMX) is an alternative for the treatment of pertussis in children who cannot
tolerate macrolides, although the experience using this agent for pertussis is limited. Furthermore,
TMP-SMX is contraindicated in infants younger than 2 months of age because of the risk of
kernicterus. First and second generation cephalosporins have no activity against pertussis.
In infants, the differential diagnosis of pertussis includes respiratory viral illnesses, infection with
Chlamydia trachomatis and with other Bordetella species, bacterial pneumonia, foreign body
aspiration, and reactive airway disease. Adenovirus can produce a clinical syndrome of prolonged
paroxysmal cough, posttussive emesis, and inspiratory whoop, which can be indistinguishable from
pertussis. The presence of associated features commonly found with adenovirus, such as pharyngitis
and conjunctivitis, can help distinguish clinically from pertussis. Respiratory syncytial virus (RSV) is a
common cause of upper and lower respiratory tract infection in neonates and infants, and can
occasionally be difficult to distinguish from pertussis. In addition, dual infection with RSV and B
pertussis can occur, and apnea is a common complication of both infections. The presence of
wheezing, fever, and ongoing symptoms between cough episodes is more suggestive of RSV infection
than pertussis. Chlamydia trachomatis, a common cause of afebrile pneumonia in young infants, can
mimic pertussis, although infants with chlamydial infection usually have a staccato rather than a
paroxysmal cough, tachypnea, rales, and often a history of conjunctivitis in the neonatal period. B
parapertussis and B bronchiseptica have been associated with a pertussis-like illness, but
characteristically cause a less protracted illness. Bacterial pneumonia caused by Staphylococcus
aureus and Streptococcus pneumoniae is not difficult to distinguish from pertussis based on the
clinical manifestations (high temperature, ill appearance, respiratory distress). However, these agents
can secondarily complicate pertussis infection.
In older children and adolescents, the differential diagnosis of pertussis includes infection with
adenovirus, Mycoplasma pneumoniae and Chlamydophila pneumoniae, asthma, and upper respiratory
tract infection. M pneumoniae is a common cause of prolonged cough; the presence of systemic
symptoms such as headache, sore throat, and rales all favor the diagnosis of M pneumoniae.
PREP Pearls
 Azithromycin, clarithromycin, and erythromycin are appropriate options for the treatment of
pertussis, but azithromycin is recommended for infants younger than 1 month of age.
 Meticulous supportive care is paramount for infants with pertussis.
 The differential diagnosis for pertussis varies according to the age and clinical manifestations.
 Formulate a differential diagnosis for a child with suspected pertussis and varying clinical
findings (paroxysmal cough, persistent cough, post-tussive vomiting, lymphocytosis)
 Plan the treatment of a patient with pertussis
Suggested Readings
 American Academy of Pediatrics. Pertussis (whooping cough). In: Kimberlin DW, Brady MT,
 Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric
stenosis. Pediatrics. 2015. DOI: http://dx.doi.org/10.1542/peds.2014-2026
 Langley JM, Halperin SA, Boucher FD, et al. Azithromycin is as effective as and better
tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics.
2004;114(1):e96-e101. DOI: http://dx.doi.org/10.1542/peds.114.1.e96
 Morrison W. Infantile hypertrophic pyloric stenosis in infants treated with azithromycin. Pediatr
Infect Dis J. 2007;26(2):186-188.
 Tiwari T, Murphy TV, Moran J. Recommended antimicrobial agents for the treatment and
postexposure prophylaxis of pertussis: 2005 CDC guidelines. MMWR Morbid Mortal Wkly Rep.
2005;54(RR14):1-16. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5414a1.htm
Question: 5
You evaluate a 4-week-old full term infant in the intensive care unit with a 2-day history of poor
feeding and lethargy followed by sudden onset fever to 39°C, bulging fontanel, and a tonic-clonic
seizure that lasted 15 min on the day of presentation. Cerebrospinal fluid (CSF) is obtained following
intubation and initiation of an epinephrine drip to maintain mean arterial pressure. Culture of the
blood and CSF reveal a Gram-negative bacillus that does not ferment lactose. Parental interview
reveals that the patient‘s 5-year-old brother had a recent diarrheal illness 1 week after he brought
home a small box turtle from a birthday party he attended.
You review the patient‘s CSF results:
 White blood cells, 2,500/μL (2.5 x 103/L) (97% neutrophils, 3% lymphocytes)

 Red blood cells, 50/μL
 Protein, 200 mg/dL
 Glucose, less than 20 mg/dL (1.1 mmol/L)
Of the following, the MOST appropriate minimum length of therapy, in days, for this patient‘s illness is
A. 7
B. 10
C. 14
D. 21
E. 28
Question: 5
You evaluate a 4-week-old full term infant in the intensive care unit with a 2-day history of poor
feeding and lethargy followed by sudden onset fever to 39°C, bulging fontanel, and a tonic-clonic
seizure that lasted 15 min on the day of presentation. Cerebrospinal fluid (CSF) is obtained following
intubation and initiation of an epinephrine drip to maintain mean arterial pressure. Culture of the
blood and CSF reveal a Gram-negative bacillus that does not ferment lactose. Parental interview
reveals that the patient‘s 5-year-old brother had a recent diarrheal illness 1 week after he brought
home a small box turtle from a birthday party he attended.
You review the patient‘s CSF results:
 White blood cells, 2,500/μL (2.5 x 103/L) (97% neutrophils, 3% lymphocytes)

 Red blood cells, 50/μL
 Protein, 200 mg/dL
 Glucose, less than 20 mg/dL (1.1 mmol/L)
Of the following, the MOST appropriate minimum length of therapy, in days, for this patient‘s illness is
A. 7
B. 10
C. 14
D. 21
E. 28
Nontyphoidal Salmonella species is the causative organism of meningitis in the vignette and the
recent acquisition of a new box turtle in the home is the likely source. Salmonella meningitis is almost
exclusively a disease of neonates. Lower inoculum required for infection (compared to 106 in healthy
adult counterparts), coupled with an inadequately functioning immune system, increase infection risk
in this young age group.
Treatment of salmonellosis is based on disease process and age of the infected individual. Infants
younger than 3 months of age that acquire Salmonella infection, at any site, should be treated with a
broad spectrum antimicrobial agent (eg, ceftriaxone) until susceptibilities are known. The
recommended treatment length is based on disease process, and is typically 7 to 10 days for
uncomplicated gastroenteritis, 10 to 14 days for bacteremia, at least 4 weeks for meningitis, and 4 to
6 weeks for osteomyelitis (Table). Treatment of healthy children 3 months of age or older and adults
with uncomplicated gastroenteritis caused by nontyphoidal Salmonella is generally not recommended,
as the disease course is not ameliorated, and shedding may be prolonged. The median time for
bacterial shedding is typically 5 weeks for older children and adults, but can be longer in the setting of
antibiotic therapy. Bacterial shedding is more likely to be prolonged in younger children and may last
as long as 20 weeks in up to 40% of children younger than 5 years of age.
A high risk of neurologic sequelae exists in the setting of Salmonella meningitis, with up to 70% of
infants ranging from mild (eg, IQ between 70-80) to severe (eg, IQ < 55) neurologic impairment at
school entry in a recent retrospective study in Taiwan. Increased risk of neurologic impairment has
been associated with seizures during hospitalization, presence of hypoglycorrhachia, cerebrospinal
fluid protein greater than 200 mg/dL, subdural empyema or brain abscess, cerebral infarction,
ventriculitis, and hydrocephalus. In addition to central nervous system infection, infants infected by
Salmonella species are also at higher risk for bacteremia, sepsis, pneumonia, and osteoarticular
infection. Other groups at high risk of developing invasive focal Salmonella infection include those with
hemoglobinopathies (eg, sickle cell disease), malignancy, inflammatory bowel disease, and HIV.
Additionally, reactive arthritis may develop in up to 2% of adolescents and adults with Salmonella
gastroenteritis, typically in association with human leukocyte antigen-B27 positivity.
Infections with Salmonella species are associated with many animals, including snakes, lizards,
turtles, geckos, crocodiles, chickens, turkeys, pigs, cattle, and hedgehogs, among others. Long
recognized to be at high risk for transmission of Salmonella species, small box turtles (shell < 4 inches
in diameter) have been banned for sale in the United States since 1975. However, some pet stores,
flea markets, street vendors, and online stores still sell these small turtles. From May 2011 through
May 2013, the US Centers of Disease Control and Prevention received reports of 391 Salmonella-
related illnesses from 40 states. Most infections occurred in children and 63 people required
hospitalization. The infecting strain was linked to the turtle or its habitat in many of the cases.
Therefore, inquiry into potential animal exposures is critical in the setting of Salmonella species
infection.
PREP Pearls
 Salmonella meningitis is almost exclusively a disease of neonates.

 Bacterial shedding may be prolonged in children younger than 5 years of age and those who
receive antibiotic treatment for gastroenteritis.
 The length of therapy is prolonged in the setting of meningitis and should be continued for 4
weeks (28 days).
 Know that Salmonella meningitis occurs almost exclusively in young infants and that
prolonged treatment is necessary
 Recognize the different clinical manifestations and potential complications of Salmonella
infection according to age
Suggested Readings
 American Academy of Pediatrics. Salmonella infections. In: Kimberlin DW, Brady MT, Jackson
MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Disease. 30th ed.
Elk Grove Village, IL: American Academy of Pediatrics; 2015:695-702.
 Reller ME. Salmonella species. In: Long S, Pickering LK, Prober CG, eds. Principles and
Practice of Pediatric Infectious Diseases. 4th ed. New York, NY: Saunders Elsevier; 2012:814-
819.
 US Food and Drug Administration. Pet turtles: cute but contaminated with salmonella. US Food
and Drug Administration website.
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048151.htm. Accessed January 26,
2015
 Wu HM, Huang WY, Lee ML, Yang AD, Chaou KP, Hsieh LY. Clinical features, acute
complications, and outcome of Salmonella meningitis in children under one year of age in
Taiwan. BMC Infectious Diseases. 2011;11:30. DOI: http://dx.doi.org/10.1186/1471-2334-
11-30
Question: 6
A 2-week-old neonate born at 26 weeks of gestation with a birth weight of 1,000 g is now being
evaluated for exhibiting signs of sepsis with hemodynamic instability, and an increased level of
respiratory support.
If the baby‘s blood culture yields a pathogen, the MOST likely isolate based on incidence in the United
States of very low birth weight infants will be
A. Candida albicans
B. Escherichia coli
D. Staphylococcus aureus
E. Staphylococcus epidermidis
Question: 6
A 2-week-old neonate born at 26 weeks of gestation with a birth weight of 1,000 g is now being
evaluated for exhibiting signs of sepsis with hemodynamic instability, and an increased level of
respiratory support.
If the baby‘s blood culture yields a pathogen, the MOST likely isolate based on incidence in the United
States of very low birth weight infants will be
A. Candida albicans
B. Escherichia coli
D. Staphylococcus aureus
E. Staphylococcus epidermidis
Very low birth weight (VLBW) infants, defined generally as babies who weigh less than 1,500 g at
birth, account for approximately 1.4% of all live births in the United States. VLBW babies frequently
develop severe infections caused by opportunistic bacteria and fungi in intensive care units. The
reasons for this susceptibility include compromised skin and epithelial barriers, use of central
catheters, immature gastrointestinal mucosa, administration of broad-spectrum antibiotics and of
dexamethasone, decreased complement, decreased neutrophil, monocyte and lymphocyte functions,
lack of maternal immunoglobulin G (IgG) transfer, and decreased production of cytokines. Most of
these pathogens result in sepsis, defined as a positive blood culture with clinical symptoms. The
incidence of sepsis in VLBW babies has been estimated to be about 20% compared to the 0.1%
incidence in term babies during their intensive care unit (ICU) stay, and up to 20% have 2 episodes of
sepsis. The incidence is even higher in infants less than 25 weeks gestation, up to a half of whom can
develop late onset neonatal sepsis. Opportunistic infections are the cause of a 3-fold higher mortality
rate for VLBW infants in neonatal ICUs compared to those without sepsis. The mortality is slightly
higher from Gram-negative bacterial infections than from Gram-positive bacteria.
The Neonatal Research Network of the National Institute of Child Health and Human Development
divided sepsis in the VLBW infants into early onset (less than 72 hours of life), late onset (greater than
72 hours of life), and very late onset sepsis (greater than 2 months of age). The incidence differs
markedly according to the time of onset, being about 1.5% for early-onset, 20% for late-onset and
1% for very late onset. The microbiology also differs by early versus late onset sepsis (Table 1). The
neonate in the vignette has late onset sepsis and so the organism that is statistically most likely to be
isolated on blood culture is a coagulase-negative staphylococcus, especially because the baby does not
exhibit any bowel pathology. Staphylococcus aureus and Candida albicans are other pathogens to be
considered in late onset sepsis in VLBW infants, and are often intravascular catheter-related
infections, but occasionally cause sepsis in the absence of catheters. Necrotizing enterocolitis or other
gastrointestinal pathology is a risk factor for candidemia and for Gram-negative bacillary (most
commonly Escherichia coli) and polymicrobial sepsis. Less common opportunistic pathogens isolated in
late onset sepsis in VLBW infants include enterococci, and Bacteroides species.
There was a major shift in the proportion of pathogens in early onset sepsis in the late 1990s, with a
reduction in group B streptococcal sepsis and an increase in E coli sepsis. Subsequently, the incidence
of E coli sepsis in VLBW infants has remained steady (Table 2).
The lack of decline is mainly due to an increase in other Gram-negative bacilli, coagulase-negative
staphylococci, and other opportunistic bacteria (Table 1).
PREP Pearls
 The overall incidence of early onset sepsis in very low birth weight (VLBW) infants has
remained steady in the era of antepartum prophylaxis, due to an increase in opportunistic
pathogens.
 Very low birth weight babies have a 20% incidence of sepsis compared to 0.1% in term babies
during their intensive care unit stay.
 The most common pathogens in VLBW infants are Escherichia coli in early onset sepsis and
coagulase negative staphylococci in late onset sepsis.
 Recognize infections caused by opportunistic pathogens in very-low- birth-weight infants in

intensive care units (eg, coagulase-negative staphylococcus, Candida)
Suggested Readings
 Bizzarro MJ, Dembry LM, Baltimore RS, Gallagher PG. Matched case-control analysis of
polymicrobial bloodstream infection in a neonatal intensive care unit. Infect Control Hosp
Epidemiol. 2008;29(10):914-920. DOI: http://dx.doi.org/10.1086/591323
 Boghossian NS, Page GP, Bell EF, et al. Late-onset sepsis in very low birth weight infants from
singleton and multiple-gestation births. J Pediatr. 2013;162(6):1120-1124. DOI:
http://dx.doi.org/10.1016/j.jpeds.2012.11.089
 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-
weight infants. Clin Microbiol Rev. 2004;17(3):638-680. DOI:
http://dx.doi.org/10.1128/CMR.17.3.638-680.2004
 Shane AL, Stoll BJ. Recent developments and current issues in the epidemiology, diagnosis,
and management of bacterial and fungal neonatal sepsis. Am J Perinatol. 2013;30(2):131-
141. DOI: http://dx.doi.org/10.1055/s-0032-1333413
 Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset
neonatal sepsis: the predominance of gram-negative infections continues in the National
Institute of Child Health and Human Development Neonatal Research Network, 2002-2003.
Pediatr Infect Dis J. 2005;24(7):635-639.
 Stoll BJ, Hansen NI, Sánchez PJ, et al. Early onset neonatal sepsis: the burden of group B
streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817–826. DOI:
Question: 7
You are asked to see a 20-month-old patient who was initially admitted to the hospital 1 week ago
with complaints of low grade fever of 38.3˚C and limping on the left leg. At the time, he had a
negative work-up that included a complete blood cell count, blood culture, and a magnetic resonance
imaging study. He was discharged home on ibuprofen with the diagnosis of toxic synovitis and
instructed to follow-up with his pediatrician. He did not receive any antimicrobials at the time.
He was readmitted to the hospital 3 days ago with ongoing left leg limp and fevers. The hospitalist
does report that the patient does not look very ill despite the fact that this is his second
hospitalization. Radiographs showed a lytic lesion in the distal epiphysis of the femur, along with some
fluid collection around the joint. Vancomycin was initiated without any significant improvement. The
mother reports that he did have a ―cold‖ prior to the first hospitalization and also that he attends
daycare. The laboratory calls and reports that both the aerobic and anaerobic blood culture bottles
(done on this admission) are growing a Gram-negative organism that appears as pairs and short
chains of plump bacilli. Some of the organisms may look Gram-positive. The laboratory is going to set
up the agar plates and the final identification would be available in approximately 48 hours.
While awaiting culture confirmation, the BEST next step in your management recommendation would
be
A. continue vancomycin, add ceftriaxone
B. continue vancomycin until final identification is available
C. discontinue vancomycin, add clindamycin and ceftriaxone
D. discontinue vancomycin, add oxacillin and ceftriaxone
E. discontinue vancomycin, add piperacillin-tazobactam
Question: 7
You are asked to see a 20-month-old patient who was initially admitted to the hospital 1 week ago
with complaints of low grade fever of 38.3˚C and limping on the left leg. At the time, he had a
negative work-up that included a complete blood cell count, blood culture, and a magnetic resonance
imaging study. He was discharged home on ibuprofen with the diagnosis of toxic synovitis and
instructed to follow-up with his pediatrician. He did not receive any antimicrobials at the time.
He was readmitted to the hospital 3 days ago with ongoing left leg limp and fevers. The hospitalist
does report that the patient does not look very ill despite the fact that this is his second
hospitalization. Radiographs showed a lytic lesion in the distal epiphysis of the femur, along with some
fluid collection around the joint. Vancomycin was initiated without any significant improvement. The
mother reports that he did have a ―cold‖ prior to the first hospitalization and also that he attends
daycare. The laboratory calls and reports that both the aerobic and anaerobic blood culture bottles
(done on this admission) are growing a Gram-negative organism that appears as pairs and short
chains of plump bacilli. Some of the organisms may look Gram-positive. The laboratory is going to set
up the agar plates and the final identification would be available in approximately 48 hours.
While awaiting culture confirmation, the BEST next step in your management recommendation would
be
A. continue vancomycin, add ceftriaxone
B. continue vancomycin until final identification is available
C. discontinue vancomycin, add clindamycin and ceftriaxone
D. discontinue vancomycin, add oxacillin and ceftriaxone
E. discontinue vancomycin, add piperacillin-tazobactam
Given the age, clinical presentation as well as the magnetic resonance image (MRI) and blood
culture findings, the patient in the vignette most likely has Kingella kingae osteomyelitis and septic
arthritis. K kingae is a facultative anaerobic, β-hemolytic, Gram-negative organism that appears as
pairs or short chains of plump bacilli with tapered ends (Figure). It may resist decolorization, thus
resulting in misidentification as Gram-positive. A carbon dioxide-enriched atmosphere enhances
growth, but only a small fraction of strains are truly capnophilic. It can be readily identified by
commercial systems.
K kingae is almost always highly susceptible to penicillins and cephalosporins, although β-lactamase
production has been reported in rare instances. With few exceptions, K kingae is also susceptible to
aminoglycosides, macrolides, trimethoprim-sulfamethoxazole, tetracyclines, chloramphenicol, and
fluoroquinolones. The organism exhibits decreased minimum inhibitory concentration to oxacillin and
is fully resistant to glycopeptide antibiotics. Nearly 40% of isolates are resistant to clindamycin.
Therefore for the patient in the vignette it would be appropriate to add a third generation
cephalosporin while awaiting confirmation of the organism and susceptibility testing. There is no
rationale for changing to clindamycin or oxacillin. Although piperacillin-tazobactam provides adequate
coverage for K kingae, it is a broader spectrum agent than is needed for this patient. After the
organism has been identified, vancomycin can be discontinued.
Once K kingae infection has been confirmed and β-lactamase production has been excluded, initial
antibiotic therapy is often changed to ampicillin or cefuroxime. Clinical response to therapy, as well as
acute phase reactants, are used as a guide to decide when to switch from intravenous to oral
antibiotics and define duration of therapy. It is possible that short antibiotic courses are adequate for
patients with bacteremia and osteoarticular infections because of the benign course followed by most
invasive Kingella infections. However, lack of controlled studies precludes any evidence-based
guidelines for length of therapy and preferred antibiotic regimen at this time.
K kingae has increasingly been recognized as a cause of osteoarticular infections, bacteremia, and
endocarditis in young children, particularly those younger than 4 years of age. The organism colonizes
the posterior pharynx of young children and is transmitted from person-to-person through close
contact. Asymptomatic colonization increases between the ages of 12 to 24 months and then gradually
decreases in older children and adults suggesting the development of an age related immune
response. Childcare attendance has been recognized as a risk factor for acquisition of the organism, as
well as development of disease, because there are increased opportunities for close personal contact,
and transmission and outbreaks have been reported in child care facilities in the United States and
Israel. K kingae infections have also been reported in children older than 48 months of age with
underlying medical conditions. A recent report has described the isolation of identical isolates
recovered from the pharynx and the blood stream suggesting that upper respiratory colonization
represents the first step in the pathogenesis of invasive disease.
Clinical manifestations among reported cases include mostly osteoarticular infections, septic arthritis,
osteomyelitis, tenosynovitis, spondylodiscitis, bacteremia without a focus or in association with a
respiratory tract infection, and endocarditis. Rare manifestations include meningitis, ocular infections,
peritonitis, and pericarditis. Affected children younger than 4 years of age are generally healthy and
signs and symptoms may be nonspecific; therefore, a high index of suspicion is required to make the
diagnosis. Constitutional symptoms generally are lacking except in patients with endocarditis.
Peripheral white blood cell count, erythrocyte sedimentation rate, and C-reactive protein may be
normal to mildly elevated, and patients may have mild to moderate fever.
K kingae septic arthritis generally affects large joints such as the knee, hip, ankle, or shoulder. Small
joints such as metacarpophalangeal, sternoclavicular, and the tarsal joints may be involved more
often than with other infections. Osteomyelitis typically affects the long bones such as the femur, but
involvement of the calcaneum, talus, sternum, or clavicle may occur. Given that the onset is often
insidious and they may not appear very ill, patients may often be diagnosed as toxic synovitis and a
delay in the actual diagnosis is not uncommon.
One-quarter of all cases of hematogenous spondylodiscitis in children younger than 4 years of age
have been attributed to K kingae. Spondylodiscitis in these cases usually involves the lumbar spine
and patients usually present with limp, low back pain, refusal to sit or walk. Magnetic resonance
imaging reveals narrowing of the intervertebral disk space. In a recent study from Switzerland, K
kingae was isolated from throat swabs in children aged 6 to 48 months with radiological evidence of
spondylodiscitis (confirmed on MRI). While the study sample was small, only 10 children over a 4-year
period, the finding of K kingae in oropharyngeal specimens provided reasonable evidence that the two
were linked.
K kingae is also included in the HACEK group of organisms that cause up to 5% of cases of bacterial
endocarditis primarily in older children and adults. Children younger than 3 years of age appear to be
at high risk for the development of cerebral infarction due to septic embolism as a result of K kingae
endocarditis.
The diagnosis of K kingae can be improved by inoculating clinical specimens into aerobic and
anaerobic blood culture bottles from a variety of automated blood-culture systems. When positive
blood culture bottles are sub-cultured onto routine solid media, K kingae grows readily. In addition, in
recent years the use of conventional and real time polymerase chain reaction (PCR) has enabled
identification of the microorganism within 24 hours and has been increasingly utilized.
Antibiotic treatment for K kingae infections has generally varied from 2 to 3 weeks for arthritis, 3 to 6
weeks for osteomyelitis, and 3 to 12 weeks for spondylodiscitis. Bacteremia has generally been
treated for 1 to 2 weeks with the decision to switch from intravenous to oral depending on clinical
response. Cases of endocarditis have been treated anywhere from 4 to 7 weeks with intravenous β-
lactam antibiotics alone or in combination with an aminoglycoside. Surgical intervention is reserved for
those with life-threatening complications.
PREP Pearls
 Kingella kingae has been recognized as an increasingly important cause of osteoarticular

infections in young children younger than 4 years of age, including discitis in infants.
 Affected children are generally healthy with no underlying health conditions, although
attendance at child care facilities has been recognized to be a risk factor.
 The organism commonly colonizes the posterior pharynx between the ages of 12-24 months
and then decreases with age; person-to-person transmission is common.
 A high index of suspicion is required to make the diagnosis of most K kingae infections, except
endocarditis because there is often a lack of symptoms, affected patients are generally not
very ill, and may be misdiagnosed as having toxic synovitis in the case of septic arthritis or
osteomyelitis.
 Recognize Kingella kingae as a causative pathogen in a suppurative skeletal infection,

including diskitis, in an infant
 Plan the diagnosis of Kingella kingae infection
 Plan the most appropriate management for a patient with Kingella kingae infection
Suggested Readings
 Ceroni D, Belaieff W, Kanavaki A, et al. Possible association of Kingella kingae with infantile
spondylodiscitis. Pediatr Infect Dis J. 2013;32(11):1296-1298. DOI:
http://dx.doi.org/10.1097/INF.0b013e3182a6df50
 Foster MA, Walls T. High rates of complications following Kingella kingae infective endocarditis
in children: a case series and review of the literature. Pediatr Infect Dis J. 2014;33(7):785-
786. DOI: http://dx.doi.org/10.1097/INF.0000000000000303
 Rubin LR. Kingella species. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice
of Pediatric Infectious Diseases. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2008:910-912.
 Yagupsky P, Dubnov-Raz G, Gené A, Ephros M. Differentiating Kingella kingae septic arthritis

of the hip from transient synovitis in young children. J Pediatr. 2014;165(5):985-989. DOI:
 Yagupsky P, Porsch E, St Geme JW III. Kingella kingae: an emerging pathogen in young
children. Pediatrics. 2011;127(3):557-565. DOI: http://dx.doi.org/10.1542/peds.2010-1867
 Yagupsky P. Outbreaks of Kingella kingae infections in daycare facilities. Emerg Infect Dis.
2014;20(5):746-753. DOI: http://dx.doi.org/10.3201/eid2005.131633
Question: 8
The microbiology laboratory supervisor notified you that Campylobacter coli was isolated from a stool
sample collected from your patient. The patient is an otherwise healthy 9-month-old infant first
evaluated in the office 2 days ago for low grade fevers and bloody diarrhea. Today, during a follow-up
visit in the office, the infant remained well hydrated, but was continuing to experience 3 or 4 episodes
of diarrhea each day. The infant‘s mother was no longer seeing blood in the stool. You discuss the
results of the stool culture with the infant‘s mother and she asks you how her baby was infected.
Of the following, the MOST likely source for this infant‘s C coli infection was from exposure to
A. contaminated diaper rash cream
B. the family puppy
C. honey
D. houseplants
E. salt water aquarium

Question: 8
The microbiology laboratory supervisor notified you that Campylobacter coli was isolated from a stool
sample collected from your patient. The patient is an otherwise healthy 9-month-old infant first
evaluated in the office 2 days ago for low grade fevers and bloody diarrhea. Today, during a follow-up
visit in the office, the infant remained well hydrated, but was continuing to experience 3 or 4 episodes
of diarrhea each day. The infant‘s mother was no longer seeing blood in the stool. You discuss the
results of the stool culture with the infant‘s mother and she asks you how her baby was infected.
Of the following, the MOST likely source for this infant‘s C coli infection was from exposure to
A. contaminated diaper rash cream
B. the family puppy
C. honey
D. houseplants
E. salt water aquarium
Campylobacter infections are among the most common causes of bacterial gastroenteritis
worldwide. While C jejuni is the most common Campylobacter species to infect humans, at least 8
other species are considered human pathogens including C coli, C fetus, C hyointestinalis, C lari, C
cinaedi, C fennelliae, and C upsaliensis. Gastroenteritis is the most common clinical presentation for
both C jejuni and C coli infections, while C fetus is notorious for causing bacteremia, sometimes with
seeding of the meninges or heart valves.
The age distribution for Campylobacter gastroenteritis is bimodal, with the first peak among children
younger than 4 years of age and the second peak during adolescence and young adulthood. The
highest incidence occurs during the first year of life. Infections in older children and adults may be
minimally symptomatic, with some infected individuals appearing completely healthy.
Campylobacter is a worldwide zoonosis. The reservoir for infection is the gastrointestinal tract of a
variety of domestic and wild animals where bacterial loads are highest in young animals. Chickens,
turkeys, and water fowl are very frequently colonized with C jejuni. Similarly, C jejuni can very often
be cultured from the feces of most farm animals and many domestic pets such as dogs, cats, and
hamsters. Transmission of bacteria from animal to human is by the fecal-oral route via direct contact
with an animal or when the person ingests contaminated water or food. Undercooked poultry and food
items contaminated by the poultry during food preparation are often implicated. Unpasteurized milk is
also a well known source of infection. Salt water aquariums, honey, contaminated diaper rash cream,
and houseplants are not associated with Campylobacter.
C jejuni infection characteristically involves the terminal ileum and colon. The diarrhea is inflammatory
in nature, with grossly visible mucous, pus, or blood. Some strains of Campylobacter produce a
cholera-like toxin. Patients infected with such strains develop high volume secretory diarrhea. Unlike C
jejuni and C coli infections, where bacteremia is a very rare complication, C fetus tends to be invasive,
penetrating the intestinal mucosa and entering the bloodstream without causing diarrhea.
The primary treatment for Campylobacter diarrhea, like other causes of gastroenteritis, is rehydration.
Mild gastrointestinal infections caused by C jejuni and C coli do not require antimicrobial therapy. More
severe or protracted diarrheal illness and gastrointestinal illness in immunocompromised patients
should be treated with azithromycin or erythromycin for 5 to 7 days. In patients who cannot tolerate
antibiotics in the macrolide class, quinolones may be effective, although these agents are not
approved by the US Food and Drug Administration for this indication and quinolone resistance among
bacteria in this genus are increasing.
PREP Pearls
 The reservoir for Campylobacter jejuni and C coli is the gastrointestinal tract of many different
wild and domestic animals, especially young animals.
 Campylobacter infections are transmitted to humans via the fecal-oral route.
 In developed countries, Campylobacter is among the most common causes of bacterial
diarrhea in humans.
 Know that the reservoir of Campylobacter jejuni and Campylobacter coli infection is the
gastrointestinal tract of wild and domesticated animals, especially young animals
 Recognize that fecal-oral transmission is mode of acquisition of Campylobacter jejuni or coli
Suggested Readings
 Longenberger AH, Palumbo AJ, Chu AK, Moll ME, Weltman A, Ostroff SM. Campylobacter jejuni
infections associated with unpasteurized milk--multiple States, 2012. Clin Infect Dis.
2013;57(2):263-266. DOI: http://dx.doi.org/10.1093/cid/cit231
 Mughini Gras L, Smid JH, Wagenaar JA, et al. Increased risk for Campylobacter jejuni and C.
coli infection of pet origin in dog owners and evidence for genetic association between strains
causing infection in humans and their pets. Epidemiol Infect. 2013;141(12):2526-2535. DOI:
http://dx.doi.org/10.1017/S0950268813000356
 Scallan E, Mahon BE, Hoekstra RM, Griffin PM. Estimates of illnesses, hospitalizations and
deaths caused by major bacterial enteric pathogens in young children in the United States.
Pediatr Infect Dis J. 2013;32(3):217-221. DOI:
http://dx.doi.org/10.1097/INF.0b013e31827ca763
December
Question: 1
You are asked to see a 16-year-old adolescent who underwent an orthotopic heart transplant for
dilated cardiomyopathy 1 day ago. The transplant team asks you to make recommendations regarding
prophylaxis for Pneumocystis jirovecii (PCP) and Toxoplasma gondii. Review of her records reveal that
she received a heart transplant from a donor who had positive serology against T gondii, while her
pre-transplant serology for T gondii is negative (Toxoplasma status D+/R-). She has a history of
severe allergy to trimethoprim-sulfamethoxazole.
Of the following, the BEST option for PCP and Toxoplasma prophylaxis in this patient is
A. atovaquone
B. azithromycin
C. clindamycin
D. pentamidine
E. primaquine
Question: 1
You are asked to see a 16-year-old adolescent who underwent an orthotopic heart transplant for
dilated cardiomyopathy 1 day ago. The transplant team asks you to make recommendations regarding
prophylaxis for Pneumocystis jirovecii (PCP) and Toxoplasma gondii. Review of her records reveal that
she received a heart transplant from a donor who had positive serology against T gondii, while her
pre-transplant serology for T gondii is negative (Toxoplasma status D+/R-). She has a history of
severe allergy to trimethoprim-sulfamethoxazole.
Of the following, the BEST option for PCP and Toxoplasma prophylaxis in this patient is
A. atovaquone
B. azithromycin
C. clindamycin
D. pentamidine
E. primaquine
The adolescent in the vignette requires prophylaxis against Pneumocystis jirovecii pneumonia
(PCP) because of her immunosuppressed status following heart transplantation. Prophylaxis against
Toxoplasma gondii is also recommended given the donor-positive status (D+/R-) and the risk of
primary Toxoplasma infection in the transplant recipient. Trimethoprim-sulfamethoxazole (TMP-SMX),
which is effective in preventing PCP and T gondii infection following solid organ transplantation, is
routinely recommended in these circumstances. Given the patient‘s severe allergy to TMP-SMX,
however, an alternative agent is required. Of the agents listed, only atovaquone provides adequate
prophylaxis against both infections. Azithromycin, clindamycin, and primaquine do not have activity
against either agent; pentamidine is an alternative agent used to prevent PCP, but does not have
activity against T gondii.
Atovaquone is a hydroxynaphthoquinone originally developed as an antimalarial drug because of its

activity against drug-resistant Plasmodium falciparum. The drug works by inhibiting the electron
transport system at the cytochrome bc1 complex. Atovaquone is combined with proguanil
(Malarone®) when used for the treatment and prophylaxis of P falciparum. In addition to activity
against falciparum malaria, the drug has in vitro activity against P jirovecii, T gondii, and Babesia
microti.
Atovaquone is highly lipophilic and has variable oral absorption that is enhanced with a fatty meal. The
drug has a significant enterohepatic circulation, which contributes to its long half-life, and is cleared
mainly in the liver and eliminated in the feces. Thus, it should be used with caution in patients with
liver dysfunction. No dosage adjustment for renal dysfunction is needed unless it is used in
combination with proguanil, which is primarily excreted in the urine. Atovaquone is highly protein-
bound, making it necessary to be aware of interactions when used concurrently with other plasma-
bound drugs that have narrow therapeutic indices. Examples include rifampin, tetracycline, and
efavirenz, which are known to reduce plasma concentrations of atovaquone because of competitive
inhibition for protein binding. Another important interaction is that atovaquone increases plasma
concentrations of zidovudine by about 33% due to inhibition of hepatic glucuronidation.
Atovaquone is approved by the US Food and Drug Administration in a fixed dose combination with
proguanil for the treatment and prophylaxis of P falciparum malaria. This combination is strongly
synergistic and prevents the development of resistance as compared to atovaquone alone for P
falciparum. In addition to being an effective alternative agent to TMP-SMX for PCP prophylaxis,
atovaquone is approved for the treatment of mild to moderate PCP in adults who are intolerant of
TMP-SMX. There is limited experience using atovaquone in children who have PCP and in treating
severe PCP. As stated previously, atovaquone is an effective alternative for secondary prophylaxis
against Toxoplasma infection in D+/R- heart transplant recipients and seropositive allogeneic
hematopoietic stem cell or bone marrow transplantation. It has also been used in combination with
pyrimethamine for the treatment of toxoplasmosis in immunocompromised patients. Finally, the
combination of atovaquone and azithromycin has been used in adults for the treatment of babesiosis.
This combination appears to be as effective as and better tolerated than the standard regimen of
clindamycin and quinine.
Atovaquone is generally well tolerated. Gastrointestinal upset, headache, fever, and transient
elevations in hepatic enzymes are the major reported adverse effects.
PREP Pearls
 The major indicated use of atovaquone is in a fixed dose combination with proguanil for the
treatment and prophylaxis of Plasmodium falciparum malaria.
 Atovaquone can be used as an alternative for prophylaxis of Pneumocystis jirovecii and
Toxoplasma gondii infections.
 Atovaquone is administered orally and is generally well tolerated.
 Know the spectrum of activity, pharmacokinetics, pharmacologic properties, and interactions

of atovaquone
 Know the clinical indications for atovaquone therapy
Suggested Readings
 Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of
babesiosis. N Engl J Med. 2000;343(20):1454-1458. DOI:
http://dx.doi.org/10.1056/NEJM200011163432004
 McCarthy JS, Price RN. Antimalarial drugs. In: Bennet JE, Dolin R, Blaser MJ, eds. Mandell,
Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA:
 Nixon GL, Moss DM, Shone AE, et al. Antimalarial pharmacology and therapeutics of
atovaquone. J Antimicrob Chemother. 2013;68(5):977-985. DOI:
http://dx.doi.org/10.1093/jac/dks504
Question: 2
You are speaking to a group of medical students about infections for which patients with X-linked
agammaglobulinemia are at high risk.
Of the following, the virus MOST associated with severe infections in this patient population is
A. adenovirus
B. caliciviridae
C. enterovirus
D. Epstein-Barr virus
E. herpes simplex virus
Question: 2
You are speaking to a group of medical students about infections for which patients with X-linked
agammaglobulinemia are at high risk.
Of the following, the virus MOST associated with severe infections in this patient population is
A. adenovirus
B. caliciviridae
C. enterovirus
D. Epstein-Barr virus
E. herpes simplex virus
X-linked agammaglobulinemia (XLA) patients are not usually more predisposed to severe viral
infections; however, they have an unusual susceptibility to severe, chronic enterovirus infections.
X-linked agammaglobulinemia is a primary immunodeficiency that is characterized by 4 distinct

findings:
1. Onset of recurrent bacterial infections in the first 5 years of life

2. Serum immunoglobulin G (IgG), immunoglobulin M, and immunoglobulin A values that are at
least 2 standard deviations below the normal for age
3. Absent isohemagglutinins or poor response to vaccines
4. Less than 2% CD19+ B cells in the peripheral circulation
Patients with XLA are usually well for the first few months of life because they are protected by
transplacentally acquired maternal immunoglobulin. The majority of patients develop symptoms of
recurrent bacterial infections, profound hypogammaglobulinemia, and less than 0.5% CD19+ B cells in
the blood within 3 months to 3 years of life, with over 50% of patients becoming symptomatic by 1
year of age and over 90% by 5 years of age. The clinical hallmark of XLA is recurrent infections
caused by encapsulated bacteria, particularly Streptococcus pneumoniae and Haemophilus influenzae.
Recurrent otitis media is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary
infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of patients with
XLA are recognized as having an immunodeficiency when they develop a severe, life-threatening
infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. Patients with
XLA are not unusually vulnerable to most viral infections; however, they are unusually susceptible to
severe and chronic enterovirus infections, but not adenovirus, caliciviridae, Epstein-Barr virus, and
herpes simplex virus infections. They are also very susceptible to prolonged infections with
Mycoplasma and Giardia organisms.
X-linked agammaglobulinemia is caused by mutations in Bruton‘s tyrosine kinase (BTK), a signal

transduction molecule that regulates B-cell proliferation, differentiation, or survival. Mutation detection
studies have found alterations in BTK in approximately 90% of male patients with XLA. The mutations
occur throughout the BTK gene and are highly variable. To date, over 500 different mutations in BTK
have been reported. Approximately 25% to 30% of the mutations are amino acid substitutions, 25%
are premature stop codons, and 25% are small insertions or deletions, resulting in frameshifts.
Another 10% of mutations are splicing defects. Most mutations in the BTK gene prevent the
production of any BTK protein.
The diagnosis of XLA is suspected in males with early onset bacterial infections, especially with
encapsulated organisms that may be recurrent, marked reduction in all classes of immunoglobulins,
and absent B cells (CD19+ cells); the decreased number of B cells is the most consistent and
distinctive feature. The diagnosis is established or confirmed only in those individuals who have a
mutation in BTK or who have a maternal uncle or cousin with absent B cells. Molecular genetic testing
of BTK is the most reliable way to identify female carriers of XLA. Wide variations exist in the severity
of the clinical phenotype in patients with mutations in BTK. There is also a broad range in
concentrations of serum immunoglobulins. All patients with XLA have some measurable serum IgG,
and 10% to 20% of patients with mutations in BTK have serum IgG values greater than 200 mg/dL (2
g/L) at the time of diagnosis. The most consistent finding in XLA is the marked reduction in the
number of B cells in the peripheral circulation. The variability in the clinical and laboratory findings in
XLA underscores the importance of mutation detection in confirming the diagnosis of XLA.
Specific blood tests that help confirm the diagnosis of XLA include:
1. Concentrations of serum immunoglobulins

2. Antibody titers to vaccine antigens
3. Lymphocyte cell surface markers
4. Severe neutropenia as demonstrated on complete blood cell count (CBC)
5. Mutation scanning/sequence analysis of BTK gene; these methods detect approximately 90%
of mutations in BTK.
6. Duplication/deletion analysis of BTK gene; this detects the 8% of mutations that are partial or
whole gene deletions, duplications, inversions, or insertions.
The goal of treating patients with XLA is to prevent infections by replacing the missing B-cell product
immunoglobulin. Gamma globulin replacement is considered to be the mainstay of treatment for
patients with XLA. In the United States, most patients with hypogammaglobulinemia are given
intravenous preparations of gamma globulin (IGIV) at a dose of 400 mg/kg every 2 to 4 weeks or
weekly subcutaneous injections of concentrated IG. There is no evidence that any one brand of IGIV is
superior to others as measured by the frequency of adverse effects or protection from infection.
Patients with chronic infections often do better if they receive higher doses of IGIV or if their IGIV is
given more frequently. The dose of IGIV should be tailored to the patient‘s clinical course rather than
their laboratory studies. Adverse effects of IGIV infusion are uncommon in patients with XLA, but may
occur when the patient has an intercurrent infection or the infusion is given too rapidly. Most reactions
subside if the infusion is stopped and then slowly restarted.
There is not a general consensus regarding the use of prophylactic antibiotics in patients with XLA.
Many experts recommend antibiotic prophylaxis for XLA patients, especially those that have chronic
infections associated with complications that are difficult to control, such as chronic sinusitis or
bronchiectasis. Trimethoprim-sulfamethoxazole is the most common antibiotic used, however,
amoxicillin, amoxicillin-clavulanate, and azithromycin may also be used. The rationale for using
antibiotic prophylaxis is that infections in patients with hypogammaglobulinemia are often insidious
and do not immediately come to medical attention. Each infection has the potential to adversely affect
the patient making them more susceptible to the next infection. Patients with XLA should be treated
aggressively with high doses of antibiotics and prolonged courses of therapy when infection is
documented. Live polio vaccines should be avoided in patients with XLA. If patients are receiving IGIV,
other live viral vaccines, such as MMR and varicella, may not be effective if given.

PREP Pearls
 X-linked agammaglobulinemia (XLA) is a primary immunodeficiency that is characterized by 4
distinct findings:
1) onset of recurrent bacterial infections in the first 2 to 5 years of life; 2)serum

immunoglobulin G, immunoglobulin M, and immunoglobulin A values that are at least 2
standard deviations below the normal for age; 3) absent isohemagglutinins or poor response
to vaccines; 4) less than 2% CD19+ B cells in the peripheral circulation
 X-linked agammaglobulinemia is caused by mutations in Bruton‘s tyrosine kinase, a signal

transduction molecule that regulates B-cell proliferation, differentiation, or survival.
 The clinical hallmark of XLA is recurrent infections caused by encapsulated bacteria,
particularly Streptococcus pneumoniae and Haemophilus influenzae. Patients are also at high
risk for severe, chronic enteroviral infections.
 Plan specific long-term preventive therapy for a patient with X-linked agammaglobulinemia
 Plan a diagnostic evaluation for a patient with suspected X-linked agammaglobulinemia
Suggested Readings
 Broides A, Yang W, Conley ME. Genotype/phenotype correlations in X-linked

agammaglobulinemia. Clin Immunol. 2006;118(2-3):195-200. DOI:
http://dx.doi.org/10.1016/j.clim.2005.10.007
 Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol.
2000;19(2):183-204. DOI: http://dx.doi.org/10.1385/CRIAI:19:2:183
 Fried AJ, Bonilla FA. Pathogenesis, diagnosis, and management of primary antibody
deficiencies and infections. Clin Microbiol Rev. 2009;22(3):396-414. DOI:
http://dx.doi.org/10.1128/CMR.00001-09
 Minegishi Y, Rohrer J, Conley ME. Recent progress in the diagnosis and treatment of patients
with defects in early B-cell development. Curr Opin Pediatr. 1999;11(6):528-532.
 Ochs HD, Smith CIE. X-linked agammaglobulinemia: a clinical and molecular analysis.
Medicine (Baltimore). 1996;75(6):287-299.
 Question: 3
A 2-week-old term newborn has herpes simplex encephalitis diagnosed by cerebrospinal fluid
polymerase chain reaction. He is on day 3 of high dose intravenous acyclovir therapy.
Of the following, a significant adverse effect of acyclovir therapy is MOST likely to be identified by
serial monitoring of
A. complete blood cell count with differential
B. serum aspartate aminotransferase
C. serum bilirubin
D. serum creatinine
E. urinalysis
Question: 3
A 2-week-old term newborn has herpes simplex encephalitis diagnosed by cerebrospinal fluid
polymerase chain reaction. He is on day 3 of high dose intravenous acyclovir therapy.
Of the following, a significant adverse effect of acyclovir therapy is MOST likely to be identified by
serial monitoring of
B. serum aspartate aminotransferase
C. serum bilirubin
D. serum creatinine
E. urinalysis
Acyclovir is a relatively safe drug, with neutropenia and nephrotoxicity being the most common
adverse effects in children receiving high dose therapy, which is recommended both for neonatal
herpes simplex virus and for serious varicella-zoster infections. In 1 study comparing adverse effects
of acyclovir at different dosages in neonates, those receiving high dose therapy (60 mg/kg per day)
had higher rates of hematologic abnormalities than did those neonates receiving intermediate doses
(45 mg/kg per day). Hemoglobin levels of less than 8 g/dL (80 g/L), platelet counts below 100 x
103/µL (100 x 109/L), and absolute neutrophil counts less than 1,000/mm3 were seen in
approximately 10% to 15% of infants in the high dose group, but very uncommonly in the
intermediate dose group. Hepatic abnormalities were very uncommon, while significant elevations of
serum creatinine occurred in 6% to 17% of infants, all with disseminated disease. Overall, the data on
adverse effects from such studies are limited, but do point to the importance of monitoring,
particularly for marrow-suppressive events. Marrow suppression generally responds to lowering the
acyclovir dose, if possible, or by administration of granulocyte colony-stimulating factor.
Nephrotoxicity with acyclovir may occur in up to 5% of recipients and can develop via a few
mechanisms, including interstitial nephritis, nephropathy caused by acyclovir crystal formation, and
renal tubular damage. Nephrotoxicity is more likely to occur if acyclovir is administered faster than the
recommended 1 hour infusion. Adequate hydration may lessen the risk of nephrotoxicity, and some
experts recommend maintaining urine specific gravity below 1.010.
Other less common adverse effects include severe tissue damage from infiltrating intravenous
solutions (acyclovir solution is highly alkaline) and neurotoxicity.
Neurotoxicity can manifest as seizures, hallucinations, and other alterations of mental status, or coma.
It occurs most commonly in individuals with renal failure for whom dosage is not decreased quickly
enough. Intravenous acyclovir dosage should be lowered if creatinine clearance falls below 50 mL/min
per 1.73 m2. Acyclovir is removed by hemodialysis.
Note that expert opinion may vary slightly on use of high dose therapy for herpes simplex encephalitis
beyond 3 months of age, with many suggesting that lower dosing (30-45 mg/kg per day) is most
appropriate for children 3 months to 12 years of age because of a higher rate of adverse events with
high dose therapy in this age range. Patients older than 12 years of age should receive regular dosing
(30 mg/kg per day) for herpes simplex encephalitis.
PREP Pearls
 Acyclovir is relatively safe, but can cause marrow suppression, renal failure, neurologic
adverse effects, and severe tissue damage if infiltrated during intravenous infusion.
 Marrow suppression can be managed by lowering acyclovir dose or by administration of
granulocyte colony-stimulating factor.
 Intravenous acyclovir dose should be adjusted if creatinine clearance is less than 50 mL/min
per 1.73 m2.
 Recognize that high dose acyclovir is appropriate in the treatment of varicella zoster and
neonatal herpes simplex virus infections
 Identify the clinical manifestations of acyclovir toxicity (eg, renal failure, CNS symptoms)
Suggested Readings
 American Academy of Pediatrics. Herpes simplex. In: Kimberlin DW, Brady MT, Jackson MA,
Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Disease. 30th ed. Elk
Grove Village, IL: American Academy of Pediatrics; 2015:432-445.
 American Academy of Pediatrics. Varicella-zoster infections. In: Kimberlin DW, Brady MT,
 Harrison GJ. Antiviral agents. In: Cherry JD, Harrison GJ, Kaplan SL, Steinbach WJ, Hotez P,
eds. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia, PA:
 Jones CA, Walker KS, Badawi N. Antiviral agents for treatment of herpes simplex infection in
neonates. Cochrane Database Syst Rev. 2009;3:CD004206. DOI:
http://dx.doi.org/10.1002/14651858.CD004206.pub2
 Kimberlin DW, Lin C-Y, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir
in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108(2):230-
238. DOI: http://dx.doi.org/10.1542/peds.108.2.230
 Kimberlin DW. Antiviral agents. In: Long SS, Pickering LK, Prober CG, eds. Principles and
Practice of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: Saunders Elsevier;
2012:1502-1518.
Question: 4
A 15-year-old adolescent boy presents to the emergency department with a 2-day history of
progressively worsening pain in his right ankle, tactile fever, malaise, and redness and discharge from
both eyes. In the past 2 weeks, he has also noticed some discomfort along his penile shaft during
micturition and intermittent crusting on his penis. He denied abdominal pain, diarrhea, vomiting,
urinary frequency, or urgency.
Your physical examination reveals a well-appearing adolescent in no acute distress, with mild swelling
and erythema over his right ankle and second toe (Figure), and mild conjunctival injection without
eye discharge. A genital examination reveals minimal crusting around his urethral meatus, but no
erythema, penile lesions, or inguinal adenopathy. No skin lesions are seen and the rest of his physical
examination is unremarkable.
Of the following, the pathogen MOST likely to have triggered this adolescent‘s illness is
A. Chlamydia trachomatis
B. herpes simplex virus
C. Mycoplasma genitalium
E. Trichomonas vaginalis
Question: 4
A 15-year-old adolescent boy presents to the emergency department with a 2-day history of
progressively worsening pain in his right ankle, tactile fever, malaise, and redness and discharge from
both eyes. In the past 2 weeks, he has also noticed some discomfort along his penile shaft during
micturition and intermittent crusting on his penis. He denied abdominal pain, diarrhea, vomiting,
urinary frequency, or urgency.
Your physical examination reveals a well-appearing adolescent in no acute distress, with mild swelling
and erythema over his right ankle and second toe (Figure), and mild conjunctival injection without
eye discharge. A genital examination reveals minimal crusting around his urethral meatus, but no
erythema, penile lesions, or inguinal adenopathy. No skin lesions are seen and the rest of his physical
examination is unremarkable.
Of the following, the pathogen MOST likely to have triggered this adolescent‘s illness is
A. Chlamydia trachomatis
B. herpes simplex virus
C. Mycoplasma genitalium
E. Trichomonas vaginalis
The adolescent in the vignette has clinical features suggestive of reactive arthritis syndrome
(formerly Reiter syndrome), urethritis, arthritis, and conjunctivitis, an autoimmune response that
frequently follows genitourinary infection or infectious dysentery. Although reactive arthritis syndrome
has been reported following infection with Neisseria gonorrhoeae, Chlamydia trachomatis infection
accounts for most cases of genitourinary origin. Gonococcal arthritis is more often an acute migratory
polyarthralgia associated with the presence of a pustule on an erythematous base on the hand or foot.
Urethritis caused by herpes simplex virus is typically associated with penile ulcerations, and is not
known to be a trigger for reactive arthritis syndrome. Although Trichomonas vaginalis and Mycoplasma
genitalium are organisms that can cause urethritis, they have also not been implicated as triggers for
Reiter syndrome.
Urethritis may occur as an isolated disorder or may be a component of a systemic syndrome including
Stevens–Johnson syndrome, Kawasaki disease, and reactive arthritis syndrome. It can be caused by a
variety of infectious and noninfectious conditions (Table), and etiologic considerations typically
depend on the patient‘s age, sexual practices, and hygienic standards.
In younger children, noninfectious urethritis resulting from irritation by physical or chemical

substances or fecal contamination are more common causes, but sexually transmitted pathogens can
occur in cases of sexual abuse with genital-to-genital contact. In adolescents, sexually transmitted
pathogens (typically C trachomatis and N gonorrhoeae) are the most common cause of urethritis, and
are normally categorized into either gonococcal urethritis (GU) or nongonococcal urethritis (NGU).
Infectious causes of nongonococcal, nonchlamydial urethritis include Ureaplasma urealyticum, T
vaginalis, M genitalium, herpes simplex virus, adenovirus, and enteric bacteria.
The clinical manifestations of urethritis range from minimal and often overlooked to disabling. Urethral
discharge may be scanty (small bead of moisture or crusting at the urethral meatus) or profuse
enough to stain the undergarments. Other symptoms include itching, urinary frequency, urgency, and
a feeling of heaviness in the genitals and dysuria. Dysuria may be localized to the meatus, the distal
portion of the penis, or anywhere along the penile shaft. The clinical manifestations of gonorrhea and
nongonococcal urethritis are similar; an accurate diagnosis must be based on laboratory examination
of the urethral specimen.
PREP Pearls
 The causes of urethritis in adolescents is similar to that in adults and typically results from
sexually transmitted pathogens, most commonly Neisseria gonorrhoeae and Chlamydia
trachomatis.
 Infectious urethritis in the younger pediatric age group is uncommon, except in children who
have been sexually abused by an adult.
 Urethritis may be a component of a systemic disease.
 Formulate the differential diagnosis, including infectious etiologies for male and female infants,
children, and adolescents with frequency, urgency, dysuria, and a urethral discharge
Suggested Readings
 Farhat W, McLorie G. Urethral syndromes in children. Pediatr Rev. 2001;22(1):17-21. DOI:

http://dx.doi.org/10.1542/pir.22-1-17
 Long SS. Urethritis, vulvovaginitis, and cervicitis. In: Long SS, Pickering LK, Prober CG, eds.
Principles and Practice of Pediatric Infectious Diseases. 3rd ed. Philadelphia, PA. Saunders
Elsevier; 2012:449-457.
 Wald ER. Urethritis. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, eds. Feigin &
Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadelphia, PA: Saunders
Elsevier; 2009:2584-2586.
 Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2010. MMWR
Recomm Rep. 2010;59(RR12):1-110.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5912a1.htm?s_cid=rr5912a1_w. Accessed
August 15, 2013
 Question: 5
A 4-year-old girl is transferred from another facility in severe respiratory distress, intubated, and on
mechanical ventilation. She has a history of surgical correction for truncus arteriosus as an infant and
subsequent frequent episodes of diarrhea and respiratory infections, usually with no etiology
identified. Her height and weight are just below the fifth percentile, with head circumference at the
50th percentile. Although facial features are difficult to identify because of her endotracheal tube
adhesive dressings, her mother shows you a cell phone photograph of the girl, which reveals a short
forehead, hooded eyelids with upslanting palpebral fissures, malar flatness, bulbous nasal tip, and
protuberant ears. A chest radiograph shows diffuse nonspecific interstitial infiltrates, and silver
staining of bronchoalveolar lavage material is shown in the Figure.
Of the following, the diagnostic test MOST likely to reveal her underlying immunodeficiency is
B. in situ hybridization test for 22q11.2 deletion
C. HIV antibody
D. interferon gamma receptor assay
E. quantitative immunoglobulins
Question: 5
A 4-year-old girl is transferred from another facility in severe respiratory distress, intubated, and on
mechanical ventilation. She has a history of surgical correction for truncus arteriosus as an infant and
subsequent frequent episodes of diarrhea and respiratory infections, usually with no etiology
identified. Her height and weight are just below the fifth percentile, with head circumference at the
50th percentile. Although facial features are difficult to identify because of her endotracheal tube
adhesive dressings, her mother shows you a cell phone photograph of the girl, which reveals a short
forehead, hooded eyelids with upslanting palpebral fissures, malar flatness, bulbous nasal tip, and
protuberant ears. A chest radiograph shows diffuse nonspecific interstitial infiltrates, and silver
staining of bronchoalveolar lavage material is shown in the Figure.
Of the following, the diagnostic test MOST likely to reveal her underlying immunodeficiency is
B. in situ hybridization test for 22q11.2 deletion
C. HIV antibody
D. interferon gamma receptor assay
E. quantitative immunoglobulins
The Figure in the vignette is a methenamine silver stain of a bronchoalveolar lavage specimen
showing Pneumocystis jirovecii, strongly suggesting this child has impaired T-cell immunity. This
finding, together with the history of congenital heart defect and facial features, points to a diagnosis of
velocardiofacial syndrome (VCF) associated with microdeletion of chromosome 22q11.2. While a
complete blood cell count might show lymphopenia, this would not lead to a definitive diagnosis.
Infection with HIV is possible, but would not be associated with congenital heart disease or facial
abnormalities. Complete interferon gamma receptor deficiency typically is manifest by increased
susceptibility to mycobacterial and Salmonella infections. Children with VCF generally have normal
quantitative immunoglobulins, but may have poor function. However, they may have a higher
incidence of immunoglobulin A (IgA) deficiency than the general population. The T-cell defects can
also be manifest by autoimmune diseases such as immune thrombocytopenia, perhaps related to the
decreased numbers of T regulatory (CD4+CD25+) cells.
Velocardiofacial syndrome occurs in approximately 1 in 4,000 births. The frequency is much higher in
children with complex congenital heart disease; for example, 7% to 50% of children with conotruncal
cardiac anomaly have this deletion. Most cases are new mutations, but with longer survival of such
patients, the prevalence is expected to increase because inheritance is in an autosomal dominant
fashion typical of microdeletion syndromes.
Classic DiGeorge syndrome is a triad of conotruncal cardiac defects (eg, interrupted aortic arch,
tetralogy of Fallot, or vascular rings), hypoplastic thymus and T-cell immunodeficiency, and
hypocalcemia caused by absent parathyroid glands. Infants with this triad generally are diagnosed
early in life due to complications related to hypocalcemia. However, the phenotypic manifestations are
quite diverse, even among affected siblings in the same family. Children with relatively minor or less
obvious manifestations comprise the bulk of children with VCF and can present with relatively mild
findings.
Most children with VCF and immunodeficiency have mildly increased susceptibility to infection, mainly
sinopulmonary infections, and thus may present to a pediatric infectious disease specialist for
screening immunologic evaluation. T-cell studies would be very helpful in evaluating these mildly
affected individuals and could lead to testing for the 22q11.2 deletion. Typical findings would be
decreased numbers of CD3+ T cells, as well as abnormal T-cell responses to mitogens. In addition to a
higher rate of IgA deficiency noted previously, these patients also may have an impaired humoral
immunity manifest by poor antibody production to polysaccharide antigens. A rare, severe form of
immunodeficiency with VCF is associated with markedly decreased numbers of T cells, with clinical
presentations more suggestive of severe combined immunodeficiency syndrome. Only half of these
patients have the 22q11.2 microdeletion.
Even with milder forms of immunodeficiency in VCF, some children are at risk for developing
complications from live virus vaccines, and it is recommended that measles-mumps-rubella and
varicella zoster vaccines should not be administered to VCF children with absolute CD4+ counts less
than 400.

PREP Pearls
 Velocardiofacial syndrome (VCF) can be associated with thymic aplasia and T-cell
immunodeficiency, with highly variable degrees of clinical immunodeficiency.
 Children with complex congenital heart disease should be screened for VCF via fluorescent in
situ hybridization for 22q11.2 microdeletions.
 Recognize the laboratory abnormalities associated with thymic aplasia (eg, DiGeorge,
velocardiofacial syndromes)
 Plan the laboratory diagnosis of thymic aplasia (eg, DiGeorge, velocardiofacial syndromes),
including genetic testing
Suggested Readings
 Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing
patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332-339. DOI:
 Cancrini C, Puliafito P, Digillo MC, et al. Clinical features and follow-up in patients with
22q11.2 deletion syndrome. J Pediatr. 2014;164(6):1475-1480. DOI:
 Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome
22q11.2 deletion syndromes. Lancet. 2007;370(9596):1443-1452. DOI:
http://dx.doi.org/10.1016/s0140-6736(07)61601-8
Question: 6
You are speaking to a group of Pediatric residents about diphtheria and the available protective
vaccines. One of the residents ask how many doses of a diphtheria-containing vaccine need to be
administered to an infant in order for them to develop protective antitoxin levels against diphtheria.
Of the following, the lowest number of doses of a diphtheria-containing vaccine needed for an infant to
develop protective antitoxin levels is
A. 1
B. 2
C. 3
D. 4
E. 5
Question: 6
You are speaking to a group of Pediatric residents about diphtheria and the available protective
vaccines. One of the residents ask how many doses of a diphtheria-containing vaccine need to be
administered to an infant in order for them to develop protective antitoxin levels against diphtheria.
Of the following, the lowest number of doses of a diphtheria-containing vaccine needed for an infant to
develop protective antitoxin levels is
A. 1
B. 2
C. 3
D. 4
E. 5
Regarding the question posed in the vignette, studies have shown that virtually all infants
develop a diphtheria antitoxin level of greater than 0.01 IU/mL, the minimally protective antitoxin
level, after 3 doses of a diphtheria toxoid containing vaccine. Nonprotective antitoxin levels are
achieved with less than 3 doses of diphtheria-containing vaccine.
Diphtheria is an acute communicable upper respiratory infection caused by the Gram-positive bacillus,
Corynebacterium diphtheriae. Diphtheria is characterized by a membranous inflammation of the upper
respiratory tract, most commonly the pharynx, but may involve the posterior nasal passages, larynx,
and trachea. It may cause widespread damage to other organs, especially the myocardium and
peripheral nerves. Prior to the introduction of diphtheria immunization, diphtheria was a major cause
of childhood mortality.
Vaccine against diphtheria consists of diphtheria toxoid that is adsorbed onto an aluminum salt,
usually aluminum hydroxide or aluminum phosphate. Currently in the United States, diphtheria toxoid
is available in combination with tetanus toxoid (DT) or tetanus toxoid and acellular pertussis vaccine
either in a formulation for use in infants (DTap) or in a formulation for use in adolescents and adults
(Tdap). Globally, diphtheria toxoid continues to be used in combination with tetanus toxoid and whole-
cell pertussis vaccine (DTP).
Both the diphtheria toxoid formulation and schedule of administration affect the level of diphtheria
antitoxin achieved and the duration of protection. There are multiple vaccine schedules that are used
globally for primary immunization of infants, however, after 3 doses of diphtheria toxoid, virtually all
infants achieve antitoxin titers greater than the minimally protective level of greater than 0.01 IU/mL.
For the primary immunization of adults, data suggest that virtually all adults develop diphtheria
antitoxin titers greater than 0.01 IU/mL after administration of 3 doses of diphtheria toxoid and that
most develop titers greater than 0.1 IU/mL, which is considered a protective level of circulating
antitoxin. Antitoxin levels of 1.0 IU/mL and greater are associated with long term protection.
Vaccination does not, however, eliminate carriage of C diphtheriae in the pharynx, nose, or on the
skin.
In the pre-vaccine era, children were susceptible to diphtheria, but adults were immune because of
frequent exposure to C diphtheriae and repeated natural boosting. Large scale immunization of
children with diphtheria toxoid-containing vaccines has resulted in high levels of immunity in this age
group. As the number of clinical cases of diphtheria has declined, asymptomatic carriage of C
diphtheriae has become rare and the reduction in the C diphtheriae reservoir means that opportunities
to build or maintain immunity are limited. In the absence of ongoing exposure, immunity wanes over
time, requiring booster doses of diphtheria toxoid to maintain protective antitoxin levels. Longitudinal
studies show that following a period of rapid decline of antitoxin levels, there is a prolonged slower
decline, followed by a sustained period of less active production of immunoglobulin. Both the 4-dose
schedule used in the United States (doses at 2, 4, 6, and 15 months of age) and a 3-dose schedule
used in other countries (administered at 2, 3, 4 months of age; 3, 5, 9 months of age; or 3, 5, 12
months of age) result in geometric mean levels well in excess of the minimally protective level when
measured at 48 months of age, suggesting that adequate protection is maintained until administration
of the preschool booster dose. Although the various schedules for primary immunization provide
adequate protection from diphtheria in the early years of life, in the absence of a booster dose at 4 to
6 years of age, protection may not be maintained throughout the school age years. Since this wane in
antitoxin level is observed, in order to maintain population immunity, high immunization coverage
should be sustained with a primary series of diphtheria toxoid among infants, administration of
booster doses at school entry, and subsequent boosters throughout life. The World Health
Organization recommends that people living in low endemic or nonendemic areas should receive
booster doses of diphtheria and tetanus toxoids approximately every 10 years after completing the
primary series, and subsequently every 10 years throughout life. In the United States, the diphtheria
toxoid administration schedule is shown in Table 1.
The catchup vaccination schedule for diphtheria toxoid administration in individuals 4 months through
18 years of age who start late or who are more than 1 month behind is shown in Table 2.
Vaccination providers are encouraged to administer vaccines as close to the recommended intervals as
possible. However, longer-than-recommended intervals between doses do not reduce final antibody
concentrations, although protection might not be attained until the recommended number of doses
has been administered. An interruption in the vaccination schedule does not require restarting the
entire series of a vaccine or toxoid or the addition of extra doses. Vaccination providers frequently
encounter individuals who do not have adequate documentation of vaccinations. Providers should only
accept written, dated records as evidence of vaccination. Although vaccinations should not be
postponed if records cannot be found, an attempt to locate missing records should be made by
contacting previous health care providers and searching for a personally held record. If records cannot
be located, these individuals should be considered susceptible and should be started on the age
appropriate vaccination schedule.
There is limited data on adverse reactions after administration of currently available preparations of
diphtheria toxoid are adsorbed because the toxoid is usually administered in combination with tetanus
toxoid and, in certain formulations, with pertussis vaccine. In general, the frequency of reported
common systemic symptoms after vaccination with DT or DTaP are comparable. The higher the
preexisting immunity and the higher the diphtheria toxoid content in the vaccine, the more significant
the systemic and local reactions may be after a booster dose. Table 3 shows the reported adverse
reactions in infants, children, adolescents, and adults that may occur after receiving a dose of a
diphtheria toxoid-containing vaccine.
PREP Pearls
 Vaccine against diphtheria consists of diphtheria toxoid that is adsorbed onto an aluminum
salt, usually aluminum hydroxide or aluminum phosphate.
 Regardless of diphtheria toxoid formulation or schedule of administration, after 3 doses of
diphtheria toxoid, virtually all infants achieve antitoxin titers greater than the minimally
protective level of greater than 0.01 IU/mL.
 In the absence of ongoing exposure to Corynebacterium diphtheriae in the population,
immunity wanes over time, requiring booster doses of diphtheria toxoid to maintain protective
antitoxin levels.
 Plan a routine schedule for diphtheria immunization, including age of the patient, number of
doses and intervals and their reasons, and recommendation if the schedule has been
interrupted
 Know the duration of immunity following diphtheria immunization, and the recommendations
for routine booster doses
 Recognize the adverse effects of diphtheria immunization at different ages
Suggested Readings
 American Academy of Pediatrics. Diphtheria. In: Kimberlin DW, Brady MT, Jackson MA, Long
SS, eds. Red Book: 2015 Report of the Committee on Infectious Disease. 30th ed. Elk Grove
 Galazka AM, Robertson SE. Immunization against diphtheria with special emphasis on
immunization of adults. Vaccine. 1996;14(9):845-857. DOI: http://dx.doi.org/10.1016/0264-
410X(96)00021-7
 Vitek CR, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines.
5th ed. Philadelphia, PA: Saunders Elsevier; 2008:139-156.
Question: 7
You are asked to see an unimmunized 14-year-old adolescent who sustained a deep laceration to his
right forearm while landscaping 7 days ago. He did not seek medical care at the time of the injury. He
has developed neck stiffness and trismus, and is admitted to the hospital. The primary service is
concerned that he may have tetanus.
Of the following, the additional feature that would be MOST consistent with tetanus in this patient is
A. autonomic hypoactivity
B. fever at the onset of illness
C. loss of consciousness
D. nonpainful back spasms
E. rigid, board-like abdomen
Question: 7
You are asked to see an unimmunized 14-year-old adolescent who sustained a deep laceration to his
right forearm while landscaping 7 days ago. He did not seek medical care at the time of the injury. He
has developed neck stiffness and trismus, and is admitted to the hospital. The primary service is
concerned that he may have tetanus.
Of the following, the additional feature that would be MOST consistent with tetanus in this patient is
A. autonomic hypoactivity
B. fever at the onset of illness
C. loss of consciousness
D. nonpainful back spasms
E. rigid, board-like abdomen
Tetanus occurs when spores of Clostridium tetani, which is widely found in soil, gains access to
damaged and devitalized tissue. The effects of tetanus occur as a result of the production of tetanus
toxin (tetanospasmin). Tetanus continues to be endemic in developing countries, but is rare in the
United States because of almost universal vaccination of children with tetanus toxoid. Cases of tetanus
continue to occur among unimmunized individuals and among the elderly, many of whom lack
protection against tetanus.
Generalized tetanus is the most common and severe form, and becomes apparent after an incubation
period of 7 to 10 days. Trismus (lockjaw) is the most common presenting symptom. A history of back
or neck stiffness or rigidity is often appreciated in retrospect. A subtle ―sarcastic smile‖ (risus
sardonicus) may be apparent, and a rigid, board-like abdomen is often detectable on examination.
Painful generalized tetanic, opisthotonic spasm that presents as a severe arching of the back is a
dramatic feature of tetanus. Patients with tetanus are alert and do not have altered mental status, and
their spasms are quite painful and can lead to fractures of the vertebrae and muscle hemorrhage. Life-
threatening complications from these spasms can include respiratory compromise, upper airway
obstruction, and apnea. Autonomic hyperactivity is a common feature of tetanus, and manifests as
irritability, restlessness, sweating, and tachycardia early in the course of illness. Autonomic features
that occur much later in the clinical course include profuse sweating, cardiac arrhythmias,
hypertension, hypotension, and fever.
Other clinical forms of tetanus include local, cephalic, and neonatal tetanus. In local tetanus, tonic and
spastic muscle contractions are limited to one extremity or body region. Cephalic tetanus can follow an
injury to the head and neck and may initially involve only the cranial nerves. Both local and cephalic
tetanus can progress to the generalized form. Neonatal tetanus occurs as a result of contamination of
the umbilical stump in neonates of mothers who lack antibody against tetanus toxin. These neonates
often present with trismus, refusal to feed, inability to suck, facial muscle spasms, and risus
sardonicus. As the disease progresses, rigidity and opisthotonus develop.
The diagnosis of tetanus is clinical and should be based on the characteristic clinical features in the
setting of risk factors, such as wounds, and the exclusion of other causes of tetanic spasms. Recovery
of C tetani from wounds is not helpful in making the diagnosis because this organism is ubiquitous in
soil, which can contaminate many wounds without toxin production. The differential diagnosis of
tetanus includes seizures, rabies, parapharyngeal or dental infection, hypocalcemic tetany, dystonic
reactions to antipsychotic medications, and strychnine poisoning. The lack of loss of consciousness can
help to differentiate the classic spasms of tetanus from seizures and from rabies. Dental infections can
produce significant trismus that can be confused with tetanus. The lack of progression of spasms and
the presence of a dental or a parapharyngeal infection can help to distinguish the 2 entities. Although
laboratory tests are not helpful in making the diagnosis of tetanus, they can help exclude other
diagnoses such as hypocalcemia. The presence of eye deviation, writhing movements of the head and
neck, and absence of persistent tonic muscular contractions between spasms that are seen with
dystonic reactions to antipsychotic medications help to differentiate them from tetanus. The lack of
trismus and abdominal rigidity with strychnine intoxication is helpful in differentiating this ingestion
from tetanus.
PREP Pearls
 Generalized tetanus is the most common and severe form of tetanus and is characterized by
trismus, painful back spasms, autonomic hyperactivity, and a rigid abdomen.
 The diagnosis of tetanus is clinical and should be based on the clinical presentation and
exclusion of other causes of tetanic spasms.
 Recognize the clinical manifestations of Clostridium tetani wound infection and tetanus and
formulate the differential diagnosis of a patient with possible tetanus (dental abscess, rabies,
hypocalcemic tetany, and extrapyramidal effects of antipsychotic drugs
 Know that the diagnosis of tetanus is clinical
Suggested Readings
 American Academy of Pediatrics. Tetanus. In: Kimberlin DW, Brady MT, Jackson MA, Long SS,
eds. Red Book: 2015 Report of the Committee on Infectious Disease. 30th ed. Elk Grove
 Roper MH, Vandelaer JH, Gasse FL. Maternal and neonatal tetanus. Lancet.
2007;370(9603):1947-1959. DOI: http://dx.doi.org/10.1016/S0140-6736(07)61261-6
 US Centers for Disease Control and Prevention (CDC). Tetanus surveillance-United States,
2001-2008. MMWR Morb Mortal Wkly Rep. 2011;60(12):365-369.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6012a1.htm
Question: 8
A 17-year-old adolescent is admitted to your hospital in January with a diagnosis of pneumonia. He

developed cough a week before admission and now reports expectoration of rust-colored sputum,
pleuritic pain, fever, chills, and mild diarrhea. On admission, his temperature is 38°C and his blood
pressure is normal. The oxygen saturation is 90% on room air. His auscultatory findings are minimal,
revealing intermittent bilateral crackles, but a chest radiograph shows consolidation of the right upper
lobe, with extensive bilateral patchy infiltrates in both lungs. His primary care physician considers
psittacosis as a possible cause of his pneumonia because of the history and clinical presentation, and
consults you to comment on the likelihood of this diagnosis, as well as diagnostic plan.
If the diagnosis is confirmed, the occupational setting that would place this adolescent at the HIGHEST
risk of Chlamydophila psittaci infection is
A. an aviary
B. pet shop
C. poultry farm
D. veterinary hospital
E. poultry processing plant
Question: 8
A 17-year-old adolescent is admitted to your hospital in January with a diagnosis of pneumonia. He

developed cough a week before admission and now reports expectoration of rust-colored sputum,
pleuritic pain, fever, chills, and mild diarrhea. On admission, his temperature is 38°C and his blood
pressure is normal. The oxygen saturation is 90% on room air. His auscultatory findings are minimal,
revealing intermittent bilateral crackles, but a chest radiograph shows consolidation of the right upper
lobe, with extensive bilateral patchy infiltrates in both lungs. His primary care physician considers
psittacosis as a possible cause of his pneumonia because of the history and clinical presentation, and
consults you to comment on the likelihood of this diagnosis, as well as diagnostic plan.
If the diagnosis is confirmed, the occupational setting that would place this adolescent at the HIGHEST
risk of Chlamydophila psittaci infection is
A. an aviary
B. pet shop
C. poultry farm
D. veterinary hospital
E. poultry processing plant
Chlamydophila psittaci, the causative agent of psittacosis (parrot fever or ornithosis) is an

obligate intracellular bacterium. The organism is distributed worldwide, and has its reservoir in
psittacine birds (parrot family birds that include parakeets, parrots, cockatiels, budgerigars, and
macaws), pigeons, turkeys, and other orders of birds. It is transmitted to humans by inhaling
aerosolized excrement or secretions from the eyes or beaks of sick or asymptomatic birds. This occurs
in the setting of handling of plumage, mouth-to-beak contact, exposure in aviaries, bird exhibits, and
pet stores, during lawn mowing, and in the laboratory setting. In the United States, Europe, and
Australia, most recent cases were traced to importation of exotic birds, but these are sporadic cases.
All the other settings listed in the vignette have been associated with outbreaks with a high attack
rate. Among these settings, there is a high attack rate in a poultry processing plant, where psittacosis
is the most common cause of pneumonia in workers, who can be exposed from carcasses of deplumed
birds. Smaller outbreaks have occurred among aviary workers, poultry farmers, students and staff at
veterinary hospitals, and pet shop owners.
The diagnosis should be considered in a person with acute respiratory tract infection that presents
with fever, nonproductive cough, headache, and malaise. The incubation period is 5 to 19 days.
Radiographs reveal extensive interstitial pneumonia out of proportion to physical examination findings.
Rare complications include endocarditis, myocarditis, pericarditis, thrombophlebitis, nephritis,
hepatitis, and encephalitis. Modalities available for diagnosis of C psittaci infection include serology,
polymerase chain reaction (PCR), and culture, but each has limitations and therapy should be initiated
based upon clinical suspicion. Complement fixation (CF) or microimmunofluorescence (MIF) is used to
detect antibodies. The US Centers of Disease Control and Prevention definition of a confirmed case is a
compatible clinical illness, along with an immunoglobulin M titer of 1:16 by MIF, a 4-fold or greater
increase in CF or MIF immunoglobulin G antibody to a titer of 1:32 in paired sera obtained after 2
weeks, or culture from respiratory secretions. A probable case is a compatible illness along with either
an epidemiological link to a confirmed human case, or a titer of 1:32 or greater in a single specimen.
Drawbacks of serology include cross-reactions with C trachomatis or C pneumoniae, with CF being less
specific then MIF. In addition, early antibiotic therapy can suppress the antibody response, so a third
serum 4 to 6 weeks after the acute sample may be needed to confirm the diagnosis. The PCR
detection of C psittaci DNA in a respiratory tract specimen can distinguish C psittaci from other
chlamydial species. Culture should be performed only in laboratories with biohazard capabilities.
PREP Pearls
 The reservoir of Chlyamdophila psittaci is not confined to psittacine (parrot family) birds; the
bird can be asymptomatic.
 Most sporadic cases are now reported in pet owners, but outbreaks occur in diverse settings.
 The initial diagnosis should be made clinically and then confirmed by serology.
 Know the major source and epidemiology of Chlamydia psittaci infections

 Plan the diagnosis of Chlamydia psittaci infection
Suggested Readings
 Schlossberg D. Psittacosis (due to Chlamydia psittaci). In: Bennett JE, Dolin R, Blaser MJ, eds.
Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed.
Philadelphia, PA: Saunders Elsevier; 2015:3904 pp.
 Stewardson AJ, Grayson ML. Psittacosis. Infect Dis Clin North Am. 2010;24(1):7-25. DOI:
http://dx.doi.org/10.1016/j.idc.2009.10.003
 Williams CJ, Sillis M, Fearne V, et al. Risk exposures for human ornithosis in a poultry
processing plant modified by use of personal protective equipment: an analytical outbreak
study. Epidemiol Infect. 2013;141(9):1965-1974. DOI:
http://dx.doi.org/10.1017/S0950268812002440
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What is the most common cause of pneumonia in workers at a poultry processing plant?

What is the most common cause of pneumonia in workers at a poultry processing plant?

What are the diagnostic modalities available for Chlamydia psittaci infection?

What are the diagnostic modalities available for Chlamydia psittaci infection?

PREP ID 2015 Dr YAMEEN ALMATAWAH

B. bone marrow suppression

B. bone marrow suppression

* Completed *Take Survey

American Board of Pediatrics Content Specification(s)

 Bozdogan B, Appelbaum PC. Oxazolidinones: activity, mode of action, and mechanism of

Of the following, the MOST common serious consequence of S pyogenes pyoderma is

E. toxic shock syndrome

Of the following, the MOST common serious consequence of S pyogenes pyoderma is

E. toxic shock syndrome

 Serious consequences of superficial skin infections include locally invasive complications,

American Board of Pediatrics Content Specification(s)

American Board of Pediatrics Content Specification(s)

 Recognize the epidemiology (ingestion of raw or uncooked freshwater crabs or crayfish

American Board of Pediatrics Content Specification(s)

B. disseminated adenovirus infection

D. iron overload state

E. X-linked lymphoproliferative disease

B. disseminated adenovirus infection

D. iron overload state

E. X-linked lymphoproliferative disease

American Board of Pediatrics Content Specification(s)

B. cerebrospinal fluid culture

C. computed tomography of the brain

D. cultures from the middle nasal meatus

B. cerebrospinal fluid culture

C. computed tomography of the brain

D. cultures from the middle nasal meatus

 Sterile cerebrospinal fluid cultures do not exclude parameningeal infection.

A. children as well as the staff

B. children younger than 3 months of age

D. children younger than 3 months of age and all staff members

E. no one because the illness is usually self limited

A. children as well as the staff

B. children younger than 3 months of age

D. children younger than 3 months of age and all staff members

E. no one because the illness is usually self limited

Nontyphoidal Salmonella gastroenteritis is generally self limited in nature.

* Required *Take Survey

American Board of Pediatrics Content Specification(s)

 Know the clinical indication and choice of antimicrobial agents in gastroenteritis

American Board of Pediatrics Content Specification(s)

Jump to Question All (8)

Measles immune globulin

Measles immune globulin

Measles immune globulin

Measles immune globulin

should be given to all exposed children regardless of immunization status or immune

Measles immune globulin

should be given to all exposed pregnant women within 6 days of exposure

Measles immune globulin

Measles immune globulin

Measles immune globulin

without evidence of 2 measles containing vaccines

Measles immune globulin