Atypical Pneumonia Syndromes

Dr.Tetty Aman Nasution, MMedSc Departemen Mikrobiologi FK USU Medan

Definition
Syndrome of pneumonitis, fever, and normal white blood cell count without demonstratable bacterial pathogen.

Common Definitions

Pneumonia (Infection involving the Alveolar spaces or interstitial spaces)

Contaminated Larynx Sterile

Common Definitions
Community

Acquired Pneumonia (CAP) Nursing Home Pneumonia Nosocomial Pneumonia Ventilator Associated Pneumonia (VAP)
These diagnoses attempt to imply a specific mechanism of acquisition and likely organisms (often erroneously)

Virulence Properties of Pathogens

Adhesion molecules that bind to cell receptors HA of influenza binds sialic acid G protein of RSV binds to glycoaminoglycans Mechanisms to evade innate host defenses NS1/2 proteins of RSV block -interferon

Virulence Properties of Pathogens

Ability to avoid adaptive immune mechanisms IgA protease of pneumococcus gene recombination by influenza Production of toxins capillary leak Hantavirus via -3 integrins EF & LF toxins of B. anthracis Pseudomonas type III protein, Exotoxin A Evolution of antibiotic resistance -lactamases by bacteria amantadine resistance by influenza

Acquisition of Infection
1. 2.

3. 4.

Colonization of upper airway followed by aspiration of a pathogen (S.pneumo) Infection of upper airway and inhalation/aspiration of infecting organism (RSV, mycoplasma) Direct lower airway inhalation of infecting organism (Influenza, M.Tb,SARS CoV) Hematogenous spread to lung (varicella)

Transmission

Person to Person Influenza, M. tuberulosis, SARS CoV, Varicella, chlamydia, group A strep

S. pneumoniae,

Environment Aspergillosis (air, water) Legionella (water) Histoplasmosis (bird droppings & bat caves) Psittacosis (pet birds) Anthrax (soil)

Definitions used for Pneumonia

Acute vs. Chronic (time) Typical vs. Atypical (clinical characteristics) Alveolar vs. Interstitial (X-ray pattern) Community Acquired vs. Nosocomial (location of illness onset)

Acute

vs.

Chronic

S. pneumoniae SARS Coronavirus Staphylococcus Klebsiella pneumoniae Influenza A Legionella Histoplasmosis Anaerobic (aspiration)

Mycobacterium Aspergillus Nocardia Actinomycosis Histoplasmosis Gram negatives Anaerobic (aspiration)

Typical

vs.

Atypical

Sudden onset Toxic patient appearance Productive cough High fever (>39 C) Elevated WBC with left shift Sputum + WBC & bugs Defined consolidation

Slow onset Patient appears relatively well Non-productive or dry cough No left shift in WBC Sputum + WBC no bugs Interstitial or patchy infiltrate

But dont count on anything Now you are getting it!

Typical

vs Atypical

S. pneumoniae Hemophilus influenza Staph aureus Klebsiella pneumoniae

Respond to -lactames

Mycoplasma Chlamydia Legionella Viruses

Respond to macrolides and quinolones

Diagnostic Tools

History Cough (>90%), sputum (66%), dyspnea (66%), chest pain (50%), fever & chills, myalgias, diarrhea, headache, sore throat, rhinitis Rate of onset, season, location, travel, exposure to ill persons, animals, environment, and immunosuppressive conditions

Physical Exam Temperature, RR, intercostal and accessory muscle use, rales, wheezes, rhonchi, pleural rubs Overall state of health (age), BP, RR, Pulse, O2 saturation (Vital Signs) Provide decision making and prognostic information

Microbiological Diagnosis
History not definitive for determining causative agent Physical Examination not definitive of causative agent Epidemiology may be helpful and in some rare cases is critical X-rays usually provide a hintat best

Microbiological Tests

Commonly available Sputum gram and acid fast stains Sputum Cultures Blood Cultures (>1) Pleural fluid gram stain and culture Nasal cultures for virus Antigen detection for viruses (RSV, Influenza) Special stains for PCP

Less Commonly available Urine antigen detection (legionella, pneumococcus) Serum antigen detection (Aspergillus, Histoplasma, Cryptococcus) RT-PCR for virus, chlamydia, Mycobacterium Serology for Psittacosis

Management Issues for CAP

Hospitalize

or Not Isolation when appropriate What antibiotics to use (IV or oral) When to Discharge

Specific therapy is generally best

S. pneumoniae -lactam Haemophilus -lactamase stable -lactam Moraxella -lactamase stable -lactam Mycoplasma Macrolide or quinolone Chlamydia Macrolide or quinolone Gram negative bacilli -lactam Influenza consider neuraminidase inhibitor

NOSOCOMIAL PNEUMONIAE

Nosocomial Pneumonia
2nd

leading cause of nosocomial infection Accounts for 13-18% on infections Leading cause on bacterial nosocomial infection related death Increases LOS by 7-9 days

VENTILATOR ASSOCIATED PNEUMONIAE

Diagnosis of VAP

Clinical criteria Exam of Endotracheal Aspirates (EA) Quantitative cultures

EA PSB BAL Elastin fibers Intracellular bacteria Procalcitonin IL-6 TREM-1

Other BAL measurements

Clinical Features Atypical Pneumonia Syndrome

Season Age of Host Onset Chills Fever Pleuritic chest pain Cough Throughout year Adolescents/Young Subacute Unusual Moderate, persistent Unusual Dry, hacking

Clinical Features Atypical Pneumonia Syndrome

Tachypnea Pulse temp dissociation Signs of consolidation Sputum Leukocytosis CXR abnormality Unusual May be present Unusual Scant, mucoid Unusual Diffuse, interstitial

Etiologies
Viruses
Influenza A & B Adenovirus Parainfluenza CMV RSV Varicella

Rickettsia
Coxiella burnetti

Bacteria
Legionella species Franciscella tularensis

Viro-bacteria
Mycoplasma pneumoniae Chlamydia pneumoniae Chlamydia psittaci

Parasites
Pneumocystis carinii

Viruses Associated with Respiratory Infections

Syndrome Coryza Influenza Croup Bronchiolitis Bronchopneumonia Commonly Associated Viruses Rhinoviruses, Coronaviruses Influenza viruses Parainfluenza viruses RSV Influenza virus, RSV, Adenoviruses Less Commonly Associated Viruses Influenza and parainfluenza viruses, enteroviruses, adenoviruses Parainfluenza viruses, adenoviruses Influenza virus, RSV, adenoviruses Influenza and parainfluenza viruses, adenoviruses Parainfluenza viruses, measles, VZV, CMV

Influenza Virus

RNA virus, genome consists of 8 segments enveloped virus, with haemagglutinin and neuraminidase spikes 3 types: A, B, and C Type A undergoes antigenic shift and drift. Type B undergoes antigenic drift only and type C is relatively stable

(Courtesy of Linda Stannard, University of Cape Town, S.A.)

Influenza A Virus

Undergoes antigenic shifts and antigenic drifts with the haemagglutinin and neuraminidase proteins. Antigenic shifts of the haemagglutinin results in pandemics. Antigenic drifts in the H and N proteins result in epidemics. Usually causes a mild febrile illness. Death may result from viral/bacterial pneumonia. complications such as

Epidemiology

Pandemics - influenza A pandemics arise when a virus with a new haemagglutinin subtype emerges as a result of antigenic shift. As a result, the population has no immunity against the new strain. Antigenic shifts had occurred 3 times in the 20th century.
Epidemics - epidemics of influenza A and B arise through more minor antigenic drifts as a result of mutation.

Past Antigenic Shifts

1918 1957 1968 H1N1 Spanish Influenza H2N2 Asian Flu H3N2 Hong Kong Flu 20-40 million deaths 1-2 million deaths 700,000 deaths

1977 H1N1 Re-emergence

No pandemic

At least 15 HA subtypes and 9 NA subtypes occur in nature. Up until 1997, only viruses of H1, H2, and H3 are known to infect and cause disease in humans.

Avian Influenza
H5N1

An outbreak of Avian Influenza H5N1 occurred in Hong Kong in 1997 where 18 persons were infected of which 6 died. The source of the virus was probably from infected chickens and the outbreak was eventually controlled by a mass slaughter of chickens in the territory. All strains of the infecting virus were totally avian in origin and there was no evidence of reassortment. However, the strains involved were highly virulent for their natural avian hosts.

H9N2

Several cases of human infection with avian H9N2 virus occurred in Hong Kong and Southern China in 1999. The disease was mild and all patients made a complete recovery Again, there was no evidence of reassortment

Theories Behind Antigenic Shift

1. Reassortment of the H and N genes between human and avian influenza viruses through a third host. There is good evidence that this occurred in the 1957 H2N2 and the 1968 H3N2 pandemics. 2. Recycling of pre-existing strains this probably occurred in 1977 when H1N1 re-surfaced.
3. Gradual adaptation of avian influenza viruses to human transmission. There is some evidence that this occurred in the 1918 H1N1 pandemic.

Reassortment

Avian H3

Human H2

Human H3

Influenza
CXR Diagnosis Perihilar bronchopneumonia Direct antigen detect. Cultures (3 - 5 days) Serology Flu A --> Amantadine Flu B -->Ribavirin (?) Vaccine; Amantadine

Therapy Prevention

Laboratory Diagnosis

Detection of Antigen - a rapid diagnosis can be made by the detection of influenza antigen from nasopharyngeal aspirates and throat washings by IFT and ELISA Virus Isolation - virus may be readily nasopharyngeal aspirates and throat swabs. isolated from

Serology - a retrospective diagnosis may be made by serology. CFT most widely used. HAI and EIA may be used to give a typespecific diagnosis

Management

Amantidine is effective against influenza A if given early in the illness. However, resistance to amantidine emerges rapidly Rimantidine is similar to amantidine but but fewer neurological side effects. Ribavirin is thought to be effective against both influenza A and B. Neuraminidase inhibitors are becoming available. They are highly effective and have fewer side effects than amantidine. Moreover, resistance to these agents emerge slowly

Parainfluenza Virus

ssRNA virus enveloped, pleomorphic morphology 5 serotypes: 1, 2, 3, 4a and 4b No common group antigen Closely related to Mumps virus

(Linda Stannard, University of Cape Town, S.A.)

Clinical Manifestations

Croup (laryngotraheobroncitis) - most common manifestation of parainfluenza virus infection. However other viruses may induce croup e.g. influenza and RSV.
Other conditions that may be caused by parainfluenza viruses include Bronchiolitis, Pneumonia, Flu-like tracheobronchitis, and Corza-like illnesses.

Laboratory Diagnosis

Detection of Antigen - a rapid diagnosis can be made by the detection of parainfluenza antigen from nasopharyngeal aspirates and throat washings.
Virus Isolation - virus may be readily nasopharyngeal aspirates and throat swabs. isolated from

Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

Respiratory Syncytial Virus (RSV)

ssRNA eveloped virus.

belong to the genus Pneumovirus of the Paramyxovirus family. Considerable strain variation exists, may be classified into subgroups A and B by monoclonal sera. Both subgroups circulate in the community at any one time. Causes a sizable epidemic each year.

Clinical Manifestations

Most common cause of severe lower respiratory tract disease in infants, responsible for 50-90% of Bronchiolitis and 5-40% of Bronchopneumonia
Other manifestations include croup (10% of all cases). In older children and adults, the symptoms are much milder: it may cause a corza-like illness or bronchitis.

Infants at Risk of Severe Infection

1. Infants with congenital heart disease - infants who were hospitalized within the first few days of life with congenital disease are particularly at risk. 2. Infants with underlying pulmonary disease - infants with underlying pulmonary disease, especially bronchopulmonary dysplasia, are at risk of developing prolonged infection with RSV. 3. Immunocompromized infants - children who are immunosuppressed or have a congenital immunodeficiency disease may develop lower respiratory tract disease at any age.

Laboratory Diagnosis

Detection of Antigen - a rapid diagnosis can be made by the detection of RSV antigen from nasopharyngeal aspirates. A rapid diagnosis is important because of the availability of therapy
Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates. However, this will take several days. Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

Adenovirus

ds DNA virus

non-enveloped
At least 47 serotypes are known

classified into 6 subgenera: A to F

(Linda Stannard, University of Cape Town, S.A.)

Clinical Syndromes
1. Pharyngitis 1, 2, 3, 5, 7 2. Pharyngoconjunctival fever 3, 7 3. Acute respiratory disease of recruits 4, 7, 14, 21 4. Pneumonia 1, 2, 3, 7 5. Follicular conjunctivitis 3, 4, 11 6. Epidemic keratoconjunctivitis 8, 19, 37 7. Pertussis-like syndrome 5 8. Acute haemorrhaghic cystitis 11, 21 9. Acute infantile gastroenteritis 40, 41 10. Intussusception 1, 2, 5 11. Severe disease in AIDS and other immunocompromized patients 5, 34, 35 12. Meningitis 3, 7

Laboratory Diagnosis

Detection of Antigen - a rapid diagnosis can be made by the detection of adenovirus antigen from nasopharyngeal aspirates and throat washings.
Virus Isolation - virus may be readily isolated nasopharyngeal aspirates, throat swabs, and faeces. from

Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

Treatment and Prevention

There is no specific antiviral therapy.

A vaccine is available against Adult Respiratory Distress Syndrome. It consists live adenovirus 4, 7, and 21 in enterically coated capsules. It is given to new recruits into various arm forces around the world.

Coronavirus

ssRNA Virus Enveloped, pleomorphic morphology 2 serogroups: OC43 and 229E

Chlamydial pneumonias
Chlamydial trachomatis

afebrile, pertussoid infantile pneumonia atypical pneumonia from infected birds

Chlamydia psittaci

Chlamydia pneumoniae

atypical pneumonia in young adults

CHLAMYDIA PNEUMONIAE
Human to human transmission (No animal reservoir) Causes bronchitis, pneumonia and sinusitis. Infection in humans very common with several hundred thousand cases each year in the US.

Causes a mild to severe atypical pneumonia similar to those

caused by Mycoplasma pneumoniae and Legionella. Diagnosis by serology and by specific PCR.

Tetracyclines and erythromycin are drugs of choice.

A lot of published data suggest an etiologic association with atherosclerosis and coronary artery disease

C. pneumoniae / Clinical features

Headache Cough Sore throat Hoarseness Temp > 37.8 C WBC > 10 ESR > 15 Pneumonitis on CXR 57% 100% 71% 14% 14% 15% 85% 100%

Chlamydia pneumoniae
CXR
Diagnosis

Therapy

Unilateral basilar subsegmental Serology (IgM > 1:16) acute Tissue culture (MAb) Macrolides or Doxy 14 - 21 days

Laboratory Diagnosis
Laboratory diagnosis is made by one or more of the following

1.

Isolation of the organism from infected tissue. The tissue is inoculated into the yolk sac of seven-day chick embryos or in McCoy human cells. Characteristic cytoplasmic inclusion bodies infected cells.
Cytoplasmic inclusion bodies

2.

3. Serological diagnosis:

a. Microimmunofluorescent tests in tears of patients with eye infections for the presence of anti-chlamydia antibody. In neonatal conjunctivitis and early trachoma, direct immunofluorescence of conjunctive cells with fluorescein conjugated monoclonal antibody is sensitive and specific. b. Delayed-type skin reaction (type IV hypersensitivity) to killed organisms in genitourinary infections (Frei test). c. Rising titer of antibody against the chlamydial family antigen in lung infections. This accomplished with the complement fixation test or the fluorescent antibody test.

M. pneumoniae
Penyebab atypical pneumoniae

Lapisan luar permukaan bakteri terdiri dari 3 lap membran sel yang fleksibel, shg dpt membentuk round hingga oblong shaped Bentuk pleomorfik, dpt melewati saringan dengan ukuran 45um Pathogen hanya pada manusia

M. pneumoniae
= Ditularkan melalui respiratory droplets
= Mucosa saluran pernapasan tidak diinvasi, ttp gerakan cilia terhambat dan terjadi nekrosis epitel = Protein P1( faktor virulensi) melekat pd sel epitel dari saluran pernapasan = Hanya mempunyai 1 jenis serotype dan antigen ini berbeda dgn jenis mycoplasma lainnya = Mengenai anak2, remaja dan dewasa

= Extra cellular pathogen

= Lower respiratory tract menjadi iritasi

Mycoplasma pneumoniae
CXR Unilateral lower lobe involvement Effusions in 10% Cold agglutinins (Titer > 1:128) Serology (IgM > 1:4) Macrolides or Doxy 14 - 21 days

Diagnosis

Therapy

M. pneumoniae
Gejala Klinis Primary atypical pneumonia-walking pneumonia Mild upper respiratory tract disease

Malaise, low grade fever, headache Batuk kering, non produktif 2-3 minggu setelah penularan 10-14 hari penyakit membaik (self-limiting pneumonia)

Laboratory Diagnosis
The laboratory diagnosis of mycoplasma infection can be accomplished by:

1. Culturing the organism from sputum, mucous membrane swabbing or other specimens by direct inoculation into liquid or solid media containing serum, yeast extract and penicillin to inhibit contaminating bacteria.

Colonies will become detectable in one to three weeks.

They stain intensely with neutral red or tetrazolium or methylene blue. The organism can be presumptively identified by its hemabsorption or B-hemolysis of guinea pig red blood cells.

It is conclusively identified by staining its colonies with homologous fluorescein-labelled antibody.

2. Quantitation of the patient antibody response to mycoplasma by complement fixation tests on acute and convalescent serum. Cold agglutinins to human O erythrocytes may also be measured.

Diagnosis Laboratorium Serology

1.

Cold agglutinins Kadar IgM thd membrane glycolipid yg bereaksi silang dg tipe O pd RBC tjd agglutinasi sel ini pd 4C disbt cold agglutinin Minggu ke1 atau 2 infeksi, puncak pd minggu ke 3 kemudian menurun stlh bbp bulan Dapat terjadi false positive pd influenza virus dan infeksi adenovirus

2. Complement fixation Test Mendeteksi IgA, dijumpai pada awal onset of infection Mencapai puncak setelah 4 minggu Menetap selama 6-12 bulan Kenaikan titer > 4x konfirmasi diagnostik Sensitivitas tinggi, dapat terjadi false positive

Diagnosis Laboratorium Serology

3. ELISA Lebih mudah dilakukan dibanding dengan complement fixation Sensitivitas tinggi Dapat terjadi false positive 4. DNA Probe Sputum dengan hibridisasi asam nukleat Sputum mixed dgn recombinan DNA sequence yg homolog dg mycoplasma tsb dan diberi label Recombinan probe akan memberi tanda jika sputum positif dng DNA mycoplasma tsb

5. Polymerase Chain Reaction (PCR) amplifikasi DNA

Legionella
Legionella pneumophila American Legion Convention in Philadelphia in 1976 42 species: 20 species human pathogens L.pneumophila: 15 serogroups The main focus: L.pneumophila serogroup1 Atypical pathogen Macrolide, quinolones

Legionella sp.
Intracellular facultative parasites Hyperendemic Primarily associated with pneumonia community acquired (10 - 15%) nosocomial (10%) Worse in immunocompromised hosts

Extrapulmonary manifestations
Gastrointestinal
Diarrhea, nausea, vomiting, abnml. LFTs

Neurologic
HA, confusion, seizures, obtundation

Renal
Microscopic hematuria, proteinuria,ARF

Hyponatremia Hypophosphatemia

Legionella roentgenograms
Rounded opacities with
poor margins Diffuse patchy shadows Peripheral shadows Lobar inbvolvement Small pleural effusions 46% 25% 21% 17% 50%

Legionnaires disease
Admission
1. Toxic prodromal illness 2. Confusion / Diarrhea / Non-productive cough 3. Lymphopenia 4. Hyponatremia

2 -3 Days Later
1. Negative microbiological data 2. Radiographic extension 3. Abnormal LFTs 4. Hypoalbuminemia

Diagnostic Test for Legionellae

Sputum culture Blood culture Direct Fluorescent Antibody Screening Urine Legionella Antigen Detection Serologic Diagnosis Polymerase Chain Reaction

Diagnostic Test for L. Pneumophila Serogroup 1

Summary
Test Culture Specimen Sensitivity Specificity Time to diagnosis Sputum <10% 100% 3-7 days Blood 0%-6% 100% 3-7 days Direct Sputum 33%-68% 99%-100% 1 hour Fluorescent Ab screen Antigen Urine 80%-90% 98%-100% <1 hour detection Serology Serum 60%-80% 95%-99% 6-10 weeks PCR Urine/blood 75%-82% 90%-100% 2-4 hours Respiratory 83%-100% 90%-100% 2-4hours secretion

Legionella / Diagnosis
Culture

Urine antigen

selective media results in 2 -7 days 90% specificity

results in 1 -6 hours serogroup 1 specific 80% sensitivity

DFA (secretions)

DNA probe

serogroup 1 specific 60 - 70% specificity

Confirms culture 75% sensitivity

Legionella
Therapy
Erythromycin 1 gm IV q6 hours Add Rifampin 600 bid if severely ill 3 weeks duration

Prevention
Hyperchlorination Superheating UV radiation Water sample testing

Legionella Clinical Pearls

Fever

unremitting No upper respiratory prodrome Relative bradycardia (60%) CNS + GI symptoms

Community Acquired Pneumonia

Etiologies requiring hospitalization
Bacterial Legionella Mycoplasma Viruses 15 - 65% 15% 10 - 40% 10 - 30%

Community Acquired Pneumonia

etiology
S.pneumoniae

H.influenzae

Other Anaerobes L.pneumophilia M.pneumoniae C.pneumoniae