Sickle Cell Disease in Children

Rehema Marando
MD, Mmed
Pediatrician
 Outline
• Introduction
• Epidemiology
• Pathophysiology
• Clinical Presentations
• Management
 Diagnosis
 Treatment – Acute &
chronic complications
 Introduction
• First described in Chicago in 1910 by James
Herrick
• An inherited disease of red blood cells
• Affects hemoglobin molecule
• Polymerization of hemoglobin leads to a
cascade of effects decreasing blood flow
• Tissue hypoxia causes acute and chronic
damage
 Epidemiology
• Genetic mutation occurred in Hb gene in parts of Africa,
Mediterranean basin, Middle East and India.
• A deadly form of malaria was very common at that time
• In areas where malaria was a problem, children who inherited
one sickle Hb gene (sickle cell trait) had a survival advantage.
• They survived the malaria epidemics they grew up, had their
own children, and passed on the gene- for sickle hemoglobin.
• Spread to other parts of the world through migration of
population
 Cont…
• More than 2.5 million Americans have the trait
• Among African-American
1 in 12 have Sickle Cell Trait (Hb SA)
1 in 600 have Sickle Cell Anemia (Hb SS)
• 70,000 or more Americans have sickle cell
disease
• About 1,000 babies are born with the disease
each year in America
 In Nigeria, 1/3 population of U.S., 45,000-90,000 babies with sickle cell
disease are born each year
• In broad terms, the prevalence of the sickle-cell
trait (healthy carriers who have inherited the
mutant gene from only one parent) ranges
between 10% and 40% across equatorial
• Africa and decreases to between 1% and 2% on
the north African coast and <1% in South Africa.
• This distribution reflects the fact that sickle-cell
trait confers a survival advantage against malaria
and that selection pressure due to malaria has
resulted in high frequencies of the mutant gene
especially in areas of high malarial transmission
Sickle Cell Gene Severe Malaria
 Pathogenesis of Sickle Cell Disease

• The genetic defect producing sickle Hb is a single

nucleotide substitution (GTG for GAG) at codon 6
of the beta globin gene on chromosome 11
• This results in the substitution of valine for
glutamic acid
• replacing the amino acid glutamic acid with the
less polar amino acid valine at the sixth position
of the β chain
 Sickle Cell Disease
SCD Genotype

Genotype Genotype prevalence

• Sickle cell anemia (SS) • 65%

• Sickle Hb C disease • 25%
(SC) • 8%
• Sickle S beta plus
(Sβ+ thalassemia ) • 2%
• Sickle Beta zero
(Sβ° thalassemia)
• Factors that contribute to red cell sickling include :

- erythrocyte dehydration
- erythrocyte and leukocyte adhesion to an
activated endothelium,
- vasoconstriction due to cold,
- and hypercoagulability
Genetics
 2 copies of the gene for
Hb (each parent)

 HbS –Recessive
 S=Sickle
 A=Normal
RBC containing mostly normal Hb

- O2

+ O2
oxygenated deoxygenated

RBC containing mostly Hb S

- O2

+ O2

+ O2

oxygenated deoxygenated
 Cont…
• Polymerization of hemoglobin leads to a
cascade of effects decreasing blood flow
• Tissue hypoxia causes acute and chronic
damage
 Normal Vs. Sickle Red Cells
Normal Sickle
• Disc-Shaped • Sickle-Shaped
• Deformable • Rigid
• Life span of 120 days • Lives for 20 days or
less
Sickle Cell Disease: Pharmacologic Treatment

Clinical Pathology of SCD

1. Anemia

2. Vasoocclusion

3. Chronic organ damage

 Clinical Presentations
• Infants are often asymptomatic in the first 3-4 months
of life due to the persistence of fetal hemoglobin
• Typically appear during infant's first year
 1st symptom: dactylitis and fever (6 mo-2 yrs)
 Pain in the chest, abdomen, limbs and joints
 Enlargement of the heart, liver and spleen; nosebleeds
 Frequent upper respiratory infections
 Chronic anemia as children grow older
• Over time Sickle Cell sufferers can experience damage to organs such as
liver, kidney, lungs, heart and spleen
• Can result in death
 Hemolysis and Vaso-occlusion
(continued)

Acute Manifestations: Chronic Manifestations:

• • Anemia
Bacterial Sepsis or meningitis*
• Jaundice
• Recurrent vaso-occlusive pain • Splenomegaly
(dactylitis, muscoskeletal or abdominal • Functional asplenia
pain) • Cardiomegaly and functional murmurs
• Splenic Sequestration* • Hyposthenuria and enuresis
• Aplastic Crisis* • Proteinemia
• Cholelithiasis
• Acute Chest Syndrome* • Delayed growth and sexual maturation
• Stroke* • Restrictive lung disease*
• Priapism • Pulmonary Hypertension*
• Hematuria, including papillary necrosis • Avascular necrosis
• Proliferative retinopathy
• Leg ulcers
• Transfusional hemosiderosis*

*Potential cause of mortality

 Management
• Diagnosis
• Health maintenance
• Infection prevention
• Pain management
• Sickle emergencies
• Chronic disease management
 Diagnosis
• Sickling test – solubility test
• Hb Electrophoresis – confirmatory
• HPLC
• Prenatal testing
 Amniocentesis
 16 and 18 weeks of the pregnancy
 small risk of causing a miscarriage (1 in 100)

 Chorionic villus sampling (CVS)

 9th or 10th week of pregnancy
 very small amount of material from the developing placenta
 slightly higher chance of miscarriage
 Health Maintenance
• Frequent visits: every 3 to 6 months
• Immunizations
– Routine immunizations
– Hib and PCV-13
• Penicillin prophylaxis beginning no later than
two months
• Malaria prevention is use of ITNs (Insecticide
treated nets)
• Nutrition and fluids
– Folate supplementation is controversial
 Health Maintenance
• Physical exam with attention to:
– Growth and development, jaundice, liver/spleen
size, heart murmur of anemia, malocclusion from
increased bone marrow activity, delayed puberty
• Lab evaluations:
– FBP with differential and reticulocyte count,
urinalysis, renal & liver function
 Health Maintenance
Special studies
• Brain- Transcranial doppler ultrasonography,
MRI/MRA
• Lungs- Pulmonary function tests, Echo cardiogram
for pulmonary hypertension
 Current Recommendations
• Penicillin Prophylaxis:
– 2 months to 3 years: 125 mg PO BID
– Over 3 years: 250 mg PO BID
• When to discontinue is controversial
• Can be stopped at 6 years
• Special Circumstances
– History of repeated sepsis, surgical splenectomy
 Emergencies
• Fever/infection
• Acute chest syndrome
• Eye trauma
• Priapism
• Stroke
• Splenic sequestration
• Severe pain
 Eye Examination
• Retinal vessel disease
– Incidence 33% in hemoglobin SC
– Incidence 3% in SS
• Annual evaluation after age 10 years by
ophthalmologist
– Laser photocoagulation for vessel disease
 Eye Trauma
Eye trauma is an emergency in ALL sickle conditions
(including sickle trait)

Sickle cells can damage blood

vessels in the eyes
New weaker vessels may form
and may bleed
Rx; Laser therapy
Complications if untreated:
-glaucoma,
-optic nerve atrophy,
-retinal artery blockage
 Priapism
• Commonly occurs in children and adolescents with SS
• Urologic emergency

Treatment is difficult
– Opioid pain medication
– Intravenous fluids
– Aspiration and irrigation of the
corpus cavernosum
– Surgery
– Blood Transfusions
• Impotence with severe
disease or recurrent episodes
Urethra Corpus cavernosum
 Stroke
Any acute neurologic symptom other than mild headache, even if transient, requires
urgent evaluation.

• Historically 8 to 10% of
children with SS

• “Silent Stroke” in 22% of

children with hemoglobin
SS

Treatment: Chronic transfusion therapy to maintain sickle hemoglobin at or below

30%
 Stroke
• Commonly ischemic stroke.
• Two types of stroke occurs,that is overt and “silent stroke.

• A functional definition of overt stroke is the presence of a

focal neurologic deficit lasting for >24 hr and/or abnormal
neuroimaging on T2-MRI

• A silent stroke, lacks focal neurologic findings lasting >24

hr and is diagnosed by abnormal neuroimaging on T2-
weighted MRI
 Fever and Infection

• Fever > 38.5° C (101°F) • Indications for

hospitalization & IV
is an EMERGENCY antibiotics:
-Child appears ill
• Basic laboratory -Any temperature > 40°C
evaluation: -Abnormal laboratory
– FBP with differential values
and reticulocyte count, • Start IV antibiotics
IMMEDIATELY if child
blood, urine, and appears ill or temperature >
throat cultures, 40°C (DO NOT WAIT FOR
urinalysis, chest x-ray LABS)
• Fever in a child with sickle cell anemia is a medical emergency,
requiring prompt medical evaluation and delivery of antibiotics .

• Infants with sickle cell anemia, as early as 6 mo of age, develop

abnormal immune function due to splenic infarction. By 5 yrs of
age, most children with sickle cell anemia have complete
functional asplenia.

• Regardless of age, all patients with sickle cell anemia are at

increased risk of infection and death from bacterial infection,
particularly encapsulated organisms such as Streptococcus
pneumoniae, Haemophilus influenzae type b, and Neisseria
meningitidis.
 crises
• Vaso-oclusive crisis (pain)
• Acute chest syndrome
• sequestration crisis
• aplastic crisis
 Acute Chest Syndrome
A leading cause of death in sickle cell disease

Clinically:
Acute onset of fever, respiratory symptoms, new
infiltrate on chest x-ray
Causes
– Infection
– Fat emboli
– Lung infarct

Since you cannot distinguish between acute chest

syndrome and pneumonia clinically there is no change in
treatment.
Acute Chest Syndrome in SCD Patients
• The treatment for ACS includes broad-
spectrum antibiotics, including a
cephalosporin and a macrolide
• Also used are oxygen, hydration, incentive
spirometry, and early intervention with simple
transfusion therapy for associated hypoxia or a
hematocrit less than 18% (0.18)
 Splenic Sequestration
• Sudden trapping of blood
within the spleen
• Usually occurs in infants
under 2 years of age with SS
• Spleen enlarged on physical
exam, may not be
associated with fever, pain,
respiratory, or other
symptoms
• Circulatory collapse and
death can occur in less than
thirty minutes
•Recurrence very common (50%)
•Associated with high mortality (20%)
 Treatments For Splenic Sequestion
• Intravenous fluids
– Maintain vascular volume
• Cautious blood
transfusion
– Sequestered blood can be
released from spleen
• Spleen removal or
splenectomy
– If indicated
Aplastic Crisis
• Human parvovirus B19 poses a unique threat for patients with
sickle cell anemia because such infections result in temporary red
cell aplasia, limiting the production of reticulocytes and causing
profound anemia.

• Any child with sickle cell disease, fever, and reticulocytopenia

should be considered to have parvovirus B19 until proven otherwise.

• The acute anemia of an aplastic crisis is treated conservatively

usingred blood cell transfusion when the patient becomes
hemodynamically symptomatic or has a concurrent illness, such as
acute chest syndrome.

• Patients with parvovirus-associated aplastic crisis are contagious

and infection precautions should be taken to avoid nosocomial
spread of the infection.
 Pain Management
Acute pain
• Hand-foot syndrome (dactylitis)
• Painful episodes: vasoocculsion
• Splenic sequestration
• Acute chest syndrome
• Cholelithiasis
• Priapism
• Avascular necrosis
• Right upper quadrant syndrome
 Pain Management
Pain is an emergency
Hospital evaluation:
• Hydration: 1.5 times maintenance unless
acute chest syndrome suspected
• Assess pain level and treat
– Do not withhold opioids
– Frequently reassess pain control
• Assess for cause of pain/complications
 Pain Management
Mild-moderate pain
• Acetaminophen
– Hepatotoxic
• Non-steroidal anti-inflammatory agents (NSAIDs)
-Contraindicated in patients with gastritis/ulcers and
renal failure
-Monitor renal function if used chronically
 Pain Management
• Moderate-severe pain
– Opioids are first-line treatment
– Morphine sulfate or hydromorphone
– Meperidine NOT recommended
• (Metabolite causes seizures & renal toxicity)
• Moderate or less severe pain
– Acetaminophen or NSAID's in combination with opioids
– Other adjuvant medications (sedatives, anxiolytics)
• May increase efficacy of analgesics
Hand Foot Syndrome - Dactylitis
• Early complication of
sickle cell disease
• Highest incidence 6
months to 2 years
• Painful swelling of hands
and feet
• Treatment involves fluids
and pain medication
• Fevers treated as medical
emergency
Complication:
Renal Disease
• Renal findings
-Seven sickle cell disease nephropathies have been identified:
(1) gross hematuria
(2) (2) papillary necrosis
(3) (3) nephrotic syndrome
(4) (4) renal infarction
(5) (5) hyposthenuria
(6) pyelonephritis
(7) renal medullary carcinoma.
• Risk factors for progressive renal failure
• Anemia, proteinuria, hematuria
 Gall Bladder and Liver
• Gall stones and biliary sludge
– Monitor by ultrasound every 1-2 years
• Cholestasis
– May progress, leading to bleeding disorders or
liver failure
• Iron overload
– Due to chronic transfusions
• Chronic hepatitis
Bone Disease Diagnosis and Treatment

• Avascular necrosis of hips and shoulders

– Index of suspicion
• Persistent hip or shoulder pain
• Plain film or MRI
• Treatment
– Conservative
• NSAID’s and 6 weeks of rest off affected limb
• Physical therapy
 Screening AVN
• Avascular Necrosis
– Hip Films
– Hip MRI
– Grading of AVN
• Grade I: MRI
• Grade II: Film/MRI
• Grade III: Film
• Grade IV: Film
• Grade V: Film
– No grade for AVN of the shoulder
 Chronic Complications
• Anemia/Jaundice
• Brain Damage/Stroke
• Kidney failure
• Decreased lung function
• Eye disease (bleeding, retinal detachment)
• Leg ulcers
• Chronic pain management
Anemia – Jaundice
• Common and starting
in the first year of life
• Decreased lifespan of
sickle red cells
– Hemolysis
– Anemia
– Hyperbilirubinemia
– Reticulocytosis
 Renal Disease
• Proteinuria/Nephrotic syndrome
• 40% of SCD patients with nephrotic syndrome
develop end-stage renal disease
• Occurs in ~ 20% of all patients
• Occurs in 4.5% of all pediatric patients- increased in
hemoglobin SS to 6.5%
– Increased incidence with age
– Increased with anemia, increased MCV, and increased
leukocyte count
• Renal failure common in adults
 Leg Ulcers
• Occurs in about 25% of all
hemoglobin SS patients
• Predominantly males
– Incidence increased with
• Age
• Decreased hemoglobin
– Incidence decreased with
alpha thalassemia
• Recurrence rate is ~ 75%
 Chronic Pain
• Pain lasting >3 to 6 months
• Patients should receive comprehensive psychologic
and clinical assessment
• Treatment
– Analgesics
– Hydroxyurea
– TENS units
– Relaxation techniques
– Physical and occupational therapy
Cognitive and Psychological Complications
• As with any child with a chronic illness, good health maintenance
must include routine psychological and social assessment.

• Children and adolescents with sickle cell disease also have

decreased quality of life, as measured on standardized
assessments, compared to their siblings and children with other
chronic diseases.

• Furthermore, children with sickle cell disease are at great risk for
academic failure and have a 20% high school graduation rate. One
reason behind the low high school graduation rate is that
approximately a third of children with sickle cell anemia have had
a cerebral infarct—either silent cerebral infarcts or overt strokes.
 Daily Preventative Measures
1. Taking the folic acid (folate) daily to help make new red
cells
2. Daily penicillin until age six to prevent serious infection
3. Drinking plenty of water daily
4. Avoiding too hot or too cold temperatures
5. Avoiding over exertion and stress
6. Getting plenty of rest
7. Getting regular check-ups from knowledgeable health care
providers
 Developing Treatments

 Hydroxyurea
 Bone marrow transplantation
 Shown to provide a cure for severely
affected children with sickle cell disease
 Only about 18 percent of children with sickle
cell anemia are likely to have a matched
sibling.
 Treatment
• Patients with sickle cell disease need continuous treatment,
even when they are not having a painful crisis.
Supplementation with folic acid, is an essential element in
producing red blood cells. It is required because of the rapid
red blood cell turnover.
• The purpose of treatment is to manage and control
symptoms, and to try to limit the frequency of crises.
• During a sickle crisis, certain treatments may be necessary.
Painful episodes are treated with analgesics and enough liquid
intake. Treatment of pain is critical. Non-narcotic medications
may be effective, but some patients will require narcotics.
 Hydroxyurea therapy
• Hydroxyurea (HU), is an S-phase cytotoxic drug used
predominantly to treat chronic myelogenous leukemia and
polycythemia vera by increasing fetal hemoglobin
• HU is used in children older than 5 years who have severe
complications of SCD
• Long-term complications of HU are unknown
• Hydroxyurea (Hydrea) was found to help some patients by
reducing the frequency of painful crises and episodes of acute
chest syndrome (which includes chest pain and difficulty
breathing). It also decreases the need for blood transfusions.
 Transfusion Therapy in SCD Patients
• Transfusion therapy frequently is used transiently in
SCD to treat acute manifestations of the disease,
such as aplastic crises, splenic sequestration,priapism
and ACS.
• Transfusion also can be used chronically to prevent
stroke. BUT, it is also associated with iron overload,
alloimmunization, and potential infectious
complications
 Treatment of VOC Pain crises
• Hospital management should include
aggressive pain management with age-
appropriate patient-controlled analgesia and
the use of opioids (morphine or
hydromorphone), nonsteroidal anti-
inflammatory agents (ibuprofen or ketorolac),
hydration, physical therapy, and ancillary
therapies such as relaxation or guided imagery
 Pneumococcal Infection in SCD Patients

• Outpatient management of fever in children

who have SCD and low-risk parameters based
on age, degree of fever, leukocyte count,
clinical presentation, and parental compliance
now is standard
• Ceftriaxone is the antibiotic of choice for 48-
hour outpatient therapy in such patients
Hematopoietic Stem Cell Transplant in SCD Patients

• The only cure for SCD today is hematopoietic stem

cell transplant (HSCT)
This requires a human leukocyte antigen-matched
sibling donor
Indications for HSCT include stroke, positive TCD
result, and multiple ACS or VOC episodes
HSCT should be performed early, before end-organ
complications such as iron overload or chronic
pulmonary disease occur
 The Ultimate Cure?
Gene Therapy
1. Correcting the “defective gene” and inserting it into
the bone marrow
2. Turning off the defective gene and simultaneously
reactivating another gene that turns on production
of fetal hemoglobin.
No real cure for Sickle Cell Anemia at this time.
“In the past 30 years, the life expectancy of people with
sickle cell anemia has increased. Many patients with
sickle cell anemia now live into their mid-forties and
beyond.”
 DIFFERENTIAL DIAGNOSIS
Acording to presentation
• Painfull crisis
• bones- arthiritis, osteomyetis,
• abdom- Surgical cond? Acute abdom
• med condition- DKA..
• CNS-Meningitis, stroke
• hemolytic crisis.
-causes of hemolytic anemia- infections,
hemoglobinopathies other than scd eg thalasemias
The Management of a child with sickle cell
disease is best when overseen by a
comprehensive sickle cell disease center

Asante