Sickle Cell Disease
Comprehensive management of sickle cell disease in children
Disease Overview
Definition & Epidemiology
Sickle cell disease (SCD) is a group of inherited red blood cell disorders characterized by the presence of hemoglobin S (HbS). It affects millions of people worldwide, with the highest prevalence in sub-Saharan Africa, Mediterranean regions, and areas with historical malaria endemicity.
Global Impact
- • ~300,000 children born with SCD annually worldwide
- • 1 in 365 births in African Americans in the US
- • 1 in 16,300 births in Hispanic Americans
- • Natural selection advantage against malaria
SCD Genotypes
HbSS (Sickle Cell Anemia)
Most severe form, homozygous for HbS
HbSC Disease
Compound heterozygous, generally milder
HbS-β⁰ Thalassemia
Severe, similar to HbSS
HbS-β⁺ Thalassemia
Variable severity, some HbA present
Clinical Features
Acute Complications
- • Vaso-occlusive crises (pain crises)
- • Acute chest syndrome
- • Stroke (silent or overt)
- • Splenic sequestration
- • Aplastic crisis
- • Acute priapism
Chronic Complications
- • Chronic hemolytic anemia
- • Growth retardation & delayed puberty
- • Chronic pain syndrome
- • Pulmonary hypertension
- • Chronic kidney disease
- • Avascular necrosis
- • Retinopathy
Functional Asplenia
- • Increased infection risk (encapsulated bacteria)
- • Streptococcus pneumoniae
- • Haemophilus influenzae
- • Neisseria meningitidis
- • Salmonella species (osteomyelitis)
Pathophysiology
Molecular Basis
Sickle cell disease results from a single nucleotide substitution (GAG→GTG) in the β-globin gene, leading to valine replacement of glutamic acid at position 6 of the β-globin chain.
Sickling Process
Deoxygenation
HbS polymerizes under low oxygen conditions
Polymerization
Rigid polymers form, distorting RBC shape
Vaso-occlusion
Sickled cells block microvasculature
Tissue Damage
Ischemia and infarction result
Sickling Triggers
- • Hypoxia (infection, high altitude)
- • Dehydration
- • Acidosis
- • Temperature extremes
- • Physical or emotional stress
Disease Mechanisms
Vaso-occlusion
- • Sickled RBCs adhere to vascular endothelium
- • Activation of coagulation cascade
- • Inflammatory response
- • Tissue ischemia and pain
Chronic Hemolysis
- • Shortened RBC lifespan (10-20 days vs 120)
- • Chronic anemia
- • Gallstone formation
- • Pulmonary hypertension
Organ Damage
- • Repeated ischemia-reperfusion injury
- • Progressive organ dysfunction
- • Chronic pain syndromes
- • Premature mortality
Typical Hemoglobin Levels by Genotype
Crisis Management
Vaso-occlusive Crisis
Emergency Assessment
- • Pain location, intensity (0-10 scale)
- • Fever, signs of infection
- • Respiratory distress (acute chest syndrome)
- • Neurological symptoms (stroke)
- • Priapism in males
Pain Management Protocol
Mild Pain (1-3/10)
- • Acetaminophen 10-15 mg/kg q4-6h
- • Ibuprofen 5-10 mg/kg q6-8h
- • Increased fluid intake
- • Rest and warmth
Moderate Pain (4-6/10)
- • Above measures PLUS
- • Codeine 0.5-1 mg/kg q4-6h (if >12 years)
- • Tramadol 1-2 mg/kg q6h
- • Consider ER evaluation
Severe Pain (7-10/10)
- • Immediate ER evaluation
- • IV morphine 0.1-0.15 mg/kg q2-4h
- • IV fluids (1.5x maintenance)
- • Oxygen if hypoxic
- • Consider hospitalization
Acute Chest Syndrome
Definition
New pulmonary infiltrate on chest X-ray with ≥1 of: fever, cough, dyspnea, hypoxia, or chest pain. Medical emergency!
Clinical Presentation
- • Fever (>38.5°C)
- • Chest pain
- • Cough, dyspnea
- • Hypoxemia (O₂ sat <95%)
- • Tachypnea, tachycardia
- • New infiltrate on CXR
Management
Immediate Care
- • Supplemental oxygen to maintain SpO₂ >95%
- • IV fluids (avoid overhydration)
- • Broad-spectrum antibiotics
- • Incentive spirometry
Severe Cases
- • Simple or exchange transfusion
- • Target Hb 10-11 g/dL, HbS <30%
- • Mechanical ventilation if needed
- • ICU monitoring
Other Acute Complications
Splenic Sequestration
Acute spleen enlargement with ↓Hb ≥2 g/dL. Emergency transfusion needed.
Aplastic Crisis
Parvovirus B19 infection causing temporary bone marrow failure. Monitor for severe anemia.
Stroke
Emergency exchange transfusion. Consider TCD screening for prevention.
Comprehensive Management
Disease-Modifying Therapy
Hydroxyurea
First-line therapy for SCD. Increases HbF levels, reduces sickling, and decreases frequency of vaso-occlusive crises.
Indications
- • All children with HbSS or HbS-β⁰ thalassemia ≥9 months
- • Frequent vaso-occlusive crises
- • History of acute chest syndrome
- • Severe anemia
Dosing
- • Start: 15-20 mg/kg/day
- • Maximum: 35 mg/kg/day
- • Monitor CBC every 2-4 weeks initially
- • Target: HbF >20%, acceptable toxicity
Monitoring & Side Effects
- • CBC with differential monthly
- • Hold if ANC <2000, Hb <5.0, platelets <80,000
- • Teratogenic - avoid pregnancy
- • Rare: leg ulcers, nail changes
Newer Therapies
L-glutamine (Endari)
Reduces oxidative stress. For patients ≥5 years with SCD.
Crizanlizumab (Adakveo)
P-selectin inhibitor. Reduces vaso-occlusive crises frequency.
Voxelotor (Oxbryta)
Increases hemoglobin oxygen affinity, reduces sickling.
Supportive Care
Infection Prevention
Prophylactic Antibiotics
- • Penicillin V: 2-5 years (125 mg BID), >5 years (250 mg BID)
- • Alternative: Erythromycin or azithromycin
- • Continue until at least age 5
Immunizations
- • Routine childhood vaccines (no live vaccines during HU)
- • Pneumococcal: PCV13 and PPSV23
- • Meningococcal: all serogroups
- • Annual influenza vaccine
- • Hepatitis B vaccine
Chronic Management
Folic Acid Supplementation
1 mg daily for chronic hemolysis and increased folate needs.
Regular Monitoring
- • CBC, reticulocyte count q3-6 months
- • Comprehensive metabolic panel
- • Liver function tests
- • Urinalysis and microalbumin
Specialty Screening
- • Annual TCD (2-16 years)
- • Annual ophthalmologic exam
- • Echocardiogram q2-3 years
- • Pulmonary function tests
Family Education
- • Recognize signs of complications
- • Maintain hydration
- • Avoid extreme temperatures
- • Seek immediate care for fever >38.5°C
- • Genetic counseling for family planning
Curative Therapies
Hematopoietic Stem Cell Transplant (HSCT)
Indications
- • Recurrent vaso-occlusive crises
- • History of stroke or acute chest syndrome
- • Chronic organ damage
- • Available HLA-matched sibling donor
Outcomes
- • Overall survival: >95%
- • Event-free survival: >90%
- • GVHD: 15-20%
- • Best outcomes in younger patients
Gene Therapy
Approaches
- • Lentiviral gene addition
- • CRISPR gene editing
- • Autologous stem cell modification
- • Clinical trials ongoing
Current Status
- • Promising early results
- • Limited long-term data
- • High treatment costs
- • Refer to specialized centers