Sickle Cell Disease in Children

Genetics, screening, and the protective role of HbF

Mechanism. Sickle cell disease is autosomal recessive. A point mutation in β-globin substitutes valine for glutamate at position 6, producing HbS, which polymerizes when deoxygenated. Hypoxia, acidosis, dehydration, and cold promote polymerization. Rigid, sticky sickled cells hemolyze after only about 10–20 days (versus 120) and occlude small vessels, so the disease combines chronic hemolytic anemia with recurrent ischemic injury.

Newborn screening. Universal screening by HPLC or isoelectric focusing shows an "FS" pattern: fetal and sickle hemoglobin with no HbA, confirmed by repeat testing. Fetal hemoglobin (α2γ2) does not sickle, so infants are protected until γ-chain production switches to β and HbF falls; problems usually surface after about 6 months. Screening lets penicillin and family education begin before the first crisis.

Functional asplenia, fever, and prevention

Autosplenectomy. Repeated splenic infarction leaves children functionally asplenic in early childhood; Howell-Jolly bodies on the smear mark the loss. Without splenic filtering and opsonization, encapsulated organisms, Streptococcus pneumoniae above all, plus H. influenzae type b and Neisseria meningitidis, can cause sepsis that kills within hours. Salmonella is also a threat.

Penicillin prophylaxis. Twice-daily oral penicillin V starts by 2 months of age and continues until at least age 5. The PROPS trial showed prophylaxis cut invasive pneumococcal infection by about 84%, and PROPS II showed stopping at age 5 is safe for children without prior invasive pneumococcal disease or splenectomy.

Vaccines. Complete the pneumococcal conjugate series plus polysaccharide coverage, meningococcal vaccines (MenACWY beginning in infancy; MenB from age 10), Hib, and yearly influenza vaccine. Folic acid is commonly given for the high marrow turnover.

Vaso-occlusive complications

Dactylitis. Hand-foot syndrome, painful symmetric swelling of the hands and/or feet from metacarpal and metatarsal infarction, is often the first manifestation, usually between 6 months and 2 years. It settles within 1–2 weeks with analgesia and hydration. Dactylitis in the first year marks a more severe course.

Pain crisis. Vaso-occlusive pain in the limbs, back, chest, or abdomen is triggered by cold, dehydration, infection, or stress. Give analgesia within about 60 minutes of arrival: IV or intranasal opioids (morphine, hydromorphone), reassessed every 15–30 minutes, with NSAIDs if renal function allows. Avoid meperidine, whose metabolite normeperidine lowers the seizure threshold. Give maintenance fluids, with boluses only for dehydration, and incentive spirometry; transfusion is not routine for uncomplicated pain.

Acute chest syndrome. A new pulmonary infiltrate plus fever, chest pain, cough, tachypnea, wheezing, or hypoxia, often arising during admission for a pain crisis. Triggers include infection (Mycoplasma, Chlamydophila, viruses, pneumococcus), fat embolism from infarcted marrow, and splinting from rib infarcts or opioid hypoventilation; regional hypoxia causes more sickling in a vicious cycle. It is a leading cause of death. Treatment: IV ceftriaxone plus azithromycin, oxygen for SpO2 <95%, incentive spirometry, careful analgesia, and judicious fluids. Simple transfusion is given for hypoxia or a Hb fall of more than 1 g/dL; exchange transfusion for rapid progression, multilobar disease, or worsening hypoxia.

Overhydration and oversedation both worsen acute chest syndrome: give maintenance fluids and pair opioids with incentive spirometry.

Priapism. Sickling in the corpora causes ischemic (low-flow) priapism. Start hydration and analgesia; if it lasts 4 hours or more, urology performs corporal aspiration and irrigation with intracavernous phenylephrine. Delay risks fibrosis and permanent erectile dysfunction. Ice packs are avoided because cold promotes sickling.

Bone. Infarcted bone and bowel ischemia with bacterial translocation make Salmonella the classic osteomyelitis organism, with S. aureus next. Separating infection from infarction requires blood cultures, MRI, and often bone aspiration. Avascular necrosis of the femoral head presents with hip pain and a limp.

Acute anemic crises

Splenic sequestration. Typically between 6 months and 3 years in HbSS (later in HbSC, whose spleen persists), blood pools in a rapidly enlarging spleen. Hb falls at least 2 g/dL below baseline with brisk reticulocytosis, often thrombocytopenia, and hypovolemic shock. Treat with fluid resuscitation and cautious RBC transfusion, because blood released from the spleen can overshoot the target Hb. Parents are taught to palpate the spleen; recurrence is common, so splenectomy or chronic transfusion follows repeated episodes.

Aplastic crisis. Parvovirus B19 enters erythroid precursors through the P antigen and halts red cell production for 7–10 days. Because sickled cells survive so briefly, Hb plummets and reticulocytes fall below 1%. Transfuse as needed; the illness is self-limited, but the child should avoid pregnant women because of the risk of fetal hydrops.

Stroke

Primary prevention. Children with HbSS or HbSβ0 have yearly transcranial Doppler of the internal carotid and middle cerebral arteries from age 2 to 16. A confirmed time-averaged mean velocity ≥200 cm/s calls for chronic transfusion to keep HbS <30%, which reduced first strokes by about 90% in the STOP trial. If there is no vasculopathy on MRA, maximum-tolerated hydroxyurea can replace transfusions after at least a year (TWiTCH trial).

Acute stroke. Sudden hemiparesis, aphasia, or seizure needs emergent imaging (CT to exclude hemorrhage, diffusion MRI) and exchange transfusion to lower HbS below 30%. If exchange is delayed, give a simple transfusion, keeping Hb ≤10–11 g/dL to avoid hyperviscosity. Thrombolysis is not standard in pediatric sickle cell stroke. About two-thirds of children have another stroke without lifelong chronic transfusion.

Disease modification, cure, and chronic complications

Hydroxyurea. Offer it to all children with HbSS or HbSβ0 from 9 months of age, even without symptoms. By inhibiting ribonucleotide reductase it raises HbF and lowers neutrophils, reducing pain crises, dactylitis, acute chest syndrome, transfusions, and hospitalizations. Titrate to the maximum tolerated dose and monitor the CBC for neutropenia and thrombocytopenia; a rising MCV reflects adherence.

Curative options. Matched-sibling hematopoietic stem cell transplant cures about 90% of children with severe disease (stroke, recurrent acute chest syndrome, frequent crises). Two gene therapies are approved from age 12 for recurrent vaso-occlusive events: exagamglogene autotemcel, which uses CRISPR editing of the BCL11A enhancer to restore HbF, and lovotibeglogene autotemcel, which adds an antisickling β-globin gene with a lentiviral vector. Both require myeloablative busulfan conditioning, with infertility and toxicity risks.

Chronic organ damage. Hemolysis causes pigment gallstones, jaundice, and high folate demand. Renal medullary ischemia causes hyposthenuria (enuresis, dehydration), papillary necrosis, and hematuria. Screen for retinopathy (worst in HbSC), avascular necrosis, and pulmonary hypertension. Chronic transfusion causes iron overload treated with deferasirox; units should be phenotype-matched and leukoreduced to limit alloimmunization.