Pediatrics (System-Integrated)

Sickle cell disease in children: management and complications

Clinical Overview and When to Suspect Sickle Cell Disease

— HbSS (sickle cell anemia) — most severe

— HbSC — milder anemia but high rates of retinopathy, AVN, splenic sequestration even in adolescence

— HbS/β⁰-thalassemia — clinically like HbSS

— HbS/β⁺-thalassemia — milder

— Sickle trait (HbAS) — generally benign but watch for exertional rhabdomyolysis, renal medullary carcinoma, hyposthenuria

— Positive newborn screen (universal in all 50 US states via isoelectric focusing/HPLC) — this is now the dominant entry point

— Dactylitis (hand-foot syndrome) in infants 6–18 months as fetal hemoglobin wanes

— Pallor, jaundice, splenomegaly in toddler

— Recurrent pain crises, acute chest syndrome, stroke, priapism

— Unexplained sepsis with encapsulated organisms (functional asplenia by age 2–4)

Board pearl: A newborn screen reporting "FS" pattern = fetal hemoglobin + sickle hemoglobin only → HbSS or HbS/β⁰-thal. "FSC" = HbSC. "FAS" = sickle trait. Confirm at 2–4 months with hemoglobin electrophoresis/HPLC, and start prophylactic penicillin by 2 months of age regardless of confirmation pending.

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy caused by a point mutation in the β-globin gene (Glu→Val at position 6), producing HbS. Deoxygenated HbS polymerizes, deforming RBCs into rigid sickled cells that cause vaso-occlusion, hemolysis, and chronic endothelial injury.

Genotypes (severity matters for the boards):

Epidemiology: ~1 in 365 Black/African American births; also seen in Hispanic, Mediterranean, Middle Eastern, and South Asian populations.

When to suspect in a child:

Pathophysiology highlights: HbF is protective — symptoms emerge as HbF drops over the first 6 months. This is why hydroxyurea works (induces HbF).

Presentation Patterns and Key History

— Sudden severe pain in back, chest, extremities, abdomen

— Triggers: dehydration, cold, infection, hypoxia, acidosis, stress, menses, high altitude

— Ask about home opioid regimen, baseline pain score, prior admissions, last transfusion

Key history to elicit:

— Newborn screen result and genotype

— Vaccination status (especially pneumococcal PCV13/PCV15, PPSV23, meningococcal, influenza, Hib)

— Penicillin prophylaxis adherence

— Hydroxyurea use and dose

— Annual TCD (transcranial Doppler) results since age 2

— Last transfusion / chronic transfusion program

— School absences, opioid use patterns, mental health

Step 3 management: In any child with SCD and fever, the move is parenteral ceftriaxone within 1 hour, blood cultures, CBC with retic, CXR — do not wait for cultures, do not send home an ill-appearing child even if labs look reassuring.

Vaso-occlusive pain crisis (VOC) — most common ED/clinic presentation:

Dactylitis: symmetric painful swelling of hands/feet in infants — often the first SCD manifestation

Acute chest syndrome (ACS): fever, cough, chest pain, hypoxia, new infiltrate — leading cause of death; may follow VOC by 2–3 days due to splinting and atelectasis

Splenic sequestration: sudden splenic enlargement + Hb drop ≥2 g/dL + reticulocytosis in a child <5 (HbSS) or older (HbSC) — parents may report rapid pallor and lethargy

Aplastic crisis: profound anemia with low reticulocyte count, usually from parvovirus B19

Stroke: focal deficits, seizure, altered mental status; peak risk 2–5 years

Priapism: prolonged painful erection >4 hours — urologic emergency

Sepsis/fever: any fever ≥38.5°C (101.3°F) in a child with SCD is an emergency — encapsulated organisms (S. pneumoniae, H. influenzae, Salmonella)

Avascular necrosis of femoral/humeral head in older children/adolescents — hip pain with limp

Cholelithiasis: pigment stones from chronic hemolysis — RUQ pain, sometimes asymptomatic on US

Physical Exam Findings and Hemodynamic Assessment

— Tachycardia and tachypnea common at baseline (chronic anemia)

— Fever ≥38.5°C = sepsis workup mandatory

— Hypoxia (SpO₂ <95% or drop ≥3% from baseline) → suspect ACS

— Hypotension is a late, ominous sign — think sequestration, sepsis, or hyperhemolysis

— Scleral icterus from chronic hemolysis

— Conjunctival pallor

— Retinal exam (older children/HbSC): proliferative sickle retinopathy, "sea-fan" neovascularization

— Frontal bossing and maxillary overgrowth from marrow expansion

— Systolic flow murmur (high-output state from anemia)

— Crackles, decreased breath sounds, splinting → ACS

— Loud P2 may signal pulmonary hypertension (older patients)

— Splenomegaly in young children; spleen typically autoinfarcts by age 5–6 in HbSS (functional asplenia even when palpable spleen is gone)

— Persistent splenomegaly in older child suggests HbSC or HbS/β⁺-thal

— RUQ tenderness → cholecystitis/choledocholithiasis

— Hepatomegaly from sequestration or intrahepatic cholestasis

— Point tenderness over long bones — distinguish VOC vs osteomyelitis (Salmonella, S. aureus)

— Limited hip ROM → AVN of femoral head

— Dactylitis in infants

— Full focal exam in every visit — silent infarcts are common

— Document baseline mental status

Hemodynamic assessment in sequestration/ACS:

— Tachycardia + falling Hb + enlarging spleen = transfuse urgently (cautiously, target Hb only to ~8 to avoid hyperviscosity)

— Widening pulse pressure + hypoxia + new infiltrate = ACS impending respiratory failure

Board pearl: A child with SCD whose spleen is suddenly large + pale + tachycardic = splenic sequestration — IV access × 2, type and crossmatch, simple transfusion, ICU. This is a top killer in toddlers.

General: growth delay, delayed puberty, fatigued appearance during crisis

Vital signs:

HEENT:

Cardiopulmonary:

Abdomen:

MSK:

Neuro:

GU: priapism assessment, Tanner staging (delayed)

Skin: leg ulcers (medial malleolus) in adolescents

Diagnostic Workup — Initial Labs, Imaging, Biomarkers

— Baseline Hb usually 6–9 g/dL in HbSS, 9–11 in HbSC

— Drop ≥2 g/dL from baseline = significant

— Reticulocyte count: low (<1%) → aplastic crisis (parvovirus); high → ongoing hemolysis or sequestration

— Elevated WBC at baseline (10–20k); concerning if left shift or bandemia

— Platelets elevated baseline (asplenia); thrombocytopenia is concerning

— Hemoglobin electrophoresis or HPLC is gold standard

— HbSS: HbS ~90%, HbF variable, no HbA

— HbSC: HbS ~50%, HbC ~50%

— Sickle solubility test (Sickledex) is screening only — cannot distinguish SS from trait — never use to diagnose

— Newborn screen DNA-based confirmation if ambiguous

CCS pearl: For a SCD child with fever in CCS, the rapid order set is: IV access, CBC + retic + type/screen, blood culture, UA + urine culture, CXR, ceftriaxone 50–75 mg/kg IV, IV fluids at 1–1.5× maintenance (NOT bolus unless dehydrated), pain control, oxygen if SpO₂ <95%. Advance clock 1 hour, then reassess.

CBC with differential and reticulocyte count — the single most important test in any acute SCD presentation:

Peripheral smear: sickled cells, target cells, Howell-Jolly bodies (asplenia), nucleated RBCs

Chemistry: LDH ↑, indirect bilirubin ↑, haptoglobin ↓ (chronic hemolysis); BUN/Cr (sickle nephropathy), electrolytes

Type and screen/crossmatch: extended phenotype matching for C, E, K antigens to reduce alloimmunization

Blood cultures × 2 if febrile

Urinalysis + urine culture if febrile or dysuria

CXR for any respiratory symptom, chest pain, hypoxia, or fever — even subtle to catch ACS early; repeat in 24h if initial negative but clinical suspicion high

Pulse oximetry continuous; compare to documented baseline

ECG if chest pain — rule out other causes

Confirmation of SCD diagnosis:

Diagnostic Workup — Advanced and Confirmatory Studies

— Annual screening from age 2 to 16 in HbSS and HbS/β⁰

— Measures time-averaged mean velocity in MCA/ICA

— <170 cm/s = normal; 170–199 = conditional, repeat in 3 months; ≥200 cm/s = abnormal/high risk for stroke

— Abnormal TCD → start chronic transfusion therapy (STOP trial); transition to hydroxyurea after 1 year if velocities normalize (TWiTCH trial)

— Baseline and periodic in adolescents

— TR jet velocity >2.5 m/s suggests pulmonary hypertension

— Right heart cath to confirm if elevated

— Annual UA for proteinuria from age 10

— Urine albumin-to-creatinine ratio; microalbuminuria precedes overt nephropathy

Key distinction: Newborn screen "FS" cannot distinguish HbSS from HbS/β⁰-thalassemia — you need HPLC + parental studies + sometimes genetic testing. Clinically they're managed identically, but this matters for counseling and prognosis nuance.

Transcranial Doppler (TCD) ultrasound:

MRI/MRA brain: for any neurologic symptom, abnormal TCD persisting, or screening for silent cerebral infarcts (occur in ~25% by age 6)

Echocardiogram:

Pulmonary function tests: in adolescents with recurrent ACS or chronic cough — restrictive pattern common

Polysomnography: nocturnal hypoxemia worsens vaso-occlusion; consider if snoring, daytime sleepiness, recurrent ACS

Hip/shoulder MRI: gold standard for AVN — sensitive before plain films show changes

Abdominal US: gallstones (annually in children >10 or with RUQ symptoms); splenic size

DEXA: low bone density common in adolescents

Renal:

Ophthalmology: annual dilated exam starting age 10, especially HbSC (sickle retinopathy)

Ferritin and liver iron quantification by MRI (T2*): for chronically transfused patients to guide chelation

Red cell alloantibody screen before each transfusion

Risk Stratification and Management Logic

— TCD velocity (see chunk 5)

— History of prior stroke → lifelong chronic transfusion (or HSCT)

— Silent infarct on MRI → consider transfusion therapy (SIT trial)

— ≥2 ACS episodes or 1 ICU-level ACS → hydroxyurea mandatory

— Reactive airway disease, OSA, chronic hypoxemia → escalate

— ≥3 crises/year requiring medical care → hydroxyurea indicated

— Newer indications: ALL children with HbSS or HbS/β⁰ ≥9 months should be offered hydroxyurea regardless of symptoms (BABY HUG, NHLBI 2014 guidelines)

— Low HbF (<8%)

— High baseline WBC, low Hb

— Dactylitis before age 1

— Recurrent ACS, stroke, priapism

— Renal dysfunction

— 0–6 months: confirm diagnosis, parental education, start penicillin prophylaxis by 2 months

— 6 months–5 years: pen V 125 mg PO BID (250 mg BID after age 3), all vaccines on schedule, hydroxyurea by 9 months, annual TCD from age 2

— 5–10 years: continue penicillin to at least age 5 (stop if fully vaccinated and no prior pneumococcal sepsis/splenectomy), continue hydroxyurea, TCD, transition planning

— >10 years: annual eye exam, urine protein, gallbladder imaging if symptomatic, transition-of-care planning

— Allogeneic HSCT from matched sibling donor: ~95% event-free survival; consider for severe phenotype

— Gene therapy (FDA-approved 2023: exa-cel, lovo-cel) for ages ≥12 with recurrent VOCs

Step 3 management: A 10-month-old with HbSS and no symptoms still gets hydroxyurea — universal early initiation has Grade A evidence for reducing VOC, ACS, transfusions, and mortality.

Risk stratification for stroke:

Risk stratification for ACS recurrence:

Risk stratification for VOC frequency:

Severity markers:

Management hierarchy by age:

Curative options:

Pharmacotherapy — First-Line Drug Regimen

— Mechanism: ↑ HbF synthesis, ↓ neutrophils/platelets/adhesion molecules, NO donor

— Start at 20 mg/kg/day PO once daily, escalate by 5 mg/kg every 8 weeks to max tolerated dose (typically 30–35 mg/kg/day), or until mild myelosuppression (ANC 2,000–4,000)

— Monitor CBC every 4 weeks during escalation, then every 2–3 months

— Hold for ANC <2,000, platelets <80k, Hb <7 with retic <80k, ALT >2× ULN

— Counseling: teratogenic — contraception in adolescents; does not cause infertility but may reduce sperm count transiently

— Reduces VOC by ~50%, ACS by ~50%, transfusions, and mortality

— 125 mg PO BID from 2 months to 3 years

— 250 mg PO BID from 3 to 5 years

— Continue past 5 if hx invasive pneumococcal disease, surgical splenectomy, or per family preference

— Erythromycin if penicillin-allergic

— PCV15 or PCV20 series + PPSV23 at age 2 and booster at age 7

— Meningococcal ACWY at 2 months (4-dose series) + MenB at age 10

— Hib, influenza annually, COVID-19, HepB, all routine vaccines on schedule

— L-glutamine (Endari): ages ≥5, reduces VOC by ~25%

— Crizanlizumab (anti-P-selectin): ages ≥16 (recently withdrawn from EU; remains FDA-approved with mixed efficacy data)

— Voxelotor (HbS polymerization inhibitor): withdrawn from market in 2024 due to safety concerns — do not select on exam if updated stem

— Mild: ketorolac, ibuprofen, acetaminophen

— Moderate-severe: morphine 0.1 mg/kg IV q2–4h or PCA; avoid meperidine (seizures)

— Adjuncts: warm compresses, IV fluids at 1–1.5× maintenance (avoid overhydration → pulmonary edema/ACS)

Board pearl: Iron is NOT given in SCD unless documented iron deficiency — chronic transfusion patients are iron-overloaded and need chelation (deferasirox, deferoxamine).

Hydroxyurea — cornerstone disease-modifying therapy:

Penicillin V prophylaxis:

Folic acid 1 mg PO daily — supports erythropoiesis given chronic hemolysis (universal practice though evidence is modest)

Vaccinations (high-yield):

Newer agents (adolescents):

Pain management in VOC (acute):

Procedures and Transfusion Management

— Symptomatic anemia, Hb drop ≥2 g/dL from baseline with symptoms

— Aplastic crisis, splenic sequestration, hepatic sequestration

— Pre-op for moderate/major surgery: target Hb 10 g/dL (TAPS trial — better outcomes vs no transfusion)

— Avoid raising Hb >10–11 g/dL → hyperviscosity, stroke risk

— Acute ischemic stroke (target HbS <30%)

— Severe ACS with respiratory failure

— Multi-organ failure

— Acute hepatic sequestration with severe disease

— Pre-op for high-risk procedures (neurosurgery, cardiac)

— Persistent priapism unresponsive to conservative measures

— Abnormal TCD (primary stroke prevention)

— Prior stroke (secondary prevention) — lifelong

— Recurrent ACS or VOC despite hydroxyurea

— Goal: HbS <30% pre-transfusion

— Schedule every 3–4 weeks

— Leukoreduced, sickle-negative, phenotypically matched (at minimum C, E, K) RBCs

— Pre-medicate if prior reactions

— Monitor for delayed hemolytic transfusion reaction (5–14 days post): fever, pain, dark urine, hemoglobinuria — can trigger hyperhemolysis syndrome (drop below pre-transfusion Hb!)

— Best with HLA-matched sibling, myeloablative conditioning

— Indications: stroke, recurrent ACS, abnormal TCD unresponsive, severe phenotype

— Risks: GVHD, infertility, graft failure

CCS pearl: For pre-op SCD child needing tonsillectomy or cholecystectomy: type/cross, simple transfusion to Hb 10, incentive spirometry teaching, avoid hypothermia/dehydration intra-op, post-op opioid + early mobilization.

Simple transfusion — indications:

Exchange transfusion (erythrocytapheresis) — indications:

Chronic transfusion program — indications:

Transfusion specifics:

Iron chelation: deferasirox PO daily when ferritin >1,000 or liver iron >3 mg/g; monitor renal function

HSCT:

Gene therapy (exa-cel CRISPR; lovo-cel lentiviral): ages ≥12, after autologous stem cell collection and busulfan conditioning; durable VOC-free outcomes in trials

Special Populations — Renal and Hepatic Considerations

— Medullary hypoxia/hyperosmolarity promotes sickling in vasa recta

— Hyposthenuria (inability to concentrate urine) starts in infancy → enuresis common

— Hyperfiltration in childhood masks declining function — "normal" creatinine can be deceptive

— Microalbuminuria by adolescence → overt proteinuria → CKD in adulthood

— Annual UA + urine albumin-to-creatinine ratio starting age 10

— Annual BMP

— Consider cystatin C — more accurate GFR estimate than creatinine in SCD

— ACE inhibitor (enalapril, lisinopril) for microalbuminuria or HTN — first-line

— Strict BP control (<95th percentile for age/sex/height)

— Hydroxyurea may slow progression

— Avoid NSAIDs chronically; use cautiously in VOC

— Rare but devastating; associated with sickle trait more than disease

— Painless hematuria, flank mass → urgent imaging

— Cholelithiasis from chronic pigment stones — laparoscopic cholecystectomy when symptomatic (transfuse to Hb 10 pre-op)

— Intrahepatic cholestasis: severe variant with bilirubin >50, coagulopathy — exchange transfusion

— Hepatic sequestration: sudden hepatomegaly + Hb drop — transfuse

— Transfusion-related iron overload: monitor liver T2* MRI

— Hepatitis B/C from older transfusions (pre-1992); vaccinate against HepB

— Hydroxyurea: reduce if CrCl <60 mL/min/1.73m²

— Deferasirox: avoid if eGFR <40

— Opioids: morphine metabolites accumulate in renal failure — use hydromorphone or fentanyl

Board pearl: A 14-year-old with HbSS, BP 130/85, urine ACR 80 mg/g → start lisinopril. Don't wait for overt proteinuria; early RAAS blockade preserves nephrons.

Sickle nephropathy is universal — pathophysiology:

Monitoring:

Management of sickle nephropathy:

Renal medullary carcinoma:

Acute kidney injury during VOC/ACS: from rhabdomyolysis, NSAIDs, contrast, sepsis, hemoglobinuria — hold nephrotoxins, IV fluids

Hepatic complications:

Dose adjustments:

Special Populations — Pregnancy, Adolescent Transition, Newborns

— HbF protective; usually asymptomatic

— Newborn screen detects all major genotypes

— Confirm with HPLC at 2–4 months

— Start penicillin V 125 mg PO BID by 2 months

— Parental education: palpate spleen, fever protocol, recognize pallor

— Pneumovax, prevnar, all routine vaccines on schedule

— Begin transition planning at age 12–14, complete by 18–21

— Adult hematologist warm handoff with shared visits

— Self-management: medication adherence, pain plan, vaccinations, contraception

— Increased mortality in 18–30 age window — transition gap is dangerous

— Address mental health, opioid stewardship, school/work accommodations

— Pregnancy risky → effective contraception encouraged

— Progestin-only methods preferred: DMPA, implant, levonorgestrel IUD — may actually reduce VOC frequency

— Combined estrogen-progestin pills: not absolutely contraindicated, but VTE risk elevated in SCD — use cautiously; ACOG and CDC MEC class 2

— High-risk: preeclampsia, IUGR, preterm birth, VTE, ACS, VOC increase

— Continue penicillin, folate (4 mg high-dose), low-dose aspirin from 12 weeks

— Stop hydroxyurea if possible during conception/pregnancy (teratogenic Category D); though emerging data suggest lower-than-expected fetal harm

— Stop ACE inhibitors

— Prophylactic transfusion controversial; reserve for severe disease, prior fetal loss

— VTE prophylaxis after delivery

— Pre-op transfusion to Hb 10

— Hydration, warmth, oxygenation

— Aggressive incentive spirometry post-op

— Avoid high altitude (>1,500 m) without supplemental oxygen

— Hydration, avoid extreme cold

— Malaria prophylaxis if endemic travel

Step 3 management: A 17-year-old with HbSS on hydroxyurea now sexually active — counsel dual contraception with condoms + progestin implant, continue hydroxyurea, document pregnancy plan, and discuss preconception transition off hydroxyurea if pregnancy desired.

Newborn (0–6 months):

Adolescent transition (Step 3 favorite):

Contraception in adolescent girls with SCD:

Pregnancy (adolescent or adult):

Surgery/anesthesia in pediatrics:

Travel counseling:

Complications and Adverse Outcomes

— Leading cause of death; treat as emergency

— Triggers: VOC with splinting, infection (Mycoplasma, Chlamydia, viral), fat embolism from marrow infarct

— Management: ceftriaxone + azithromycin, oxygen, incentive spirometry, judicious fluids, transfusion (simple → exchange if severe), bronchodilators if wheezing

— Overt ischemic stroke: peak 2–10 years; recurrence ~70% without transfusion

— Silent cerebral infarcts: ~25% by age 6, associated with cognitive decline

— Treat acute stroke with exchange transfusion (HbS <30%) within hours

— Hemorrhagic stroke more common in young adults

— Stuttering (<4h, recurrent) → pseudoephedrine, hydration

— Major (>4h) → urology emergency: aspiration + phenylephrine irrigation, possible exchange transfusion

Key distinction: Bone pain + fever in SCD child — start with empiric VOC + antibiotics, but if persistent localized tenderness, swelling, or no improvement at 48–72h → MRI and bone aspirate for osteomyelitis (think Salmonella first).

Acute chest syndrome (ACS):

Stroke:

Splenic sequestration: sudden pooling, hypovolemic shock — transfuse cautiously; splenectomy after recurrent episodes

Aplastic crisis: parvovirus B19 — transfuse, isolate from pregnant women/immunocompromised; recovers in 7–10 days

Priapism:

Avascular necrosis: femoral head most common; analgesics, PT, eventual arthroplasty

Pulmonary hypertension: TRV >2.5 m/s screen; right heart cath confirm

Leg ulcers: medial malleolus in adolescents; debridement, compression

Retinopathy: proliferative, especially HbSC; laser photocoagulation

Osteomyelitis: Salmonella > S. aureus — biopsy and culture if differentiating from VOC

Cholelithiasis: pigment stones — cholecystectomy when symptomatic

Functional asplenia: encapsulated organism sepsis risk

Iron overload from chronic transfusion: cardiomyopathy, endocrinopathies, liver fibrosis

Alloimmunization and delayed hemolytic transfusion reactions

Chronic pain syndrome: emerges in adolescence

Growth and pubertal delay

Mental health: depression, anxiety, PTSD from chronic illness

When to Escalate — ICU, Consults, Inpatient Triage

— VOC failing outpatient/ED management

— Fever in any SCD child <5 (low threshold even older)

— New CXR infiltrate (ACS)

— Hb drop >1.5–2 g/dL from baseline

— Priapism >2–4 hours

— Dehydration, vomiting

— Inadequate home pain control

— ACS with hypoxia despite supplemental O₂ or bilateral infiltrates

— Acute stroke

— Multi-organ failure

— Hemodynamic instability (sequestration, sepsis, severe DHTR)

— Need for exchange transfusion

— Status epilepticus

— Acute hepatic sequestration with coagulopathy

— Priapism requiring exchange

— Always for new SCD presentation, abnormal TCD, recurrent crises, transfusion decisions, HSCT/gene therapy candidacy, hyperhemolysis

— Neurology + neurosurgery: stroke, intracranial bleed

— Urology: priapism >4h

— Orthopedics: suspected osteomyelitis, AVN

— Pulmonology: recurrent ACS, sleep apnea, pulmonary hypertension

— Cardiology: TRV elevation, iron cardiomyopathy

— Ophthalmology: vision change, retinopathy

— Nephrology: declining GFR, refractory proteinuria

— Pain/palliative: chronic pain, opioid management

— Psychiatry/psychology: depression, school avoidance, opioid use disorder

— Surgery: cholecystectomy, splenectomy

— Transfusion medicine: alloimmunization, exchange access

— HSCT/gene therapy evaluation

— Pediatric ICU not available locally

— Need for apheresis/exchange not available

— Complex multi-organ disease

CCS pearl: Hypoxia + new infiltrate + chest pain in SCD child = call it ACS, admit, broad-spectrum antibiotics covering atypicals (ceftriaxone + azithromycin), oxygen, incentive spirometry q1h, simple transfusion early — don't wait for crash before escalating to exchange.

Admit to inpatient floor:

Admit to ICU:

Consult hematology:

Consult subspecialists:

Transfer to tertiary center:

Key Differentials — Hematologic Mimics

— Severe microcytic anemia from infancy

— Frontal bossing, hepatosplenomegaly, growth delay — overlaps with SCD

— Electrophoresis: predominant HbF, no/low HbA, no HbS

— Transfusion-dependent

— Mild hemolytic anemia, target cells, splenomegaly

— No vaso-occlusion or pain crises

— Distinguish from HbSC (which DOES have crises)

— Hemolysis, jaundice, splenomegaly, gallstones — mimics chronic SCD

— Smear: spherocytes; osmotic fragility test or EMA binding positive

— Negative HbS on electrophoresis

— Episodic hemolysis after oxidative trigger (fava beans, sulfa, infection)

— Heinz bodies, bite cells

— Normal electrophoresis

— X-linked; consider in any boy with hemolytic crisis

— Generally asymptomatic

— Exertional rhabdomyolysis, splenic infarct at high altitude, hyposthenuria, increased UTI risk, renal medullary carcinoma

— Genetic counseling for carrier couples

Board pearl: Newborn with positive sickle screen — always confirm with HPLC and parental studies. A baby with "FS" pattern who turns out to have HbS/β⁰-thal looks identical clinically to HbSS, but a baby with "FAS" (sickle trait) needs only counseling, no penicillin, no hydroxyurea.

Beta-thalassemia major:

Hemoglobin C disease (CC):

Hereditary spherocytosis:

G6PD deficiency:

Pyruvate kinase deficiency: chronic hemolytic anemia; PK enzyme assay

Autoimmune hemolytic anemia: positive Coombs (DAT); spherocytes; not microvascular occlusion

Sickle cell trait (HbAS):

Other hemoglobinopathies: HbE, HbD, unstable hemoglobins

Iron deficiency anemia: low Hb, low MCV, but no hemolysis markers — and a SCD patient can have BOTH; check ferritin if microcytic

Aplastic anemia: pancytopenia, hypocellular marrow — distinguish from aplastic CRISIS (which is transient and isolated to RBCs)

Key Differentials — Non-Hematologic Mimics

— Pain is real until proven otherwise — but ALSO rule out:

— Osteomyelitis (Salmonella, S. aureus): persistent localized pain, fever, swelling, elevated CRP/ESR — MRI

— Septic arthritis: joint effusion, decreased ROM — aspirate

— Appendicitis: RLQ pain, anorexia, leukocytosis above baseline — US/CT

— Cholecystitis/choledocholithiasis: RUQ pain, Murphy sign, elevated LFTs/lipase — US, MRCP

— Pancreatitis: epigastric pain, vomiting, elevated lipase

— Pyelonephritis: flank pain, fever, dysuria — UA, culture

— Splenic infarct/abscess: LUQ pain, fever — CT

— AVN: chronic worsening hip/shoulder pain — MRI

— PID in adolescent girls

— Renal vein thrombosis, mesenteric ischemia

— Community-acquired pneumonia (overlap — treat for both)

— Pulmonary embolism — higher incidence in SCD; consider in chest pain + hypoxia without infiltrate

— Fat embolism syndrome from marrow infarct

— Asthma exacerbation

— CHF (iron cardiomyopathy)

— Acute mediastinitis

— Migraine, seizure with Todd paralysis, hypoglycemia, posterior reversible encephalopathy syndrome (PRES), CNS infection, fat embolism

— Bacteremia (S. pneumoniae, H. flu, Salmonella, E. coli)

— Viral (parvovirus → aplastic crisis)

— Atypical pneumonia

— Osteomyelitis

— UTI/pyelonephritis

— Drug fever (rare)

Key distinction: A SCD adolescent with sudden pleuritic chest pain, hypoxia, and a clear CXR — don't anchor on ACS. Consider PE: get D-dimer (low specificity in SCD), CTPA if clinical suspicion. SCD confers a 3–4× VTE risk.

Pain crisis vs alternative causes of acute pain in a child with known SCD:

Acute chest syndrome differentials:

Stroke-like symptoms:

Fever workup:

Secondary Prevention and Long-Term Plan

— Hydroxyurea at max tolerated dose — continue indefinitely; do not stop during well periods

— Monitor CBC q2–3 months, ANC goal 2,000–4,000

— Adherence counseling — most common reason for "failure" is missed doses

— Penicillin V to age 5 minimum (longer if invasive pneumococcal hx)

— Vaccines current: PCV15/20, PPSV23 (boost at age 7, then q5y in adults), MenACWY + MenB, Hib, annual flu, COVID-19, HepB, HPV at age 11, varicella, MMR

— Travel: malaria prophylaxis, hep A

— Annual TCD ages 2–16

— Abnormal TCD → chronic transfusion ≥1 year → consider transition to hydroxyurea (TWiTCH)

— Annual: CBC, retic, comprehensive metabolic panel, UA, urine ACR (age 10+), ferritin if transfused

— Annual dilated eye exam from age 10

— Echo every 1–3 years in adolescents

— Pulse ox at every visit; baseline established

— Hip/shoulder MRI if symptomatic

— Written individualized pain plan for ED visits

— Home regimen: scheduled NSAIDs/acetaminophen, short-acting opioid for breakthrough

— Non-pharmacologic: heat, hydration, CBT

— Hydration goals

— Avoid temperature extremes, high altitude

— School plan / 504 plan for missed days, accommodations

— Genetic counseling for family planning

— Re-evaluate for HSCT or gene therapy at each major milestone or after sentinel event (stroke, recurrent ACS)

Step 3 management: At every well-child visit for SCD: verify hydroxyurea adherence, vaccine status, pain plan, TCD compliance, school accommodations, mental health screen, and contraception (if adolescent). Document each.

Disease-modifying maintenance:

Infection prevention:

Stroke prevention:

Organ surveillance:

Pain plan:

Mental health: annual depression and anxiety screening (PHQ-9, GAD-7 in adolescents); social work involvement

Education and lifestyle:

Curative consideration:

Follow-Up, Monitoring, and Counseling

— Infants 0–12 months: q1–2 months (peds + hematology)

— Ages 1–5: q3 months

— Ages 5–adolescence: q3–6 months

— More frequent if on chronic transfusion (q3–4 weeks for transfusion) or post-acute event

— Interval crises, hospitalizations, ED visits, school absences

— Pain diary review

— Medication adherence (hydroxyurea, penicillin, folate)

— Growth parameters, Tanner staging

— BP, SpO₂, baseline exam including spleen

— CBC + reticulocyte count; chemistries periodically

— CBC every 4 weeks during titration, every 2–3 months at maintenance

— ANC, platelets, Hb, MCV (rising MCV = drug effect/adherence marker), HbF (target >20%)

— Pre-transfusion Hb and HbS%

— Ferritin q3 months; liver T2* MRI annually

— Cardiac T2* MRI in older patients

— Antibody screen each transfusion

— TCD (ages 2–16)

— Eye exam (age ≥10)

— Urine ACR (age ≥10)

— Pulmonary, cardiac as indicated

— Dental exam (caries risk)

— Audiology if iron overload or chronic ototoxin exposure

— Physical therapy for AVN, post-stroke recovery

— Occupational therapy

— Neuropsych testing after stroke or silent infarcts (academic support)

— School 504 plan: hydration access, bathroom breaks, missed-day accommodations, modified PE

— Social work: insurance navigation, transportation, food security

— Genetic counseling for siblings, future pregnancies

— Sibling HLA typing if HSCT considered

— Support group referral (SCDAA, local chapters)

Board pearl: A rising MCV in a SCD child on hydroxyurea is a good sign — indicates adherence and drug effect. A stable or falling MCV with breakthrough crises suggests nonadherence; address rather than escalate dose first.

Visit cadence:

At every visit:

Hydroxyurea monitoring:

Chronic transfusion monitoring:

Annual screenings recap:

Rehabilitation and counseling:

Family counseling:

Transition to adult care: structured program age 12–21, written transfer summary, warm handoff

Ethical, Legal, and Patient Safety Considerations

— SCD patients face systemic undertreatment of pain — racial bias and "drug-seeking" stigma are well-documented

— Use objective pain scales + the patient's known regimen; do not undertreat based on appearance

— Establish individualized pain plans documented in chart and shared across EDs

— Opioid stewardship is appropriate, but for chronic SCD pain consider multimodal approach without abandoning analgesia

— Hydroxyurea in young children: counsel parents on teratogenicity, growth/fertility data (reassuring), need for adherence; informed assent from older children

— HSCT and gene therapy: complex risk/benefit; infertility, conditioning toxicity, mortality risk vs durable cure — multidisciplinary consent including reproductive counseling and fertility preservation discussion

— Chronic transfusion: iron overload, alloimmunization — informed ongoing consent

— Pediatric assent for older children, especially around HSCT

— Suspected child neglect (missed appointments, lack of penicillin/hydroxyurea adherence putting child at risk): engage social work first; report if pattern of preventable harm

— Some states require reporting positive newborn screens to public health registries — generally automatic

— Mortality spikes in 18–25 age window during transition from pediatric to adult care

— Document structured transition plan beginning age 12–14

— Warm handoff with shared visits, complete records transfer, named adult provider

— Contraception, sexual activity, substance use discussed confidentially per state law

— Pregnancy testing before hydroxyurea adjustments / radiology

— Carrier testing for partners; genetic counseling

— Preimplantation genetic diagnosis available

— Equitable access historically a problem in SCD — advocate for trial referral

— Comprehensive SCD center access correlates with better outcomes — refer if rural/community setting

— Insurance challenges for hydroxyurea, gene therapy, chronic transfusion — engage social work and patient advocacy

Step 3 management: A 19-year-old with HbSS is being discharged after first adult-hospital admission post-transition. Required actions: confirm adult hematologist appointment within 1–2 weeks, reconcile hydroxyurea + folate + penicillin (if still indicated) + pain plan, share records, screen for depression, document contraception plan. Transition-related discharge gaps are tested as patient safety events.

Pain management ethics:

Informed consent:

Mandatory reporting:

Transition-of-care risks:

Confidentiality in adolescents:

Reproductive ethics:

Research/clinical trial enrollment:

Health systems:

High-Yield Associations and Rapid-Fire Facts

Board pearl: Iron is rarely needed; most SCD patients are iron-OVERLOADED from transfusion and need chelation (deferasirox).

Glu→Val at position 6 of β-globin = HbS mutation

Howell-Jolly bodies on smear = functional asplenia (also nucleated RBCs, target cells)

Dactylitis 6–18 months = often the first SCD manifestation

Pen V prophylaxis 2 months → age 5

Penicillin allergy? → erythromycin

Universal hydroxyurea for HbSS/HbS-β⁰ starting age 9 months regardless of symptoms

Hydroxyurea increases HbF and MCV — both are markers of adherence

TCD screening ages 2–16; abnormal ≥200 cm/s

STOP trial: chronic transfusion prevents first stroke in abnormal TCD

TWiTCH trial: hydroxyurea non-inferior to transfusion after 1 year of transfusion + normal velocities

BABY HUG trial: hydroxyurea safe and beneficial starting at 9 months

Acute chest syndrome: leading cause of death; treat with ceftriaxone + azithromycin, transfusion, incentive spirometry

Aplastic crisis: parvovirus B19 — low reticulocytes

Splenic sequestration: enlarging spleen + falling Hb + reticulocytosis

Osteomyelitis in SCD: Salmonella > S. aureus

Pre-op transfusion: target Hb 10 g/dL

Acute stroke: exchange transfusion to HbS <30%

Pigment gallstones common; cholecystectomy when symptomatic

Priapism: pseudoephedrine for stuttering; aspiration/phenylephrine for major; exchange if refractory

Renal medullary carcinoma: rare, associated with sickle trait

Avoid: meperidine (seizures), high-altitude unpressurized travel, dehydration, NSAIDs in renal dysfunction, iron supplements without confirmed deficiency

Vaccines: PCV15/20 + PPSV23, MenACWY + MenB, Hib, annual flu, HepB, HPV

Newborn screen patterns: FS = HbSS/HbS-β⁰; FSC = HbSC; FAS = trait; FA = normal

Hydroxyurea teratogenic — contraception in adolescents; progestin-only preferred

Cure options: matched-sibling HSCT, gene therapy (exa-cel CRISPR, lovo-cel lentiviral) for age ≥12 with severe disease

Voxelotor withdrawn 2024 — don't pick on updated stems

Fever ≥38.5°C in SCD child = parenteral ceftriaxone within 1 hour, full workup

Hyperhemolysis syndrome: post-transfusion Hb drops below baseline — exchange, IVIG, steroids, avoid more transfusion

Board Question Stem Patterns

Key distinction: Reticulocyte count is the differentiator — high in sequestration/hyperhemolysis, low in aplastic crisis. Master this one number.

The fever stem: "3-year-old with known HbSS presents with temperature 39°C, fussy, no focal exam findings." → Best next step: IV ceftriaxone after blood culture + CBC + CXR. Not "observe at home," not "amoxicillin PO," not "wait for cultures."

The dactylitis infant: "9-month-old African American infant with swollen, tender hands and feet, family history of anemia." → Next step: hemoglobin electrophoresis (HPLC); start penicillin prophylaxis if newborn screen wasn't done.

The TCD stem: "5-year-old with HbSS, screening TCD shows MCA velocity of 215 cm/s." → Initiate chronic transfusion therapy to keep HbS <30%. Repeat MRI/MRA, neurology consult.

The CXR + chest pain stem: "10-year-old SCD admitted for VOC, now develops new fever, cough, hypoxia, RML infiltrate." → Acute chest syndrome: ceftriaxone + azithromycin, oxygen, transfusion, incentive spirometry; exchange transfusion if worsens.

The aplastic stem: "7-year-old with HbSS, profound fatigue, Hb 4, reticulocyte count 0.2%, recent viral illness." → Parvovirus B19 aplastic crisis — transfuse, isolate from pregnant contacts.

The sequestration stem: "2-year-old HbSS, abrupt pallor, lethargy, spleen tip 6 cm below costal margin, Hb 4 from baseline 8, retic 18%." → Splenic sequestration — IV access, cautious transfusion, ICU, plan for splenectomy if recurrent.

The pre-op stem: "12-year-old HbSS scheduled for elective cholecystectomy, current Hb 7.5." → Transfuse to Hb 10 pre-op (simple transfusion), continue hydroxyurea, ensure hydration, warm, oxygenation.

The contraception stem: "16-year-old HbSS, wants contraception." → Progestin-only (DMPA, implant, LNG-IUD) preferred over estrogen-containing.

The hydroxyurea stem: "9-month-old HbSS, asymptomatic, parents ask if any treatment recommended." → Start hydroxyurea 20 mg/kg/day per NHLBI guidelines.

The osteomyelitis stem: "14-year-old HbSS with focal tibial tenderness, fever, swelling, persistent pain x 5 days despite IV opioids." → MRI; aspirate for culture; cover Salmonella + S. aureus (ceftriaxone + clindamycin or vancomycin).

The stroke stem: "8-year-old HbSS with sudden right hemiparesis." → STAT non-con CT (rule out bleed), then exchange transfusion to HbS <30%, neurology, transition to chronic transfusion.

The transition stem: "18-year-old HbSS moving from pediatric clinic." → Adult hematology referral with shared visit, complete record transfer, reconcile meds, mental health screen.

The trait stem: "Asymptomatic college football player, sickle solubility positive." → Confirm with electrophoresis (HbAS = trait); counsel on exertional precautions and genetic counseling.

The hyposthenuria/enuresis stem: 8-year-old HbSS still wetting bed → reassure, hydration during day; not psychiatric.

One-Line Recap

Sickle cell disease in children is a lifelong vasculopathic hemoglobinopathy whose modern pediatric management — early hydroxyurea, penicillin prophylaxis, full vaccination, annual TCD with transfusion for abnormal velocities, aggressive treatment of fever and ACS, and structured transition to adult care — has converted a once-fatal childhood disease into a chronically managed condition with curative options (HSCT, gene therapy) for severe phenotypes.

Universal moves at diagnosis: penicillin V by 2 months, full vaccine schedule (PCV + PPSV23, MenACWY + MenB, Hib, flu), hydroxyurea by 9 months for HbSS/HbS-β⁰, parental education on fever and spleen palpation, annual TCD from age 2.

Acute emergencies = fever (ceftriaxone <1h), ACS (ceftriaxone + azithromycin + transfusion + spirometry), stroke (exchange transfusion to HbS <30%), splenic sequestration (cautious transfusion, ICU), aplastic crisis (transfuse; parvovirus B19), priapism (urology, exchange if refractory).

Long-term surveillance: annual CBC/retic/chemistries, urine ACR from age 10, dilated eye exam from age 10, echo periodically, hip MRI if symptomatic, ferritin/iron MRI if transfused, mental health screening, growth/Tanner staging.

Pearls that move questions: Howell-Jolly bodies = asplenia; reticulocyte count distinguishes aplastic (low) from sequestration/hyperhemolysis (high); osteomyelitis is Salmonella > S. aureus; pre-op target Hb 10; progestin-only contraception preferred; voxelotor withdrawn 2024; transition-of-care gap is a tested patient-safety hazard; iron supplementation is rarely indicated and chelation is the rule in chronically transfused patients.