1 Sickle Cell Anemia JFK Pediatric Core Curriculum Edited byVenée Tubman, MDHEARTTDepartment of PediatricsChildren’s Hospital Boston
2 Definition and Molecular Basis of Disease Sickle cell disease (SCD): a recessively inherited chronic hemolytic anemiaCaused by a single nucleotide substitution in the β globin gene on chromosome 11Hemoglobin S (most common): GTG GAG results in substitution of valine (hydrophobic) for glutamate (hydrophilic)Many other variant hemoglobins are describedMutant hemoglobin polymerizes under low oxygen conditions and form bundles that distort red cells into the classic sickle shape
3 Pathophysiology Deoxygenation polymerization of hemoglobin sickling of red cellsendothelial damage/activationRBC and leukocyte adhesion to endothelium, vasoconstrictionvascular occlusion, organ ischemia and end-organ damage
4 PathophysiologySeverity of disease varies widely among individuals and disease type:SS disease is most severeSC and S-beta thal0 disease portend intermediate severitySA (one normal allele=trait) is generally asymptomatic
5 Sickle Cell Anemia and Malaria Children with sickle trait (heterozygotes) have a milder course of P. falciparum. However, children with SS disease have more severe courses with a very high mortality rate.
6 EpidemiologyHb S, thalassemia, G6PD, HPHF all confer malaria survival advantageUp to 30% of population carriers for Hb S allele in many parts of West AfricaHb S carrier estimate for Liberia: 15%
7 PrognosisOver the past 30 years in US/Europe, median survival has increased from 14yrs to 45-55yrs for SS diseaseFigures not available for Africa but estimated 50% of affected die before 5yrsWHO estimates that SCD complicates up to 9% of under 5 deaths in West Africa
8 Initial Clinical Presentation Typically presents in infancy after 6 months of age, when Hb F is waningBirth hemoglobin F: α2γ2Hemoglobin A: α2β2Hemoglobin S: α2S2Pain and anemia are hallmarks of disease
9 Initial Clinical Presentation Suggestive historical findings:Family history of known SCDFamily history of sudden death in young childFrequent painFrequent chest infectionsFailure to gain weight despite good nutritionPersistent jaundiceClassic sequelae (hand/foot syndrome, priapism)
10 Initial Clinical Presentation Physical Exam findings are nonspecific:scleral icteruspale mucous membranessystolic murmur throughout precordiumsplenomegaly
11 Initial Clinical Presentation Predictors of adverse outcome at presentation:dactylitis in infant <1y/oHb<7g/dLleukocytosis absent infectionpriapism
12 Laboratory Findings and Diagnosis Hemolytic anemia: low hemoglobin, high reticulocyte count, elevated LDH and decreased haptoglobinPeripheral blood smear:
13 Diagnosis: Sodium metabisulfite Screening for SCD with sodium metabisulfiteAdd Na metabisulfite to bloodSeal mixed sample in airtight container or under coverslipLook for sickling under microscopeDoes not differentiate trait from disease
15 Sequelae: Vaso-occlusive/pain crisis Occurs in 60% of SS patients when vaso-occlusion tissue ischemiaMay be triggered by infection, temperature extremes, dehydration or stress but usually w/o identifiable cause.Characterized by severe pain often in extremities, involving the long bones, or the abdomen. May last hours to days.Number of pain crises/year varies widely between individuals with some patients w/ constant low level pain.
16 Sequelae: Vaso-occlusive/pain crisis Management:Hydration: 20cc/kg NS bolus, then PO/IV hydration at 1.5 x maintenance (not for acute chest)Pain ladder:Paracetamol 15mg/kg PO q4hr ADD Ibuprofen 10 mg/kg PO q6hr ADDCodeine 1mg/kg PO q4hrCHANGE Codeine to Tramadol (need dose)CHANGE Tramadol to Morphine 0.1mg/kg q4hrAmbulation to prevent acute chestOxygen to maintain O2 sat > 95%
17 Sequelae: InfectionBy age 1 30% of Hb SS pts are asplenic, by age 6, 90% are asplenic due to microinfarcts.This makes children especially vulnerable to infection/sepsis with encapsulated organisms, esp. Strep pneumoniae (400x higher risk vs. general population)Sickle Cell patients are also more susceptible to osteomyelitis (Salmonella and Staph spp.)
18 Sequelae: Infection(cont’d) Management of fever:For T ≥38, send: Hb, malaria smear, CXR, UA (under 2 years or symptoms)Administer Ceftriaxone 50 mg/kg QD until clinically improving OR 3 daysChange to amoxclav or ampicillin to complete 14 days
19 Sequelae: Acute Chest Syndrome Characterized by new respiratory distress, CXR infiltrate, hypoxia(O2<95%) and/or chest painOccurs in 40% of patients with SS diseaseCan progress rapidly to ARDSMay be caused by viral or bacterial infection, fat embolism(2/2 bone marrow infarction), cause unknown in most cases
20 Sequelae: Acute Chest Syndrome Management :Ceftriaxone 50mg/kg IV daily, then when pain improving ampicillin or amoxclavIf O2<94 and Hb < 6 g/dL, consider transfusionDo not hydrate > 1x maintenance (furosemide with transfusion)
21 Sequelae: Stroke11% of SS patients have a stroke by age 20 with peak incidence between 2 and 10Presents as focal neurologic deficit or seizureManagement: Transfusion
22 Sequelae: Acute Splenic Sequestration Sudden enlargement of the spleen accompanied by a >2g/dL decrease in Hb from baseline, often w/ thrombocytopeniaOccurs in children <3y/oCan cause sudden circulatory collapseManagement:Immediate volume expansion with crystalloidTransfusionIf >2 episodes splenectomy
23 Sequelae: Aplastic Crisis Caused by infection with Parvovirus B19 (fifth disease) which invades young erythroblasts in bone marrowOften presents with fever, URI sx and drop in HbRBC life expectancy in SS disease is days, thus decrease in RBC production has profound effect.Bone marrow recovery typically within 7-10 daysManagement:Transfusion if symptomatic with Hb drop.
24 Sequelae: Anemia Compensated anemia at baseline Baseline Hb normally 8-9 g/dlOvertransfusion can predispose to transfusion transmitted infections and iron overloadManagementTransfuse for Hb < 5g/dL or <6g/dL with cardiac decompensation
25 Indications for Simple Transfusion Final hematocrit after transfusion <30%.Simple Transfusion for:aplastic crisessplenic sequestrationAcute chest syndromeBefore surgeryPriapism resistant to medical managementStrokePersistent pain despite proper pain management
26 Indications for Exchange Transfusion For stroke, severe ACS
27 Other SequelaePriapism: May require surgical drainage, phenylephrine injection, exchange transfusionDactylitis (hand-foot syndrome): painful swelling of hands and feet which occurs in infants.Avascular necrosis of the humeral/femoral headCholelithiasisRetinopathyChronic leg ulcers
28 Preventive Care:Daily Penicillin VK 125mg BID from time of diagnosis (ideally<3mos) through 5 years of age (increase dose to 250mg BID at age 3yrs.)May use erythromycin in penicillin allergic patientsFolic Acid 1mg daily started by 1y/oPneumococcal Vaccine (if available)All standard vaccines
29 Preventive Care: Stroke Prevention Trial in SCD (STOP): A two year trial of children 2-16y/o screened with transcranial Doppler ultrasonography and found to be high risk (flow velocity>200cm/sec)The children then randomly assigned to receive either standard care or prophylactic transfusions to keep their HbS concentrations<30%In the group that received prophylactic transfusions, 2% had strokes, compared with 16% in the control group.Therefore, current recommendations are to screen all children >2y/o with transcranial doppler ultrasound and offer prophylactic transfusion to children with a flow velocity>200cm/sec (high risk of stroke)Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. NEJM 1998;339:5-11
30 Definitive Treatment: Hydroxyurea therapy Indicated for children >5y/o who have severe complications of SCDEffective because increases HbF, decreases leukocytes, platelets and reticulocytesCBC must be monitored regularly when on therapy for leukopenia
31 Definitive Treatment: Bone Marrow Transplant Definitive cure for SCDOnly 14% of SCD patients have a human-leukocyte antigen matched donorAssociated with a peri-transplant morbidity of ~10%
32 ReferencesDriscoll, C. Sickle Cell Disease. Pediatrics in Review 2007;28:Steinberg, M Management of Sickle Cell Disease. New England Journal of Medicine 1999; 340:Claster, S Managing Sickle Cell Disease. British Medical Journal 2003; 327:Serjeant, G Mortality from sickle cell disease in Africa. British Medical Journal 2005; 330:Distenfeld, A Sickle Cell Anemia. eMedicine.comPaediatric Treatment Protocols in Island Hospital, 2007Adapted from a lecture by: Kevin Schwartz, MD
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