1. DR SANDIP GUPTA PGT, PEDIATRICS

2. Prevalence/Incidence of SCD In African-Americans the incidence of SCD is 1 in 375 for HbSS, 1 in 835 for HbSC and 1 in 1,667 for Sickle beta-thalassemia. In addition, 1 in 12 African-Americans are carriers for the disorder In other U.S. populations, the prevalence of sickle cell disease is 1 in 58,000 Caucasians; 1 in 1,100 Hispanics (eastern states); 1 in 32,000 Hispanics (western states); 1 in 11,500 Asians; and 1 in 2,700 Native Americans 3. Sickle Cell Disorders in India 4. What Is Sickle Cell Disease? An inherited disease of red blood cells Affects hemoglobin Polymerization of hemoglobin leads to a cascade of effects decreasing blood flow Tissue hypoxia causes acute and chronic damage -globin gene (chromosome 11q) mutation GAGGTG at 6th codon Glutamic Acid Valine at the 6th amino acid along the -globin chain 5. Why Do Cells Sickle? Sickling Mechanism 1. Deoxygenation HgbS protein conformational change 2. Hydrophobic Valine exposed at molecular surface 3. Val6 of B2 chain of 1st Hgb S chain forms hydrophobic bond with Phe85 and Leu88 of a 2nd Hgb S B1 chain 4. Pairing Hgb S monomers polymerize to form Hgb S chains 5. Hgb S polymers precipitate in RBCs as long, rigid fibers. 6. Pathophysiology HgbS fibers are rigid Hgb S fibers deform RBC membranes Membrane disruption exposes transmembrane proteins and lipids that are pro-inflammatory Progressive sickling makes cells dense and inflexible Frenette et al., Journal of Clinical Investigation 117(4): 850-858, 2007 7. Pathophysiology Factors that Promote Hgb S polymerization: Low pO2 / Hypoxia Prolonged Delay Time time RBC spends in microcirculation Low pH High Hgb S concentration Genotype-dependent Cellular Dehydration Volume depletion (total body) Sickling Activation K+ / Cl- cotransporter and Gardos Ca2+- activated K+ efflux channels ion and water efflux Low Hgb F concentration 2S: gamma globin chains bind Hgb S chains and inhibit Hgb S polymerization, thus countering sickling process 8. Normal Vs. Sickle Red Cells Normal Disc-Shaped Deformable Life span of 120 days Sickle Sickle-Shaped Rigid Lives for 20 days or less 9. Clinical Syndromes Disease Severity is Genotype Dependent Genotype Hgb SS Hgb S / 0 thalassemia Hgb SC Hgb S / thalassemia Hgb S / D Hgb S / A Hgb S / E Hgb S / + thalassemia Hgb S / HPFH WorseningDiseaseSeverity Asymptomatic + / - Mild Anemia 10. Interpreting Newborn Screening Results Sickle Hemoglobinopathies Screening Results* Associated Disorder FS SS or Sthalassemia FSC SC FSA S + thalassemia FSE S Hemoglobin E FS Variant S Variant FAS Sickle Cell Trait FAC Hb C Carrier FAE Hb E Carrier FA Variant Hb Variant Carrier onfirmation. 11. Hemolysis and Vaso-occlusion Vaso-occlusion: Occurs when the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs. Hemolysis: The anemia in SCD is caused by red cell destruction, or hemolysis, and the degree of anemia varies widely between patients. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction. 12. Chronic Manifestations: Anemia Jaundice Splenomegaly Functional asplenia Cardiomegaly and functional murmurs Hyposthenuria and enuresis Proteinemia Cholelithiasis Delayed growth and sexual maturation Restrictive lung disease* Pulmonary Hypertension* Avascular necrosis Proliferative retinopathy Leg ulcers Transfusional hemosiderosis* Acute Manifestations: Bacterial Sepsis or meningitis* Recurrent vaso-occlusive pain (dactylitis, muscoskeletal or abdominal pain) Splenic Sequestration* Aplastic Crisis* Acute Chest Syndrome* Stroke* Priapism Hematuria, including papillary necrosis Hemolysis and Vaso-occlusion (continued) *Potential cause of mortality 13. Fever and Infection Fever > 38.5 C (101F) is an EMERGENCY Basic laboratory evaluation: CBC with differential and reticulocyte count, blood, urine, and throat cultures, urinalysis, chest x-ray Indications for hospitalization & IV antibiotics: -Child appears ill -Any temperature > 40C -Abnormal laboratory values Start IV antibiotics IMMEDIATELY if child appears ill or temperature > 40C (DO NOT WAIT FOR LABS) 14. Acute Chest Syndrome Clinically: Acute onset of fever, respiratory distress, chest pain, 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. A leading cause of death in sickle cell disease 15. ACS : Treatment Oxygen ( Spo2>90%) Blood transfusion therapy Emperical antibiotics( cephalosporin+ macrolides) Cont respiratory therapy( incentive spirometry,physio) Optimum pain control Fluid management. 16. Priapism: INVOLUNTARY ERECTION FOR>30 min STUTTERING&REFRACTORY Treatment is difficult Opioid pain medication Intravenous fluids Aspiration and irrigation of the corpus cavernosum(>4hr) Blood Transfusions Impotence with severe disease or recurrent episodes Prevention: Hydroxyurea,Etilefrine Surgical shunt procedures Urethr a Corpus cavernosum Commonly occurs in children and adolescents with SS or SC Age of onset is 5-35 yrs. Early morning 17. Stroke: Any focal neuro deficit>24hr&/orintT2W MRI Historically 8 to 10% of children with SS Silent Stroke in 22% of children with hemoglobin SS Any acute neurologic symptom other than mild headache, even if transient, requires urgent evaluation. Treatment: Chronic transfusion therapy to maintain sickle hemoglobin at or below 30% 18. Splenic Sequestration Sudden trapping of blood within the spleen Usually occurs in infants under 2 years of age with SS Spleen enlarged ,hypovolemia, Hb>2% ,reticulocytosis ,pl atelet count,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%) 19. Splenic Sequestration Hemoglobin SS Incidence increased: 6 and 36 months Overall incidence about 30% Hemoglobin SC Incidence increased: 2 and 17 years Mean age 8.9 years Can occur in adolescence and adulthood Incidence about 5% 20. Treatments For Splenic Sequestion Intravenous fluids Maintain vascular volume Cautious blood transfusion Treat anemia with 5ml/kg of PRBC splenectomy If indicated 21. Pain Management Acute pain Hand-foot syndrome (dactylitis) Painful episodes: vasoocculsion Splenic sequestration Acute chest syndrome Cholelithiasis Priapism Avascular necrosis Right upper quadrant syndrome 22. PRECIPTATING FACTORS: physical stress, infection , dehydration,hypoxia ,exposure to cold, acidosis 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 23. 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 24. 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 25. 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 26. Renal Disease Renal findings Decreased ability to concentrate urine Decreased ability to excrete potassium Inability to lower urine pH normally Hematuria / papillary necrosis Risk factors for progressive renal failure Anemia, proteinuria, hematuria 27. 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 28. 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 NSAIDs and 6 weeks of rest off affected limb Physical therapy 29. Chronic Complications Anemia/Jaundice Brain Damage/Stroke Kidney failure Decreased lung function Eye disease (bleeding, retinal detachment) Leg ulcers Chronic pain management 30. GENETIC COUNSELLING Who should receive counseling? -Parents of newborns with sickle disorders or traits -Pregnant women/ prenatal counseling What is the purpose of counseling? -Education -Informed decision-making Content should include: -Genetic basis, chances of disease or trait (potential pregnancy outcome), disease-related health problems, variability/unpredictability of disease, family planning, average life span 31. Health Maintenance Frequent visits: every 3 to 6 months Immunizations Routine immunizations Hib- 6 months and older 23 valent Pneumovax at five years Penicillin prophylaxis beginning no later than two months Nutrition and fluids Folate supplementation is controversial 32. 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: CBC with differential and reticulocyte count, urinalysis, renal & liver function 33. Health Maintenance Special studies Brain- Transcranial doppler ultrasonography, MRI/MRA Lungs- Pulmonary function tests, Echo cardiogram for pulmonary hypertension Neurologic- neuropsychological testing 34. Current Recommendations Penicillin Prophylaxis: SS, S Thalassemia 2 months to 3 years: 125 mg PO BID Over 3 years: 250 mg PO BID When to discontinue is controversial Penicillin Prophylaxis: SC and S + Thalassemia SC warrants penicillin prophylaxis similar to SS S + Thalassemia: penicillin prophylaxis can be safely discontinued at 5 years Routine use in infants and children is controversial Special Circumstances History of repeated sepsis, surgical splenectomy 35. Therapy Hydroxyurea S-phase cytotoxic, myelosuppressive drug: inhibits ribonucleotide reductase Induces proliferation of early erythroid progenitors Leads to Hgb F production (22) subunit production 2 S does not polymerize Additional effects of hydroxyurea: Neutrophil numbers and neutrophil activation stress reticulocytes, reticulocyte adhesion endothelial adhesion properties (VCAM-1, laminin, thrombospondin) Improved RBC hydration and MCV Increased [Hgb] 36. Therapy Hydroxyurea Dosing: Initiation of Treatment: Hydroxyurea 15-20mg/kg/day in single daily dose Check CBC Q 2wks, Hgb F Q 6-8 wks, serum chem Q 2-4 wks May require Tx Continuation: If no major toxicity, escalate dose Q 6-8wk by 2.5-5 mg/kg until desired endpoint reached may go upto 35mg/kg Reduces painful episodes, ACS by 50%. Treatment Endpoints: Decreased pain / pain crises Hgb F 15-20% Acceptable myelotoxicity: 16 have demonstrated poor outcomes d/t comorbidities Two multicentre series of allogeneic SCTs have been undertaken, 1 in US, 1 in Europe 39. 2002 NIH Guidelines for SCT Eligibility in Sickle Cell Disease 40. Therapy Gene Therapy Goal: Transfer anti-sickling -globin genes Obstacles: poor onco-retroviral vector stability low viral titres and gene transfer efficiency difficulty packaging large -globin gene and regulatory elements safety concerns 41. THANK YOU