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Namibia Medical Society Paediatric Congress October 2012 THE MANAGEMENT OF SICKLE CELL DISEASE

Learn about the background, pathophysiology, clinical features, and management principles of sickle cell disease. Topics include blood transfusion, hydroxyurea, stem cell transplantation, and future prospects. Presented at the Namibia Medical Society Paediatric Congress in October 2012.

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Namibia Medical Society Paediatric Congress October 2012 THE MANAGEMENT OF SICKLE CELL DISEASE

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  1. Namibia Medical Society Paediatric Congress October 2012 THE MANAGEMENT OFSICKLE CELL DISEASE Alan Davidson Haematology / Oncology Service Red Cross Children’s Hospital

  2. A hereditary haemolytic anaemia characterised by:Recurrent vaso-occlusive crises Predisposition to serious bacterial infection • BACKGROUND • PATHOPHYSIOLOGY • CLINICAL FEATURES • ACUTE CRISES AND CHRONIC COMPLICATIONS • MANAGEMENT: PRINCIPLES AND SPECIFIC ISSUES • Blood Transfusion • Hydroxyurea • Stem Cell Transplantation • THE FUTURE? Namibian Medical Society Paediatric Congress, 12 October 2012

  3. GENETIC INHERITANCE SCA is one of the major genetic illnesses in sub-Saharan Africa Autosomal recessive with an asymptomatic carrier state (AS) The defect is a point mutation on the β-globin gene of Chr 11 … (valine for glutamic acid) Resulting in HbS RISK PER EACH PREGNANCY: Namibian Medical Society Paediatric Congress, 12 October 2012

  4. EPIDEMIOLOGY The heterozygous carrier state (AS) provides a measure of protection against infection by Falciparum malaria …

  5. THE SCOPE OF THE PROBLEM [WHO Bulletin. 2008; 86: 480-487 ] Where the trait prevalence is above 20%, the disease affects about 2% of the population! But of course prevalence decreases to 1-2% in north Africa and to less than 1% in Southern Africa.

  6. PATHOPHYSIOLOGY:HAEMOGLOBINOPATHY • Abnormal red cell shape shortens red cell survival resulting in: • HAEMOLYTIC ANAEMIA • Moderate to severe • Normocytic and normochromic • Reticulocytosis (nucleated red cells) • Target cells • Sickle cells • Howell-Jolly bodies (hyposplenism) • Increased neutrophils and platelets • UNCONJUGATED JAUNDICE •  LDH  uBRN  Haptoglobin • ESR is low … sickle cells don’t Rouleaux Namibian Medical Society Paediatric Congress, 12 October 2012

  7. PATHOPHYSIOLOGY:VASCULOPATHY • Sickle cells obstruct capillaries  causing ischaemia and infarction  resulting in multiple acute and chronic complications. •  WCC and platelets also  viscosity • Precipitated or aggravated by: • Hypoxia • Stasis • Dehydration • Cold temperature • Acidosis Namibian Medical Society Paediatric Congress, 12 October 2012

  8. PATHOPHYSIOLOGY:VASCULOPATHY • Obstruction of splenic capillaries  causing recurrent splenic infarction and eventually AUTO-SPLENECTOMTY • Results in … • Loss of phagocytic function AND increased risk of infection by encapsulated bacteria • Loss of filtration function … leads to the persistence of senescent red cells in the circulation … these are the Howell-Jolly bodies Namibian Medical Society Paediatric Congress, 12 October 2012

  9. CLINICAL FEATURES:BACKGROUND Maxillary Hyperplasia • Family History … in areas of high prevalence many parents are aware of their carrier status. • Symptoms of chronic anaemia • Jaundice • Stunted Growth and Delayed puberty • Recurrent infections … from as early as 6 months • Pneumococcus, Haemophilus Influenzae & Meningococcus are 300-600 times more likely to cause infection than in normal children. • The commonest cause of death in young children with sickle cell anaemia is pneumococcal sepsis and malaria. Namibian Medical Society Paediatric Congress, 12 October 2012

  10. CLINICAL FEATURES:BACKGROUND • Seldom symptomatic before the age of 6 months ... a characteristic shared with other β-chain disorders … • LAB DIAGNOSIS: • Sickle Prep • Hb Electrophoresis HbF and HbS (no HbA) Namibian Medical Society Paediatric Congress, 12 October 2012

  11. CLINICAL FEATURES:THE CRISES …. • HAEMOLYTIC CRISES • Anaemia with  retics & Jaundice; usually caused by infection • APLASTIC CRISIS • Profound  in Hb with Low reticulocytes • Caused by Parvovirus B19 • Recovers spontaneously over 10-14 days • VASO-OCCLUSIVE CRISES • SEQUESTRATION CRISES Namibian Medical Society Paediatric Congress, 12 October 2012

  12. CLINICAL FEATURES:VASO-OCCLUSIVE CRISES • Bone and Joints • Dactylitis ... Common in infants and toddlers • Bone Crisis ... Spine, limbs (multifocal) • ΔΔ Septic Arthritis and Osteitis esp. with non-typhi Salmonellae • Abdominal Crises • Vaso-occlusion of mesenteric vessels ⇨ ΔΔ Acute Abdomen • Acute Chest Syndrome • Chest pain, fever, hypoxia, dyspnoea • Infiltrates on CXR quite variable … • Precipitated by Infection, Pulmonary sickling, Chest wall sickling, fat embolism … ΔΔ Pneumonia

  13. CLINICAL FEATURES:VASO-OCCLUSIVE CRISES Namibian Medical Society Paediatric Congress, 12 October 2012 • Diffuse pattern on CXR reminiscent of ARDS probably represents that end of the spectrum referred to as pulmonary sequestration … and explains the drop in Hb that occurs with ACS.

  14. CLINICAL FEATURES:VASO-OCCLUSIVE CRISES • CNS Vaso-occlusive Crises • CVAs • Seizures • Meningeal symptoms and signs • Blindness • Radiculopathy • Vertigo • STROKE is overt in 7% and subclinical in another 20% … • Mean age of onset is 7-8 years • Usually involves internal Carotid (less frequently MCA or ACA) • Subclinical events cause significant Neurocognitive fallout! Namibian Medical Society Paediatric Congress, 12 October 2012

  15. CLINICAL FEATURES:SEQUESTRATION CRISES AND RARE EVENTS • SPLENIC SEQUESTRATION • Usually occurs between the ages of 6 and 24 months • Rapid pooling of blood in spleen results in abdominal pain, nausea, severe anaemia and shock which can be fatal … • one of the rare indications for splenectomy in SCA • Family History … in areas of high prevalence • RARE ACUTE EVENTS • Priapism – Vaso-occlusion prevents blood flow out of the penis in older boys and adolescents • Papillary Necrosis of the kidneys • Hepatic Sequestration – Sudden painful Hepar / Anaemia / Jaundice Namibian Medical Society Paediatric Congress, 12 October 2012

  16. CLINICAL FEATURES:CHRONIC COMPLICATIONS • Occur as a result of chronic tissue ischaemia and hypoxia: • Neuropsychiatric fallout (e.g. learning disability) • Pulmonary Hypertension and pulmonary fibrosis • Retinopathy • Nephrotic syndrome and chronic renal failure • Avascular necrosis and Osteonecrosis • Impotence • Leg Ulcers • Gallstones • Those receiving regular BTF are at risk for iron overload: • Hypothyroidism/ Hypoparathyroidism/ Cirrhosis/ Cardiomyopathy Namibian Medical Society Paediatric Congress, 12 October 2012

  17. MANAGINGSICKLE CELL DISEASE PRINCIPLES AND GENERAL ADVICE CRISIS MANAGEMENT SPECIFIC ISSUES [1] Blood Transfusion [2] Hydroxyurea [3] Stem Cell Transplantation THE FUTURE … Namibian Medical Society Paediatric Congress, 12 October 2012

  18. GENERAL PRINCIPLES:EARLY DIAGNOSIS AND INITIATION OF CARE • High index of suspicion: [1] family history [2] normocytic anaemia [3] episodes of bone pain [4] and country of origin … Hb Electrophoresis at 3 months to avoid false negatives • Primary goal is to prevent or minimize complications that impair quality of life … and that should start as early as possible … • A comprehensive care plan, known to parents and caregivers, is the single most important step for any centre looking to improve care for Sickle Cell Anaemia: • Family education: parents counselled to identify fever, respiratory distress, splenomegaly and jaundice • Vaccination (particularly pneumococcal vaccine) • Initiation of prophylactic penicillin (or erythromycin if allergic) • Genetic counselling (prenatal diagnosis is available)

  19. GENERAL PRINCIPLES:COMPREHENSIVE CARE …. The tools that one needs are guidelines and information sheets … Namibian Medical Society Paediatric Congress, 12 October 2012

  20. GENERAL PRINCIPLES:COMPREHENSIVE CARE …. And there is very good evidence for efficacy! Namibian Medical Society Paediatric Congress, 12 October 2012

  21. GENERAL PRINCIPLES:LIFESTYLE ADVICE AND CLINIC MONITORING • LIFESTYLE ADVICE: • Folic acid supplementation [to support erythroid hyperplasia] • Avoid dehydration by drinking plenty of water [trigger] • Avoid extremes of temperature [trigger] • Avoid stress where possible [trigger] • Moderate exercise is recommended • Avoid unpressurised aircraft and high altitude areas [trigger] • IN THE CLINIC • Watch Growth, Development and School Performance • Monitor BP, Spleen size (and Transcranial Dopplers if you can) • Prevanar < 2 years, then PneumoVac at 2 years and every 5 years • Flu Vaccine annually • Annual eye evaluation from the time of school going.

  22. MANAGING ACUTE PROBLEMS AND CRISES:ANAEMIA • PATIENT WITH Hb LOWER THAN USUAL: • Clinical evaluation: Shock? Fever / signs of infection? Jaundice? Splenomegaly? • FBC: MCV low or high? / Nucleated red cells on Differential? • Reticulocyte Count: Low or high? • APLASTIC CRISIS • Admit, BTF urgently, Discharge when Hb stabilises. • HAEMOLYTIC CRISIS • Look for and treat underlying cause, BTF if Hb < 6g%. • SPLENIC SEQUESTRATION • Beware giving large volumes of clear fluid before Transfusion • If recurrent consider [1] Hypertransfusion [2] Splenectomy Namibian Medical Society Paediatric Congress, 12 October 2012

  23. MANAGING ACUTE PROBLEMS AND CRISES:VASO-OCCLUSION • MILD TO MODERATE PAINFUL CRISIS: • Increase fluid intake • Regular oral analgesia (Not PRN) – paracetamol, NSAIDs, valeron drops • Look for and treat any underlying cause • MODERATE TO SEVERE PAIN • Admit to hospital, exclude infection (cover with antibiotics if any doubt) • IV fluids  Maintenance + generous Rehydration • Analgesia – brief trial of oral analgesia  progressing to IVI morphine • Usually takes +/- 5-7 days to recover spontaneously Namibian Medical Society Paediatric Congress, 12 October 2012

  24. MANAGING ACUTE PROBLEMS AND CRISES:VASO-OCCLUSION • AND IF IT’S NOT RESPONDING? • ΔΔ Osteomyelitis / Septic Arthritis … WCC? ESR? B/C? … Bone scan? • BTF may help by diluting out HbSS • Methylprednisone 15mg/kg daily x 2 • AND FOR RECURRENT MODERATE PAIN … • Try Aspirin in older kids • AND THE USE OF ADJUVANTS IS GROWING … • Clonidine for short term use to avoid or wean opiates • Gabapentin for chronic pain (first in / last out) Namibian Medical Society Paediatric Congress, 12 October 2012

  25. MANAGING ACUTE PROBLEMS AND CRISES:VASO-OCCLUSION • ACUTE CHEST SYNDROME: • Oxygen, IV fluids, Analgesia, Sedation if necessary • Cover with IV antibiotics • Bronchodilator therapy may help • BTF or Exchange transfusion if that fails • Methylprednisone may help • CVA: • IV fluids and close monitoring • Urgent CT / MRI / MRI-Angiogram • Blood transfusion is mandatory and Exchange transfusion (where possible and ASAP) may ameliorate stroke in evolution • Hypertransfusion (pre-BTF HbS < 30%) decreases recurrence to < 10% • Stem cell transplantation • Hydroxyurea Namibian Medical Society Paediatric Congress, 12 October 2012

  26. MANAGING ACUTE PROBLEMS AND CRISES:FEBRILE ILLNESS • Thorough clinical examination  Labs … • FBC diff retics / CRP • Blood culture / Urine dipstix (+/- culture) / Stool culture if diarrhoea • CXR and consider Mycoplasma titre if chest symptoms • LP if <1year • Admit if oral To > 38.5oC • Antibiotics – • IVI 3rd generation cephalosporin e.g. Ceftriaxone 100mg/kg • Continue till fever settled x 72hrs if B/C neg, and discharge on oral antibiotics • AND if it’s not responding? Look for pneumonia, osteomyelitis, septic arthritis Namibian Medical Society Paediatric Congress, 12 October 2012

  27. SPECIFIC ISSUES:THE ROLE OF BLOOD TRANSFUSION • Regular or intermittent blood transfusions in SCD aim to: • Increase blood Hb content and oxygen-carrying capacity • Decrease the proportion of sickle cells in the circulation • Chronic transfusions are effective for prevention of complications: • Acute chest syndrome • Stroke (untreated overt stroke has a 70% recurrence rate within 3 years) • Sequestration • Increased life expectancy of SCD patients means: • Greater potential to receive long-term transfusion therapy • Increased likelihood of iron overload (distribution different to that seen in thalassemia patients … Less cardiac and endocrine deposition) Namibian Medical Society Paediatric Congress, 12 October 2012

  28. SPECIFIC ISSUES:THE ROLE OF BLOOD TRANSFUSION Namibian Medical Society Paediatric Congress, 12 October 2012

  29. THE ROLE OF BLOOD TRANSFUSION:PRIMARY STROKE PREVENTION • SECONDARY PREVENTION IS NOT IN QUESTION! • Stroke has a 70% recurrent rate within 3 years if not treated with hypertransfusion … • And it has a very POOR outcome • A ROLE FOR PRIMARY PREVENTION? • But we can’t hypertransfuse all Sicklers! • TRANSCRANIAL DOPPLER FLOW VELOCITY • TCD flow velocity has emerged as an excellent prognostic factor: • TCD > 200cm/s … abnormal … high risk • TCD < 170 cm/s … normal … low risk • Where possible TCD should be checked annually from the age of 3 years … Namibian Medical Society Paediatric Congress, 12 October 2012

  30. THE ROLE OF BLOOD TRANSFUSION:PRIMARY STROKE PREVENTION Namibian Medical Society Paediatric Congress, 12 October 2012

  31. SPECIFIC ISSUES:BLOOD AND PRIMARY STROKE PREVENTION • STROKE PREVENTION TRIAL IN SCA: STOP I • 130 SCD patients aged 2–16 years; mean internal carotid/middle cerebral artery blood flow velocity 200 cm/s (transcranial Doppler) received regular BTF (every 3-4 weeks) • Key Finding: Risk of first stroke in at-risk children decreased from 10% to <1% per year • Results: [1] Early termination of the study [2] Widespread implementation of transfusion therapy as the standard of care in high-risk pediatric patients • DISCONTINUATION OF TRANSFUSION WAS TESTED in STOP II • Subjects were randomized to either continue (n=38) or discontinue (n=41) chronic red cell transfusion. In the transfusion-halted group there were: [1] 14 (34%) reversions to high risk of stroke by TCD screening [2] Stroke in two patients (mean 4.5 months since last transfusion) • These events did not occur in the children on BTF.

  32. SPECIFIC ISSUES:THE ROLE OF BLOOD TRANSFUSION:

  33. SPECIFIC ISSUES:THE ROLE OF HYDROXYUREA • Mechanism of action: • Augments foetal Hb (HbF) synthesis by Interfering with polymerisation of HbS • Improves RBC hydration and decreases adhesiveness • Increases Hb (less BTF) and Decreases vaso-occlusion (Less admissions) • Evidence from HUG-KIDS and BABYHUG (9-18month olds): •  acute painful crises but NO change in chronic organ dysfunction • Hydroxyurea lowers TCD flow velocities in children with SCD … but there is insufficient evidence to support it’s use for secondary prevention of stroke … SWITCH trial (changing BTF to Hydroxyurea) failed and the TWITCH trial (HU for primary prevention) is ongoing • Dose 15-30mg/kg daily using 500mg tablets • Compliance is vital … can be tracked with HbF () and MCV () Namibian Medical Society Paediatric Congress, 12 October 2012

  34. SPECIFIC ISSUES:THE ROLE OF HYDROXYUREA • Moderate to Strong Indications: • > 3 painful crises / year • Recurrent ACS •  TCDs and primary stroke prevention • Side effects: • Myelosuppression (neutropaenia in BABYHUG but no  sepsis) • Hair loss • GIT disturbances • Teratogenesis (birth control!) • Concerns about Malignancy (⇧ DNA mutation rate) but no evidence • BOTTOM LINE: Current evidence suggests that all but the mildest phenotypes should be on HYDROXYUREA! Namibian Medical Society Paediatric Congress, 12 October 2012

  35. SPECIFIC ISSUES:STEM CELL TRANSPLANTATION … A CURE? • Donor Source • Traditionally only fully HLA-matched sibling donors have been considered, but attention is turning to alternative donor sources such as matched unrelated donors and cord bloods. • Patient selection • Aimed at identifying individuals with SCD who will benefit most from BMT, while excluding those at an unacceptably high risk of transplant-related morbidity and mortality due to pre-existing organ damage. • Publically funded transplantation • Clear guidelines have been designed to optimise risk-benefit and cost-benefit … to ensure the appropriate use of resources. “Might benefit” may not buy you the treatment! • Privately funded transplantation • The guidelines help to weed out those who won’t benefit but … “Might benefit” could be enough!

  36. SPECIFIC ISSUESSCT: NO QUESTION THAT IT WORKS! Excellent outcomes for MSD SCT with disease free survival of 75-85% Major toxicities were intracranial haemorrhage and seizures Death was from GvHD (5) and ICH (1) ISSUE: Risk of death from GVHD vs. Risk of failure from graft rejection?

  37. SPECIFIC ISSUESSCT: NO QUESTION THAT IT WORKS? COCHRANE REVIEW Hematopoietic SCT for children with sickle cell disease No RCTs to provide concrete evidence The complexity of the condition makes it unethical to conduct RCTs (transplant versus no transplantation or transplant versus standard of care such as hydroxyurea). This leaves observational studies … Due to limitations in the methodology of these types of studies, valid conclusions cannot be drawn as to improving the survival or in preventing symptoms and complications associated with SCD, neither can the balance of risks versus benefits be measured.

  38. SPECIFIC ISSUESSCT: CRITERIA FOR TRANSPLANT • British Paediatric Haematology Forum, 1993

  39. SPECIFIC ISSUESSCT: CRITERIA FOR TRANSPLANT • Seattle collaborative study

  40. SPECIFIC ISSUES:DO WE NEED OTHER APPROACHES? • Although approximately 38% of patients meet the current criteria for SCT, it’s estimated that only 14% of patients will have an HLA-matched sibling donor. • LACKING A SUITABLE STEM CELL DONOR REMAINS THE PRINCIPLE BARRIER TO HSCT FOR SICKLE CELL ANEAMIA. • OPTIONS: • MUD SCT OR Cord Blood Transplant? • Gene Therapy? • Other medical therapies to improve quality of life? Namibian Medical Society Paediatric Congress, 12 October 2012

  41. SPECIFIC ISSUES:WHAT MIGHT BE IN OUR FUTURE?

  42. THANKS FOR YOUR ATTENTION Red Cross Children’s Hospital, University of Cape Town, South Africa 12 October 2012

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