Biance Rowe Chris Hani Baragwanath Hospital Paediatric Haematology Oncology University of the Witwatersrand

Transcription

1 Biance Rowe Chris Hani Baragwanath Hospital Paediatric Haematology Oncology University of the Witwatersrand

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3 SCD affects million people globally million in Africa children with SCD are born annually worldwide of those are born in Sub Saharan Africa (75%) of those are born in Nigeria The incidence in SA is <1%, but migration across borders has increased the SA & North European prevalence of SCD Red cross Children s Hospital in CT showed an annual frequency increase over 10 years by % Patients mainly from the DRC Davidson A, Wonkam A, Ponde C et al. The burden of sickle cell disease in Cape Town. SAMJ 2012;102(9):27-38.

4 Highest incidence in tropical Africa (equatorial) Cameroon, DRC, Gabon, Ghana, Nigeria, Uganda Also in Arabian peninsula, India, Mediterranean, Caribbean, South America Smaller populations in US & UK Mostly from Sub Saharan african descent

5 Malaria hypothesis states that there is a selective advantage for the heterozygous state (sickle cell trait HbAS) as this is protective against Plasmodium falciparum malaria; not true for HbSS Red cells lyse too quickly for the parasite to complete its life cycle Parasites don t survive in sickle polymers

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7 There is a higher mortality rate in SCD compared to the non SCD population SCD in Africa Greatest burden of disease & highest mortality Under 5 mortality rate is 50-80% Similar to those reported in the early 1960 s in UK, USA Killers: Infection, acute chest syndrome, acute splenic sequestration More developed countries 85.6% survive to age 18yrs in USA 84% in Jamaica, 99% in USA Savers: Early diagnosis, comprehensive care, access to immunisations & prophylactic antibiotics, hydroxyurea, regular transfusion programme, bone marrow transplant

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9 Ogbanje is an evil spirit that would deliberately plague a family with misfortune Literal translation is children who come and go It was believed that after a certain amount of time from birth the Ogbanje would deliberately die and then come back and be reborn as another child and die again and cause the family grief and so the cycle will continue Strong beliefs in reincarnation theory

10 Reincarnate child (Ogbanje) was well at birth, from early childhood suffered poor growth, body aches and pains, fevers, protuberant abdomen and yellow eyes Seen as a weakling by peers,was thin Died repeatedly (usually before age of 5) and would be reborn to go through the same cycle again Suffered from SCD Initial well period was the time before the switch to HbS occurred. Chronic ill health was the result of chronic haemolytic anaemia, painful crises, fevers from bacterial infection and malaria Reincarnation was the birth of another affected child (25% chance) OGBANJE SICKLE CELL CHILD

11 1846 Autopsy of an executed runaway slave key finding was the absence of a spleen Reports among African slaves in the USA exhibiting a resistance to malaria but are prone to leg ulcers 1910 Dr James Herrick, Chicago Peculiar, elongated and sickle-shaped red blood cells in a dental student from West Africa Presented with anaemia, rheumatism, bilious attacks completed dental studies but died of pneumonia 1933 Distinguish SCD from trait 1950 s Molecular change in HbS described & malaria link described 1954 HB electrophoresis allowed classification of different types of SCD Infectious prophylaxis, antibiotics 1990 Development of Hydroxyurea 2007 Reports of cure through bone marrow transplantation

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13 HbS results from the substitution of Valine for Glutamic acid at position 6 of the Beta-globin polypeptide chain of Hb Caused by a singlebase mutation in codon 6 within the B-globin gene on chromosome 11

14 The abnormal amino acid in the beta chain forms long, insoluble polymers when deoxygenated and the RBC becomes less deformable Abnormal rigid shape occlude small blood vessels PLUS Expression of adhesion molecules (integrins, selectins) interacting with endothelial cells and plasma proteins PLUS Reduced NO levels due to free Hb consuming NO and reducing vasodilator tone

15 Widespread multiorgan damage and dysfunction caused by episodes of tissue ischaemia Leads to a myriad of acute and chronic complications

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19 Image of man p3 of new opportunities article with clinical consequences

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21 The most common acute presentation Caused by microvascular occlusion/sludging and tissue ischaemia and infarction Common in hands & feet of young children Also in arms, legs, axial skeleton (back & shoulders), abdomen (mesenteric vessels), ribs, soft tissues, kidneys, eyes, lungs Can occur in the spleen and lead to an acute splenic sequestration crisis with exsanguination and severe anaemia Episodes of ischaemia & infarction lead to PAIN and MULTI-ORGAN DAMAGE

22 A: Acidosis, anaesthesia, anxiety, altitude (high) B: Bouts of infection, bad habits (smoking, alcohol) C: Cold exposure D: Dehydration E: Exercise (vigorous) F: Folate deficiency G: General surgery H: Hypoxia I: Infection

23 Hydration Oral or IV Pain management Simple oral analgesia NSAIDS, paracetamol, codeine Tilidine Strong opioids Morphine drug of choice parenteral infusion titrated against pain (PCA-devices in older patients) Analgesia should be administered within 30 minutes of arrival at the hospital Pain often excruciating and lead to despair and panic Inadequate pain management can lead to chronic pain syndromes Incentive spirometry NB. especially with chest pain/rib pain to avoid progression to acute chest syndrome Antibiotics Fever often accompany a crisis guided investigations to exclude a source (blood, urine) & empiric antibiotics Individualised plan for managing a painful crisis

24 Avoid / early management of triggers +

25 Cytotoxic agent that inhibits ribonucleotide reductase Used in myeloproliferative disorders Mechanisms of action: INCREASES THE LEVEL OF HbF HbF retards the sickling process & does not participate in the formation of sickle tactoids More HbF = Less HbS DECREASES EXPRESSION OF ADHESION MOLECULES ON TACTOIDS Makes them less sticky UPREGULATES NITRIC OXIDE EXPRESSION Vasodilates CAUSES MILD MYELOSUPPRESSION Reduces adherent leukocytes to the walls of small venules and improves the flow of blood

26 Multicenter Hydroxyurea Trial 1995 Clearly demonstrated the efficacy and safety of hydroxyurea in reducing the frequency of painful crises, acute chest syndrome and transfusions in patients with sickle cell disease of all ages

27 BABY HUG Trial (2011) Multicentre, randomised, double-blind placebo-controlled trial on the use of hydroxyurea in infants (from 9-18 months of age)with SCD Statistically significant lower rates of initial & recurrent episodes of pain, dactylitis, acute chest syndrome, hospitalization and mortality Infants who were asymptomatic at enrollment also had less dactylitis and fewer hospitalisations and transfusions if treated with hydroxyurea It did not show a decrease in splenic and renal damage Mild myelosuppression noted but hydroxyurea was NOT associated with an increased risk of bacteraemia or serious infections nor any longterm complications of carcinogenicity, infertility Provides evidence that hydroxyurea can be safely used even in very young infants regardless of symptoms SA RECOMMENDATION is that hydroxyurea therapy should be instituted in children with SCD >2years of age 10-15mg/kg/d increased to 30mg/kg/d Stop only if neutrophil count below 1000 or when conception planned

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29 Devastating complication Due to the occlusion of cerebral microvasculature Usually ischaemic in children The incidence is highest between 2-11 years At age 14 years: 10% of children with HbS will have OVERT stroke 20-35% will have silent infarctions with changes on MRI causing cognitive decline, developmental delays, school failure

30 Children at high risk for stroke can be identified with transcranial Doppler imaging (TCD) High cerebral vessel bloodflow velocities correlate with an increased risk for stroke Conditional: cm/s Elevated: >200cm/s

31 TCD measures the flow velocities in the large intracranial arteries of the circle of Willis Sickle occlusive vasculopathy and resultant large arterial stenosis occurs in the internal carotid artery, middle cerebral and anterior cerebral artery Reduced vessel diameter (stenosis) is inversely proportional to the blood flow through the artery TCD is safe, non-invasive, cost effective and well tolerated by children Recommendation: Screen children with SCD between 2-16years of age ANNUALLY with TCD

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33 1998 Children with sickle cell disease with a high risk of stroke by transcranial Doppler imaging (>200 cm/s) were randomized to chronic transfusion or usual care Transfusion greatly reduced the risk of a FIRST stroke (90% absolute risk reduction) Recommendation: Children with abnormal TCD should be on a chronic transfusion programme aiming to keep the HbS <30%

34 2005 Randomized controlled trial in which children with sickle cell disease on chronic transfusions as a primary stroke prevention were randomized to continue transfusion or discontinue transfusion. The trial stopped early due to the high rate of reversion to high-risk TCD s % of patients with a first ischaemic stroke had a risk of a second stroke if untreated Chronic transfusions reduce the risk for a second stroke to 10% Recommendation: Patients with abnormal TCD s or following a first stroke should continue indefinitely with long-term transfusions

35 Simple blood transfusions in the acute setting: Splenic sequestration crisis Aplastic crisis Acute chest syndrome Pre-operatively Chronic transfusion therapy refers to regular simple blood transfusions to keep the HbS <30% Prevention of first or subsequent strokes with abnormal TCD Recurrent debilitating VOC Different from exchange transfusions usually done during the acute phase of a stroke, acute chest crisis or priapism to quickly decrease the level of HbS to <30%

36 Red cell and HLA allo-immunisation Red cell allo-antibodies occur in 20-30% of transfused SCD patients Occurs in response to other antigens present on the surface of transfused red cells (E,C,K,Duffy) Cause difficulty in matching blood for transfusion and can cause delayed hemolytic transfusion reactions Cause complications if bone marrow transplantation is considered May be overcome by extended phenotype matching Expensive, availability

37 Iron overload Each transfused unit of blood has 250mg iron The body has no means to excrete extra iron Iron accumulates in the liver (>>), heart, endocrine organs, lungs etc. Risk of cirrhosis & hepatocellular carcinoma Monitoring for transfusional iron overload s-ferritin MRI (Ferriscan) Measures LIC (liver iron concentration) Chelation Indicated when s-ferritin >1000 or >120ml/kg packed cell transfusion Deferioxamine Deferasirox (Exjade) daily oral tablet dispersed in water or fruit juice Automated erythrocyte apheresis (exchange) Carries less risk of iron overload than top-up simple transfusion

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39 Children with SCD have an increased susceptibility to infection Functional asplenia Damaged by repeated infarctive VOC episodes Increased susceptibility to infections with encapsulated organisms Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenza (Africa: Additional risk of Staph, Klebsiella, E.coli) Impaired complement activity Zinc deficiency Iron overload Presence of necrotic tissue (leg ulcers) Risk of osteomyelitis Salmonella osteomyelitis Staphylococcus aureus

40 Preventive measures: Prophylactic antibiotics Pneumococcal prophylaxis Penicillin VK 125mg bd for children <3years Penicillin VK 250mg bd for children >3years until adolescence Malaria prophylaxis Bed-nets, protective clothing, chemoprophylaxis Pneumococcal vaccine Children >2yrs Unconjugated vaccine (Pneumovax) Children <2yrs Conjugated vaccine (Prevenar) Conjugated meningococcal C vaccine (Menactra) Haemophilus influenza B vaccine Annual influenza vaccine Specific measures: Early recognition and treatment of infections especially if fever 38.5 C Atypical bacterial cover (Mycoplasma) for ACS Incentive spirometry Surgical debridement, IV antibiotics, dressings for leg ulcers

41 Early diagnosis and entry into care programme Newborn screening Genetic councelling/family planning/prenatal diagnosis Identification of heterozygous carriers & pre-marital testing Parental education Folic acid supplementation & good nutrition Early management of complications Appropriate management of pain, anaemia Prophylactic & directed antibiotics Bacterial infection and malaria prophylaxis Immunisations National schedule plus extra Hydroxyurea In all from 9 months Screening TCD, echo in symptomatic patients, opthalmologic checks, microalbuminuria screening Transfusions Exchange Chronic (with ferritin monitoring & chelation)

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43 The only curative treatment is an allogeneiec bone marrow transplant where the defective host s bone marrow stem cells are replaced with stem cells containing the normal B-globin genotype Major advantage is that SCT controls & stabilises SCD-related organ damage Differs from Hydroxyurea and chronic transfusion therapy which are largely supportive Donor choice historically Best results with matched sibling donor Donor availability a major problem Haploidentical donors.

44 Center for International Blood and Marrow transplant research database 85% of BMT for SCD were from MSD >80% done in children <16 years of age Problem of disease complications and co-morbidities increasing morbidity of BMT in older patients Established nephropathy, pulmonary hypertension, cardiac failure, cerebrovascular disease all worsen the toxicity of the conditioning regimen and increase post-transplant complications Preferred source of stem cells are bone marrow as opposed to peripheral blood stem cells Peripheral blood stem cells have higher risk of GvHD and mortality

45 Clinical variability in the manifestations of sickle cell disease Can range from minimally affected to severely symptomatic BMT generally indicated in individuals with more severe disease but how will one predict which patients will become severely affected before they have too much organ damage? BMT may be considered even in young patients with milder disease with a well-matched sibling donor Want to transplant when the patient is still functionally well with minimal organ damage (young)to minimize the toxicity of the conditioning regimen RISK:BENEFIT RATIO

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47 Replacing the defective gene (with mutation) with a normal gene Done successfully in the sickle transgenic mouse Progress in humans limited by identification of appropriate vectors & efficacy of gene transfer & low level of expression of globin genes Still in the development phase

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