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Sickle cell disease: an update on management
SYMPOSIUM: HAEMATOLOGY
Sickle cell disease: an update on management
high early mortality but in the UK life expectancy has improved markedly with 99% survival to adulthood. A single base change in the beta globin gene causes an amino acid change of glutamic acid to valine. This structural variant of the adult haemoglobin, termed sickle haemoglobin or HbS, has unique properties and in the context of hypoxia, acidosis and dehydration can form polymers within the red blood cell. This polymerization can cause a conformational change of the red cell, from its archetypal doughnut shape into the pathognomonic sickle cell shape. This more rigid form causes microvascular occlusion, ischaemia and reperfusion injury. A chronic inflammatory state is established with endothelial and intravascular activation that perpetuates further ischaemia-reperfusion injury. In addition, the chronic haemolysis of sickle cells results in anaemia, hypoxia, cholelithiasis, fatigue, hypercoagulability and vasculopathy. Several genotypes make up the diagnosis of SCD. The most common and most severe of these is homozygous sickle cell disease, HbSS, which accounts for over 70% of all cases but the sickle phenotype is also seen with compound heterozygosity of HbS in combination with certain other beta globinopathies (HbC, Dpunjab, O-Arab and beta thalassaemias).
John Brewin Jo Howard
Abstract Sickle cell disease (SCD) is a common inherited disease affecting 12e15,000 individuals in the UK with approximately 250 new births per annum. Life expectancy has improved with the majority of those affected now surviving to adulthood, but it is associated with acute and chronic complications including haemolytic anaemia and intermittent episodes of severe bony pain, which may need hospital admission for management. Other acute complications include acute chest syndrome, stroke, priapism, splenic sequestration and red cell aplasia. Individuals with SCD also have an increased risk of infection and may develop renal dysfunction, respiratory complications and bony complications including avascular necrosis. Newborn screening will identify affected individuals and ensures early entrance into comprehensive care, which should include infection prophylaxis and primary stroke prevention by trans-cranial doppler screening. In addition annual review by a specialist team should continue throughout life. Optimal care provision comes from a strong multidisciplinary approach, with easy access to psychological services and an active community support team. With these measures, patients and their families can be educated to manage the minor complications of SCD with minimal impact to their daily lives and to recognize the more serious complications early, allowing quick and effective intervention to reverse the sickling process. Current treatments options are hydroxycarbamide (hydroxyurea), blood transfusion and haematopoietic stem cell transplant.
National newborn screening programme Early identification of SCD infants reduces morbidity and mortality. Guidelines from the NHS Sickle Cell and Thalassaemia Screening Programme advise that all newborn infants should be screened for sickle cell disease and this is done as part of the newborn blood spot test (heel prick test), typically on day 5 after birth. Positive results are sent to a named representative in the local service who ensures that parents are informed within 4 weeks of birth, informs the GP so that prophylactic antibiotics can be started and refers for specialist care.
Outpatient management of sickle cell disease
John Brewin MA MBBS MRes MRCP is a Clinical Research Fellow in Paediatric Haematology, Molecular Haematology, at Kings College London, London, UK. Conflict of interest: none declared.
All newborns with a positive screening test should be seen in a haemoglobinopathy clinic within 8 weeks of birth and confirmatory testing should be performed. Clinic review should be offered every 3 months for the first two years of life and every 6 months thereafter. The local unit may offer shared care with a specialist centre, with the latter providing at least annual review. Good communication between local and specialist centre and with primary and community care is vital and parents should be offered follow up at home by the community nurse specialists to provide additional support. Clinic review should include measurement of height, weight, examination and review of development, blood pressure, urinalysis and oxygen saturations (see Box 1). Blood tests providing steady state levels of haemoglobin (Hb), markers of haemolysis, percentage of fetal haemoglobin (HbF%) and renal function provide important prognostic and clinical information and should be checked at least annually. Many centres have developed proformas to help navigate these consultations. Parental consent should be sought to register the child with the National Haemoglobinopathy Registry (NHR) and data should be updated annually.
Jo Howard MB BChir MRCP FRCPath is a Consultant Haematologist with Guy’s and St Thomas’ NHS Foundation Trust and Honorary Reader, King’s College London, Guy’s Hospital, London, UK. Conflict of interest: none declared.
Infection prophylaxis Splenic infarction leads to hyposplenism, usually by the age of 6 months, meaning that patients with SCD are at high risk of
Keywords anaemia; hydroxycarbamide; hydroxyurea; sickle cell; stroke; trans-cranial Doppler; transfusion; vaso-occlusive crisis
Introduction Sickle cell disease (SCD) is one of the most common monogenic disorders in the world. It is estimated that around 350,000 babies are born with the condition every year. In the UK, the national screening programme reveals a birth prevalence of around 1 in 2000. SCD is most common in Sub-Saharan Africa, where carrier frequency approaches 20e25% but it is also common in the Caribbean, Eastern Mediterranean, Middle East, India and in South/Central America. In the past it has been associated with
PAEDIATRICS AND CHILD HEALTH --:-
1
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
SYMPOSIUM: HAEMATOLOGY
patients have an annual stroke risk of 10%. The STOP trial showed that if patients with abnormal TCDs are commenced on a blood transfusion program, aiming to maintain the HbS level below 30%, the risk of stroke is reduced by 92%. Since publication of this trial, TCDs have been introduced as standard of care and screening should commence promptly at 2 years of age, and, with ongoing normal measurements, continue on a yearly basis. Children with abnormal TCDs should be offered long term transfusion but this represents a significant burden, for both the patient and medical services. The STOP 2 trial demonstrated that simply stopping transfusions once TCD velocities had reverted to normal was associated with an increased stroke risk. More recently the TWiTCH trial showed that patients who had completed 12 months of transfusion therapy and with no evidence of moderate or severe stenoses seen on MRA, could be safely transitioned to hydroxycarbamide therapy. Once the patient is on hydroxycarbamide TCD measurements should be monitored trimestially. There is particular interest in this option in low and middle income countries, where disease burden can be high and access to safe blood transfusion services low. Patients with conditional readings have a higher risk of stroke than those with normal readings, and should be intensively monitored with MRA and repeated TCDs. The role of hydroxycarbamide in reducing TCD velocities in this group is currently being investigated. The incidence of SCI is 27% and 37% by age 5 and 15 years respectively. The SIT trial enrolled patients with SCI and found that the incidence of further SCI or overt stroke was 14%, but this was reduced to 6% in those commenced on a transfusion programme, suggesting a clear benefit of routinely offering a transfusion programme to these patients. This poses questions about identification of SCIs as MRI screening in young children requires some form of sedation incurring a degree of risk and is resource intense. Currently, UK national guidelines do not advocate routine MRI screening, however, it should be considered in those who are performing below expectation at school and if SCIs are found, patients should be referred for further psychometric assessment and consideration of transfusion. Stroke is far less common in the milder genotypes of SCD such as HbSC. There is no evidence to support a primary stroke prevention program and centres may offer less intensive TCD screening (e.g. at ages 2, 5 and 10 years of age.)
Key aims of paediatric outpatient services Key aims of paediatric outpatient services C C C C C
C C
Education and support of parents and patient Ensure adherence to prophylaxis against pneumococcal infection. Primary Stroke Prevention programme Checking developmental milestones Ensuring supportive environment at school, including a care plan with school nurse. Screening for early signs of chronic organ complications. Annual review
Box 1
certain types of infection. Invasive pneumococcal infection is a devastating complication that prior to the widespread use of penicillin prophylaxis occurred at a rate of 10 episodes per 100 patient years and was a major cause of early mortality. A randomised controlled trial in the early 1980s demonstrated that prophylactic oral penicillin reduced the incidence of pneumococcal infection by about 90% and its subsequent introduction vastly improved outcomes in paediatric SCD. Therefore, all patients should be commenced on prophylactic penicillin V by 3 months of age and offered pneumococcal vaccination. This currently comprises a 13-valent conjugate vaccine (Prevenar 13Ò), given at 2 and 4 months, which protects against 80e90% of serotypes followed by the 23-valent polysaccharide pneumococcal vaccine (PneumovaxÒ) at 2 years. Unfortunately, whilst covering a wide spectrum of pneumococcal variant, the Pneumovax is poorly immunogenic prior to the age of two years and requires booster vaccinations every subsequent 5 years to maintain efficacy. It is important to ensure adherence to this regimen in clinic. Patients should also receive vaccination for Hepatitis A and B and Meningitis ACWY as well as the routine vaccines offered to all children. They should also receive the yearly flu vaccine from 6 months onwards. Primary stroke prevention A key aspect of paediatric outpatient management is the stroke prevention programme. Untreated, up to 10% of children with HbSS disease will have a stroke by the age of 10 years with an incidence of 1.02% per year between 2 and 5 years. This can leave them with profound long-term cognitive and physical deficits. Furthermore, patients can have smaller infarcts, seen on MRI, but without overt physical signs, termed silent cerebral infarcts (SCIs). These are increasingly recognised to have an impact on IQ and cognitive performance. Stroke in the SCD population is usually due to a cerebral vasculopathy caused by a combination of microvascular ischaemia-reperfusion injury and the hyperdynamic blood flow typical of patients with SCD. Elevated blood flow velocities which can be measured by performing transcranial doppler (TCD) scanning. The most important measurement is the timeaveraged mean velocity (TAMV) taken from the proximal MCA and distal ICA. Those less than 170 cm/second are considered normal, those between 170 and 199 cm/s are termed conditional and those 200 cm/s or greater are considered abnormal and these
PAEDIATRICS AND CHILD HEALTH --:-
Respiratory complications Respiratory complications arise in 20e48% of all children with SCD and are associated with an increased risk of mortality. Asthma is particularly common in children with SCD. Sleep disordered breathing, including obstructive sleep apnoea (OSA) and nocturnal hypoxia, is also very common, and is associated with an increased risk of stroke. It is important to take a good respiratory history and ask about sleeping habits including snoring. If indicated, consider sleep studies and/or pulmonary function tests to assess further. OSA is often secondary to adenotonsillar hypertrophy and these patients may benefit from tonsillectomy. Renal complications Renal complications, termed sickle cell nephropathy (SCN) arise in around 30% of children with SCD. Many go on to develop
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Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
SYMPOSIUM: HAEMATOLOGY
renal failure as adults, and with a population that is now living longer, the need for renal replacement therapies is becoming more commonplace. The early features of SCN in children include hyperfiltration, microalbuminaemia, hyposthenuria (urine of low specific gravity) and distal renal tubular acidosis. Many children have persistent nocturnal enuresis due to deregulation of the urinary concentration mechanism in SCD. It is important to explore this in the clinic and emphasise this is a part of SCD and not a failure of the child to “grow up” per se. Renal function, blood pressure and microalbuminaemia should be monitored regularly in clinic and abnormalities should be referred to a renal specialist for investigation and management.
hydration (whilst avoiding over-hydration), appropriate analgesia and IV antibiotics, including atypical cover. Simple transfusion should be considered if there is a decrease in Hb >10 g/L from baseline and oxygen saturations on air are <93% or oxygen requirements are increased. If there are features of severe disease, and there has not been a significant drop in Hb or if there is progression despite simple transfusion, an exchange transfusion should be performed aiming to reduce HbS to below 30% whilst maintaining Hb below 110 g/L. In this situation transfer to a high dependency unit should be considered and non-invasive ventilation may be required. Chest physiotherapy and incentive spirometry have been shown to improve outcomes.
Bone complications Children with SCD are at high risk of avascular necrosis (AVN) most typically in pre-pubertal teenagers. Presentation is with chronic joint pain and stiffness most commonly in the hip. X-rays are abnormal with advanced disease but in early disease MRI is needed to confirm the diagnosis. Initial management is with analgesia and physiotherapy, whilst hip replacement surgery is usually avoided in children unless there is irreversible severe damage or deformity. Vitamin D deficiency is common in children with SCD and should be screened for routinely and aggressively replaced if deficient.
Acute stroke Effective implementation of primary prevention means acute ischaemic stroke (AIS) is now less common. If it occurs urgent exchange transfusion is the standard of treatment. Following this, the usual multidisciplinary approach to stroke rehabilitation can help speed recovery. The risk of recurrent AIS is high and only a regular transfusion programme seems effective in reducing this risk. The SWiTCH study demonstrated that switching to hydroxycarbamide after 18 months of transfusions was associated with recurrence of disease and is therefore not advised unless transfusions are contraindicated. Children with SCD are also at increased risk of haemorrhagic stroke.
Management of the acute complications of sickle cell disease
Acute splenic sequestration (ASS) Acute splenic sequestration is a potentially life-threatening complication that is seen predominantly in infants with HbSS. It is important parents are taught to palpate the infant’s abdomen and to recognize enlargement of the spleen and then seek urgent medical advice. ASS is characterized by a 20% drop in Hb and at least a 2 cm enlargement of the spleen. Platelets are typically low and reticulocytes are raised. Sequestration of red cells in the spleen can be rapid and progressive. Simple transfusion, aiming for baseline Hb usually resolves the acute episode. Recurrence occurs in approximately 50% and may be an indication for a period of regular transfusion, e.g. for 6e12 months, or even splenectomy, although this is only usually done after 3 years of age.
Vaso-occlusive painful episodes (VOC) This is by far the most common complication of SCD and can affect any area of the body. Dactylitis, pain and swelling in the fingers and toes, is often the earliest complication in children with SCD with up to 40% experiencing it by age of 2 years but it is uncommon after 5 years old and in older children pain in the limbs and girdle is more common. Young children may be irritable, or may refuse to mobilise, older children will be able to express that they have pain. Bones may be swollen or hot, but examination may be normal. With increased oral fluids, paracetamol and ibuprofen the symptoms generally resolve after a day or two but may last up to a couple of weeks. Mostly, families can manage minor episodes with simple analgesia (e.g. paracetamol, NSAID) oral hydration and heat packs. It is important families are able to recognise when symptoms are not being controlled, or if other symptoms, e.g. fever, are emerging that require medical attention. All patients should have a personalised care plan that is available to local emergency department staff to guide on appropriate analgesia administration. National guidance advises patients presenting with VOC, should receive their first dose of analgesia within 30 minutes of presentation to acute services. This should be audited locally to ensure targets are met.
Priapism Painful persistent erection of the penis is often under-reported due to patient embarrassment or failure to connect this to their SCD. It is important to educate young boys and their families from an early age. It typically affects adolescents, but can occur at younger ages. If persisting longer than 2 hours, tissue damage can occur potentially leading to erectile dysfunction and impotence in the future. Simple measures such as passing urine, a warm bath, jogging and pain relief can help, but if prolonged, corpus cavernosa aspiration and irrigation may be necessary. Aplastic crisis Although a drop in haemoglobin from steady state can occur during many of the acute SCD complications, infection with human erythrovirus B19 (parvovirus) should be considered in patients with acute anaemia and reticulocytopenia. This virus causes a transient red cell aplasia, lasting around 2e3 weeks and can lead to profound anaemia which should be treated with simple transfusion.
Acute chest syndrome (ACS) This remains the most common cause of mortality in patients with SCD. It is defined as any acute respiratory disorder associated with a new pulmonary infiltrate seen on chest x-ray. Patients present with rapidly progressive respiratory distress. Fever, pleuritic pain, dyspnoea and progressive hypoxia are common features. Initial treatment includes high-flow oxygen, IV
PAEDIATRICS AND CHILD HEALTH --:-
3
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
SYMPOSIUM: HAEMATOLOGY
Current treatment options
Future developments
Hydroxycarbamide Hydroxycarbamide (HC) also known as hydroxyurea, is the only drug currently licensed for use in SCD. It has been widely used in the management of SCD since the Multicentre Study of Hydroxyurea (MSH) in 1995 showed its efficacy in patients with severe disease. It was shown to significantly increase fetal haemoglobin (HbF) levels and alleviate complications of SCD such as ACS and VOC. The HUSOFT and BABY HUG trials have demonstrated the safety and efficacy of HC in very young children with no deleterious effect on growth and development. Further long term data are being accumulated, but there is now a strong argument to suggest all children with HbSS and HbSBothalassaemia, regardless of disease severity, should be offered HC from an early age. Indeed, U.S. guidelines recommended this approach, but many clinicians still reserve HC for those with severe phenotype. HC can cause myelosuppression and patients should have a blood count done a fortnight after commencement or dose escalation, and if on a stable dose, at least every 3 months. Shortmedium term side effects include nausea, which usually settles after a few weeks, hair thinning and nail hyperpigmentation. Long-term safety data on HU use have also been reassuring. There has been no evidence to support the fear that it may be leukaemogenic, with the risk of cancer being no different to the general population. However, patients/parents should be counselled on the theoretical risk of teratogenicity and of reduced spermatogenesis, which occurs particularly whilst taking the medication, but in rare cases may persist long term.
Improving understanding of multiple contributing pathophysiological mechanisms leading to vaso-occlusion and tissue injury in SCD have resulted the development of new drugs, several of which are currently being investigated in clinical trials. Inhibitors of cell adhesion The adherence of RBCs and neutrophils to the endothelium is crucial in vaso-occlusion and depends selectins, expressed primarily on the activated endothelium. Rivipansel is a pan-selectin inhibitor being used in acute VOC that has now reached phase 3 trials. Crizanlizumab, a P-selectin specific monoclonal antibody given as monthly infusions, reduced frequency of painful crises in phase 2 trials and is now entering phase 3 trials. Poloxomer 188 is a surfactant that acts to inhibit cell adhesion in the vascular beds resulting in improved microvascular blood flow. A phase 3 trial showed modest efficacy during acute VOC and a second phase 3 trial is currently ongoing. Antiplatelet agents Platelets contribute to SCD pathology through multiple mechanism including formation of intravascular aggregates, release of pro-inflammatory cytokines and activation of coagulation. Prasugrel showed promise in early trials, however, a multinational phase 3 study recently completed failing to show a significant difference in VOC events. Ticagrelor, another platelet inhibitor, is currently in phase 2 trials. Antisickling and oxygen donation Haemoglobin modifiers (e.g. Aes-103 and GBT440) are a promising new class of drugs which act by increasing haemoglobin oxygen affinity. In vitro and in vivo studies have demonstrated their potent anti-sickling properties. A recent phase I/II trial of GBT440 saw a significant reduction in markers of haemolysis and reduction in circulating sickle cells seen on peripheral blood smears. Phase 3 trials have commenced. Carbon monoxide has potent anti-sickling properties as, when attached to Hb, it can prevent or reverse HbS polymerisation and at very low levels may even have anti-inflammatory effects and early phase trials are investigating agents designed to deliver CO to HbS and carry O2.
Blood transfusion Blood transfusion is an important treatment for both acute and long-term complications of SCD. In the acute setting (e.g. ACS, acute stroke, acute anaemia, acute multi-organ failure) it can be life-saving and should proceed with minimum delay. There are numerous beneficial effects of blood transfusion including correction of anaemia, improved oxygen carrying capacity and reversal of acute sickling complications. These benefits should be balanced against its side-effects which include infection, alloimmunisation and hyperhaemolyis. Exchange transfusion, whereby patients’ blood is removed at the same time as non-sickle RBC is transfused is the most effective way of reducing the HbS percentage, without excessively increasing the blood volume or haematocrit. Ideally an automated erythrocytapheresis machine is used, however, these machines and the operational expertise are usually only available at large SCD centres. Exchange transfusions have the additional benefit of avoiding iron loading.
Gene therapy This is an exciting prospect that has been tantalisingly out of reach until recently. The challenge of harvesting patient haematopoeitic cells, successful genetic manipulation, then reintroduction to the patient by autologous SCT have proved greater than perhaps initially expected. However, a recent update on the first such case in a patient with SCD is promising -18 months on from the transplant, the patient is well and disease free. Alternative approaches using gene editing tools such as CRISPR/Cas9 or zinc fingers are also being actively investigated. A
Stem cell transplant (SCT) Stem cell transplant offers a chance of complete cure for patients with SCD and should be considered in children with sibling donors and severe disease. With sibling allografts the cure rate is 90% and associated mortality is quoted at 5e7% but the availability/suitability of sibling donors is limiting. A recent report on SCT with unrelated donors had a mortality rate of 25% due to complications from graft versus host disease and is therefore not currently recommended. Approaches with haploidentical donors are currently being explored in clinical trials.
PAEDIATRICS AND CHILD HEALTH --:-
FURTHER READING Gluckman E, Cappelli B, Bernaudin F, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood 2017; 129: 1548e56.
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Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
SYMPOSIUM: HAEMATOLOGY
Hankins JS, Aygun B, Nottage K, et al. From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Med (Baltimore) 2014; 93: e215. Howard J, Telfer P. Sickle cell disease in clinical practice. London: Springer-Verlag, 2015. Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica 2007; 92: 905e12. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet (London, England) 2011; 377: 1663e72. Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD with Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet (London, England) 2016; 387: 661e70. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 2017 Jan 31. S0140e6736(17)30193-9.
PAEDIATRICS AND CHILD HEALTH --:-
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: recommendations from the 2014 Expert Panel report. Am Fam Phys 2015; 92: 1069e76.
Practice points C
C
C
C
5
Children with SCD will be identified via the Newborn Screening blood spot programme and should be referred for comprehensive follow up. This will include infection prophylaxis and specialist annual review Children with HbSS and HbSBothalassaemia should undergo trans-cranial Doppler screening annually between two and sixteen years of age and offered long term transfusion therapy if they have abnormal readings. Acute sickle pain should be treated rapidly with effective analgesia within 30 minutes of arrival in hospital Hydroxycarbamide therapy should be discussed with parents of children with HbSS/HbSBothalassaemia
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
Sickle cell disease: an update on management
high early mortality but in the UK life expectancy has improved markedly with 99% survival to adulthood. A single base change in the beta globin gene causes an amino acid change of glutamic acid to valine. This structural variant of the adult haemoglobin, termed sickle haemoglobin or HbS, has unique properties and in the context of hypoxia, acidosis and dehydration can form polymers within the red blood cell. This polymerization can cause a conformational change of the red cell, from its archetypal doughnut shape into the pathognomonic sickle cell shape. This more rigid form causes microvascular occlusion, ischaemia and reperfusion injury. A chronic inflammatory state is established with endothelial and intravascular activation that perpetuates further ischaemia-reperfusion injury. In addition, the chronic haemolysis of sickle cells results in anaemia, hypoxia, cholelithiasis, fatigue, hypercoagulability and vasculopathy. Several genotypes make up the diagnosis of SCD. The most common and most severe of these is homozygous sickle cell disease, HbSS, which accounts for over 70% of all cases but the sickle phenotype is also seen with compound heterozygosity of HbS in combination with certain other beta globinopathies (HbC, Dpunjab, O-Arab and beta thalassaemias).
John Brewin Jo Howard
Abstract Sickle cell disease (SCD) is a common inherited disease affecting 12e15,000 individuals in the UK with approximately 250 new births per annum. Life expectancy has improved with the majority of those affected now surviving to adulthood, but it is associated with acute and chronic complications including haemolytic anaemia and intermittent episodes of severe bony pain, which may need hospital admission for management. Other acute complications include acute chest syndrome, stroke, priapism, splenic sequestration and red cell aplasia. Individuals with SCD also have an increased risk of infection and may develop renal dysfunction, respiratory complications and bony complications including avascular necrosis. Newborn screening will identify affected individuals and ensures early entrance into comprehensive care, which should include infection prophylaxis and primary stroke prevention by trans-cranial doppler screening. In addition annual review by a specialist team should continue throughout life. Optimal care provision comes from a strong multidisciplinary approach, with easy access to psychological services and an active community support team. With these measures, patients and their families can be educated to manage the minor complications of SCD with minimal impact to their daily lives and to recognize the more serious complications early, allowing quick and effective intervention to reverse the sickling process. Current treatments options are hydroxycarbamide (hydroxyurea), blood transfusion and haematopoietic stem cell transplant.
National newborn screening programme Early identification of SCD infants reduces morbidity and mortality. Guidelines from the NHS Sickle Cell and Thalassaemia Screening Programme advise that all newborn infants should be screened for sickle cell disease and this is done as part of the newborn blood spot test (heel prick test), typically on day 5 after birth. Positive results are sent to a named representative in the local service who ensures that parents are informed within 4 weeks of birth, informs the GP so that prophylactic antibiotics can be started and refers for specialist care.
Outpatient management of sickle cell disease
John Brewin MA MBBS MRes MRCP is a Clinical Research Fellow in Paediatric Haematology, Molecular Haematology, at Kings College London, London, UK. Conflict of interest: none declared.
All newborns with a positive screening test should be seen in a haemoglobinopathy clinic within 8 weeks of birth and confirmatory testing should be performed. Clinic review should be offered every 3 months for the first two years of life and every 6 months thereafter. The local unit may offer shared care with a specialist centre, with the latter providing at least annual review. Good communication between local and specialist centre and with primary and community care is vital and parents should be offered follow up at home by the community nurse specialists to provide additional support. Clinic review should include measurement of height, weight, examination and review of development, blood pressure, urinalysis and oxygen saturations (see Box 1). Blood tests providing steady state levels of haemoglobin (Hb), markers of haemolysis, percentage of fetal haemoglobin (HbF%) and renal function provide important prognostic and clinical information and should be checked at least annually. Many centres have developed proformas to help navigate these consultations. Parental consent should be sought to register the child with the National Haemoglobinopathy Registry (NHR) and data should be updated annually.
Jo Howard MB BChir MRCP FRCPath is a Consultant Haematologist with Guy’s and St Thomas’ NHS Foundation Trust and Honorary Reader, King’s College London, Guy’s Hospital, London, UK. Conflict of interest: none declared.
Infection prophylaxis Splenic infarction leads to hyposplenism, usually by the age of 6 months, meaning that patients with SCD are at high risk of
Keywords anaemia; hydroxycarbamide; hydroxyurea; sickle cell; stroke; trans-cranial Doppler; transfusion; vaso-occlusive crisis
Introduction Sickle cell disease (SCD) is one of the most common monogenic disorders in the world. It is estimated that around 350,000 babies are born with the condition every year. In the UK, the national screening programme reveals a birth prevalence of around 1 in 2000. SCD is most common in Sub-Saharan Africa, where carrier frequency approaches 20e25% but it is also common in the Caribbean, Eastern Mediterranean, Middle East, India and in South/Central America. In the past it has been associated with
PAEDIATRICS AND CHILD HEALTH --:-
1
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
SYMPOSIUM: HAEMATOLOGY
patients have an annual stroke risk of 10%. The STOP trial showed that if patients with abnormal TCDs are commenced on a blood transfusion program, aiming to maintain the HbS level below 30%, the risk of stroke is reduced by 92%. Since publication of this trial, TCDs have been introduced as standard of care and screening should commence promptly at 2 years of age, and, with ongoing normal measurements, continue on a yearly basis. Children with abnormal TCDs should be offered long term transfusion but this represents a significant burden, for both the patient and medical services. The STOP 2 trial demonstrated that simply stopping transfusions once TCD velocities had reverted to normal was associated with an increased stroke risk. More recently the TWiTCH trial showed that patients who had completed 12 months of transfusion therapy and with no evidence of moderate or severe stenoses seen on MRA, could be safely transitioned to hydroxycarbamide therapy. Once the patient is on hydroxycarbamide TCD measurements should be monitored trimestially. There is particular interest in this option in low and middle income countries, where disease burden can be high and access to safe blood transfusion services low. Patients with conditional readings have a higher risk of stroke than those with normal readings, and should be intensively monitored with MRA and repeated TCDs. The role of hydroxycarbamide in reducing TCD velocities in this group is currently being investigated. The incidence of SCI is 27% and 37% by age 5 and 15 years respectively. The SIT trial enrolled patients with SCI and found that the incidence of further SCI or overt stroke was 14%, but this was reduced to 6% in those commenced on a transfusion programme, suggesting a clear benefit of routinely offering a transfusion programme to these patients. This poses questions about identification of SCIs as MRI screening in young children requires some form of sedation incurring a degree of risk and is resource intense. Currently, UK national guidelines do not advocate routine MRI screening, however, it should be considered in those who are performing below expectation at school and if SCIs are found, patients should be referred for further psychometric assessment and consideration of transfusion. Stroke is far less common in the milder genotypes of SCD such as HbSC. There is no evidence to support a primary stroke prevention program and centres may offer less intensive TCD screening (e.g. at ages 2, 5 and 10 years of age.)
Key aims of paediatric outpatient services Key aims of paediatric outpatient services C C C C C
C C
Education and support of parents and patient Ensure adherence to prophylaxis against pneumococcal infection. Primary Stroke Prevention programme Checking developmental milestones Ensuring supportive environment at school, including a care plan with school nurse. Screening for early signs of chronic organ complications. Annual review
Box 1
certain types of infection. Invasive pneumococcal infection is a devastating complication that prior to the widespread use of penicillin prophylaxis occurred at a rate of 10 episodes per 100 patient years and was a major cause of early mortality. A randomised controlled trial in the early 1980s demonstrated that prophylactic oral penicillin reduced the incidence of pneumococcal infection by about 90% and its subsequent introduction vastly improved outcomes in paediatric SCD. Therefore, all patients should be commenced on prophylactic penicillin V by 3 months of age and offered pneumococcal vaccination. This currently comprises a 13-valent conjugate vaccine (Prevenar 13Ò), given at 2 and 4 months, which protects against 80e90% of serotypes followed by the 23-valent polysaccharide pneumococcal vaccine (PneumovaxÒ) at 2 years. Unfortunately, whilst covering a wide spectrum of pneumococcal variant, the Pneumovax is poorly immunogenic prior to the age of two years and requires booster vaccinations every subsequent 5 years to maintain efficacy. It is important to ensure adherence to this regimen in clinic. Patients should also receive vaccination for Hepatitis A and B and Meningitis ACWY as well as the routine vaccines offered to all children. They should also receive the yearly flu vaccine from 6 months onwards. Primary stroke prevention A key aspect of paediatric outpatient management is the stroke prevention programme. Untreated, up to 10% of children with HbSS disease will have a stroke by the age of 10 years with an incidence of 1.02% per year between 2 and 5 years. This can leave them with profound long-term cognitive and physical deficits. Furthermore, patients can have smaller infarcts, seen on MRI, but without overt physical signs, termed silent cerebral infarcts (SCIs). These are increasingly recognised to have an impact on IQ and cognitive performance. Stroke in the SCD population is usually due to a cerebral vasculopathy caused by a combination of microvascular ischaemia-reperfusion injury and the hyperdynamic blood flow typical of patients with SCD. Elevated blood flow velocities which can be measured by performing transcranial doppler (TCD) scanning. The most important measurement is the timeaveraged mean velocity (TAMV) taken from the proximal MCA and distal ICA. Those less than 170 cm/second are considered normal, those between 170 and 199 cm/s are termed conditional and those 200 cm/s or greater are considered abnormal and these
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Respiratory complications Respiratory complications arise in 20e48% of all children with SCD and are associated with an increased risk of mortality. Asthma is particularly common in children with SCD. Sleep disordered breathing, including obstructive sleep apnoea (OSA) and nocturnal hypoxia, is also very common, and is associated with an increased risk of stroke. It is important to take a good respiratory history and ask about sleeping habits including snoring. If indicated, consider sleep studies and/or pulmonary function tests to assess further. OSA is often secondary to adenotonsillar hypertrophy and these patients may benefit from tonsillectomy. Renal complications Renal complications, termed sickle cell nephropathy (SCN) arise in around 30% of children with SCD. Many go on to develop
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SYMPOSIUM: HAEMATOLOGY
renal failure as adults, and with a population that is now living longer, the need for renal replacement therapies is becoming more commonplace. The early features of SCN in children include hyperfiltration, microalbuminaemia, hyposthenuria (urine of low specific gravity) and distal renal tubular acidosis. Many children have persistent nocturnal enuresis due to deregulation of the urinary concentration mechanism in SCD. It is important to explore this in the clinic and emphasise this is a part of SCD and not a failure of the child to “grow up” per se. Renal function, blood pressure and microalbuminaemia should be monitored regularly in clinic and abnormalities should be referred to a renal specialist for investigation and management.
hydration (whilst avoiding over-hydration), appropriate analgesia and IV antibiotics, including atypical cover. Simple transfusion should be considered if there is a decrease in Hb >10 g/L from baseline and oxygen saturations on air are <93% or oxygen requirements are increased. If there are features of severe disease, and there has not been a significant drop in Hb or if there is progression despite simple transfusion, an exchange transfusion should be performed aiming to reduce HbS to below 30% whilst maintaining Hb below 110 g/L. In this situation transfer to a high dependency unit should be considered and non-invasive ventilation may be required. Chest physiotherapy and incentive spirometry have been shown to improve outcomes.
Bone complications Children with SCD are at high risk of avascular necrosis (AVN) most typically in pre-pubertal teenagers. Presentation is with chronic joint pain and stiffness most commonly in the hip. X-rays are abnormal with advanced disease but in early disease MRI is needed to confirm the diagnosis. Initial management is with analgesia and physiotherapy, whilst hip replacement surgery is usually avoided in children unless there is irreversible severe damage or deformity. Vitamin D deficiency is common in children with SCD and should be screened for routinely and aggressively replaced if deficient.
Acute stroke Effective implementation of primary prevention means acute ischaemic stroke (AIS) is now less common. If it occurs urgent exchange transfusion is the standard of treatment. Following this, the usual multidisciplinary approach to stroke rehabilitation can help speed recovery. The risk of recurrent AIS is high and only a regular transfusion programme seems effective in reducing this risk. The SWiTCH study demonstrated that switching to hydroxycarbamide after 18 months of transfusions was associated with recurrence of disease and is therefore not advised unless transfusions are contraindicated. Children with SCD are also at increased risk of haemorrhagic stroke.
Management of the acute complications of sickle cell disease
Acute splenic sequestration (ASS) Acute splenic sequestration is a potentially life-threatening complication that is seen predominantly in infants with HbSS. It is important parents are taught to palpate the infant’s abdomen and to recognize enlargement of the spleen and then seek urgent medical advice. ASS is characterized by a 20% drop in Hb and at least a 2 cm enlargement of the spleen. Platelets are typically low and reticulocytes are raised. Sequestration of red cells in the spleen can be rapid and progressive. Simple transfusion, aiming for baseline Hb usually resolves the acute episode. Recurrence occurs in approximately 50% and may be an indication for a period of regular transfusion, e.g. for 6e12 months, or even splenectomy, although this is only usually done after 3 years of age.
Vaso-occlusive painful episodes (VOC) This is by far the most common complication of SCD and can affect any area of the body. Dactylitis, pain and swelling in the fingers and toes, is often the earliest complication in children with SCD with up to 40% experiencing it by age of 2 years but it is uncommon after 5 years old and in older children pain in the limbs and girdle is more common. Young children may be irritable, or may refuse to mobilise, older children will be able to express that they have pain. Bones may be swollen or hot, but examination may be normal. With increased oral fluids, paracetamol and ibuprofen the symptoms generally resolve after a day or two but may last up to a couple of weeks. Mostly, families can manage minor episodes with simple analgesia (e.g. paracetamol, NSAID) oral hydration and heat packs. It is important families are able to recognise when symptoms are not being controlled, or if other symptoms, e.g. fever, are emerging that require medical attention. All patients should have a personalised care plan that is available to local emergency department staff to guide on appropriate analgesia administration. National guidance advises patients presenting with VOC, should receive their first dose of analgesia within 30 minutes of presentation to acute services. This should be audited locally to ensure targets are met.
Priapism Painful persistent erection of the penis is often under-reported due to patient embarrassment or failure to connect this to their SCD. It is important to educate young boys and their families from an early age. It typically affects adolescents, but can occur at younger ages. If persisting longer than 2 hours, tissue damage can occur potentially leading to erectile dysfunction and impotence in the future. Simple measures such as passing urine, a warm bath, jogging and pain relief can help, but if prolonged, corpus cavernosa aspiration and irrigation may be necessary. Aplastic crisis Although a drop in haemoglobin from steady state can occur during many of the acute SCD complications, infection with human erythrovirus B19 (parvovirus) should be considered in patients with acute anaemia and reticulocytopenia. This virus causes a transient red cell aplasia, lasting around 2e3 weeks and can lead to profound anaemia which should be treated with simple transfusion.
Acute chest syndrome (ACS) This remains the most common cause of mortality in patients with SCD. It is defined as any acute respiratory disorder associated with a new pulmonary infiltrate seen on chest x-ray. Patients present with rapidly progressive respiratory distress. Fever, pleuritic pain, dyspnoea and progressive hypoxia are common features. Initial treatment includes high-flow oxygen, IV
PAEDIATRICS AND CHILD HEALTH --:-
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SYMPOSIUM: HAEMATOLOGY
Current treatment options
Future developments
Hydroxycarbamide Hydroxycarbamide (HC) also known as hydroxyurea, is the only drug currently licensed for use in SCD. It has been widely used in the management of SCD since the Multicentre Study of Hydroxyurea (MSH) in 1995 showed its efficacy in patients with severe disease. It was shown to significantly increase fetal haemoglobin (HbF) levels and alleviate complications of SCD such as ACS and VOC. The HUSOFT and BABY HUG trials have demonstrated the safety and efficacy of HC in very young children with no deleterious effect on growth and development. Further long term data are being accumulated, but there is now a strong argument to suggest all children with HbSS and HbSBothalassaemia, regardless of disease severity, should be offered HC from an early age. Indeed, U.S. guidelines recommended this approach, but many clinicians still reserve HC for those with severe phenotype. HC can cause myelosuppression and patients should have a blood count done a fortnight after commencement or dose escalation, and if on a stable dose, at least every 3 months. Shortmedium term side effects include nausea, which usually settles after a few weeks, hair thinning and nail hyperpigmentation. Long-term safety data on HU use have also been reassuring. There has been no evidence to support the fear that it may be leukaemogenic, with the risk of cancer being no different to the general population. However, patients/parents should be counselled on the theoretical risk of teratogenicity and of reduced spermatogenesis, which occurs particularly whilst taking the medication, but in rare cases may persist long term.
Improving understanding of multiple contributing pathophysiological mechanisms leading to vaso-occlusion and tissue injury in SCD have resulted the development of new drugs, several of which are currently being investigated in clinical trials. Inhibitors of cell adhesion The adherence of RBCs and neutrophils to the endothelium is crucial in vaso-occlusion and depends selectins, expressed primarily on the activated endothelium. Rivipansel is a pan-selectin inhibitor being used in acute VOC that has now reached phase 3 trials. Crizanlizumab, a P-selectin specific monoclonal antibody given as monthly infusions, reduced frequency of painful crises in phase 2 trials and is now entering phase 3 trials. Poloxomer 188 is a surfactant that acts to inhibit cell adhesion in the vascular beds resulting in improved microvascular blood flow. A phase 3 trial showed modest efficacy during acute VOC and a second phase 3 trial is currently ongoing. Antiplatelet agents Platelets contribute to SCD pathology through multiple mechanism including formation of intravascular aggregates, release of pro-inflammatory cytokines and activation of coagulation. Prasugrel showed promise in early trials, however, a multinational phase 3 study recently completed failing to show a significant difference in VOC events. Ticagrelor, another platelet inhibitor, is currently in phase 2 trials. Antisickling and oxygen donation Haemoglobin modifiers (e.g. Aes-103 and GBT440) are a promising new class of drugs which act by increasing haemoglobin oxygen affinity. In vitro and in vivo studies have demonstrated their potent anti-sickling properties. A recent phase I/II trial of GBT440 saw a significant reduction in markers of haemolysis and reduction in circulating sickle cells seen on peripheral blood smears. Phase 3 trials have commenced. Carbon monoxide has potent anti-sickling properties as, when attached to Hb, it can prevent or reverse HbS polymerisation and at very low levels may even have anti-inflammatory effects and early phase trials are investigating agents designed to deliver CO to HbS and carry O2.
Blood transfusion Blood transfusion is an important treatment for both acute and long-term complications of SCD. In the acute setting (e.g. ACS, acute stroke, acute anaemia, acute multi-organ failure) it can be life-saving and should proceed with minimum delay. There are numerous beneficial effects of blood transfusion including correction of anaemia, improved oxygen carrying capacity and reversal of acute sickling complications. These benefits should be balanced against its side-effects which include infection, alloimmunisation and hyperhaemolyis. Exchange transfusion, whereby patients’ blood is removed at the same time as non-sickle RBC is transfused is the most effective way of reducing the HbS percentage, without excessively increasing the blood volume or haematocrit. Ideally an automated erythrocytapheresis machine is used, however, these machines and the operational expertise are usually only available at large SCD centres. Exchange transfusions have the additional benefit of avoiding iron loading.
Gene therapy This is an exciting prospect that has been tantalisingly out of reach until recently. The challenge of harvesting patient haematopoeitic cells, successful genetic manipulation, then reintroduction to the patient by autologous SCT have proved greater than perhaps initially expected. However, a recent update on the first such case in a patient with SCD is promising -18 months on from the transplant, the patient is well and disease free. Alternative approaches using gene editing tools such as CRISPR/Cas9 or zinc fingers are also being actively investigated. A
Stem cell transplant (SCT) Stem cell transplant offers a chance of complete cure for patients with SCD and should be considered in children with sibling donors and severe disease. With sibling allografts the cure rate is 90% and associated mortality is quoted at 5e7% but the availability/suitability of sibling donors is limiting. A recent report on SCT with unrelated donors had a mortality rate of 25% due to complications from graft versus host disease and is therefore not currently recommended. Approaches with haploidentical donors are currently being explored in clinical trials.
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FURTHER READING Gluckman E, Cappelli B, Bernaudin F, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood 2017; 129: 1548e56.
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Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005
SYMPOSIUM: HAEMATOLOGY
Hankins JS, Aygun B, Nottage K, et al. From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Med (Baltimore) 2014; 93: e215. Howard J, Telfer P. Sickle cell disease in clinical practice. London: Springer-Verlag, 2015. Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica 2007; 92: 905e12. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet (London, England) 2011; 377: 1663e72. Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD with Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet (London, England) 2016; 387: 661e70. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 2017 Jan 31. S0140e6736(17)30193-9.
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Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: recommendations from the 2014 Expert Panel report. Am Fam Phys 2015; 92: 1069e76.
Practice points C
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Children with SCD will be identified via the Newborn Screening blood spot programme and should be referred for comprehensive follow up. This will include infection prophylaxis and specialist annual review Children with HbSS and HbSBothalassaemia should undergo trans-cranial Doppler screening annually between two and sixteen years of age and offered long term transfusion therapy if they have abnormal readings. Acute sickle pain should be treated rapidly with effective analgesia within 30 minutes of arrival in hospital Hydroxycarbamide therapy should be discussed with parents of children with HbSS/HbSBothalassaemia
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Brewin J, Howard J, Sickle cell disease: an update on management, Paediatrics and Child Health (2017), http:// dx.doi.org/10.1016/j.paed.2017.07.005