July 2007: Prophylaxis crucial in sickle cell disease
How is sickle cell disease diagnosed?
What are its clinical consequences?
What treatments are available?
How is sickle cell disease diagnosed?
What are its clinical consequences?
What treatments are available?
Sickle cell disease comprises a heterogeneous family of disorders characterised by the tendency of erythrocytes to ‘sickle' when deoxygenated. It is an autosomal recessive condition that occurs when sickle haemoglobin (HbS), encoded by the gene ßs, combines with another abnormal haemoglobin gene. The most common form is homozygous sickle cell disease (SS), commonly known as sickle cell anaemia.
The ßs gene can also interact with ß thalassaemia genes and other structurally abnormal haemoglobins, such as HbC, found in parts of Ghana, and HbDPunjab, found in parts of India, to produce other forms of sickle cell disease – SC and SD respectively. The sickle gene is widely distributed throughout Central and Southern Africa, the Eastern Mediterranean and the Indian subcontinent.
Sickle cell disease is the most common serious genetic disorder in England. Currently it is estimated that there are 12,500 people in the UK with sickle cell disease. Thus a GP working in an inner city area may have around 50 patients who are asymptomatic carriers, and one or two patients with a form of sickle cell disease.1,2
Patients whose origins can be traced to Africa, the Carribean, the Mediterranean, South East Asia and the Middle East are at highest risk. Ethnic groups at highest risk include:
• West Africans (1:5 patients)
• Afro-Caribbeans (1:8-10 patients)
• Patients from the Mediterranean or Middle East (1:100 patients).
Sickle haemoglobin, HbS, occurs because of a single base mutation in the ßs gene on chromosome 11, causing the substitution of valine for the normal glutamic acid into the beta haemoglobin chain. This results in a change in the molecule's charge, reduced solubility of HbS in the deoxygenated state and polymerisation of HbS – sickling – under certain conditions. This leads to the classical morphological change seen in irreversibly sickled erythrocytes.
At least 6% of the UK population belong to an ethnic group at risk of having a haemoglobinopathy, such as sickle cell disease. Currently an estimated 300 children are born in England each year with sickle cell disease. Early diagnosis allows early intervention.3,4
Neonatal screening for haemoglobinopathies, performed on the Guthrie blood spot, is now provided for all babies born in England as a part of the NHS Sickle Cell and Thalassaemia Screening Programme.
A national antenatal screening programme, linked to the neonatal screening programme, is now in place in England. The aim of antenatal screening is to identify at-risk pregnancies and allow informed choices to be made. Primary care plays a pivotal role in this process as the first point of contact for pregnant women.
Early booking is advised to allow detection of carriers, paternal testing where appropriate and counselling of at-risk couples. Some couples may opt for prenatal diagnosis, which can be performed by analysis of fetal DNA obtained by amniocentesis or from chorionic villus biopsy.
Pre-implantation genetic diagnosis for high-risk couples is available at some centres.
Termination of the pregnancy may not be acceptable or appropriate for a number of reasons, of which delayed referral to a specialist centre is an important factor.
Currently there is no accepted policy for haemoglobinopathy screening except antenatally and neonatally. Prior to surgery and anaesthesia, screening is usually performed if the patient is identified as belonging to an at-risk group. Otherwise it is generally performed in patients with a symptomatic presentation. Thus GPs are ideally placed for opportunistic screening, and should have a low threshold to screening requests.
The diagnosis of sickle cell disease relies on the demonstration and quantification of HbS.5 Screening tests include the ‘sickle prep', where sickled erythrocytes can be viewed microscopically within hours.
However, in the UK the sickle solubility test is preferred. A positive test confirms the presence of HbS, but fails to distinguish between asymptomatic carriers and those with sickle cell disease. The test can also result in false negatives in the first few months of life because of the high levels of HbF present in the infant, which interfere with the test.
As a minimum, a full blood count and sickle screen should be requested – both of which can be performed on a single EDTA (FBC) sample. U&Es and LFTs may be helpful if sickle cell disease is confirmed.
Sickle cell disease is characterised by reduced red cell survival due to haemolysis. This results in anaemia and often jaundice; functional hyposplenism, leading to an increased susceptibility to infection; and microvascular occlusion, causing tissue ischaemia and/or necrosis.
The condition is associated with considerable morbidity and early mortality. While SS is considered the most severe form of the disease, there is considerable variability in clinical severity between individuals, and even between affected family members.
The most common clinical manifestation of the disease is pain caused by vaso-occlusion.6 This accounts for the majority of interactions with medical services. In infants this commonly affects the bones of the hands and feet, causing dactylitis (see figure 1,above).
Older children tend to experience pains in the long bones, whereas in adults pain often occurs in the chest, back and thighs.
Many patients will experience painful crises on a monthly basis and the majority of these episodes are managed in the community.
Patients should be taught to use an analgesic ladder, commencing with paracetamol plus an NSAID such as diclofenac, progressing to co-dydramol or dihydrocodeine for moderate pain. If these measures fail to provide adequate relief, transfer to hospital is usually needed for stronger opiate analgesia, together with hydration, monitoring and further investigations.7
Recognised precipitating factors of crisis include:
• Changes in the weather
Infection is a common precipitant in both adults and children. It is the most common cause of death in children with sickle cell disease. Patients have an increased susceptibility to infection by encapsulated organisms, such as pneumococcus, Haemophilus influenzae, and meningococcus, because of red cell sickling leading to vaso-occlusion within the splenic vaculature, resulting in splenic infarction and hypofunction.
Daily oral penicillin has been shown to be highly effective in preventing pneumococcal infection and together with vaccination constitute the most important prophylactic measures in children with sickle cell disease.
Individuals with sickle cell trait living in malaria-endemic areas are less susceptible to the severe forms of malaria in early childhood – therefore they have a survival advantage. However, those with sickle cell disease have an increased susceptibility to infection mainly because of splenic hypofunction; thus they are susceptible to malaria.
Sickle cell disease is a multisystem disorder that leads to a myriad of complications (see table 2, attached).
Life-threatening complications include aplastic crisis and acute splenic sequestration. This occurs predominantly in children, where progressive anaemia will lead to hypovolaemic shock if untreated.
Stroke affects around 11% of SS patients by the age of 20 years. Transcranial Doppler ultrasonography (TCD) is a reliable, non-invasive tool allowing measurement of mean blood flow velocities in the internal carotid and middle cerebral arteries. Studies have shown that children with velocities above 200cm/sec have a 40% risk of developing stroke over three years. Institution of a regular blood transfusion programme in the high-risk group led to a 90% reduction in the incidence of stroke.8 Thus it is recommended that children with sickle cell disease should be screened for stroke annually from the age of three years, using TCD.9,10
Blood transfusion causes iron overload when performed repeatedly, but in sickle cell disease, as in a few other instances, this may be lifesaving. However, transfusion also carries the risks of alloimmunisation, transfusion-transmitted infection and transfusion reactions.
Acute chest syndrome is the most common acute cause of death in adults with sickle cell disease.11 It often presents insidiously, with chest pain, tachypnoea and hypoxia; this will progress to respiratory failure if untreated.
Improved survival has resulted in more patients reaching adulthood. However, increasingly adult patients have evidence of chronic organ damage, such as pulmonary hypertension, chronic renal failure (which may require dialysis) and avascular necrosis of joints or the spine, causing chronic pain.
At the other end of the spectrum, gallstones are a common finding reflecting chronic haemolysis. Patients are generally asymptomatic and therefore do not require intervention.
Preventive measures play an important role in the management of patients with sickle cell disease. They include the avoidance of crisis-precipitating factors and prophylaxis with penicillin and folic acid. Penicillin should be commenced once diagnosis has been confirmed. In addition to the 7-valent pneumococcal vaccine given to all infants as part of their primary immunisations, the 23-valent pneumococcal vaccine should be given at two years of age and every five years thereafter.
As with other haemolytic anaemias, folate deficiency can occur and will exacerbate the anaemia. Thus lifelong folic acid supplementation is recommended. Iron supplements should only be given if a deficiency has been demonstrated.
Referral to hospital
Many painful crises are managed in the community with oral analgesia, warmth, fluids, and massage. However, GPs may be required to evaluate an atypical or prolonged crisis and to administer analgesia. Table 4, attached, outlines situations in which transfer to hospital is indicated.
Acute hospital management of sickle cell disease is largely supportive and comprises hydration, provision of analgesia and antibiotic therapy where indicated.
Patients with SS often have a haemoglobin concentration of 6-9g/dl. This is well tolerated, although easy fatiguability and exertional dyspnoea on climbing stairs are not uncommon.
Blood transfusion is not indicated for patients in a steady state. A ‘top-up' transfusion is recommended for severe anaemia caused by acute splenic sequestration or an aplastic crisis.
Exchange transfusion is required for serious complications, such as stroke, acute chest syndrome, severe mesenteric syndrome and priapism.
Hydroxycarbamide is used by consultants on a named patient basis in moderate to severely affected patients.12 It is an orally active chemotherapeutic agent that is well tolerated. It has been shown to decrease the frequency of painful crises, reduce the number of episodes of acute chest syndrome and reduce blood transfusion requirements. It increases the levels of HbF, improves red cell hydration and reduces the degree of leucocytosis and thrombocytosis commonly seen in sickle cell disease. Patients receiving this agent require regular monitoring, as it may cause myelosuppression in the short-term and its long-term safety profile in sickle cell disease is unknown.
New therapies are now becoming available. These include oral iron chelation, which should improve outcomes. New treatments for pulmonary hypertension are being developed.
Bone marrow transplantation
The only definitive cure for sickle cell disease is allogeneic bone marrow transplantation. This is currently performed in children who are severely incapacitated by sickle cell disease, meet specified criteria and have an HLA-matched sibling. More than 200 such transplants have been performed worldwide. Current results from Europe and the US give a survival rate of 90-95% and cure rate of sickle cell disease of around 85%.
All patients with sickle cell disease should be offered regular hospital follow-up, with annual review at a specialist centre. Further advice and support can be obtained from the Sickle Cell Society and local support groups.useful information sickle cell disease Useful information
The Sickle Cell Society provides support and advice for health professionals and patients with sickle cell disease.
helpline: 0800 001 5660
MB BS MRCPCH MRCPath
consultant paediatric haematologist, North Middlesex Hospital, London
Professor Sally C Davies
MBChB MSc FRCP FRCPath
Imperial College Faculty of Medicine, London and Director General for Research and Development, Department of Health