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The potential severity and multi-system effects of sickle cell disease, combined with its relatively high prevalence both in the UK and globally, make it an important disease to understand as fully as possible.
Firstly, the basics of the disease itself, including its pathogenesis and clinical features, will be discussed. A paediatric case report of a sickle cell crisis will help to illustrate how patients with sickle cell can typically present to hospital, and how such presentations can be managed. The use of hydroxyurea in sickle cell disease, especially in children, is then considered, before other potential therapeutic options are briefly considered in the concluding section.
Sickle cell disease is a hereditary haemoglobinopathy which is caused by a single amino acid change at the 6th position of the Î²-globin chain. Normally, the majority of adult haemoglobin has the structure Î±2Î²2 (HbA), although adults also have some Î±2Î´2 (HbA2) and Î±2Î³2 (HbF, or fetal haemoglobin). The single amino acid change that occurs in sickle cell, which involves the substitution of valine for glutamic acid, changes the characteristics of those haemoglobin molecules containing the affected Î²-globin chains (Î²S) and, by extension, the characteristics of the red blood cells themselves. In individuals who are homozygous for this mutation, nearly all the haemoglobin is of the HbS (Î±2Î²2S) phenotype; they therefore have sickle cell disease. The haemoglobin of those who are heterozygous, meanwhile, is approximately 60% HbA and 40% HbS(1). Such individuals are said to have sickle cell trait rather than the full-blown disease.
Sickle cell disease is most common in those of African origin - for instant, the gene responsible is found in approximately 10% of the UK Afro-Caribbean population(2). It is, however, also widespread in the Middle East, India and Southern Europe. Such a distribution led to the so-called "malaria hypothesis"; that is, that the high prevalence of the sickle cell gene in these populations is due to the fact that having sickle cell trait confers a selective advantage by rendering the carrier less susceptible to infection with Plasmodium falciparum malaria(3). Such a selective advantage for heterozygous sickle cell trait would explain why the gene continues to persist at such high frequencies in these areas, despite the numerous deleterious effects of suffering from homozygous sickle cell disease. This geographical relationship between high rates of malaria infection and high frequencies of the sickle cell gene is illustrated in Figure 1.
Figure 1: The upper map depicts the frequency of the sickle cell (HbS) gene, while the lower one
shows the rates of malaria. Adapted from Global Distribution of the Sickle Cell Gene and
Geographical Confirmation of the Malaria Hypothesis by Piel et al. (2010)(4)
The key characteristic of HbS is that, in conditions of low oxygen tension, the molecules will polymerise and aggregate. This results in the HbS molecules forming needle-shaped structures, and it is these structures which then result in the sickling of red blood cells from which this disease derives its name. Such sickling is reversible at first, but with time and repeated episodes of deoxygenation, the red cells become permanently sickled(5).
Figure 2: A - Low magnification view of a blood film containing sickle cells
B - High magnification view showing an irreversibly sickled cell in the centre
Adapted from Robbins & Cotran Pathologic Basis of Disease (7th ed.)(5)
These sickled red blood cells are more prone to becoming trapped in blood vessels, especially so in the microcirculation. For many years, it was thought that this tendency merely related to their reduced deformability. However, it is now understood that while this does indeed play a role, also of importance is the increased adhesion of the sickled cells to the vascular endothelium(6). In addition, due to its effects as a vasodilator and an inhibitor of platelet aggregation, there is increasing focus on the role played by nitric oxide (NO) in these episodes of vaso-occlusion(7). Of course, once the cells become trapped in, and therefore occlude, the microvasculature, this induces conditions of local hypoxia which will only serve to exacerbate the sickling, which will then lead to further occlusion of the surrounding vessels. Thus, it is plausible that the vaso-occlusive crises which can occur so frequently in those with sickle cell disease arise from a vicious cycle of sickling, hypoxia and then further sickling.
A number of factors are known to have an impact on the rate of HbS polymerisation, and therefore the level of sickling that occurs(8). One such factor is the nature of the other haemoglobin chains present within the red blood cells. For instance, HbF (Î±2Î³2) acts to inhibit HbS polymerisation and, in so doing, will reduce the rate and degree of sickling. One therapeutic target in those with sickle cell disease has therefore been to increase HbF levels. Hydroxyurea, a drug which will be discussed in greater detail later on, is believed to have at least part of its action in this way. Other factors influencing the degree of sickling include the amount of HbS within the red blood cells (demonstrated by the fact that signs and symptoms of sickling do not manifest in people with sickle cell trait, unless they are exposed to extreme hypoxia), the intracellular concentration of HbS, the pH, and the length of exposure to conditions of low oxygen tension(8).
As well as vaso-occlusion, another key feature of sickle cell disease is the haemolysis that invariably occurs. There are two elements to this reduced red cell survival. Firstly, as already mentioned, sickled cells are more susceptible to becoming trapped in the microvasculature, such as that found in the splenic sinusoids for instance. Here they are phagocytosed and therefore removed from the circulation(9). Secondly, in addition to this extravascular haemolysis, red blood cells in sickle cell disease are also haemolysed intravascularly due to the increased fragility of their membranes. However, it is the former means of their removal which is thought to be more significant, as demonstrated by the fact that there is a strong correlation between the number of irreversibly sickled cells and overall red cell survival(10).
The clinical features of sickle cell disease are dominated by the manifestations of these two pathogenetic mechanisms of vaso-occlusion and haemolysis. Such features tend to be kept to a minimum in the first six months of life when levels of fetal haemoglobin are at their highest.
The vaso-occlusive crises can take a number of forms, but most commonly present with pain. In infants, this pain often occurs in the small bones of the hands and feet (dactylitis), while pain in other bones (e.g. the long bones, vertebrae, ribs, and pelvis) is seen more often in older children and adults(11). Vaso-occlusion can also lead to pulmonary infarction, which underlies the acute chest syndrome seen in sickle cell disease, as well as cerebral infarction. This latter complication has led to the introduction of transcranial doppler screening in affected children. The rationale for this is that the rate of stroke is 10-15% per year in children with both sickle cell disease and increased velocity measurements on a transcranial doppler scan; this rate drops dramatically to 0.5-1% per year in those with normal velocity measurements(12). The spleen is another organ which is adversely affected by repeated bouts of vaso-occlusion, such that patients with sickle cell undergo so-called "autosplenectomy" in early infancy as a result of infarction and fibrosis(13). The resultant hyposplenism renders patients susceptible to infection with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Some of these consequences of vaso-occlusion, such as infection (in the form of pneumococcal sepsis), the acute chest syndrome and stroke, have traditionally been the leading causes of mortality in those with sickle cell disease(14).
Figure 3: A splenic remnant from a patient with sickle cell
disease. From Robbins & Cotran Pathologic
Basis of Disease (7th ed.)(5)
The chronic haemolysis, meanwhile, manifests itself as a fairly stable anaemia, with patients generally having a haemoglobin level of around 6-9g/dL (normal range: 13-18g/dL in men; 11.5-16g/dL in women). This stability can be disrupted in the event of either a sequestration or an aplastic crisis(15). A sequestration crisis usually involves the pooling of blood in the spleen (and occasionally the liver), and so is therefore more common in young children who have not yet undergone autosplenectomy. The anaemia can become severe, in which case an urgent transfusion will be needed. Aplastic crises, on the other hand, tend to be less severe and are often self-limiting. They result from a temporary cessation in red blood cell production by the bone marrow, and are normally triggered by an infection with parvovirus B19.
In addition, important potential long-term consequences of sickle cell disease include proliferative sickle retinopathy, cardiac complications such as congestive heart failure, pulmonary hypertension, cholelithiasis and cholecystitis, avascular necrosis of bones, and acute and chronic renal failure(16).
The management of sickle cell disease can separated into that for the acute, crisis episodes, and that for the long-term sequelae of the disease.
As many patients are known to prefer to manage their painful crises at home, presentation to hospital may often be taken as a sign of severe pain. The patient should be provided with prompt analgesia (using the analgesic ladder as necessary), oral or IV fluids, oxygen, and antibiotics (if infection is suspected as the trigger for the crisis)(17). Transfusions are rarely necessary for a simple painful crisis. They may, however, be required in the form of a top-up transfusion during a sequestration or aplastic crisis, or in the form of an exchange transfusion following the development of the acute chest syndrome or a stroke(18).
In terms of the long-term sequelae of sickle cell disease, arguably the most important intervention is prophylactic penicillin combined with the relevant immunisations . The aim of this is to try to reduce the risk of infection with encapsulated bacteria as much as possible(19). Transfusions can also be used as a form of long-term therapy, but if this is the case, they should be accompanied by iron chelation (e.g. desferrioxamine) to prevent the toxic effects of iron overload(18). Finally, hydroxyurea can be considered, which is currently the only drug used in the UK to treat the sickle cell disease itself, rather than simply manage the complications.
Our understanding of the pathogenesis of sickle cell disease has improved dramatically over recent years, and with it our methods of managing this condition. This has been reflected by a concurrent improvement in prognosis. For instance, a 40-year prospective cohort study of 1056 patients with sickle cell disease by Powars et al.(20) demonstrated that the survival of children to age 20 has improved from 79% in those born pre-1975 to 89% to those born in or after that year. They also estimated that the median survival of those born after 1975 was 57 years, an increase of 16 years compared to those born pre-1975. However, while such data indicate that there have been improvements, they also show that there is room for further progress to be made.
Sickle Cell Disease: A Paediatric Case Report
Patient RO is a 16-year-old Afro-Caribbean female who was diagnosed with sickle cell disease at birth. On 21st October 2010, she presented to the A&E department at King's College Hospital suffering from a painful vaso-occlusive crisis caused by her disease. This will be a brief discussion of how she presented and how she was managed, in terms of both this crisis and her disease overall.
Her presenting complaint in A&E was a 2-hour history of severe ("10 out of 10") generalised body pain which started in her arms before spreading to her legs and elsewhere. This pain was throbbing in nature, and had been unresponsive to the Nurofen she'd taken at home. In terms of associated symptoms, she reported no fever or cough, and no nausea or vomiting. She did, however, report a cold and sore throat that she had been suffering from two weeks prior to this visit to A&E. Documenting any potential infective symptoms is important as infection is known to be a trigger for some vaso-occlusive crises
Her last admission to hospital had been in January 2009, when she presented with a vaso-occlusive crisis affecting predominantly her back and shoulders. Since then, she has attended A&E twice (not including this most recent episode); once in April 2010, due to neck pain, and again in September 2010 as a result of eye pain. The relative infrequency of her visits to hospital, combined with the fact that she reported normally managing her sickle cell crises at home, was reassuring with regards to the current severity of her disease.
On presentation, her routine observations were normal with the exception of a slightly raised respiratory rate (22/minute; normal range 14-20/minute). Significantly, she was afebrile (36.3°C). Examination was unremarkable except for the pain elicited when examining her arms, legs and neck. A chest x-ray was ordered and showed no evidence of acute chest syndrome, which is diagnosed by the presence of fever, respiratory symptoms and radiologically new pulmonary infiltrates. The results of other investigations were as follows:
17.08 â†‘ (4-11 x 109/L)
2.63* â†“ (3.8-5.8 x 1012/L)
8.2* â†“ (11.5-15.5g/dL)
464 â†‘ (150-400 x 109/L)
11.12 â†‘ (2.2-6.3 x 109/L)
*To put these in context: At an outpatient appointment on 22/06/2010, her
Hb was 8g/dL and her RBC was 2.55 x 1012/L
57* â†‘ (3-20Î¼mol/L)
*This was 64Î¼mol/L on 22/06/2010
9.1 â†‘ (<5mg/L)
The patient was admitted to one of the wards where treatment was started for a sickle vaso-occlusive crisis. She was provided with analgesia in the form of regular paracetamol, ibuprofen and Oramorph (10mg 4-hourly), as well as PRN Oramorph for any breakthrough pain. She had no response to the Oramorph, and so was switched to tramadol (50mg qds; later increased to 100mg qds). She was also started on IV fluids as she wasn't eating or drinking, and dehydration can both precipitate and exacerbate a sickle cell crisis.
One day post-admission, the patient spiked a fever of 38.3°C, and so was started on IV cefuroxime and PO erythromycin. Blood cultures were taken but showed no growth. While it is therefore possible that a combination of dehydration and infection triggered this crisis, this is by no means certain. Other possible triggers for a crisis include cold temperatures and vascular stasis, but often no definite cause is found. Patient RO improved rapidly and was discharged home on 24th October, with instructions to complete the course of oral antibiotics at home.
The usual drug management of Patient RO's sickle cell includes penicillin V 250mg twice-daily (a prophylactic dose), folic acid 5mg once-daily (to counter the increased folate demand caused by increased red cell turnover in sickle cell) and Hemoxide. This last drug is a vitamin and mineral supplement, which is popular in Africa for the treatment of sickle cell.
In the past, Patient RO had also been taking the drug hydroxyurea. She was started on it in October 2003 as she had been suffering from frequent (almost monthly) severe painful crises requiring hospitalisation. She continued on it until August 2007, when it was stopped because the frequency of her crises had decreased so dramatically. Patient RO therefore responded very well to hydroxyurea, and the careful monitoring she underwent while taking the drug demonstrated no evidence of any toxicity as a result of taking it. As this indicates, hydroxyurea can be a very successful drug for those with sickle cell disease, and as such it will now be considered in greater detail, especially regarding its use in children
Hydroxyurea Therapy In Sickle Cell Disease
Mechanism of action
Hydroxyurea is a cytotoxic chemotherapeutic agent which acts via inhibition of ribonucleotide reductase, a key enzyme for DNA synthesis. This then leads to the death of affected cells in the S-phase of the cell cycle(21). A possible therapeutic use for it in the management of sickle cell disease was postulated after it was shown that 5-Azacytidine, another cytotoxic agent, caused an increase in the production of fetal haemoglobin (HbF) in anaemic baboons(22). The potential benefits of HbF in sickle cell disease are well-known; patients with a HbF level which is persistently above 20% have fewer clinical events compared to those with a lower HbF level(23). A great deal of attention has therefore been focused on trying to find agents that can increase HbF levels in those with sickle cell disease.
After a very preliminary study, looking at just two patients with sickle cell, suggested that hydroxyurea may indeed cause an increase in HbF levels in humans(24), its possible use in the treatment of this disease began to be investigated more thoroughly. For instance, its stimulation of gamma-globin gene expression (and ergo HbF production) is now thought to be mediated via nitric oxide-dependent activation of soluble guanylyl cyclase in human erythroid cells(25). In addition, with time it has become apparent that any effect that hydroxyurea has in sickle cell disease may be due to more than just an increase in HbF synthesis. It has also been shown to reduce the levels of white blood cells, reticulocytes and platelets, stimulate the production of nitric oxide, and increase the water content of red blood cells, as well as reducing the adhesion of these cells to the vascular endothelium(26). Any or all of these actions could logically be beneficial in those with sickle cell disease, given what is currently understood about its pathogenesis.
Its use in children with sickle cell disease
While the potential benefits of hydroxyurea in adults with sickle cell disease are well documented(27, 28), there appears to be less certainty surrounding its place in the management of children with the disease. However, a review of the literature covering this matter reveals that there is clear evidence supporting its use.
Three studies published in 1996-97 looked at the use of hydroxyurea in children with severe sickle cell anaemia(29, 30, 31). In each case, children were considered to have severe disease if they had had more than 3 vaso-occlusive crises (including pain and acute chest syndrome) in the year leading up to entry in the study. All three were able to demonstrate improvements in those children who had been given hydroxyurea therapy.
In the first of these studies(29), Ferster et al. carried out a randomised trial involving 25 children, with a median age of 9 years (range 2-22 years), who had been classified as having severe sickle cell disease. The children were randomised to the hydroxyurea arm of the trial, where they were given the drug at an initial dose of 20mg/kg per day, or to the placebo arm. After six months, the two groups then switched over, and the study continued for a further six months. Three children were excluded from the study for failing to attend evaluation sessions. Of the 22 children remaining, 16 required no hospitalisation while they were in the hydroxyurea arm of the study, and those who did have to go into hospital spent less time there compared to those receiving the placebo (see Figure 4). Moreover, haematological parameters such as mean corpuscular volume (MCV), white blood cell count and reticulocytes all improved in the children while they were taking hydroxyurea.
Figure 4: The children represented by the dotted line started on hydroxyurea and
then switched to placebo after 6 months; those represented by the solid
line did the opposite. Both groups spent fewer days in hospital (Y-axis)
whilst on hydroxyurea. Adapted from the paper by Ferster et al.(29)
In the second study(30) by Scott et al., there was no placebo arm; instead, the 15 children involved were used as their own controls. The children (age range 10-17 years) were given hydroxyurea for a median of 24 months, starting on a dose of 10-20mg/kg per day. This dose was subsequently escalated as far as tolerance would allow. Again, the "end goal" being looked at was the rate of hospitalisation. In this case, the number of inpatient days while taking the hydroxyurea was compared with the number of inpatient days for each child before they had started treatment. In the 10 children who completed more than a year of hydroxyurea therapy, there was a statistically significant drop in the median number of days spent as an inpatient, from 4.1 ± 2.2 days per month prior to starting hydroxyurea, to 1.0 ± 1.7 days per month of therapy. As in the other study, there was also an improvement in haematological parameters, including haemoglobin levels and MCV.
Finally, de Montalembert et al.(31) carried out another uncontrolled study in which 35 children (age range 3-20 years) with severe sickle cell were given hydroxyurea therapy for a mean duration of 32 months. A reduction in the frequency of painful crises was reported by all except two of the participants. One especially interesting part of this study is that the results obtained appeared to suggest a lack of correlation between increasing HbF levels and improving clinical symptoms. This lends further support to the notion that hydroxyurea has its effects in sickle cell disease via more than a simple increase in HbF production.
These studies have therefore helped to demonstrate that hydroxyurea can be of benefit in older children with sickle cell disease. Two more recent studies(32, 33) have focused on its potential use in infants, i.e. its use in those who are not yet suffering from the more long-term consequences of the disease. Wang et al.(32) investigated the effects of 2 years of hydroxyurea therapy (20mg/kg/day) on 28 infants with a median age of 15 months. 7 left the study early; of the 21 left, their haematological values were each compared with 3 cohort-matched patients from the Cooperative Study of Sickle Cell Disease (CSSCD). Such a comparison showed improved values in the infants who had been taking hydroxyurea for two years (Table 1).
Table 1: Comparison of the haematological values at the end of the study, both with what they were at
the beginning, and with those of cohort-matched controls (the "expected" values) from the
CSSCD. From the paper by Wang et al(32)
Hankins et al.(33) then carried out an extension study looking at the long-term use of hydroxyurea in these same 21 infants. 17 of them went on to take hydroxyurea for 4 years, and 11 took it for a total of 6 years. This helped to demonstrate that the haematological benefits of hydroxyurea were sustained over longer time periods. Moreover, clinical events were reduced in these infants compared to cohort-matched controls, again provided by the CSSCD. For instance, the rate of acute chest syndrome was 7.5 events per 100-person years in the hydroxyurea-treated group, compared with an expected incidence of 24.5 events per 100-person years in the control group.
While studies such as these appear to support the use of hydroxyurea in children with sickle cell disease, concerns remain regarding its safety in this age group. The HUG-KIDS study by Kinney et al.(34) was designed specifically to look at this issue. 84 children (age range 5-15 years) entered the study; of these, 68 reached the maximum tolerated dose (MTD) of 30mg/kg/day, and 52 continued to take hydroxyurea at this dosage for a year. The study concluded that any laboratory toxicities (e.g. cytopenia) associated with hydroxyurea therapy were not severe and reversed upon temporary cessation of the treatment. This was consistent with the side-effects of hydroxyurea therapy that had been noted in adults. Moreover, this study did not find any association between hydroxyurea and growth failure. A study by Zimmerman et al.(35), investigating the long-term effects of hydroxyurea in 122 children (median age 11.1 years) if given at the MTD, supported these findings. Once more, hydroxyurea was found not to cause any significant toxicities, either in the short- or long-term, and again had no adverse effects on the growth rates of the children (Figure 5).
Figure 5: Hydroxyurea was found to have no adverse effects on the growth rate in children, either in
terms of increase in weight (A) or height (B). This was true for therapy of up to 7-years
duration. From the study by Zimmerman et al(35)
Questions do however remain over the very long-term consequences of hydroxyurea therapy, especially with regards concerns over its leukaemogenic potential, and association with other secondary malignancies(36). More research is therefore needed on this matter. Nevertheless, it would appear that hydroxyurea can be a safe and efficacious treatment of sickle cell disease in children, especially in the short- and medium-term. Knowledge of the laboratory toxicities (albeit generally mild and temporary) associated with such therapy makes the careful monitoring of those children started on hydroxyurea imperative.
Indications for the use of hydroxyurea in children with sickle cell disease
At King's College Hospital, where patient RO presented with her sickle cell crisis, there are guidelines for the use of hydroxyurea in children with sickle cell disease(37). As well as discussing potential dosages and the importance of careful monitoring in such patients, these guidelines also suggest possible reasons for the use of hydroxyurea. This helps to outline the current place that hydroxyurea has in the management of these children.
The two main indications stated for starting hydroxyurea are if the child is having more than three episodes of pain per year, and these episodes are causing disruption to the patient's life, or if the child has had repeated or severe attacks of the acute chest syndrome. It is for the former indication that patient RO was started on her hydroxyurea therapy. In addition to these two main indications, other possible reasons for a child with sickle cell to be started on hydroxyurea include significant cerebral vasculopathy, persistently low haemoglobin levels (<6g/dL) or if blood transfusions are not an option for some reason.
It would therefore seem that, at present, the use of hydroxyurea in children with sickle cell appears to be limited to those with severe disease.
While there is still significant morbidity and mortality associated with sickle cell disease, especially in the developing world, there is no doubt that the prognosis for those with this condition has improved dramatically in recent years. This has been in no small part due to improvements in our understanding of its pathogenesis. For instance, this improved understanding has helped lead to the introduction of prophylactic penicillin and immunisations to help reduce rates of infection, to the use of transcranial doppler scanning to detect children at high risk of stroke, and also to the search for agents, such as hydroxyurea, which increase HbF levels.
As far as future management of sickle cell disease goes, there is the possibility that other HbF-inducing agents will one day have a role. Such agents include those which have already been investigated to some extent in adults with sickle cell disease (e.g. decitabine, and butyrate derivatives), as well as some whose effects on HbF production are still being studied (e.g. thalidomide and lenalidomide)(38).
In addition, there are a number of other therapeutic targets which have been focused on in the search to find new ways to treat sickle cell disease. This has led to the investigation of drugs which potentially improve the hydration of red blood cells (e.g. senicapoc), increase the availability of nitric oxide (e.g. sildenafil), or act as anti-inflammatories (e.g. statins)(39). It is possible that drugs such as these will also one day have a place in the management of sickle cell, either alone or in combination.
At present, the only cure available for those with sickle cell is a bone marrow transplant, which is a drastic measure and and one which comes with plenty of side-effects of its own. The hope must therefore be that by continuing to develop our knowledge of how sickle cell causes disease in those affected by it, we get ever closer to finding a safer and more practical cure which more people will be able to benefit from.