Current Trends in the Management of Sickle Cell Disease : REVIEW ARTICLE

Sickle cell disease (SCD) is common in Sudan and in sub-Saharan Africa. It is also prevalent in the Arabian Gulf countries and in India. Despite the tremendous advances in diagnostic and therapeutic modalities, Children with sickle cell anemia continue to suffer from repetitive crisis and have frequent severe complications. These morbid events as well as mortality can be greatly reduced by specialized medical care that focuses on prevention and active intervention. This article reviews the most recent and evidence-based guidelines for preventive care and medical management of SCD and its most commonly encountered complications.


Background
Sickle cell disease (SCD) denotes all genotypes that contain at least one sickle gene in which hemoglobin-S (HbS) makes up at least half of the hemoglobin present.In addition to the homozygotic HbSS (sickle cell anemia), in which only HbS is produced, at least 5 other major genotypes are linked to the disease.These include the following: • HbS-beta-thalassemia: Severe form of disease; almost indistinguishable from sickle cell anemia phenotypically.Sickle cell anemia (SCA) is common in tropical Africa and the clinical manifestations of the disease were recognized by the native Africans centuries 1 before the first case report appeared in the medical literature in 1910 2 .Since then, several studies have documented the presence of the disease in other parts of the world particularly in the Arabian Peninsula, the Mediterranean, India and the United States [3][4][5] .SCA is the most severe and most common form.It is characterized by persistent hemolysis due to the short life span of the sickled red cells and repetitive painful crisis that result from vascular obstruction, ischemia, and incremental infarction..Although a diagnosis of the disease can be made at birth, clinical abnormalities usually do not occur before the age of 6 months, when fetal hemoglobin, which has protective effect, fades away and gets replaced by HbS.functional asplenia develops by the end of first year of life

Preventive measures
It is estimated that there were about 80 million carriers of sickle cell trait in the world in 1992 and each year 156 000 infants are born with SCD 6 .Prenatal diagnosis of SCD is now technically possible from the 9th weeks of gestation 7 .In some countries the prenatal diagnosis is followed by abortion of homozygous fetuses if parents requested.This practice, however, is illegal in many countries.Screening to recognize couples at risk and diagnosis of SCD in the neonatal period are universally accepted and recommended.It is very useful for education of the parents and genetic counseling and allows the prevention of some of the expected complications.Preventive care should begin at three months of age.Complete blood count including reticulocyte count is essential to determine baseline values.A leucocyte differential count is important since many children have high levels of nucleated red cells which will result in spuriously elevated leucocyte count.The problems encountered by children with SCD should be discussed with the parents at each visit.They should be taught how to recognize the sickling crisis and what steps to take when complications arise; the most important issue is when to bring the child to medical attention.By six months of age, penicillin prophylaxis should be started for all children who are homozygous for Hb-S and continued till the age of 16 years.This practice has proved to be valuable in reducing the frequency of Streptococcus pneumoniae bacteraemia and its associated high mortality rate 8 .Oral penicillin should be given at a dose of 125 mg twice daily until age three after which the dose is increased to 250 mg twice daily.Some authorities prefer amoxycillin 250 mg for children, who are younger than 10 years of age in order to cover the risk of Haemophilus influenzae infection.Children allergic to penicillin should take erythromycin: 250 mg 12-hourly for children aged 2 years or more; 125 mg 12-hourly for children under the age of 2 years.The other macrolides Azithromycin once daily and Clarithromycin twice daily can also be used.The use of Benzathine penicillin for prophylaxis in patients with SCD was evaluated in Jamaica.The study was terminated when significant compliance problems were encountered due to the discomfort caused by the intramuscular injections given at three weeks interval 9 .Although fewer infections were detected in those children receiving this form of penicillin, the difference was not statistically significant.Penicillin prophylaxis has not been evaluated for children with Hb-SC disease, but the finding that their incidence of bacteraemia during the first two years of life is similar to that of children with sickle cell anemia 10 caused some physicians to recommend it for these children as well.In fact, some hematologists recommend penicillin prophylaxis for all variants of SCD 11 .
At 18 months, conjugated Heamophilus influenzae vaccine should be given as recommended by the American Academy of Pediatrics 12 .Although no conclusive studies have yet been reported in children with SCD, immunization with heamophilus influenzae vaccine has been shown to be effective in normal children 13 and in splenectomized children and adolescents 14 .This is followed at 24 months of age by polyvalent pneumococcal vaccine 15 .The current pneumococcal vaccine is unconjugated and is less effective in children under 2 years of age compared to its effect in older children.This is because unconjugated polysaccharides do not produce adequate antibody response in young children.Booster doses of the latter vaccine at 5-10 years intervals have been suggested by some investigators and have been administered with no reported complications 16 .Other workers do not recommend re-immunization because a severe arthus type-III immune reaction might occur.In the absence of consensus, the decision to reimmunize must be individualized and if believed appropriate, undertaken with caution.Unfortunately, the use of these measures does not ensure freedom from infection.Pneumococcal bacteraemia has been documented shortly after a dose of prophylactic penicillin was missed 17 .In addition bacteraemia has been detected in children immunized with the pneumococcal vaccine 18 .Since the current vaccine contains only those serotypes most frequently causing infection in patients with SCD, the observed bacteraemia could be due to one of the less common serotypes 19   .However, it has also been described with serotypes included in the vaccine but which provoke an inadequate antibody response 20 .

Medical management
Pain: Although pain is the hallmark of SCD, many affected children never have pain sufficiently severe to require treatment.The cause for this differential severity is one of the many mysteries of this disease.When pain is encountered it is almost always due to erythrocyte sickling, thrombosis, vaso-occlusion and infarction.Precipitating factors include upper respiratory tract infection, fever, dehydration, hypoxemia; exposure to cold temperatures, weather changes, and emotional stress.Mechanical or traumatic events that result in an interruption of blood flow to tissue can also result in ischemia and subsequently severe pain.For mild pain, the parents should be advised to encourage oral fluids intake to ensure good hydration and to give acetaminophen or paracetamol for analgesia.The application of warm compresses may also be helpful.However, the greatest benefit will be derived from the parents' calm approach and reassurance that the pain will disappear.If the pain is too severe to respond to these simple measures, the child should be seen at hospital.If the pain is believed to be due to a vaso-occlusive crisis, subcutaneous morphine at a dose of 0.1 mg/kg may provide sufficient relief to allow the child to return home 21 .There, acetaminophen with codeine or meperidine suspension may provide adequate relief for the duration of the painful episode.Children two years old or younger are more prone to develop dactylitis and the hand-foot syndrome.These result in tender swelling of fingers and toes and considerable pain, which is usually so severe that parenteral narcotic analgesics are required 22 .Pain that does not respond to this regimen or that persists for more than two days deserves hospitalization.In hospital intravenous hydration with a crystalloid solution should be started and a narcotic, morphine sulphate or pethidine, should be given intravenously at a dose of 0.2 mg per kg every two hours till the episode is over 23 .Injectable meperidine at a dose of 1 mg/kg every 3 hours is an alternative.Repeated doses of this drug should be given with caution since seizures can result from the accumulation of one of its metabolites 24 .The intravenous route is preferred s131 because it provides a more predictable analgesic response.In addition it avoids the fibrosis that accompanies prolonged intramuscular administration of certain analgesics especially meperidine.Parenteral narcotic analgesics should be administered on a regular basis and not on as needed basis since the pain can be expected to continue at same degree of severity for several days.Additionally it has been established that narcotic analgesics given only on request result in poorer pain control and the need for larger doses.The hand-foot syndrome may persist for 2-3 weeks and when the pain begins to diminish the dose of the parenteral narcotics should be decreased gradually until analgesia can be accomplished by oral medications.Oral morphine sulphate or codeine can be used till the episode is over and the child is pain-free.
Bacterial infections: Bacteraemia and meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae occur with an extremely high incidence in children with sickle cell anemia during the first five years of life 25 .Children with Hb-SC disease have been shown to have a comparable rate during the first two years of age, but the risk decreases as they grow older.Fever is the initial presentation of sepsis in children with SCD.The frequency with which pneumococcal bacteraemia occurs in children with SCD and the reported 24% mortality for such episodes requires a different approach from what would be considered appropriate for fever in normal children 26 .Parents must be instructed to watch carefully for fever and when a fever is found, they should avoid the common practice of treating the fever rather than its cause.Since a minor temperature elevation might indicate a serious infection, any febrile child with SCD should be evaluated by a doctor without waiting to see if the child is going to get better or worse.It cannot be over emphasized that sepsis can occur even when the child is immunized and using prophylactic penicillin.Parents should be informed that an extra dose of penicillin prophylaxis is not a substitute for bringing their febrile child for medical checkup.However, physicians know that the evaluation of these children is not easy.Leucocyte counts cannot be relied upon to distinguish between viral and bacterial infections in normal children and seem to be even less reliable in children with SCD where baseline values are elevated 27 .Similarly, the erythrocyte sedimentation rate and the Creactive protein levels have both been shown not to be helpful in identifying the presence or severity of infection in children with SCD 28,29 .Finally, even the spinal fluid leucocyte count cannot be relied upon as an indicator of meningitis as shown in a report of six febrile patients with SCD who had normal spinal fluid cell count with culture documented Streptococcus pneumoniae meningitis 30 .Since there is no reliable laboratory test to distinguish viral from bacterial infections in the initial evaluation of febrile children, the imprecision of clinical judgment requires that in most instances the child should be hospitalized, appropriate cultures obtained and suitable parenteral antibiotics given as empirical measure.Following admission, if the child became afebrile and the blood cultures show no growth at 72 hours, treatment can be completed with oral antibiotics at home.When the child is found to have meningitis or septicemia the course of treatment is completed with parenteral antibiotics according to the sensitivity of the isolated organism.
Malaria: Individuals with sickle cell trait are known to be resistant to malaria infection 31 .Parasite growth is reduced in red cells containing Hb-S.Because of increased oxygen consumption in the parasitized erythrocytes, these cells sickle more rapidly than unparasitized cells and are easily removed from the circulation by phagocytosis.Unfortunately, protection against plasmodium falciparum is not complete for patients with sickle cell anaemia 32,33 .In countries where falciparum malaria is prevalent children with SCD are at increased risk of developing severe complicated malaria or cerebral malaria.In such places regular drug prophylaxis is recommended.Proguanil is still the prophylactic of choice, being safe and effective 34 .However, long-term prophylaxis is difficult to maintain in developing countries and with the recent reports of multiple drug resistance the desired protection may not be achieved.On the other hand, because malaria may present with a wide spectrum of symptoms and signs any ill child with SCD, whether febrile or not, should has several blood smears examined for malaria parasites and anti malarial therapy started until the cause of the illness is identified.Splenic Sequestration: This severe life threatening complication may be encountered in any of the variants of SCD. usually occurring when the child is very young 35 .It is commonly associated with febrile illnesses and enlarged spleen but splenomegaly is not a necessary prerequisite.The problem results from the sudden shunting of a volume of blood to the spleen s132 sufficiently large to result in hypovolaemic shock.Parents of children with splenomegaly should be taught how to monitor its size by abdominal palpation.They should be informed of the implications of sudden onset of pallor and weakness and advised to determine if the spleen size has increased.If their child becomes symptomatic they should proceed immediately to the nearest medical facility.There they should provide this information to the medical personnel at once since considerable time might be lost if the child is assigned to the routine evaluation process common in busy emergency departments.For the child who presents with sudden onset of pallor, tachypnoea, hypotension and increasing splenomegaly, laboratory data will show low haemoglobin with reticulocytosis and thrombocytopenia.Treatment is directed toward correction of shock and includes crystalloid or colloid restoration of the circulatory volume.Blood transfusion is usually required as 10 ml/kg infusion of packed red cells.Such treatment may cause the spleen to disgorge a large proportion of the trapped blood which can result in an unexpectedly high haematocrit and significantly increased viscosity which may then cause vasoocclusive complications.If splenic sequestration recurs, splenectomy should be considered.For the young child chronic transfusion therapy has been recommended to prevent further sequestration episodes while preserving splenic function 36 .
Stroke: Cerebral vascular accidents occur in patients with SCD with an incidence much higher than that found in normal subjects.In children, the strokes are usually caused by thrombosis of the cerebral vessels.Large blood vessels are usually involved which results in extensive neurologic damage 37 .Adolescents and adults are more likely to have subarachnoid hemorrhages 38 .Patients may present with seizures, hemiplegia, speech disorder, difficulty with swallowing, impaired vision or disturbed sensorium.When a stroke occurs, CT examination is very useful but should be done without contrast media since its use might increase blood viscosity sufficiently to cause further interruption of the already compromised circulation 39 .Certain types of contrast are said to cause few problems 40 but their use in vessels which are only minimally patent must be undertaken with caution.Once the diagnosis is made, Hb S or SC concentration should be reduced to below 30% as promptly as possible using exchange transfusion or erythrocytopheresis 41,42 .Care must be taken to ensure that the haematocrit remains low until HbS is reduced to the desired level since viscosity increases exponentially with increasing haematocrit when Hb S level is high.To avoid the 66% stroke recurrence rate 38 , transfusion therapy must be given at a frequency sufficient to maintain Hb S below 30% 41 .This usually requires blood transfusion at four week intervals.Unfortunately, the duration of this treatment has not yet been established.In one report, when transfusions were stopped in ten patients after one to two years, strokes recurred in seven 43 .This finding and the progressive neurologic damage caused by recurrent strokes has led many pediatricians to continue blood transfusions indefinitely.
Acute Chest Syndrome: Chest pain, cough, haemoptysis, low grade fever and pulmonary infiltrates occur frequently in patients with SCD.Since it is usually impossible to determine whether pneumonia, pulmonary infarction or some combination of the two is causing such symptoms, the clinical presentation is referred to as the acute chest syndrome 44 .In children the predominant cause is infection.Many of the infections are due to Streptococcus pneumoniae but viruses are responsible for a considerable proportion.Other bacterial infections were reported including mycoplasma pneumoniae, which causes unusually severe pulmonary infections in these children 45 .Pulmonary infarction is thought to be the most common cause of the syndrome in adolescents and adults.However, since infection cannot be easily excluded and pulmonary infarction has no specific therapy, antibiotics are usually prescribed for these patients too.With any pulmonary complication in SCD oxygenation is a major concern.To compensate for chronic anaemia the oxygen dissociation curve is shifted to the left in affected patients.This allows more efficient oxygen delivery to the tissues.As a result, if the haemoglobin is not fully oxygenated in the lungs, deoxygenating at the tissue level may be sufficient to cause sickling.Consequently patients with the acute chest syndrome should have their oxygen saturation maintained at normal levels by increasing the concentration of inspired oxygen.Blood transfusion is indicated for those patients who showed evidence of respiratory failure.The use of partial or complete exchange transfusion has been reported to be beneficial in such instances 46 .The simple transfusion of blood without exchange must be approached cautiously to avoid the problems associated with increased blood viscosity.

Priapism:
The incidence of priapism among children with SCD is grossly underestimated because many parents do not regard it as a complication of the disease while other families are too embarrassed to report its occurrence unless specifically asked 47 .This complication should be discussed with the child and his parents who can be informed that its usual manifestation is a brief painful erection which generally responds to various interventions at home.Possible approaches include micturition, relaxation in a warm bath and distraction with any type of physical activity.Masturbation should not be tried as it is unlikely to result in either ejaculation or detumescence.In a study conducted in adult with SCD, Serjeant has described the occurrence of frequent brief episodes of painful erections which he called "stuttering priapism".He showed that the problem could be treated and prevented by daily administration of stilbesterol 48 .Certain side effects such as gynaecomastia and failure of normal erection were reported which could be avoided by manipulation of the dose.No experience has been published regarding this form of therapy in children.If an erection persists for more than three hours it is unlikely to resolve spontaneously and hospital treatment is needed.Parenteral hydration and effective narcotic analgesics should be initiated and Hb S reduced as quickly as possible to about 20% using exchange transfusion or erythrocytopheresis.If detumescence does not occur within 24 hours surgical intervention is necessary.It has been reported that the use of winter procedure has resulted in a decreased rate of impotence, which frequently follows severe episodes of priapism 49 .
Aplastic Crisis: The sudden cessation of erythropoiesis has been shown to result from a parovirus infection but may have additional etiologies 50 .Due to extremely short red cell survival in SCD, the haemoglobin will fall rapidly when red cell production is interrupted.Pallor, weakness and signs of severe anaemia develop gradually.Pancytopenia with low reticulocyte count is demonstrated.Patients can be observed at two to three days intervals until reticulocytosis occurs and the haemoglobin increases to its baseline value.However, if the hemoglobin level drops to 3-4 g/dl or signs of heart failure develop, a packed red cells transfusion of 10 ml/ kg should be given.The need for subsequent transfusion is very unusual.
Osteomyelitis: Osteomyelitis is a common complication of SCD.Salmonella or staphylococci are the responsible bacteria in the majority of patients but others organisms such as streptococcus pneumoniae are occasionally isolated 51 .The differentiation between an acute bone infarction and acute osteomyelitis is difficult to make 52 .Both conditions present with fever, pain and leucocytosis.Conventional radiology is not helpful in the early stages.A variety of radioisotope techniques have been proposed but to date none have proved reliable 53 .Ultrasound examination is useful in detecting pus collection and periosteal reactions, but the magnetic resonance imaging is the most helpful investigation.Blood culture is mandatory to confirm the diagnosis and to determine the offending organism.Salmonella osteomyelitis is so often thought of in association with SCD that other possible etiologies are ignored 54 .While waiting for culture results or if no organism is isolated, antibiotics effective against both salmonella and staphylococci should be used.Aseptic ,ecrosis of Bone: Aseptic necrosis of the femoral or humeral head is seen with high frequency in adolescents with SCD 55 .Usually it follows an episode of a vaso-occlusive crisis.Parents and children should be instructed to report pain that persists in their shoulders or hips during periods between painful crisis episodes.When the diagnosis is made, symptomatic treatment should be provided to minimize pain and discomfort.Necrosis of the humeral head seldom causes significant problems while necrosis of the head of the femur causes hip joint dysfunction.Minimization of weight bearing may allow some degree of healing to occur, but the usual treatment is surgery.Several approaches are adopted including head resection, bone grafting and implantation of a prosthetic device.Hip protheses are frequently implanted in adults but surgeons are reluctant to provide this type of surgery to children and adolescents since the protheses may need to be replaced as frequently as every 10 years 56 .
Leg Ulcers: Chronic leg ulcers are most often encountered between the age of 10 and 30 years 57 .Their underlying cause is unknown but since they are thought to be related to vascular stasis and trauma, subjects with SCD should be advised to avoid standing for long periods and to protect their feet and ankles by wearing shoes and stockings.Patients should be instructed to seek medical attention for any slowly healing lesion that occurs below the knee.When an ulcer develops, it must be debrided at frequent intervals to promote healing.If it persists, the skin of the s134 affected extremity can be immobilized using a dressing.Rarely, ulcers are resistant to treatment and warrant transfusion therapy.Skin grafting is another possible approach, but transfusion therapy is also a prerequisite to facilitate successful engraftment.Unfortunately, new ulcers will appear after transfusions are discontinued.
Cholelithiasis: One third of children who have SCD can be shown to have gallstones by the time they are 18 years old.This increases to 70% by age 30 58 .Although such stones can result in right upper quadrant abdominal pain, it is important to distinguish between pain caused by vaso-occlusive crisis and cholecystitis.The high rate of surgical complications in SCD makes it unwise to perform cholecystectomy unless the stones are causing problems.If the patient develops cholecystitis, medical treatment including blood transfusion should be given while preparations are made for elective cholecystectomy.
Bone marrow transplantation: Bone marrow transplant (BMT) offers a cure for some patients with SCD.Experience is increasing relating to outcome and problems of this procedure since the start of BMT for SS patients in Seattle, USA and the initiation of collaborative study in three specialized centres in Britain.The criteria for selection of patients with SCD for BMT set by the British Pediatric Hematology Forum (BPHF) are the following [59][60]  It is estimated that only 10% of all SS children fulfill these criteria of whom about one in five will have a donor 6  . Worlwide, around 100 children with SCD have so far been treated by BMT most of them in Belgium and France 64 .There is evidence that splenic reticuloendothelial dysfunction can improve after BMT 65 .The survival rate following the procedure is 95% and the causes of death recorded were graft-versushost disease and intracranial hemorrhage.Other complications include: transient ischemic attacks, aseptic necrosis, erythroblastopenia and pneumococcal infection.The rate of graft rejection reported is 10-15% 66 . Inerestingly, several of the patients who have rejected their grafts have developed increased concentration of fetal haemoglobin in conjunction with autologous marrow recovery and remained symptom-free for over 2 years despite previously severe disease 67 .The long term effect of BMT for SCD is not yet known, but it is encouraging that the Belgian group has seen no tumor or leukaemia with 8 years follow up for some of their patients 64 .In addition, no recurrence of stroke in eight children with a pre-BMT history of stroke has been reported from France 68 . Th future may bring improvements in prevention and treatment of graft-versus-host disease allowing BMT using matched unrelated donors.An alternative approach is infusion of haploidentical maternal marrow cells early in gestation to induce fetal tolerance to maternal antigens; this might allow subsequent BMT using haploidentical maternal marrow , thus obviating the need for an HLA identical sibling 69 .Transplantation using cord blood stem cells is promising.Several cryopreserved placental stem cell banks have now been established 70 .Intrauterine BMT has been attempted for b-thalassaemia major where termination was not acceptable 71 .Although successful engraftment has been described, this approach has not yet been tried for SCD.Gene therapy, using autologous placental stem cells, as carried out recently for adenosine deaminase deficiency with good results, remain a tantalizing prospect for the future [72][73] .
New Pharmacological Treatment: New strategies, such as fetal haemoglobin induction, are under intensive evaluation for the management of the patients with SCD for whom BMT is not a feasible option.Vaso-occlusive complications can be significantly reduced by treatment with hydroxyurea [74][75][76] .Its main mode of action is thought to be by inducing the v-globulin chains resulting in increased concentration of fetal haemoglobin that interfere with the intracellular polymerization of Hb S. Due to increased survival s135 of red blood cells that contain both Hb S and Hb F, as little as 4-8% fetal globulin synthesis in the bone marrow can produce levels of Hb F of approximately 20% in the peripheral circulation.Other fetal haemoglobin inducers include 5azacytidine.growth factors (erythropoietin) and short chain fatty acids such as butyrate 77,80 .Cetiedil, a smooth muscle relaxant.and a chemical substance designated BW12c are said to stabilize the erythrocyte membrane and the oxyconfiguration of Hb S thus reducing the sickling phenomenon.However.most of these agents have toxic adverse effects.Hydroxyurea is known to cause neutropenia, thrombocytopenia and reversible azoospermia.It is also likely to be teratogenic and may have.as yet unknown, longterm squeal 81 .In conclusion, supportive care including analgesia, fluids and blood transfusion remain the mainstay of treatment of SCD. :