EXCITING NEW TREATMENT APPROACHES FOR PATHYPHYSIOLOGIC MECHANISMS OF SICKLE CELL DISEASE

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vaso occlusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.     

Cerebral blood flow in sickle cell cerebrovascular disease

Cerebral blood flow (CBF) has been studied by the xenon-133 (133Xe) inhalation method in 16 children with suspected sickle cell cerebrovascular disease. Abnormalities consisting of decreases in total, hemispheral, or regional CBF were found in 17 of 26 studies. Eleven studies performed immediately after stroke, transient ischemic attack, or depression of state of alertness showed abnormalities. In addition to confirming regional cerebrovascular insufficiency in children with stroke due to major cerebral artery occlusion, the method detected diffuse decrease in CBF in children with stupor, coma, and seizures who had normal angiographic findings. In contrast, six of seven studies obtained after exchange transfusion or during maintenance on hypertransfusion therapy showed normal findings. The difference between results in patients with acute neurologic disturbances and those receiving transfusion therapy was statistically significant (P less than .005). The data indicate that the 133Xe method reliably demonstrates cerebrovascular impairment in sickle cell disease. They also suggest that CBF changes in patients with sickle cell disease can be reversed by exchange transfusion and by hypertransfusion therapy. The 133Xe CBF method may be useful for following up children with sickle cell disease who are at high risk for recurrent stroke.     

Bone marrow transplantation in the treatment of sickle cell anemia

The possibility of using bone marrow transplantation to treat selected patients with sickle cell anemia has recently been raised by the effectiveness of this approach in an 8-year-old girl suffering from both acute myeloblastic leukemia and sickle cell anemia. The child's sickle cell anemia was converted to the donor's sickle cell trait and she remains in complete remission from her leukemia 22 months following transplantation. This paper considers the therapeutic implications of this child's progress and discusses the major immunological complications, particularly graft-vs.-host disease, which currently limit the more widespread use of marrow transplantation in the therapy of sickle cell anemia.     

Acute myocardial infarction in sickle cell anemia

Cardiovascular dysfunction consistent with ischemia has been observed during episodes of painful crisis and following periods of heavy physical exertion in individuals with sickle cell disease. Similar findings have been observed in other individuals while taking the alpha-adrenergic agonist pseudoephedrine. However, acute myocardial infarction is extremely rare. The authors describe a case of sudden death in a child with sickle cell disease due to acute myocardial infarction and suggest that heavy exertional stress and use of pseudoephedrine may have precipitated the event.     

Pediatric stroke: current developments

PURPOSE OF REVIEW: Pediatric arterial ischemic stroke is relatively rare but carries a considerable impact and high risk of recurrence--especially in patients with sickle cell disease and various forms of vasculopathy. We will discuss risk factors, vascular physiology, and primary/secondary/rehabilitative therapies. Goals for future investigation and treatment are suggested. RECENT FINDINGS: Risk factors include chronic disease, vasculopathy, acute illness, cardiac disease, head and neck trauma, infection, and prothrombic disorders. Research has begun to implicate genetic risk factors--initially in sickle cell disease and more recently in prothrombotic disorders, moyamoya, and nitric oxide regulation. The vascular physiology of pediatric arterial ischemic stroke, especially sickle cell disease stroke, is currently undergoing study in animal models and in humans. No primary prevention therapy for pediatric arterial ischemic stroke is known. Various primary and secondary prevention therapies are used, however, in at-risk sickle cell disease patients. Aspirin, coumadin, and heparin are often initiated as secondary prevention therapies for non-sickle cell disease-associated arterial ischemic stroke, but no studies have assessed efficacy. SUMMARY: Pediatric arterial ischemic stroke is under-recognized and under-studied. Investigation into the hemodynamic aspects of arterial ischemic stroke, although best studied thus far in sickle cell disease, has been neglected. It is likely that enhanced study of hemodynamics and autoregulation will elucidate both new prevention opportunities and novel treatments.     

Nitric oxide metabolism and the acute chest syndrome of sickle cell anemia.

OBJECTIVE: To review the role of endothelial dysfunction and nitric oxide metabolism in the pathogenesis of the acute chest syndrome. DATA SOURCE: A thorough literature search of PubMed for publications relevant to acute chest syndrome and nitric oxide metabolism in sickle cell disease was performed using search terms that included acute chest syndrome, sickle cell disease, nitric oxide metabolism, arginine, nitrite, nitrate, exhaled nitric oxide, nitric oxide synthase, and oxidant injury. We identified randomized controlled trials, case reports, editorials, and review articles from English-language and non-English-language studies of adult, pediatric, animal, and human subjects that describe the pathophysiology of acute chest syndrome, the biology of nitric oxide relevant to the pathophysiology of sickle cell disease, and the evidence for the role of endothelial dysfunction and abnormal nitric oxide metabolism in acute chest syndrome. We identified and reviewed 350 publications by the initial search and subsequent bibliography review. The articles most pertinent to the topic of this article were selected to support the discussion. RESULTS: Acute chest syndrome is the leading cause of acute respiratory system dysfunction and a leading cause of morbidity and mortality among patients with sickle cell disease. Evidence is available to support decreased nitric oxide production, increased nitric oxide consumption, and abnormal metabolism of nitric oxide in patients with acute chest syndrome. Moreover, substrate availability is disturbed, and alternate pathways for substrate and nitric oxide metabolism exist. CONCLUSIONS: Abnormalities of nitric oxide metabolism are prevalent during acute illness and baseline health in patients with sickle cell disease. Further investigation is needed to understand the clinical significance of aberrant nitric oxide metabolism as well as the potential for therapeutic manipulation of the arginine-nitric oxide pathway in patients with sickle cell disease.     

Acute splenic sequestration in female children with sickle cell disease in the North of Jordan

The objective of this study was to evaluate the rate of acute splenic sequestration (ASSC) in patients with sickle beta-thalassaemia and sickle cell anaemia, the risk of recurrence in those who survive the first episode, and the relationship between ASSC episodes and subsequent hypersplenism. All patients with confirmed diagnosis of sickle cell disease at a tertiary referral teaching hospital, between January 1994 and December 2002 were interviewed and had their medical records reviewed. Seventy-seven patients with sickle cell disease were identified. Their ages ranged between 2 and 18 years (mean, 10.1 years). There were 35 females and 38 males. Thirty-seven (50.6%) had sickle beta-thalassaemia, and 36 (49.4%) had homozygous sickle cell anaemia. Of these, 26 had high level of Hb F and 11 had normal level of fetal haemoglobin (Hb F). Twenty-one patients (28%) had 63 episodes of acute splenic sequestration. Thirty-seven episodes were experienced by 12 patients with sickle beta-thalassaemia; of these 11 were major attacks with one fatality. Twenty-six episodes were experienced by nine patients with sickle cell anaemia. Splenomegaly and hypersplenism were greater in the acute splenic sequestration group than in the rest of the sickle cell anaemia patients, and the differences were extremely significant. ASSC was found in nine siblings of sickle beta-thalassaemia group, while none were found in the sickle cell anaemia group. The mean age of the first episode was significantly higher in sickle beta-thalassaemia, with significant differences in the levels of Hb F, Hb S, size of spleen and severity of crisis between both groups. In the sickle cell anaemia group the only significant difference between patients with and these without acute splenic sequestration was the difference in the size of spleen. In this study, the rate of ASSC in the sickle beta-thalassaemia patients was 32%, in contrast to 25% in the sickle cell anaemia patients. The risk of recurrence was about 70% in those who survived their first episodes. There was a close relationship between ASSC and subsequent hypersplenism. Important predictable factors for ASSC in sickle beta-thalassaemia patients were the presence of splenomegaly of more than 5 cm below the costal margin, history of acute splenic sequestration in siblings and high Hb F. Most of first episodes in sickle cell anaemia occur under the age of 2 years, while in sickle beta-thalassaemia the majority of patients have their first crisis at the age of > or =3.5 years.     

The effect of acute pain crisis on exhaled nitric oxide levels in children with sickle cell disease

Exhaled nitric oxide (FE(NO)) has been shown to be decreased in children with sickle cell disease. We sought to evaluate the effect of sickle cell vaso-occlusive crisis (VOC) on FE(NO) levels. We measured FE(NO) levels in 42 children with sickle cell disease, 29 in their baseline health and 13 during an acute VOC. There was no difference in FE(NO) levels between children at baseline (15.12 +/- 9.32 ppb) and those during an acute VOC (15.68 +/- 7.26 ppb; P = 0.794). FE(NO) is not a useful marker of acute VOC in children with sickle cell disease.     

Acute cholestatic jaundice in children with sickle cell disease: hepatic crises or hepatitis?

Differentiating acute cholestatic jaundice resulting from hepatic vasoocclusive crises and hepatitis in children with sickle cell disease can be difficult. Both conditions result in hyperbilirubinemia, mainly of the conjugated type, and in elevation of serum transaminases. Five children with sickle cell disease, acute severe cholestatic jaundice and negative serology for hepatitis A and B presented in good general condition, with modest elevation of serum transaminases, and had an early uneventful recovery. Five children with sickle cell disease and serologically proved hepatitis A infection were sicker, exhibited a similar elevation of bilirubin concentration with marked elevation of the serum transaminases and recovered more slowly. The clinical course and outcome of hepatitis A in children with sickle cell disease was similar to that of hepatitis A in normal children. Unlike early reports acute cholestatic jaundice in our patients with sickle cell disease, whether caused by hepatitis or by hepatic vasoocclusive crises, was found to be benign with an uneventful recovery.     

A single-institution experience with treatment of severe acute chest syndrome: lack of rebound pain with dexamethasone plus transfusion therapy

The use of corticosteroid therapy for the treatment of acute chest syndrome (ACS) in patients with sickle cell disease has been infrequently used owing to concerns for rebound pain. Here, we report a cohort of patients<21 years of age with sickle cell disease treated between January 2001 and June 2006 for severe ACS with both corticosteroids and transfusion therapy. We reviewed 53 episodes of severe ACS with an average hospital duration of 4.9 days. Only 1 patient out of 6 who were transferred to the intensive care unit required intubation. None of the ACS episodes resulted in death and none of the 4 readmissions after discharge were due to pain. There was no acute toxicity related to either corticosteroid or transfusion therapy.     

Coping and health service utilisation in a UK study of paediatric sickle cell pain.

AIMS: To assess sickle cell pain and coping in children and to examine the relation between these factors and the utilisation of health services. METHODS: Cross sectional study involving 67 children with sickle cell disease attending three London hospitals. Interviews and questionnaires involved measures of pain, health service utilisation, and coping responses (measured with the Coping Strategies Questionnaire (CSQ), revised for children with sickle cell disease). Medical data on complications, haemoglobin (Hb) levels, and foetal haemoglobin (HbF) percentage were also collected. RESULTS: Pain accounted for about 24% of hospital service use, independent of age, sex, number of with sickle cell disease complications, and Hb levels. However, 42% of patients had not utilised hospital services in the past 12 months. Three higher order factors emerged from analysis of the CSQ (active coping, affective coping, passive adherence coping). Pain severity was predicted by passive adherence coping, while utilisation of hospital services was predicted by active coping. CONCLUSIONS: Sickle cell disease in children involves severe recurrent pain leading to hospitalisation in some cases. Psychological coping patterns are relevant to both pain experience, and the use of acute hospital services. It is likely that children would benefit from community based interventions that incorporate both medical and psychological assessments.     

Coping and health service utilisation in a UK study of paediatric sickle cell pain

Aims: To assess sickle cell pain and coping in children and to examine the relation between these factors and the utilisation of health services. Methods: Cross sectional study involving 67 children with sickle cell disease attending three London hospitals. Interviews and questionnaires involved measures of pain, health service utilisation, and coping responses (measured with the Coping Strategies Questionnaire (CSQ), revised for children with sickle cell disease). Medical data on complications, haemoglobin (Hb) levels, and foetal haemoglobin (HbF) percentage were also collected. Results: Pain accounted for about 24% of hospital service use, independent of age, sex, number of with sickle cell disease complications, and Hb levels. However, 42% of patients had not utilised hospital services in the past 12 months. Three higher order factors emerged from analysis of the CSQ (active coping, affective coping, passive adherence coping). Pain severity was predicted by passive adherence coping, while utilisation of hospital services was predicted by active coping. Conclusions: Sickle cell disease in children involves severe recurrent pain leading to hospitalisation in some cases. Psychological coping patterns are relevant to both pain experience, and the use of acute hospital services. It is likely that children would benefit from community based interventions that incorporate both medical and psychological assessments.     

Magnetic resonance imaging of bone marrow in sickle cell patients

Assessment of the bone marrow in sickle cell patients with or without pain crises can be accomplished using a variety of imaging techniques. Conventional radiography is the least sensitive of all imaging modalities in the early stages of the bone marrow infarct. Radionuclide imaging using 99mTc sulfur colloid shows sharply demarcated photon-deficient regions that are slow to resolve. Cumulative exposure to ionizing radiation would be of concern if repeated examinations with conventional x-rays and radionuclides were carried out. Magnetic resonance imaging (MRI) is a noninvasive technique that differentiates the bone marrow of sickle cell patients from that of normal controls. Furthermore, at least in some patients, acute tissue changes can be detected during early stages of pain crises using magnetic resonance. Further investigations are necessary to optimize the use of MRI in sickle cell patients with pain crises.     

Diverse manifestations of acute sickle cell hepatopathy in pediatric patients with sickle cell disease: A case series

The hepatic complications of sickle cell disease (SCD) are associated with increased morbidity and mortality in adults; children usually survive but may suffer significant sequelae. Few diagnostic tools differentiate the various hepatic manifestations of SCD. Why patients exhibit one hepatic pathology versus another is unclear. We report four pediatric patients with hemoglobin SS disease with diverse manifestations of acute hepatic involvement including acute sickle hepatic crisis, hepatic sequestration, sickle cell intrahepatic cholestasis, and a non‐SCD cause of hepatopathy in a patient with viral hepatitis. These complications require a systematic approach to extensive evaluation and coordinated multidisciplinary care.     

Haploidentical bone marrow transplantation in a patient with sickle cell disease and acute myeloid leukemia

Myeloid neoplasms in children with sickle cell disease have been rarely reported, and the exact underlying connection between these two conditions is not clearly understood. Whether the acute myeloid leukemia in hydroxyurea‐treated sickle cell patients is co‐incidental or related to therapy remains an unanswered question. Herein, we report a 14‐year‐old girl of Haitian descent with sickle beta zero thalassemia on chronic hydroxyurea therapy who developed FMS‐like tyrosine kinase 3 (FLT3)‐mutated acute myeloid leukemia and underwent a complete disease remission following a combination chemotherapy with sorafenib and was subsequently treated using a T cell replete unmanipulated haploidentical bone marrow transplantation followed by post‐transplant cyclophosphamide.     

Cholelithiasis in a toddler with sickle cell disease

Cholelithiasis is rarely seen in toddlers and school-aged children, even in the setting of sickle cell anemia. In addition to more common etiologies, such as gastroenteritis, constipation, and urinary tract infection, the differential diagnoses of acute abdominal pain in young children with sickle cell disease include vaso-occlusive pain crisis and splenic sequestration. We describe a case of a toddler with sickle cell disease initially presenting with abdominal pain who was found to have symptomatic cholelithiasis.     

Sickle cell morbidity profile in Omani children

In order to define the morbidity profile of sickle cell disease in Omani children, we analysed data on 97 children (53 boys, 44 girls) aged < or = 12 years admitted under our care in a regional referral hospital between July 1999 and June 2000. Ninety of them had sickle cell anaemia (HbSS disease) and seven had sickle cell thalassaemia (beta zero). Their mean (SD) steady-state Hb was 7.9 (1.2), range 6-10 g/dl. They were admitted on 316 occasions during the 12-month period. The number of admissions per child ranged from one to 12 (mean 3.3). Vaso-occlusive crises were the main reason for admission (83%), followed by severe anaemia (12%) and infections (4%). During the study period, 31% received blood transfusions. Weight faltering was very common, 68% falling below the 5th percentile of the National Center for Health Statistics reference curves compared with 28% of age- and sex-matched non-sicklers (p < 0.001). Other complications included hypersplenism (four), ischaemic necrosis of the femoral head (two), and one case each of acute chest syndrome, acute splenic sequestration, cholelithiasis and pathological fracture of a lumbar vertebra. Overall, 71% of the children had moderately severe or severe disease. This pattern seems to be attributable, at least in part, to meteorological and genetic factors. The severe morbidity profile reported in this study underscores the need to continue the search for optimal management modalities, including the often emotion-laden issue of prevention.     

Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis.

BACKGROUND: Ketorolac is a parenteral, nonsteroidal analgesic that does not have a narcotic's risks of respiratory depression, hypotension, or dependence. Its usefulness in providing pain relief in pediatric patients with acute vaso-occlusive crisis of sickle cell disease has not been studied to date. METHODS: Twenty-nine patients with sickle cell disease between the ages of 5 and 18 years who presented to The Children's Hospital of Alabama emergency department (ED) with 41 distinct episodes of acute vaso-occlusive pain crisis were enrolled prospectively and randomized to receive either 0.9 mg/kg intravenous (IV) ketorolac or placebo in a double-blind fashion. All patients also received IV fluids and an initial 0.1 mg/kg of IV morphine. Subsequent standardized doses of morphine were given every 2 hours over a 6-hour observation period based upon severity of pain as scored by a 10-cm linear visual analog scale (VAS). Vital signs and pain severity were recorded initially and assessed hourly. Disposition was made at the end of the observation period. RESULTS: Patients receiving ketorolac and those receiving placebo were of similar age, weight, gender, number of prior ED visits, number of prior hospital admissions, duration of pain prior to presentation, and initial pain score. The total dose of morphine received, reduction in severity of pain as measured by VAS, rate of hospital admission, and rate of return to the ED for discharged patients did not differ significantly between the two groups. CONCLUSION: We were unable to demonstrate a synergistic analgesic effect for ketorolac in the treatment of pain from acute vaso-occlusive crisis in pediatric sickle cell disease. Further investigations involving larger samples of sickle cell patients may be needed to further define a role for ketorolac in the acute management of sickle cell vaso-occlusive pain.     

"Sickle Cell Disease in the Emergency Department: Atypical Complications and Management"

Sickle cell disease is the most common inherited blood disorder in the United States. This disorder of hemoglobin structure leads to a chronic hemolytic anemia and complex chronic disease manifested by sudden, severe, and life-threatening complications. These acute complications can occur in any organ system beginning in early childhood and lasting throughout life. The intermittent nature and acuity of these complications lend the emergency department to be an important site of care. The hallmark of sickle cell disease is the vasoocclusive painful event. Other more "typical" complications include fever, acute chest syndrome, priapism, and ischemic stroke. Children with sickle cell disease can also present with other "atypical" complications that can have devastating consequences if they are unrecognized. Detailed discussion of these "atypical" sickle cell disease complications, organized by organ system involved, will be the focus of this article.     

Acute splenic rupture in an adult with homozygous sickle cell anemia treated with chronic transfusions

Splenic rupture is a very rare event in adult homozygous sickle cell patients. The authors describe a 19-year-old patient with homozygous sickle cell disease who experienced an acute splenic rupture crisis requiring emergent splenectomy. He had been receiving chronic blood transfusions regularly for 7 years secondary to a previous stroke. It is possible that these transfusions contributed to regeneration of splenic red pulp, which allowed a crisis to occur at an advanced age.