Drugs for preventing red blood cell dehydration in people with sickle cell disease.

BACKGROUND: Sickle cell disease is an inherited disorder of haemoglobin, which results in abnormal red blood cells. These can deform and cause blockages in blood vessels, leading to acute crises such as pain; stroke and splenic sequestration; and chronic organ and tissue damage. Recently research has begun to focus on therapies which prevent the red blood cells deforming by reducing the loss of water and ions from the cells. However, little is known about the effectiveness and safety of such drugs. OBJECTIVES: To assess the relative risks and benefits of drugs which aim to prevent sickle cell-related crises by reducing red blood cell dehydration. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: November 2006. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of drugs which aim to prevent sickle cell crises by reducing red cell dehydration, compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data from the included studies. MAIN RESULTS: Of the 39 studies identified, one met the inclusion criteria. This study tested the effectiveness of zinc sulphate to prevent sickle cell-related crises in a total of 145 participants and showed a significant reduction in the total number of pain, haemolytic, aplastic and sequestration crises over one and a half years, WMD -2.83 (95% CI -3.51 to -2.15). However, our analysis was limited by non-reporting of standard deviations for some data. Changes to red cell parameters and blood counts were inconsistent. No serious adverse events were noted in the study. AUTHORS' CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicentre studies over a number of years are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.

Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease.

Patients with sickle cell disease (SCD) often require blood transfusion starting in early childhood. Multiple blood transfusions on a chronic basis lead to excessive accumulation of iron, especially in adults with sickle cell anemia (SS) that is progressively increasing in size. Blood exchange transfusion and the use of iron chelation therapy may prevent or delay the onset of iron overload. The majority of adults with SS, however, require episodic blood transfusions on a chronic basis and, hence, are at risk to develop iron overload. Recent reports suggest an association between iron overload and organ failure in chronically transfused patients. Patients with SCD and iron overload may thus be at increased risk to develop organ failure compared to those with normal iron stores. In order to clarify this issue we have prospectively collected the following data on our adult patients with SCD between 1978 and 1998: (1) the amount of blood transfused; and (2) the status of iron stores determined with serum ferritin, serum iron, total iron binding capacity (TIBC), and percent transferrin saturation (% Sat). Between 1987 and 1998, 247 adult patients with SS were regularly followed in our sickle cell center. Of these, 152 (62%) were transfused with 4,875 units of red blood cells (RBCs). Transfused patients received an average of 10 units of RBCs per year, which is equivalent to about 2.0 g of iron per year. This does not include transfusions at other institutions or before 1987. About one third of the adult patients with SS had % Sat greater than 50 in the steady state, suggesting iron overload. During painful episodes serum ferritin increased significantly in paired observations. Serum iron and TIBC decreased during painful episode disproportionately so that there was a significant net decrease in % Sat in paired observations. Patients with low values of serum ferritin and % Sat had lower incidence of acute painful episodes (38% v 64%) and organ failure (19% v 71%) than those who had iron overload, respectively. Mortality was significantly higher in the iron overload group: 64% versus 5%, respectively. Taken together, the data indicate that (1) the status of iron stores in adults with SS is best determined by keeping accurate records of the amount of blood transfused and serial determinations of ferritin levels in the steady state; (2) a significant number of adults with SS have iron overload; and (3) iron overload seems to be a predisposing factor of disease severity.

Nesidioblastosis in sickle cell disease.

Although the endocrine pancreas appears to play an important role in the pathophysiology of sickle cell disease, very little is known about the morphologic changes in this tissue. Our study was initiated to delineate the microscopic features of the endocrine pancreas in a large autopsy series of sickle cell hemoglobinopathies. From more than 650 cases archived at the Centralized Pathology Unit for Sickle Cell Disease (Mobile, AL), 224 autopsy cases were identified for review of clinical and gross autopsy findings and/or for microscopic studies, including histochemical stains (trichrome, reticulin, iron), and immunohistochemical stains (insulin, glucagon, somatostatin, and pancreatic polypeptide). The gross examinations were recorded as unremarkable in 65% of the autopsies. In childhood and adolescence (< or = 18 years), pancreas weights (50.76 +/- 5.16SE gm) were significantly greater (p < 0.0001) than age-matched controls (30.42 +/- 3.59SE gm). In adulthood, pancreas weights (108.34 +/- 5.29SE gm) were not significantly different from controls (110 gm). Microscopic findings included vascular congestion (48%), edema (65%), siderosis (31%), and nesidioblastosis (76%), which included islet cell dispersion (53%), hyperplasia (23%), and hypertrophy (25%). Analysis by age groups suggested that islet cell dispersion/hyperplasia persists unchanged, whereas diameters of compact islets tend to increase with age. These findings may be related to local tissue hypoxia and/or increased metabolic energy needs in sickle cell disease.

Elevated serum and bronchoalveolar lavage fluid levels of interleukin 8 and granulocyte colony-stimulating factor associated with the acute chest syndrome in patients with sickle cell disease.

The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL-8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL-8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso-occlusive crises. The differences in mean IL-8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0.0001 and 0.04 respectively). The mean IL-8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 +/- 1400 pg/ml vs. 1900 +/- 470 pg/ml, P = 0.03). Granulocyte colony-stimulating factor (G-CSF) (2000 +/- 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL-8 and other chemokines. These findings suggest that IL-8 and G-CSF may play a role in the development of the ACS and the complications associated with it.

The reactions of myoglobin, normal adult hemoglobin, sickle cell hemoglobin and hemin with hydroxyurea.

The kinetics of the reaction of hydroxyurea (HU) with myoglobin (Mb), hemin, sickle cell hemoglobin (HbS), and normal adult hemoglobin (HbA) were determined using optical absorption spectroscopy as a function of time, wavelength, and temperature. Each reaction appeared to follow pseudo-first order kinetics. Electron paramagnetic resonance spectroscopy (EPR) experiments indicated that each reaction produced an FeNO product. Reactions of hemin and the ferric forms of HbA, HbS, and myoglobin with HU also formed the NO adduct. The formation of methemoglobin and nitric oxide-hemoglobin from these reactions may provide further insight into the mechanism of how HU benefits sickle cell patients.

Successful medical management of orbital abscess in a patient with sickle cell anemia.

The authors describe a patient with sickle cell anemia who had an orbital abscess at the site of a bone infarct during hospitalization for a painful crisis. Because the patient was in close medical observation, the orbital abscess was diagnosed within 48 hours of the onset of symptoms. The patient was treated with a 2-week course of intravenous antibiotics. This resulted in complete resolution of the abscess, as evidenced by clinical improvement and findings on computerized axial tomography scanning. The authors conclude that a heightened suspicion of orbital abscess in sickle cell patients with ocular symptoms will allow the diagnosis of an orbital abscess that can then be cured with antibiotic treatment but without orbital surgery.

Postmortem diagnosis of hemoglobin SC disease complicated by fat embolism.

A case is reported of a previously healthy 52-year-old African American male who presented with acute onset of abdominal pain. Progressive increase in his abdominal symptoms led to an exploratory laparotomy; however, no pathology was discovered. Postoperatively, the patient became hypoxemic which progressed to diffuse infiltrates on chest x-ray, suggestive of adult respiratory distress syndrome. He had a rapidly fatal course. Autopsy showed bone marrow infarction, fat embolism, splenomegaly, and widespread congestion with sickle erythrocytes. Hemoglobin electrophoresis done postmortem showed hemoglobin (Hb) SC disease that was undiagnosed antemortem. To the best of our knowledge, it is unusual for Hb SC to be diagnosed postmortem in adults. This case suggests that sickle cell disorders should be ruled out in patients at risk for hemoglobinopathy in the presence of signs and symptoms compatible with the disease, irrespective of age.

Sickle cell disease: clinical management.

Sickle cell syndromes are a group of inherited disorders of haemoglobin structure that have no cure in adults at the present time. Bone marrow transplantation in children has been shown to be curative in selected patients. The phenotypic expression of these disorders and their clinical severity vary greatly among patients and longitudinally in the same patient. They are multisystem disorders and influence all aspects of the life of affected individuals including social interactions, family relations, peer interaction, intimate relationships, education, employment, spiritual attitudes and navigating the complexities of the health care system, providers and their ancillary functions. The clinical manifestations of these syndromes are protean. In this review emphasis is placed on four sets of major complications of these syndromes and their management. The first set pertains to the management of anaemia and its sequelae; the second set addresses painful syndromes both acute and chronic; the third set discusses infections; the fourth section deals with organ failure. New experimental therapies for these disorders are briefly mentioned at the end. Efforts were made to include several tables and figures to clarify the message of this review.

Molecular mimicry between the rabies virus glycoprotein and human immunodeficiency virus-1 GP120: cross-reacting antibodies induced by rabies vaccination.

The 160-170 sequence of human immunodeficiency virus (HIV)-1 gp120 mimics a nicotinic receptor-binding motif of rabies virus glycoprotein and snake neurotoxins. This sequence has been proposed to be involved in the binding of HIV-1 gp120 to the acetylcholine binding sites of nicotinic receptors. By using biomolecular interaction analysis (BIA) technology we have found that HIV-1 gp120 can bind to detergent-extracted nicotinic receptor from fetal calf muscle. The binding is inhibited by nicotine and by a synthetic peptide reproducing the gp120 160-170 sequence. The molecular mimicry between gp120 and rabies virus glycoprotein is confirmed by cross-reacting antibodies. We have found that vaccination against rabies can induce the production of anti-HIV-1 gp120 antibodies in humans. The cross-reacting antibodies are directed to the gp120 sequence involved in the mimicry with the rabies virus glycoprotein. The cross-reactivity between the rabies virus and HIV-1 has important implications in transfusion medicine. Moreover, the presence of cross-reacting antibodies between the nicotinic receptor binding site of rabies virus glycoprotein and a fragment of HIV-1 gp120 strengthens the hypothesis about the possible role of nicotinic receptors as potential receptors for HIV-1 in the central nervous system.

Cytologic diagnosis of fat emboli in peripheral blood during sickle cell infarctive crisis.

A diagnosis of fat emboli can be suspected in a patient presenting with the typical symptoms of the fat embolism syndrome, but is rarely proved pathologically, except at autopsy. We described a 25-yr-old man with sickle cell anemia who developed an infarctive crisis complicated by unexplained fever, neurologic change, and respiratory abnormalities. Blood drawn from the femoral vein and examined cytopathologically yielded necrotic bone marrow elements admixed with fat. The cytologic finding of fat emboli from necrotic bone marrow provided the diagnosis and helped guide subsequent medical intervention. This sample test is recommended for patients at risk for fat emboli to aid in the clinical diagnosis.

Pathophysiology of vaso-occlusion.

Sickle cell anemia is a very complex disease. Vascular occlusion, the major event that accompanies SS, is itself a complex and multifactional process. Microvascular occlusion results in acute painful crises, whereas macrovascular occlusion seems to be the cause of organ failure. Understanding the basic pathophysiologic events of vascular occlusion may elucidate the clinical manifestations of SS, its natural history, and complications, and it may give new insights into preventive and curative therapy.

Revised transthyretin Ile 122 allele frequency in African-Americans.

The transthyretin (TTR) Ile 122 variant is associated with cardiac amyloidosis in individuals of African descent. To determine the prevalence of the allele encoding TTR Ile 122 in African-Americans, we have used PCR and restriction analysis to test DNA from African-Americans from various geographic areas, and found an allele frequency of 66/3376 (0.020), which is higher than the value we previously reported in a much smaller pilot study. Our data indicate that this TTR variant is present at equal frequency in African-Americans throughout the U.S., and suggest that this mutation may be a common, often unrecognized cause of cardiac disease in African-Americans.

False-positive human immunodeficiency virus screening test related to rabies vaccination.

We report a false-positive result on an enzyme immunoassay screening test for antibodies to human immunodeficiency virus in a 32-year-old nonpregnant woman who belonged to none of the usual risk groups. Because of the patient's employment in an animal care facility, she had received a series of three vaccinations for rabies, and 16 days after the last vaccination, she had donated a unit of blood. It was during routine screening on a sample drawn at the time of donation that the repeatedly reactive enzyme immunoassay screening test occurred. The results of a Western blot were indeterminant. A polymerase chain reaction assay was negative for proviral DNA.

Abdominal iron distribution in sickle cell disease: MR findings in transfusion and nontransfusion dependent patients.

OBJECTIVE: Our goal was to determine the difference in iron distribution between transfusion dependent (TD) and nontransfusion dependent (NT) patients with sickle cell disease (SCD). MATERIALS AND METHODS: The T2-weighted and T2*-weighted abdominal MR images in nine cases of homozygous SCD were reviewed to determine the distribution of low signal from iron in five TD and four NT patients. RESULTS: All eight patients with visualized spleens had decreased splenic signal intensity. One patient who had no history of splenectomy had no visualized splenic tissue. The majority of both groups had renal cortex of low signal intensity that was attributable to iron deposition from intravascular hemolysis and was not correlated with clinical renal abnormalities. None of the NT group had liver or pancreas of low signal intensity, while all five TD patients had decreased liver signal intensity and three of five had decreased pancreatic signal intensity. CONCLUSION: Decreased pancreatic signal intensity can occur in TD patients, perhaps suggesting total body iron overload. Nontransfusion dependent sickle cell patients usually have normal hepatic signal intensity and do not have total body iron overload, even in the presence of renal and splenic iron deposition.

Evaluation of serum immunoglobulins by protein electrophoresis and rate nephelometry before and after therapeutic plasma exchange.

One hundred fourteen pre- and postplasma exchange (PE) serum protein electrophoretograms and serum IgG, IgA, and IgM levels obtained during a 4-month period from 23 patients were evaluated. The interval between PE sessions varied from once daily to approximately once monthly. Typically, post-PE patterns had decreased alpha-1, decreased alpha-2, decreased beta, and decreased gamma fractions. The average percentage decreases of the immunoglobulins subsequent to PE were as follows: IgG, 52%; IgA, 55%; and IgM, 51%. There was a high linear correlation between the pre- and post-PE concentrations of IgG and IgA, whereas correlation of pre- and post-PE IgM concentrations was much lower. All IgG, IgA, and IgM levels (100%) returned to their respective reference intervals before subsequent PE when procedures were scheduled at least 2 weeks apart. When procedures occurred 1 week apart or less, only 1 IgG level (1%) returned to its reference interval, whereas 68 IgA (73%) and 74 IgM levels (80%) returned to their respective reference intervals. During this study, a faint monoclonal band was discovered in each of two patients. One had a normal baseline serum protein electrophoretogram before initiation of PE therapy, and the gammopathy was of uncertain significance. In the other patient, a vertebral plasmacytoma was discovered. It is concluded that PE reduces IgG, IgA, and IgM by approximately the same percentages; however, reference interval levels of IgA and IgM are restored more rapidly than IgG levels. Because monoclonal proteins may be present before or may appear during PE therapy, patients should be monitored by baseline and subsequent periodic serum protein electrophoresis.

Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.