MRSA pyomyositis complicating sickle cell anaemia

A patient being treated for sickle cell crisis developed swollen, painful, indurated, discoloured thighs after several days in hospital. Imaging revealed the presence of multiple small abscesses in the muscle and methicillin resistant Staphylococcus aureus (MRSA) was cultured from aspirated fluid. Pyomyositis usually occurs in association with damaged muscle and impaired host defences. Staphylococcus is the most frequent organism involved. It is not a common complication of sickle cell disease, although it may be under diagnosed. Availability of advanced imaging techniques facilitates early diagnosis of pyomyositis.     

Myonecrosis and myofibrosis as complications of sickle cell anemia

Painful crises in sickle cell anemia are associated with infarction and subsequent fibrosis of many different organs. Myonecrosis secondary to muscle infarction during a crisis and subsequent fibrosis are often not recognized as complications of sickle cell anemia. We describe four patients, all of whom had recurrent episodes of symmetric proximal muscle pain and swelling as prominent features of their crises. Muscle biopsies showed acute myonecrosis with a minimal inflammatory reaction as well as myofibrosis with abundant collagen deposition. Chronic sequelae consisted of muscle induration, atrophy, and contractures.     

Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes

Hemolysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemolysis and its effects on nitric oxide (NO) biology and further examination of the subphenotypes of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemolysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasodilatation. When plasma hemoglobin liberated from intravascularly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodilation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be linked to the intensity of hemolysis. Hemolysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemolytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials.     

Cell-bound autologous immunoglobulin in erythrocyte subpopulations from patients with sickle cell disease

Previously, we have demonstrated a parallel between most-dense (bouyant density) sickle erythrocyte subpopulations and most-dense aged normal red cells in the organization of membrane components in the intact cell. The present study has addressed the possibility that a corresponding similarity may exist between most-dense sickled red cell subpopulations and aged normal erythrocytes in the development of membrane protein components that function as receptors for autologous immunoglobulin (Ig). Autologous IgG retained by density-fractionated erythrocytes has been estimated by a nonequilibrium 125I-protein A (Staphylococcus aureus) binding assay. Results show that most-dense sickle cell fractions contain more (2.7-fold and 1.8-fold, P less than .005) cell-bound IgG in comparison to younger sickle erythrocyte fractions sedimenting at low density. Parallel findings were obtained after similar analyses of normal (homozygous-A) erythrocyte fractions. Detection of the presence of specific IgG was also carried out by direct binding of fluorescein isothiocyanate-conjugated anti-human IgG to density-separated red cell fractions followed by analyses of the fluorescent cell populations by flow cytometry. Results showed significantly higher levels of IgG bound to most-dense (12.1% +/- 2.5% and 8.8% +/- 0.5%-) sickle red cell subpopulations (P less than .005) in comparison to younger sickle erythrocyte fractions sedimenting at low densities (3.8% +/- 0.32% and 4.7% +/- 1.6% IgG-positive red cell subpopulation). These results indicate that some of the same membrane changes that occur at about 120 days in normal red cells are also apparent in the chronologically younger (life span in vivo, ten to 40 days) sickle erythrocyte. The increased retention of IgG by most-dense irreversibly sickled cell-enriched fractions in comparison to least- dense reversibly sickled cells or pre-irreversibly sickled erythrocyte fractions, suggests that alterations in the topography of the sickle cell membrane during the transformation in vivo to the most-dense irreversibly sickled cell morphology may produce the unmasking of cryptic antigenic sites. In addition, these findings may indicate that opsonization of specific erythrocyte subpopulations may play a role in the pathophysiology of sickle cell disease.     

Mitral valve prolapse in sickle cell disease. Presumptive evidence for a linked connective tissue disorder

To determine the prevalence of mitral valve prolapse in sickle cell disease, M-mode echocardiography was performed on 57 patients with sickle cell disease and 35 patients with chronic anemia of end-stage renal disease (anemic control group). In 25% (14/57) of patients with sickle cell disease, unequivocal mitral valve prolapse was diagnosed by echocardiography; all these patients had a mobile systolic click and/or late systolic murmur. This figure was significantly greater than the reported 5% to 6% prevalence in the general adult population, the 1% to 3% prevalence in the black population, and the 3.0% prevalence (1/35) in the anemic control group. The association of mitral valve prolapse and sickle cell disease cannot be explained on the basis of left ventricular size, systolic function, ischemic left ventricular or papillary muscle dysfunction, or chronic anemia. Therefore, a linked connective tissue defect in these two diseases is a hypothesis worthy of further investigation.     

Serum concentrations of meperidine in patients with sickle cell crisis

We compared mean serum concentrations of meperidine in sickle cell patients in crisis and control patients receiving meperidine prior to incision and drainage of abscesses. Eight sickle cell and five control patients without confounding illnesses consented to participate and received 100 mg meperidine in the deltoid or gluteal muscle for pain. Blood samples were drawn at baseline, 0.25, 0.50, 0.75, 1.0, 1.5, and 2.0 hours postinjection. In the sickle cell group, mean peak concentration of meperidine was 0.32 +/- 0.08 micrograms/mL at an average of 0.5 +/- 0.07 hours postinjection. Among controls mean peak concentration was 0.72 +/- 0.37 micrograms/mL at an average of 0.6 +/- 0.11 hours. The difference in peak concentrations was significant at all time intervals (P less than .01); the difference in times to peak was not significant. We conclude that, given a standard dose, serum concentrations of meperidine differ between sickle cell and control patients, which may suggest reasons for the relatively poor pain control often noted in sickle cell patients.     

Cerebrovascular disease associated with sickle cell pulmonary hypertension

In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension.     

Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation

OBJECTIVE: Clinically, the vascular pathobiology of human sickle cell disease includes an abnormal state of chronic inflammation and activation of the coagulation system. Since these biologies likely underlie development of vascular disease in sickle subjects, they offer attractive targets for novel therapeutics. Similar findings characterize the sickle transgenic mouse, which therefore provides a clinically relevant inflammation model. METHOD: The authors tested two polyhydroxyphenyl hydroxamic acid derivatives, didox and trimidox, in sickle transgenic mice. Animals were examined by intravital microscopy (cremaster muscle and dorsal skin fold preparations) and by histochemistry before and after transient exposure to hypoxia, with versus without preadministration of study drug. Previous studies have validated the application of hypoxia/reoxygenation to sickle transgenic mice as a disease-relevant model. RESULTS: Animals pretreated with these agents exhibited marked improvements in leukocyte/ endothelial interaction, hemodynamics and vascular stasis, and endothelial tissue factor expression. Thus, these drugs unexpectedly exert powerful inhibition on both the inflammation and coagulation systems. CONCLUSIONS: Each of these changes is expected to be therapeutically beneficial in systemic inflammatory disease in general, and in sickle disease in particular. Thus, these novel compounds offer the advantage of having multiple therapeutic benefits in a single agent.     

The possible role of red blood cell microvesicles in atherosclerosis

The tendency of sickle cells to adhere to the endothelium reflects the surface features not only of the red cells but also of the endothelial cells. Sickle cell disease is a prototype of a condition where the erythrocyte is under stress, ischemic, oxidative, or shear stress, that causes changes in the erythrocyte morphology. This change leads eventually to enhanced erythrocyte-endothelial cell adhesion.Reactive oxygen species generated by cytokine-activated inflammatory cells oxidize lipoproteins such as LDL and lipoprotein(a) within the vessel wall, facilitating uptake of these particles by activated macrophages and smooth muscle cells, with conversion into lipid-laden foam cells. Notably, the membranes of sickle RBCs have undergone excessive cytoskeletal protein thiol oxidation, and sickle RBCs are abnormally prone to vesiculation during mechanical stress in vitro and apparently in vivo.This abnormality was successfully reproduced in normal RBCs by causing stress conditions using PMS-induced stimulation of intracellular superoxide generation, a process similar to that occurring in sickle RBCs. It could be that the generation of reactive oxygen species in atherosclerosis activates red blood cells, and microvesicles of red blood cells are formed, enhancing the activation of the vascular endothelium and leading to vascular inflammation and atherogenesis.     

Results of bronchoscopically obtained lower airway cultures from adult sickle cell disease patients with the acute chest syndrome

PURPOSE: The purpose of this study was to determine the frequency of bacterial pneumonia as a cause of the acute chest syndrome in adult patients with sickle cell disease based on bronchoscopically obtained lower airway cultures and to describe the clinical, laboratory, and roentgenographic features of the acute chest syndrome in a series composed entirely of adult patients with sickle cell disease. PATIENTS AND METHODS: We reviewed the hospital records from 19 episodes (18 patients) of acute chest syndrome in adult patients with sickle cell disease (greater than or equal to 19 years of age) who had undergone flexible bronchoscopy to obtain lower airway cultures between January 1979 and July 1987. We also recorded patients' clinical, laboratory, and roentgenographic characteristics. RESULTS: Pneumonia was diagnosed in four of 19 episodes (21%) of acute chest syndrome based on quantitative cultures obtained at bronchoscopy. The pneumonia was caused by Streptococcus pneumoniae in two patients and mixed aerobic and anaerobic organisms in the other two patients. Forty-four of 45 blood cultures were negative, and one grew Staphylococcus epidermidis, which was considered a contaminant. Chest roentgenograms revealed lower lobe involvement in 17 episodes (90%) and bilateral infiltrates in six (32%). Pleural effusions occurred in seven episodes (37%), and pleural fluid samples obtained from five of these revealed sterile exudates. CONCLUSION: The results of this retrospective study suggest that bacterial pneumonia is an uncommon cause of acute chest syndrome in adult patients with sickle cell disease. These results are consistent with previous retrospective studies using noninvasive techniques to diagnose pneumonia. Nevertheless, there appeared to be no reliable noninvasive variables that could accurately differentiate between patients with and without pneumonia and, consequently, we recommend empiric antibiotic therapy in addition to usual supportive care of these patients.     

Septic arthritis in childhood

We studied retrospectively the pattern of septic arthritis in childhood at a major municipal hospital during a ten-year period. Hemophilus influenzae was the most common organism in septic arthritis in patients less than two years old and was associated with upper respiratory tract infections in nine of 12 patients (75%). Staphylococcus aureus was seen in seven of eight (87.5%) children above the age of five and was associated with history of trauma. All patients were black. Despite the high incidence of sickle cell disease in our hospital population, not one patient had sickle cell disease.     

Serum autoantibodies in patients with sickle cell anemia

The prevalence of serum autoantibodies was determined in 50 black adult patients with sickle cell anemia, and in 33 age- and sex-matched healthy black individuals. Twenty-seven of the patients (54%) had at least one type of autoantibody, in contrast to only four (18.2%) of the control subjects (P less than .01). Antismooth muscle, antiskeletal muscle and antinuclear antibodies were the most frequently seen autoantibodies. There was no correlation between the presence of autoantibodies and history of hepatitis, number of blood transfusions or concurrent drug therapy. Sickle cell anemia is associated with the induction of autoimmune phenomena.     

Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation

Increased leukocyte adhesion to vascular endothelium contributes to vaso-occlusion in sickle cell disease. Since nitric oxide bioavailability is decreased in sickle cell disease and nitric oxide may inhibit leukocyte adhesion, we investigated whether stimulation of NO-signaling pathways can reduce the adhesive properties of neutrophils from sickle cell disease individuals (sickle cell diseaseneu). sickle cell diseaseneu presented greater adhesion in vitro to both fibronectin and ICAM-1 than control neutrophils. Co-incubation of sickle cell diseaseneu with the nitric oxide-donor agents, sodium nitroprusside and dietheylamine NONOate (DEANO), and the guanylate cyclase stimulator, BAY41-2272, all significantly reduced the increased adhesion to fibronectin/ICAM-1. Oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, reversed sodium nitroprusside/DEANO-diminished adhesion to fibronectin, implicating cGMP-dependent signaling in this mechanism. Interestingly, intracellular cGMP was significantly higher in neutrophils from sickle cell disease individuals on hydroxyurea (sickle cell diseaseHUneu). Accordingly, sickle cell diseaseHUneu adhesion to fibronectin/ICAM-1 was significantly lower than that of sickle cell diseaseneu. Agents that stimulate the nitric oxide/cGMP-dependent pathway may have beneficial effects on leukocyte function if used in these subjects.     

In vivo studies of sickle red blood cells

The defining clinical feature of sickle cell anemia is periodic occurrence of painful vasoocclusive crisis. Factors that promote trapping and sickling of red cells in the microcirculation are likely to trigger vasoocclusion. The marked red cell heterogeneity in sickle blood and abnormal adhesion of sickle red cells to vascular endothelium would be major disruptive influences. Using ex vivo and in vivo models, the authors show how to dissect the relative contribution of heterogeneous sickle red cell classes to adhesive and obstructive events. These studies revealed that (1) both rheological abnormalities and adhesion of sickle red cells contribute to their abnormal hemodynamic behavior, (2) venules are the sites of sickle cell adhesion, and (3) sickle red cell deformability plays an important role in adhesive and obstructive events. Preferential adhesion of deformable sickle red cells in postcapillary venules followed by selective trapping of dense sickle red cells could result in vasoocclusion. An updated version of this 2-step model is presented. The multifactorial nature of sickle red cell adhesion needs to be considered in designing antiadhesive therapy in vivo.     

Decompensated Cirrhosis and Sickle Cell Disease: Case Reports and Review of the Literature

Although its prevalence is unknown, liver involvement by sickle cell disease is not uncommon and encompasses different clinical spectra including non cholestatic and cholestatic disorders. Few data have been provided on chronic sickle cell intrahepatic cholestasis (SCIC) clinical course, although cirrhosis has been reported in sickle cell disease. However, no effective therapeutic approaches have been recognized either to prevent or treat this condition. Here we present two cases of adult sickle cell disease patients with decompensated cirrhosis. Their liver biopsies showed sickle cell thrombi within the hepatic sinusoids. Despite erythroexchange (EEX) transfusions, both patients suffered from major sickle cell disease-related events, suggesting that EEX transfusions may not be enough to impact on advanced liver involvement by sickle cell disease.     

Sickel cell anemia, the nephrotic syndrome and hypoplastic crisis in a sibship

A family is presented with five siblings, three with sickle cell anemia and two with thalassemia trait. In all three children with sickle cell anemia hypoplastic crises developed after a viral infection. Two of these children were found to have the nephrotic syndrome, as did one of their siblings with thalassemia trait.Renal biopsy in the female patient with sickle cell anemia and the nephrotic syndrome revealed focal and segmental glomerulosclerosis. The biopsies of the other two patients (one with sickle cell anemia and one with thalassemia trait) revealed minimal changes. Hemosiderosis was present only in the biopsy specimens of the two patients with sickle cell anemia. All three patients were steroidresistant. Neither the other two siblings (one with sickle cell anemia and hypoplastic crisis) nor the parents have the nephrotic syndrome.The pathogenesis of nephrotic syndrome in patients with sickle cell anemia is discussed in detail. The current hypotheses relating renal disease to the sickling process are considered. The nephrotic syndrome observed in our patients appears to be familial and unrelated to sickle cell anemia, having been found in family members without, as well as with, sickle cell anemia. The findings in this family suggest that the nephrotic syndrome found in sickle cell anemia may not be causally related, but may be fortuitous, at least in some patients.     

Leg ulcers in patients with sickle cell disease [see comments]

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.     

Sickle red cell microrheology and sickle blood rheology

The hallmark of the phenotypic expression of sickle cell disease is the remarkable degree of heterogeneity in the clinical manifestations. They vary latitudinally among patients and longitudinally in the same patient. The pathogenesis of sickle cell anemia centers on the sequence of events that occur between polymerization of deoxy hemoglobin S and increased red cell destruction, vasoocclusion, and end organ damage. Cellular dehydration, changes in sickle red blood cell rheology, adhesion of sickle red cells to vascular endothelium, inflammatory response, and tissue injury are some of the factors that contribute to hemolytic anemia, vasoocclusion, and eventual multiorgan damage. The focus of this review is on the rheology of sickle blood and microrheology of sickle RBC. Determinants of sickle RBC rheology and the factors that modulate its severity are discussed.     

Maternal and Perinatal Outcome of Women With Sickle Cell Disease of a Tribal Population in Central India

Pregnancy in sickle cell disease is associated with increased risk of maternal and fetal morbidity and mortality. Sickle cell disease is very common in tribal populations. The objective of this study was to review the maternal and perinatal outcome in patients with sickle cell disease of tribal populations. This is a retrospective study. The data extracted from the patients’ case files included age, gravidity, family history, complications during pregnancy or at time of delivery or postpartum period, mode of delivery, and fetal outcome. There were 25 deliveries to women with sickle cell disease and 54 with sickle cell trait. Preeclampsia and disseminated intravascular coagulation were common problems associated with sickle cell disease as compared to the sickle cell trait and normal groups. No maternal mortality occurred during the period under study. However, a total of five intrauterine fetal deaths and one early neonatal death did occur. The present study confirms the previous reports, the increased risk of fetal death in women with sickle cell disease, however, in contrast to previous studies, no maternal mortality was found.     

Lung function and airway hyperresponsiveness in adult patients with sickle cell disease

BACKGROUND: Lung disease is a major cause of morbidity and death in sickle cell disease. Although airway hyperresponsiveness has been noted in children, there are no studies in adult sickle cell patients. The aim of this study was to investigate the prevalence of airway hyperresponsiveness in adult sickle cell patients. METHODS: Twenty-six patients with sickle cell disease (10 HbSC, 9 HbSS, and 7 HbSbeta) were compared with 28 normal control subjects. Pulmonary function tests, including spirometry, measurements of single-breath diffusing capacity and the methacholine challenge test were performed. RESULTS: There were no significant differences in age, gender, or height between groups. Restrictive ventilatory defect was observed in six patients (24%) in the sickle cell disease group. Obstructive ventilatory defect and reduced diffusing lung DLCO capacity was observed in all sickle cell disease subgroups. A positive methacholine challenge test was obtained in eight (31%) sickle cell patients and in two of the 28 controls (7%). CONCLUSION: These features suggest that there is a high prevalence of airway hyperresponsiveness in adult patients with sickle cell disease without a history of reactive airway disease.