Johnson Haynes

Causes of death in sickle cell disease: an autopsy study

Summary. More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33–48%). The terminal infection was heralded by upper respiratory tract syndromes in 72·6% and by gastroenteritis in 13·7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9·8%, therapy complications 7·0%, splenic sequestration 6·6%, pulmonary emboli/thrombi 4·9%, renal failure 4·1%, pulmonary hypertension 2·9%, hepatic failure 0·8%, massive haemolysis/red cell aplasia 0·4% and left ventricular failure 0·4%. Death was frequently sudden and unexpected (40·8%) or occurred within 24 h after presentation (28·4%), and was usually associated with acute events (63·3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted.

Pulmonary edema: Complication in the management of sickle cell pain crisis

Over a 12-month period, there were 51 admissions for sickle cell pain crisis. Of these, the course of four patients (two with hemoglobin SS, one with hemoglobin SC, and one with hemoglobin S-Thal) was complicated by the development of pulmonary edema. Pulmonary edema complicating the management of sickle cell pain crisis has not previously been described. Vigorous fluid replacement with hypotonic saline and parenteral narcotic analgesics are conventional modalities of therapy, but may contribute to the development of pulmonary edema. Narcotic analgesics causing increased permeability are well established. In pulmonary vascular beds predisposed to injury, hypotonic saline administration causing an increased hydrostatic pressure and decreased oncotic pressure may further compound pulmonary edema development. On the basis of the experience in this study, a conservative approach to the use of fluid administration and narcotic analgesics is advised.

The Acute Chest Syndrome of Sickle Cell Disease

The acute chest syndrome (ACS), characterized by fever, chest pain, leukocytosis and a new infiltrate on chest roentgenogram, is a common complication of sickle hemoglobinopathies. The major differential diagnoses of ACS are pneumonia and pulmonary vaso-occlusive disease, which may occur simultaneously. Bacterial pulmonary infections are documented infrequently in ACS with the exception being in the pediatric population under 5 years of age. Because there are no clinical or laboratory parameters that clearly allow for distinction between pneumonia and vaso-occlusive disease, empiric use of antibiotics directed against S. pneumoniae and other pathogens commonly seen in community-acquired pneumonias remain a mainstay of therapy.

A double‐blind, placebo‐controlled phase II study of the efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

This placebo‐controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), a fetal globin gene‐inducing short‐chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12–55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β0 thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK‐1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1–1.6%) with HQK‐1001 and 0.2% (95% CI: −0.7–1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK‐1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK‐1001 and 1.7 with placebo. The most common adverse events in the HQK‐1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK‐1001 at this dose and schedule are not recommended in SCD. Intermittent HQK‐1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. Am. J. Hematol. 89:709–713, 2014.

Misclassification of pulmonary hypertension in adults with sickle hemoglobinopathies using Doppler echocardiography.

Objective To compare the diagnostic utility of Doppler echocardiography–derived tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s to right heart catheterization (RHC) in defining pulmonary hypertension (PH) in adult patients with sickle cell disease (SCD). Methods This is a retrospective chart review of adults with SCD who had a TRV ≥2.5 m/s and RHC. A TRV ≥2.5 m/s is suggestive of PH. Pulmonary arterial hypertension (PAH) was defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg and pulmonary capillary wedge pressure ⩽15 mm Hg. Pulmonary venous hypertension was defined as an mPAP ≥25 mm Hg and pulmonary capillary wedge pressure >15 mm Hg. Results Twenty-five patients with SCD met the inclusion criteria. Nine of the 25 (36%) patients had an mPAP ≥25 mm Hg. Of these 9, 3 (33%) had PAH and 6 (66%) had pulmonary venous hypertension. Patients with PH did not have a higher TRV (3.1 ± 0.68 vs 2.70 ± 0.16 m/s; P = 0.12), but they did have higher cardiac outputs (10.4 ± 2.7 vs 7.81 ± 1.85 L/min; P = 0.012. The specificity of TRV equal to 2.51 m/s in diagnosing PH was 18.8%. At a TRV of 2.88 m/s, the specificity increased to 81%. Conclusions In adults with SCD, a TRV of 2.5 m/s lacks specificity for use as a screening tool in the diagnosis of PH. Using a TRV of ≥2.88 m/s allows the TRV to be used as a screening tool and reduces the false-positive rate and need for unnecessary RHC.

5-(N-ethylcarboxamido)adenosine desensitizes the A2b-adenosine receptor in lung circulation.

The adenosine agonist 5-(N-ethylcarboxamido)adenosine (NECA) induces vasodilation in the pulmonary circulation via A2-adenosine-receptor activation. We addressed whether prolonged treatment with NECA desensitizes in A2-adenosine- receptor function in isolated lung and pulmonary artery smooth muscle cells (PASMC). In lung microcirculation preconstricted with a hypoxic gas, initial administration of NECA caused a 57% vasodilatory response after 3-4 min. Readministration of NECA after 45 min resulted in minimal vasodilation. The highest accumulation of PASMC cAMP occurred 3-5 min after NECA, coincident with NECA-induced vasodilation. In PASMCs treated with NECA for 45 min, cAMP did not increase. Isoproterenol- and indolidan-induced vasodilation remained intact in NECA-desensitized lungs. In NECA-desensitized PASMCs, isoproterenol-induced cAMP accumulation was decreased, suggesting a common mechanism of desensitization. cAMP accumulation was decreased in cholera toxin-treated NECA-desensitized PASMCs compared with cholera toxin-treated control PASMCs, demonstrating that Gsalpha-adenylyl cyclase signaling contributes to desensitization. The A2a-adenosine-receptor agonist CGS-21680C neither increased cAMP accumulation in PASMCs nor attenuated NECA-induced vasodilation. These data support that the A2b-adenosine receptor is responsible for pulmonary vasodilation and desensitization through mechanisms(s) involving Gsalpha-adenylyl cyclase signaling.The adenosine agonist 5-( N-ethylcarboxamido)adenosine (NECA) induces vasodilation in the pulmonary circulation via A2-adenosine-receptor activation. We addressed whether prolonged treatment with NECA desensitizes in A2-adenosine- receptor function in isolated lung and pulmonary artery smooth muscle cells (PASMC). In lung microcirculation preconstricted with a hypoxic gas, initial administration of NECA caused a 57% vasodilatory response after 3-4 min. Readministration of NECA after 45 min resulted in minimal vasodilation. The highest accumulation of PASMC cAMP occurred 3-5 min after NECA, coincident with NECA-induced vasodilation. In PASMCs treated with NECA for 45 min, cAMP did not increase. Isoproterenol- and indolidan-induced vasodilation remained intact in NECA-desensitized lungs. In NECA-desensitized PASMCs, isoproterenol-induced cAMP accumulation was decreased, suggesting a common mechanism of desensitization. cAMP accumulation was decreased in cholera toxin-treated NECA-desensitized PASMCs compared with cholera toxin-treated control PASMCs, demonstrating that Gsα-adenylyl cyclase signaling contributes to desensitization. The A2a-adenosine-receptor agonist CGS-21680C neither increased cAMP accumulation in PASMCs nor attenuated NECA-induced vasodilation. These data support that the A2b-adenosine receptor is responsible for pulmonary vasodilation and desensitization through mechanisms(s) involving Gsα-adenylyl cyclase signaling.

Iron overload in adults with sickle cell disease who have received intermittent red blood cell transfusions.

Objective:To assess the prevalence of iron overload in adults with sickle cell disease (SCD) not on a chronic transfusion protocol. Design:Retrospective chart review. Data source:University of South Alabama Comprehensive Sickle Cell Center adult outpatient clinic. Results:There was no significant difference in units transfused across the four genotypes (HbSS, HbSC, HbS&bgr;0‐thalassemia, and HbS&bgr;+‐thalassemia). Only individuals with HbSS (n = 63) met criteria for iron overload with ferritins of ≥1500 ng/mL. Forty‐eight had ferritins <1500 ng/mL, eight (13%) had ferritins ≥3000 ng/mL, and seven (11%) had ferritins ≥1500 and <3000 ng/mL. The overall prevalence of iron overload was 9.74% in SCD cohort and 23.8% in the HbSS genotype. Conclusions:Our data support that patients with HbSS are at a particularly high risk for inadvertent iron overload as compared to HbSC, HbS&bgr;0‐thalassemia, and HbS&bgr;+‐thalassemia. Implications for practice:This study supports the need for healthcare providers to closely monitor the number of red blood cell (RBC) transfusions, RBC units transfused, and serial baseline, steady‐state ferritin levels. With closer monitoring, the clinical significance of iron overload in SCD can be established and guide the healthcare providers management in the prevention of iron overload.

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 (≤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.