Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis

Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.     

Acute and chronic pain management in patients with sickle cell disease in the modern era: a comprehensive review

Sickle cell disease (SCD) is the most common inherited red blood cell (RBC) disorder worldwide, resulting in chronic hemolytic anemia, vaso-occlusion, tissue hypoxia, and ultimately end organ damage. The hallmark of the disease is manifested by vaso-occlusive crisis (VOC) resulting in acute on chronic pain, and the most common cause for presentation to the emergency department and hospital admission. The management of pain for patients with SCD in the U.S. has historically been socially and politically complex with most patients experiencing pain on a daily basis but not seeking immediate medical attention. The pathophysiology of acute and chronic pain in SCD is multifactorial and complex. Here, we describe factors contributing to acute and chronic pain in SCD and management strategies.     

CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions

Hemolytic transfusion reactions (HTRs) can produce serious and potentially life-threatening complications in sickle cell disease (SCD) patients; however, the mechanisms underlying these complications remain undetermined. We established a model of alloimmune, IgG-mediated HTRs in a well-characterized humanized murine model of SCD. HTRs induced acute vaso-occlusive crisis (VOC), resulting in shortened survival of SCD mice. Acute VOC was associated with elevated circulating inflammatory chemokine levels, including striking elevation of the levels of the neutrophil chemoattractant CXCL1. Recombinant CXCL1 administration was sufficient to induce acute VOC in SCD mice, characterized by leukocyte recruitment in venules, capture of circulating red blood cells, reduction of venular flow, and shortened survival. In contrast, blockade of the CXCL1 receptor, CXCR2, prevented HTR-elicited acute VOC and prolonged survival in SCD mice. These results indicate that CXCL1 is a key inflammatory mediator of acute VOC in SCD mice. Targeted inhibition of CXCL1 and/or CXCR2 may therefore represent a new therapeutic approach for acute VOC in SCD patients.     

High lactate dehydrogenase levels at admission for painful vaso-occlusive crisis is associated with severe outcome in adult SCD patients

Objectives

The aim of this study is to assess biological prognostic factors at the onset of vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD).

Methods

A monocentric prospective study including all patients admitted for VOC in a reference center for SCD was utilized. We used multivariate logistic regression to find independent predictors of severe evolution, defined by death or a worsening clinical state indicating transfusion or transfer to the intensive care unit.

Results

Eighty eight patients were included, 63% were women, median age of 23 years, and 90% of patients were homozygous SCD, 10% compound heterozygous. VOC became severe in 17 patients. Patients with severe VOC were more frequently males, who also had higher white blood cell (WBC) count, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels. LDH level was the best predictor of the outcome; WBC and PCT had no significant added predictive values when coupled with LDH in multivariable models, even in patients with fever or acute chest syndrome. Severe evolution always occurred when LDH levels were over 4 times the upper limit of the normal range at admission and never occurred when LDH levels were within the normal range.

Conclusion

Further studies should confirm the predictive value of LDH before its widespread use as a prognostic factor. If it is confirmed, the benefit of preemptive transfusion when LDH levels at admission are very high could be investigated.     

Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.     

Evaluation of sex disparities in opioid use among ED patients with sickle cell disease, 2006–2015

BackgroundAcute pain from a vaso-occlusive crisis (VOC) is a leading reason patients with sickle cell disease (SCD) visit the emergency department (ED). Prior studies suggest that women and men receive disparate ED treatment for acute pain in EDs. We aim to determine sex differences in analgesic use among patients with SCD presenting to the ED.MethodsThis cross-sectional study uses data from the National Hospital Ambulatory Medical Care Survey (NHAMCS), 2006–2015. We identified ED patients with a primary diagnosis of SCD. Among patients with SCD, we evaluated sex differences in the use of opioid analgesia using logistic regression (adjusting for patient and visit characteristics). Analyses accounted for survey design and weighting.ResultsWhen evaluating the effect of sex on any opioid medication use in this population, though not significant, the odds that male patients were prescribed opioids was 1.5 (95% CI 0.8–2.8) times that of female patients after adjusting for age, the reason for visit, region, insurance status, and pain score. There was no significant difference in pain scores between male patients, 8.1 (95% CI 7.55–8.68) compared to female patients, 7.4 (95% CI 6.7–8.12).ConclusionsIn this nationally representative sample of ED visits among patients with SCD, there was no conclusive evidence of sex disparities in opioid prescribing. Though there is evidence of a trend signaling that male patients with SCD were more likely than female patients to be prescribed an opioid.     

The apoptosis of blood polymorphonuclear leukocytes in sickle cell disease

BACKGROUND: The apoptosis of human polymorphonuclear leukocytes (PMNs) in patients with sickle cell disease (SCD) is not well understood. The goal of this study was to examine the apoptosis of PMNs in patients with SCD and in controls. METHODS: Flow cytometric quantitation of PMN apoptosis was performed in 17 patients during and after sickle cell vasoocclusive crisis and in 17 healthy volunteers. Plasma nitric oxide concentrations were also measured in patients with SCD. RESULTS: The mean of annexin-V and annexin-V/PI staining (early and late apoptotic cells) increased to a greater degree in patients with SCD than in healthy controls for patients with SCD during and after vasoocclusive crisis. The mean of PI staining showing dead cells was higher only in patients after SCD crisis than in healthy controls. In the SCD groups during and after vasoocclusive crisis, there was no difference between PMN apoptosis levels. Furthermore, plasma nitric oxide concentrations were not correlated with PMN apoptosis. CONCLUSIONS: There was an evidence that the alteration of blood PMN apoptosis could contribute to the pathogenetic mechanisms of vasoocclusion in patients with SCD. This can be attributed to the effects of numerous inflammatory mediators rather than simply the effects of nitric oxide.     

Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death

BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication in sickle cell disease (SCD) characterized by recurrence of disease complications, recipient red blood cell (RBC) destruction, and frequently no detectable antibody. Phosphatidylserine (PS) exposure signs suicidal RBC death or eryptosis and is involved in vasoocclusive crisis (VOC).
STUDY DESIGN AND METHODS: Transfusion was monitored in 48 SCD patients for up to 20 days. PS exposure was evaluated in vivo on patient RBCs (PS-RBCs) at five time points and in vitro after incubation of donor RBCs with pretransfusion plasma.
RESULTS: Three VOC patients displayed DHTR with recurrent SCD features and no detectable antibody in two cases. In vitro, PS-RBC percentage was significantly increased by incubating donor RBCs with pretransfusion plasma samples from DHTR patients with no detectable antibody. No such increase was observed with samples from other patients. This result indicates that donor RBCs may be damaged by the environment of SCD patients, increasing the physiologic clearance of apoptotic RBCs. In vivo, PS-RBC percentage increased in all three cases after destruction of transfused RBCs, indicating that DHTR induces PS-RBCs and, possibly, subsequent VOC and autologous RBC destruction.
CONCLUSION: This study clearly demonstrates that DHTR can occur in the absence of detectable antibody. In these cases, a mechanism of excessive eryptosis is proposed.     

Spontaneous circulation of myeloid-lymphoid-initiating cells and SCID-repopulating cells in sickle cell crisis

The only curative therapy for sickle cell disease (SCD) is allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy approaches for autologous HSC transplantation are being developed. Although earlier engraftment is seen when cells from GCSF-mobilized blood are transplanted than when bone marrow is transplanted, administration of GCSF to patients with SCD can cause significant morbidity. We tested whether primitive hematopoietic progenitors are spontaneously mobilized in the blood of patients with SCD during acute crisis (AC-SCD patients). The frequency of myeloid-lymphoid-initiating cells (ML-ICs) and SCID-repopulating cells (SRCs) was significantly higher in blood from AC-SCD patients than in blood from patients with steady-state SCD or from normal donors. The presence of SRCs in peripheral blood was not associated with detection of long-term culture-initiating cells, consistent with the notion that SRCs are more primitive than long-term culture-initiating cells. As ML-ICs and SRCs were both detected in blood of AC-SCD patients only, these assays may both measure primitive progenitors. The frequency of ML-ICs also correlated with increases in stem cell factor, GCSF, and IL-8 levels in AC-SCD compared with steady-state SCD and normal-donor sera. Because significant numbers of ML-ICs and SRCs are mobilized in the blood without exogenous cytokine treatment during acute crisis of SCD, collection of peripheral blood progenitors during crisis may yield a source of autologous HSCs suitable for ex-vivo correction by gene therapy approaches and subsequent transplantation.     

Effects of poloxamer 188 treatment on sickle cell vaso-occlusive crisis: computer-assisted intravital microscopy study.

Nine patients with sickle cell disease (SCD) who were hospitalized at UC Davis Medical Center for vaso-occlusive crisis (VOC) were studied as part of a randomized double-blind phase III clinical trial to investigate the real-time effects of poloxamer 188 on VOC. All patients showed significant microvascular changes from normal (steady-state) values during VOC (diminished venular diameter and red cell velocity). The patients were randomly assigned to be treated with poloxamer 188 or placebo. Poloxamer 188 (n = 4) but not placebo (n = 5) significantly reversed these microvascular changes approximately 2 hours postinitiation of loading infusion (100 mg/kg in 1 hour). Further significant improvement induced by poloxamer 188 but not placebo was observed > or = 7 hours postinfusion, resulting in a significant reversal of the microvascular changes to steady-state values.     

Probing the role of stearoyl-CoA desaturase-1 in hepatic insulin resistance

Previous studies using stearoyl-CoA desaturase–1–deficient (SCD1-deficient) mice have shown that this enzyme plays an important role in many diseases of altered cellular metabolism including obesity, insulin resistance, and dyslipidemia. Although SCD1 activity is highest in lipogenic tissues such as the liver and adipose tissue, it is also present at lower levels in most tissues. To better understand the role of SCD1 in liver metabolism it is necessary to explore SCD1 deficiency in a more focused, tissue-specific manner. This commentary focuses on 2 recent studies published in the JCI that address this question using antisense oligonucleotide inhibition of SCD1. First, Jiang et al. have previously reported that long-term inhibition of SCD1 prevents the development of high-fat diet–induced obesity and hepatic steatosis. Second, Gutiérrez-Juárez et al. show in this issue that short-term inhibition of hepatic SCD1 is sufficient to prevent diet-induced hepatic insulin resistance, signifying an important role of hepatic SCD1 in liver insulin sensitivity (see related article beginning on page 1686).     

Urinary incontinence: why women do not ask for help

During the past decade, many medical conditions previously thought to be unmentionable are now being talked about more openly. Breast cancer, for example, has had a great deal of media attention, particularly when women in the public eye reveal that they have been diagnosed with it. This publicity helps to increase awareness of the condition. In comparison with breast cancer, the common female problem of urinary incontinence receives scant attention in the media, yet it has been estimated that there may be 4,000,000 women in the UK suffering from urinary incontinence at one time (Hunskaar et al, 2004).     

Comparison of the performance of two comorbidity measures, with and without information from prior hospitalizations.

OBJECTIVES: This study compares the performance of two comorbidity risk adjustment methods (the Deyo et al adaptation of the Charlson index and the Elixhauser et al method) in five groups of California hospital patients with common reasons for hospitalization, and assesses the contribution to model performance made by information drawn from prior hospital admissions. METHODS: California hospital discharge abstract data for the calendar years 1994 through 1997 were used to create a longitudinal data set for patients in the five disease groups. Eleven logistic regression models were estimated to predict the risk of in-hospital death for patients in each group, with both comorbidity risk adjustment methods applied to patient information available from only the index hospitalization, and to information available from both the index and prior hospitalizations. RESULTS: For every comparison made, the level of statistical performance (area under the receiver operating characteristics curve) demonstrated by models using the Elixhauser et al method was superior to that of models using the Deyo et al adaptation method. Although most patients have information available from prior hospital admissions, this additional information yields only small improvements in the performance of models using either comorbidity risk adjustment method. CONCLUSIONS: Better discrimination is achieved with the Elixhauser et al method using only information from the index hospitalization than is achieved with the Deyo et al adaptation using information from all identified hospital admissions. Both comorbidity risk adjustment methods achieve their best performance when information from the index hospitalization and prior admissions is separated into independent indicators of comorbid illness.     

Increased Circulating Copeptin Levels Are Associated with Vaso-Occlusive Crisis and Right Ventricular Dysfunction in Sickle Cell Anemia

ObjectiveVaso-occlusive crisis (VOC) is a common clinical manifestation of sickle cell anemia (SCA) and is associated with increased proinflammatory mediators. Copeptin is the C-terminal part of the prohormone for provasopressin and seems clinically relevant in various clinical conditions. Right ventricular (RV) dysfunction significantly appears in SCA patients due to pulmonary hypertension. This study aimed to investigate the association of copeptin levels in VOC patients and evaluate RV dysfunction.Materials and MethodsA total of 108 patients were enrolled in the study. Twenty-eight SCA patients in steady state (30.2 ± 0.9 years), 25 SCA patients in VOC (36.8 ± 11.8 years), and 55 healthy individuals (31.9 ± 9.4 years) with HbAA genotype were included. Clinical, echocardiographic, and laboratory data were recorded. ELISA was used for the determination of serum levels of copeptin.ResultsVOC patients had significantly higher copeptin level compared both with controls and SCA subjects in steady state (22.6 ± 13.0 vs. 11.3 ± 5.7 pmol/L, 22.6 ± 13.0 vs. 12.4 ± 5.8 pmol/L, p = 0.009 for both). Additionally, the copeptin level was significantly higher in SCA patients with RV dysfunction than those without RV dysfunction (23.2 ± 12.2 vs. 15.3 ± 9.5 pmol/L, p = 0.024). Multiple logistic regression analysis revealed that high-sensitivity C-reactive protein and copeptin levels were found to be associated with VOC.ConclusionThis study showed that copeptin and hs-CRP levels were increased in patients with VOC, and it was found that RV dysfunction was more common in SCA patients with VOC than in the control group. Copeptin can be considered for use as a potential biomarker in predicting VOC crisis in SCA patients and in the early detection of patients with SCA who have the potential to develop RV dysfunction.     

Effects of hydroxyurea treatment on cerebral oxygenation in adult patients with sickle cell disease: an open-label pilot study

BACKGROUND: In patients with sickle cell disease (SCD), cerebral oxygen saturation (rSO(2)) has been reported to be below normal and to increase after red blood cell transfusion. OBJECTIVE: This study was designed to determine the effects of long-term and short-term hydroxyurea (HU) treatment on cerebral oxygenation in patients with SCD. METHODS: This open-label pilot study was conducted at the Department of Anesthesiology and the Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC. Adult African American outpatients with SCD and hemoglobin (Hb) genotype HbSS (homozygous sickle Hb) who were receiving long-term (>6 months) HU treatment (15-30 mg/kg . d PO) or who had never received this treatment (control group) were enrolled. Patients in the treated and control groups were matched for age, sex, race, and Hb genotype. Cerebral oximetry (near-infrared spectroscopy) was performed to determine rSO(2) index. In a separate analysis to determine the effects of short-term HU treatment on cerebral oxygenation, hospitalized patients with SCD and vaso-occlusive crisis (VOC)receiving long-term therapy with HU were enrolled. We performed cerebral and pulse (fingernail) oximetry to determine rSO (2)index and arterial oxygen saturation (SpO(2)) after the administration of a single oral dose of HU (500-mg tablet) alone and again after dosing concomitantly with inhaled oxygen. RESULTS: The study enrolled 11 patients in the HU group (6 women, 5 men; mean [SD] age, 37 [8] years) and 20 controls (8 women, 12 men; mean [SD] age, 35 [6] years). Mean (SD) rSO(2) index was significantly increased (but still low) in patients receiving long-term HU treatment compared with controls (46.1% [6.6%] vs 41.2% [7.6%]; P< 0.025). Hb concentration (9.6 [1.4] g/dL vs 8.5 [1.2] g/dL; P< 0.027), hematocrit (28% [3%] vs 24% [4%]; P < 0.028), and mean corpuscular volume (102% [7%] vs 89% [8%]; P < 0.027) also were significantly higher in the HU group compared with controls. In 8 patients with SCD and VOC (6 men, 2 women; mean [SD] age, 28 [5] years), single-dose HU, either alone or in combination with inhaled oxygen, did not significantly affect cerebral oxygenation, and SpO(2) failed to correlate with rSO(2) index in these patients. CONCLUSIONS: The results of this open-label pilot study in patients with SCD suggest that the low cerebral oxygenation in these patients is significantly improved but not normalized with long-term HU treatment. A single dose of HU, either alone or in combination with inhaled oxygen, did not appear to influence cerebral oxygenation in patients with VOC.     

Pancreaticopleural fistula,a rare mediastinal emergency

A pancreaticopleural fistula (PPF) is a rare condition that causes thoracic symptoms such as dyspnea and chest pain secondary to exudative pleural effusions. While PPF is a very rare complication with only 52 cases reported between 1960 and 2007, they typically occur in patients who are male, middle aged, and have a history of chronic alcohol use and chronic pancreatitis (Aswani and Hira, 2015; Francisco et al., n.d.; Valeshabad et al., 2018; Ali et al., 2009). The fistula between the pancreas and pleural cavity causes large, rapidly accumulating, and recurrent pleural effusions which cause symptoms that can be difficult to differentiate from other acute thoracic pathologies (Francisco et al., n.d.). As a result, it is essential that providers have a high index of suspicion for PPF in these appropriate populations. We present a case study to review the typical presentation, pathophysiology, and current approach to treatment of PPF. This case is unique as the patient had no known risk factors. Due to limited data on this topic, there are no evidence-based guidelines on this topic, leaving a variety of case reports to inform clinical management in the emergency department.     

Admission and length of stay due to painful vasoocclusive crisis in children

Purpose

To identify demographic, clinical, and laboratory characteristics associated with admission and a longer length of stay (LOS) due to vasoocclusive crisis (VOC) in children with sickle cell disease (SCD).

Methods

Retrospective chart review at a large tertiary pediatric center. Patients younger than 18 years with VOC due to SCD presenting to the emergency department were included. We performed multivariate regression analyses to predict characteristics associated with admission and LOS of 4 days or more.

Results

A total of 428 visits for VOC were documented in 2005 to 2006. In a multivariate regression analysis higher pain score at triage (P < .001), older age (P = .04), and increased systolic blood pressure (P = .02) were predictors of admission. Higher pain score at triage (P = .046), older age (P = .002), increased polymorphonuclear count (P = .02), and homozygous SCD type (P = .03) were associated with prolonged hospital LOS.

Conclusion

These characteristics will help healthcare providers predict and plan admission and management of children with SCD.     

Biochemical and therapeutic effects of Omega-3 fatty acids in sickle cell disease

Sickle cell disease (SCD) is a hematologic disorder with complex pathophysiology that includes chronic hemolysis, vaso-occlusion and inflammation. Increased leukocyte-erythrocyte-endothelial interactions, due to upregulated expression of adhesion molecules and activated endothelium, are thought to play a primary role in initiation and progression of SCD vaso-occlusive crisis and end-organ damage. Several new pathophysiology-based therapeutic options for SCD are being developed, chiefly targeting the inflammatory pathways.Omega−3 fatty acids are polyunsaturated fatty acids that are known to have effects on diverse physiological processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the principal biologically active omega-3 fatty acids. The therapeutic effects of DHA and EPA on chronic inflammatory disorders and cardiovascular diseases are well recognized. The therapeutic effects of omega-3 fatty acids are attributed to their anti-inflammatory and anti-thrombotic eicosanoids, and the novel class of EPA and DHA derived lipid mediators: resolvins, protectins and maresins.Blood cell membranes of patients with SCD have abnormal fatty acids composition characterized by high ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (high omega-6/omega-3 ratio). In addition, experimental and clinical studies provide evidence that treatment with DHA does confer improvement in rheological properties of sickle RBC, inflammation and hemolysis. The clinical studies have shown improvements in VOC rate, markers of inflammation, adhesion, and hemolysis. In toto, the results of studies on the therapeutic effects of omega-3 fatty acids in SCD provide good body of evidence that omega-3 fatty acids could be a safe and effective treatment for SCD.