Crisis In Sickle Cell Disease Research Articles

Phytomedicines (medicines derived from plants) for sickle cell disease.

Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an update of a Cochrane Review first published in 2004, and updated in 2010, 2013, and 2015. To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International StandardRandomised Controlled Trial NumberRegister (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 10 April 2017; ISRCTN: 26 July 2017; AMED: 24 August 2017; ClinicalTrials.gov: 02 August 2017; and the WHO ICTRP: 27 July 2017. Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. Both authors independently assessed trial quality and extracted data. Two trials (182 participants) and two phytomedicines Niprisan® (also known as Nicosan®) and Ciklavit® were included. The Phase IIB (pivotal) trial suggests that Niprisan® was effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not affect the risk of severe complications or the level of anaemia (low-quality evidence). No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises (low-quality evidence), and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in the management of people with sickle cell disease and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit®. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in sickle cell disease. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines used in managing sickle cell disease.

Sickle cell disease in southwestern Nigeria: assessment of knowledge of primary health care workers and available facilities.

Patients with sickle cell disease (SCD) benefit optimally from comprehensive care. In Nigeria, despite the huge burden, involvement of community health workers (CHWs) in the management of SCD is poor. This community-based study assessed SCD-related knowledge of 182 CHWs from the 46 primary health care (PHC) centres in Ilesa, southwestern Nigeria. Available facilities and management practices for SCD care at these centres were also evaluated using pretested self-administered questionnaires and observational checklists. The majority of CHWs (167/182 [91.8%]) knew that SCD is an inheritable blood disorder. However, only 32.4% and 26.4% knew that SCD can be diagnosed in the prenatal and neonatal periods, respectively. Also 37.4%, 49.5% and 67.6% knew about the role of chemoprophylaxis (folic acid/penicillin), adequate fluids and malaria prevention, respectively, in SCD care. Overall, 37.9% had good knowledge on the nature and care of the disease. Just 2/46 (4.3%) PHC centres treat patients with SCD. SCD-targeted nutritional counselling and referral to secondary/tertiary hospitals were poor and unorganized. No centre offered SCD screening, home visits or recordkeeping. The level of SCD care and knowledge of CHWs at PHC centres in southwestern Nigeria of early SCD diagnosis and crisis prevention is poor. CHWs should be regularly trained and equipped for basic SCD management, including early detection, crisis prevention, prompt referral and provision of basic genetic counselling, to dispel associated myths and stigma.

Estimation of cognitive brain activity in sickle cell disease using functional near-infrared spectroscopy and dynamic systems modeling

Estimation of cognitive brain activity in sickle cell disease using functional near-infrared spectroscopy and dynamic systems modeling

Coagulation Changes in Children with Sickle Cell Anaemia during Painful Crises and Steady State at Federal Medical Centre Abeokuta, Nigeria

Background: The pathophysiology of vaso-occlusive crises in sickle cell anaemia (SCA) is multifactorial and hypercoagulability is believed to play a role. The association between hypercoagulabilty and vaso-occlusive disease has been extensively studied in adult SCA patients, there is however paucity of data on the subject regarding paediatric SCA. Objective: This study set out to determine the presence of hypercoagulable states specifically in paediatric SCA subjects through quantification of specific coagulation markers during painful crises and steady state. Methodology: The study was a hospital- based longitudinal study carried out between May and October 2015 at Federal Medical Center, Abeokuta, Nigeria. Fifty SCA subjects were consecutively recruited during painful crises and followed up into their respective steady states. Twenty-five subjects with HbAA phenotype served as controls. Assays of coagulation markers, D-dimer and prothrombin fragment (F1 2) were carried out by sandwich ELISA method using MyBiosource？ D-dimer and F1 2 ELISA kits. Results: Mean D-dimer level was 7358 ± 4354.33 ng/ml in the SCA subjects during painful crises, 5509 ± 3506.2 ng/ml during steady state, and 800 ± 1874.14 ng/ml in HbAA controls. Mean (F1 2) level was 0.84 ± 0.43 nmol/l in the SCA subjects during painful crises, 0.64 ± 0.25 nmol/l during steady state, and 0.41 ± 0.28 nmol/l, in HbAA controls. The mean values of both coagulation markers assayed were significantly higher during painful crises than at steady state (P = 0.002), while steady state values were also significantly higher than that of haemoglobin AA individuals (P = 0.001). Conclusions: This study suggests the presence of hypercoagulable states in paediatric SCA during steady state which is exacerbated during painful crises. The clinical imports of this finding require further elucidation.

Relative adrenal insufficiency in adults with sickle cell disease.

Rheological modifications observed in sickle cell anemia are associated with ischemic complications that can cause target organ functional impairment. The objective was to investigate adrenal function of adult patients with sickle cell disease. In this cross-sectional study conducted in a tertiary referral hospital of the capital city of Cameroon, we enrolled ten crisis-free adult patients with sickle cell disease (SCD) and ten age- and sex-matched healthy individuals. We assessed adrenal function by testing basal cortisol levels and 60 min after tetracosactide (Synacthen®) injection using immuno-chemiluminescence method. Post-stimulatory cortisol was defined as primary endpoint and secondary endpoints include basal cortisol levels, post-stimulatory cortisol increments and the fold increase of cortisol one hour after stimulation. Sickle cell patients had an impairment of adrenal function despite no significant difference between patients’ and controls’ for basal or post-stimulatory cortisol levels. In fact, one patient in two failed to achieve a two-fold increase in cortisol levels after stimulation (5/10) as opposed to 1 in 10 in the control population (1/10), P = 0.070. The percent increment of cortisol after stimulation was lower in patients versus controls (133 vs 207, P = 0.047). Relative adrenal insufficiency is frequent in sub-Saharan adult patients with sickle cell disease despite normal basal cortisol levels. Our results suggest that adrenal function require further investigation during SCD crises as these represent an important stress and may worsen the prognosis.

Correlation Between the Frequency of Painful Crises in Sickle Cell Anemia and the Biomarkers of Inflammation, Endothelial Dysfunction, Coagulation Activation and Bone Metabolism

Objective: Sickle cell anemia is a widespread inherited hemolytic anemia, characterized by chronic hemolysis, infections, recurrent occlusion of the microcirculation and painful crises. In this cross-sectional study, we investigated the correlation between biomarkers of inflammation, endothelial dysfunction, coagulation activation and bone metabolism, with the frequency of painful crisis in sickle cell anemia adult patients, to understand the potential role of these biomarkers in the management of sickle cell anemia.
 Methods: Sixty-three sickle cell anemia patients were enrolled in this study. They were divided into three groups based on the frequency of pain crises to mildly, moderately, and severely affected. Twenty-five healthy volunteers were enrolled as controls. Plasma levels of different biomarkers were tested, including tumor necrosis factor alpha, soluble intercellular adhesion molecule-1, D-dimer, sclerostin, and nitric oxide.
 Results: Tumor necrosis factor alpha, soluble intercellular adhesion molecule-1, and D-Dimer plasma levels were significantly higher in sickle cell anemia patients when compared to the controls, while nitric oxide levels were notably lower in the patients' group. Sickle cell anemia patients with severe pain showed higher tumor necrosis factor alpha, soluble intercellular adhesion molecule-1 and D-dimer levels than those mildly and moderately affected with painful crisis. Positive correlations were observed between all measured biomarkers and the frequency of the painful crisis, except for nitric oxide, which showed a negative correlation.
 Conclusion: Tumor necrosis factor alpha, soluble intercellular adhesion molecule-1, nitric oxide, and D-dimer can be used to assess sickle cell anemia severity and prognosis, and thus may affect determining appropriate management strategies.

Mentha pulegium crude extracts induce thiol oxidation and potentiate hemolysis when associated to t-butyl hydroperoxide in human's erythrocytes.

Mentha pulegium (Lamiaceae) tea has been used as a traditional medicine; however, the modulatory effect of M. pulegium extracts on damage to human erythrocytes associated to t-butyl hydroperoxide (t-BHP) exposure remains to be investigated. Accordingly, we perform this study in order to test the hypothesis that aqueous and ethanolic extracts of M. pulegium could modulate the hemolysis associated to t-BHP exposure, non-protein thiol (NPSH) oxidation and lipid peroxidation (measured as thiobarbituric acid reactive substances - TBARS) in human erythrocytes. Samples were co-incubated with t-BHP (4 mmol/L) and/or aqueous or ethanolic extracts (10-1000 mg/mL) during 120 min to further analysis. We found that both extracts, when associated to t-BHP, potentiate NPSH oxidation and hemolysis. Moreover, both extracts significantly prevents against t-BHP-induced TBARS production. A significant correlation among hemolysis and NPSH levels was found. Taking together, our data points that the association of M. pulegium extracts with t-BHP culminates in toxic effect to exposed erythrocytes, besides its protective effect against t-BHP-induced TBARS production. So, we infer that the use of this extract may exert negative effect during painful crisis in sickle cell anemia. However, more studies are still necessary to better investigate/understand the mechanism(s) involved in the toxic effect resultant from this association.

Protective Role of HO-1 Expressing CD16+ Patrolling Monocytes Against Hemolysis-Induced Endothelial Damage and Vaso-Occlusive Crisis in Sickle Cell Disease

Causing leukocyte activation and upregulation of adhesion molecules on endothelial cells. CD16+ monocytes, also known as endothelial patrolling monocytes, normally scavenge the damaged cells and debris from the vasculature. As compared to other monocyte subsets or immune cell types, the CD16+monocyte subset expresses higher levels of the anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Given the role of CD16+ monocytes as scavengers of debris on endothelial cells, we tested the hypothesis that this subset may protect SCD vasculature from the ongoing hemolytic insult through expression of high levels of HO-1. We found roughly 35% of circulating CD16+ monocytes from SCD patients expressed very high levels of HO-1 as compared to 5% in healthy controls. The HO-1hi SCD monocytes expressed significantly (30%) less TNF-a compared to HO-1lo monocytes following stimulation, consistent with anti-inflammatory effects of HO-1. We hypothesized that uptake of free hemoglobin/heme was responsible for high HO-1 expression levels in SCD CD16+ monocytes. To test this, healthy donors (HDs) or SCD patient monocytes were treated with different doses of free heme or hemolysed RBCs. We found dose-dependent HO-1 induction (five-fold at 20mM heme) in purified CD16- monocytes, but surprisingly none in CD16+ subset. However, upon co-culture with human umbilical vein endothelial cells (HUVEC), continuous or prior exposure to heme induced HO-1hi expression exclusively in CD16+ monocytes (5 fold in HD and further two fold in SCD compared to non-heme treated cocultures, p<0.001). Using imagining flow cytometric analysis, we found marked increase in uptake of heme-exposed endothelial cell-derived material by CD16+ monocytes (HD: 2% to 13% ± 3%; in SCD: 20% ± 3% to 30% ± 4%, p< 0.001) but none by CD16- monocytes. Our transwell studies demonstrated that cell-cell contact between CD16+ monocytes and heme-exposed HUVEC was required for HO-1hi expression. We found roughly 4-fold increase in expression of phosphatidylserine (PS, annexin V+), ICAM-1 and vCAM-1 on heme-treated HUVEC cells. Antibody blocking studies identified PS moieties as well as ICAM-1 as key molecules involved in monocyte-HUVEC interactions that mediated HO-1hi induction, suggesting that high levels of HO-1 expression in SCD CD16+ monocytes is in part the result of attachment to and engulfment of apoptotic, activated endothelial cells damaged by heme. SCD patients suffer from vaso-occlusive crisis (VOC), resulting from increased attachment of SCD RBCs to damaged and activated endothelium. We hypothesized that inadequate numbers or lower HO-1hi levels in CD16+ monocyte will predispose SCD patients to episodes of VOC due to decreased removal by CD16+ monocytes of damaged endothelial and sickle RBCs. Amongst SCD patients receiving chronic transfusions, we found a two-fold lower frequency of circulating CD16+ monocytes and half the numbers of CD16+HO-1hi monocytes in patients with a recent history of VOC episode as compared to those without VOC (p< 0.01); the former group also expressed higher levels of circulating sVCAM-1 (997 ± 210 vs 765 ± 236 ng/m, p=0.02), a marker of endothelial activation. To formally test the role of patrolling monocytes in endothelial damage induced by SCD RBCs and heme, we injected RBCs from Townes SCD mice alone or after 24hrs with heme into Nr4a1-knockout mice which have a selective loss of patrolling monocytes. Immunofluorescence analysis of liver vasculature showed a 3 fold increase in the activated endothelial marker, ICAM-1 within 24hrs following injection of sickle RBCs and two-fold increase in circulating sVCAM-1 levels in mice treated with sickle RBC plus heme (p <0.001). Transfer of HO-1+ patrolling monocytes (LY6Clo), but not a classical monocyte subset (LY6C+) reversed activated endothelial phenotype, indicating that patrolling monocytes can inhibit SCD-induced endothelial activation. Altogether, these data suggest that SCD patrolling monocytes remove hemolysis-damaged endothelial cells, resulting in HO-1 upregulation and dampening of vascular inflammation. Perturbations in CD16+ monocyte numbers resulting in lower local HO-1 levels can predispose SCD patients to VOC, thus identifying HO-1+ patrolling monocytes as key players in VOC pathophysiology and as therapeutic targets. DisclosuresNo relevant conflicts of interest to declare.

Clinical and genetic factors are associated with pain and hospitalisation rates in sickle cell anaemia in Cameroon.

We aimed to investigate the clinical and genetic predictors of painful vaso-occlusive crises (VOC) in sickle cell disease (SCD) in Cameroon. Socio-demographics, clinical variables/events and haematological indices were acquired. Genotyping was performed for 40 variants in 17 pain-related genes, three fetal haemoglobin (HbF)-promoting loci, two kidney dysfunctions-related genes, and HBA1/HBA2 genes. Statistical models using regression frameworks were performed in R® . A total of 436 hydoxycarbamide- and opioid-naïve patients were studied; median age was 16years. Female sex, body mass index, Hb/HbF, blood transfusions, leucocytosis and consultation or hospitalisation rates significantly correlated with VOC. Three pain-related genes variants correlated with VOC (CACNA2D3-rs6777055, P=0·025; DRD2-rs4274224, P=0·037; KCNS1-rs734784, P=0·01). Five pain-related genes variants correlated with hospitalisation/consultation rates. (COMT-rs6269, P=0·027; FAAH-rs4141964, P=0·003; OPRM1-rs1799971, P=0·031; ADRB2-rs1042713; P<0·001; UGT2B7-rs7438135, P=0·037). The 3·7kb HBA1/HBA2 deletion correlated with increased VOC (P=0·002). HbF-promoting loci variants correlated with decreased hospitalisation (BCL11A-rs4671393, P=0·026; HBS1L-MYB-rs28384513, P=0·01). APOL1 G1/G2 correlated with increased hospitalisation (P=0·048). This first study from Africa has provided evidence supporting possible development of genetic risk model for pain in SCD.

Implications of a paediatrician-psychologist tandem for sickle cell disease care and impact on cognitive functioning.

Findings suggest that the concept of a "partnership practice" can improve children's ability to grapple with SCD and is a promising approach for long-term care of SCD. What is Known: • Painful crises of sickle cell disease are unpredictable and appear in early childhood • Stress as well as the complex psychological and intercultural issues associated with SCD may aggravate the children's symptoms • Standard pediatric care and research deal primarily with medical issues What is New: • Evidence-based research examining the psychological repercussions of SCD in pediatric treatment as well as the parental distress • First study using standardized culture-free tools • Cognitive functioning improves under an innovative "partnership" model.

Acute chest syndrome among children hospitalized with vaso-occlusive crisis: A nationwide study in the United States.

Acute chest syndrome (ACS) is a common complication among pediatric inpatients with sickle cell disease and vaso-occlusive crisis (VOC). However, little is known about the factors associated with ACS complication. The present study assessed the epidemiological features of children hospitalized with VOC and ascertained factors associated with ACS complication. Hospital discharge records of patients with VOC aged<20 years were obtained for the years 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates with respect to gender and race/ethnicity in the United States. Multivariable logistic regression was conducted to ascertain factors associated with ACS complication after adjusting for patient and hospital characteristics. The total annual hospitalizations for VOC increased from 22,511 in 2003 to 24,292 in 2012. Multivariable logistic regression analysis showed that children aged 5-9years had 2.59 times higher odds of ACS than children aged 15-19years (95% confidence interval [CI], 2.32-2.88). Comorbidity of asthma (odds ratio [OR], 1.42; 95% CI, 1.31-1.54) and obstructive sleep apnea (OR, 1.70; 95% CI, 1.31-2.20) were associated with ACS development. ACS was also associated with male gender and the summer and fall seasons. We reported nationwide estimates of the annual hospitalization rate for childhood VOC in the United States and demonstrated the major risk factors associated with ACS complication. Vigilance is needed for ACS complications in high-risk VOC admissions.

Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease.

Adenosine A2A receptor (A2AR) agonists have been shown to decrease tissue inflammation induced by hypoxia/reoxygenation in mice with sickle cell disease (SCD). The key mediator of the A2AR agonist's anti-inflammatory effects is a minor lymphocyte subset, invariant natural killer T (iNKT) cells. We tested the hypothesis that administration of an A2AR agonist in patients with SCD would decrease iNKT cell activation and dampen the severity of vaso-occlusive (VO) crises. In a phase 2, randomized, placebo-controlled trial, we administered a 48-hour infusion of the A2AR agonist regadenoson (1.44 μg/kg per hour) to patients with SCD during VO crises to produce a plasma concentration of ∼5 nM, a concentration known from prior studies to suppress iNKT cell activation in SCD. The primary outcome measure was a >30% reduction in the percentage of activated iNKT cells. Ninety-two patients with SCD were randomized to receive a 48-hour infusion of regadenoson or placebo, in addition to standard-of-care treatment, during hospital admission for a VO crisis and had analyzable iNKT cell samples. The proportion of subjects who demonstrated a reduction of >30% in activated iNKT cells was not significantly different between the regadenoson and placebo arms (43% vs 23%; P = .07). There were also no differences between regadenoson and placebo groups in length of hospital stay, mean total opioid use, or pain scores. These data demonstrate that a low-dose infusion of regadenoson intended to reduce the activity of iNKT cells is not sufficient to produce a statistically significant reduction in such activation or in measures of clinical efficacy. This trial was registered at www.clinicaltrials.gov as #NCT01788631.

Subdissociative intranasal ketamine plus standard pain therapy versus standard pain therapy in the treatment of paediatric sickle cell disease vaso-occlusive crises in resource-limited settings: study protocol for a randomised controlled trial

IntroductionPediatric sickle cell disease, highly prevalent in sub-Saharan Africa, carries great morbidity and mortality risk. Limited resources and monitoring make management of acute vaso-occlusive crises challenging. This study aims to...

Low-dose methotrexate in sickle-cell disease: a pilot study with rationale borrowed from rheumatoid arthritis

BackgroundInflammation is a major feature of sickle cell disease (SCD). Low-dose methotrexate (MTX) has long been used in chronic inflammatory diseases. This pilot study examined the MTX effect on acute vaso-occlusive pain crises (VOC) in SCD patients.MethodsFourteen adults on hydroxyurea with severe and refractory VOC received one intramuscular injection of 10 mg of MTX per week for 12 weeks. A single weekly dose of 5 mg of leucovorin was administered orally 48 h after each MTX injection. The primary outcome was reduction in number/intensity of acute pain episodes. The secondary outcomes were improvement of quality of life (QOL) and reduction of the inflammatory status.ResultsMTX did not significantly change the median VOC frequency (12 before vs 10.5 during treatment, P = 0.6240) or the median McGill pain index (45 at week 0 vs 39.5 at week 12, P = 0.9311). However, there was a decrease of ≥50% in chronic pain resulting from avascular osteonecrosis (AVN) in 5 out of 7 patients with radiologic evidence of AVN, with the perception of longer pain-free periods. There was a 44.4% median gain in physical function in the SF-36 QOL questionnaire (P = 0.0198). MTX treatment up-regulated two C-X-C motif chemokines (CXCL), CXCL10 (P = 0.0463) and CXCL12 (P < 0.0001), without significant effect on 14 additional plasma inflammatory markers. Adverse events: One individual had fever of unknown origin. Respiratory tract infections were recorded in five patients. Among the latter, one also had dengue fever and another had a central venous line infection and died of pneumonia and septic shock. Three patients with previous history of hydroxyurea-induced hematological toxicity developed low blood platelet counts while receiving simultaneously MTX and hydroxyurea.ConclusionsAlthough MTX did not reduce acute VOC frequency/intensity, it decreased chronic pain and led to QOL improvement.Trial registrationhttp://www.who.int/ictrp/en/ and http://www.ensaiosclinicos.gov.br, RBR-2s9xvn, 19 December 2016, retrospectively registered

Body Mass Index and the Association With Vaso-occlusive Crises in Pediatric Sickle Cell Disease.

Children with sickle cell disease (SCD) historically have been underweight and have poor overall growth. Recent studies have demonstrated a trend toward obesity in pediatric SCD populations. Through retrospective chart review of patients with SCD followed at our center, we collected patient's data, including body mass index (BMI), weight percentiles, sickle cell genotype, baseline hemoglobin, medical and psychiatric comorbidities, 25-hydroxy vitamin D level, treatment with hydroxyurea, and chronic transfusions. We identified hospitalizations to St. Christopher's Hospital for vaso-occlusive crisis (VOC) and duration of hospitalization and intravenous opioid use were recorded. Student t test, Mann-Whitney U test, and analysis of variance were used to examine associations between variables and frequency and duration of hospitalizations for VOC. Among 328 patients with SCD, overweight and obese children constituted 19% of hospitalized and nonhospitalized patients. BMI status did not influence frequency (P=0.90) or duration of hospitalization (P=0.65) for VOC. Obesity was more associated with HbSC than HbSS (P=0.025) genotype. Our study did not demonstrate an association between extremes of BMI of patients and hospitalization for VOC. Considering current trend toward obesity, further prospective and interventional research are required to define the effects of extremes of BMI on pain crises in SCD.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

BackgroundThe up-regulation of P-selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.MethodsIn this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell–related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.ResultsA total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.ConclusionsIn patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361.)

Effect of &lt;i&gt;Carica papaya&lt;/i&gt; (Linn) aqueous leaf extract on pharmacokinetic profile of ciprofloxacin in rabbits

Purpose: To investigate the fate of ciprofloxacin, after concomitant administration with the aqueous leaf extract of Carica papaya, which herbal practitioners in Nigeria have found helpful in the treatment of painful crisis in sickle cell anaemia (SCA) patients.Method: Thirteen rabbits were fasted for 12 h and given by oral route 20 mg/kg ciprofloxacin (control group); after a 3-week crossover period, the animals were given 500 mg/kg aqueous extract of Carica papaya followed by 20 mg/kg ciprofloxacin (treatment group). Blood samples were collected over a period of 0 - 24 h post-dosing, and pharmacokinetic profile of ciprofloxacin in plasma sample determined using a validated high performance liquid chromatography (HPLC) method.Results: Time to attain maximum plasma ciprofloxacin concentration (Tmax), lag time and clearance (CL/F) were higher in the treated group; all other pharmacokinetic parameters showed significant decrease in the treated group (p &lt; 0.005) compared to the control group. The slow rate of elimination of ciprofloxacin in the control group (0.32 ± 0.11 h-1) compared to the treated group (0.21 ± 0.07 h-1) was not due to kidney impairment as plasma creatinine level indicated that kidney function was within normal range (0.68 ± 2.78 mg/dl).Conclusion: The results of the study show that there is interaction between ciprofloxacin and Carica papaya. This interaction can be avoided by taking ciprofloxacin at least 3 h prior to administration of the leaf extract of C. papaya.Keywords: Carica papaya, Ciprofloxacin, Sickle cell anaemia, Herb-drug interaction, Pharmacokinetics

A Prospective Emergency Department Quality Improvement Project to Improve the Treatment of Vaso-Occlusive Crisis in Sickle Cell Disease: Lessons Learned

Guidelines recommend rapid, aggressive management of vaso-occlusive crisis (VOC) for patients with sickle cell disease (SCD). A large prospective research and quality improvement (QI) project was conducted to measure changes in clinical outcomes in two EDs-academic medical centers with emergency medicine residency programs and Level 1 trauma centers-during a 2.5-year time period (October 2011-March 2014). A QI team used a Plan-Do-Study-Act approach to modify and implement changes to opioid analgesic protocols for the emergency department (ED) treatment of VOC. Data were collected quarterly; the team reviewed the results and made modifications to improve outcomes. A structured health record review was conducted to assess clinical outcomes (10 records/quarter/site). Patient interviews were conducted to measure satisfaction with pain management. Outcomes were compared before (T1) and after (T2) implementation of an electronic health record (EHR). One hundred ninety-six ED health records (118 unique patients, mean age = 32 [standard deviation, 11], 51% male) were analyzed. Before implementation, trends in decreasing time to initial analgesic administration were noted. There was a statistically significant increase in arrival to administration of first analgesic time between T1 and T2 at Site 1 but not at Site 2. Neither site showed significant changes in time between the administration of the first and second opioid doses, total opioid dose administered, or patient satisfaction. While QI efforts initially shortened door-to-analgesic times, these gains were not sustained. The lessons learned can help other EDs improve the timely delivery of analgesics to patients with SCD.

PEARL-Pain in Early Life: A New Network for Research and Education.

Andersen, Randi Dovland MSc, RN; Axelin, Anna PhD, RN; Kristjánsdóttir, Guðrún PhD, RN; Eriksson, Mats PhD, RN Author Information

The Bone Pain Crisis of Sickle Cell Disease and Malaria: Observations from Gujarat, India.

Background:Sickle cell disease is a common problem across central India, but its clinical features may differ from that in African populations. There is a need to define the features of sickle cell disease in India, and the current study addresses some features of the bone pain crisis.Objectives:The objective of the study was to describe the epidemiology of the bone pain crisis of sickle cell disease in Gujarat and explore the relationship with infection by Plasmodium vivax.Materials and Methods:This was a prospective review of all admissions in patients with sickle cell disease to a private pediatric institution in Bardoli, Gujarat, in the year 2015. Hemoglobin electrophoresis of all patients was consistent with homozygous sickle cell disease, but family studies indicated that at least seven cases had the severe sickle cell-beta + thalassemia presumed to be the common IVS1-5G>C mutation. Clinical, hematological, and parasitological features were recorded.Results:There were 914 admissions among 654 patients who had between one and seven admissions. The bone pain crisis accounted for 763 (83%) of admissions and increased between July and October coinciding with the monsoon period. Blood smears were examined for malarial parasites in 811 admissions and were positive for P. vivax in 73% patients. There was no evidence that P. vivax infections varied with the cause of admission or increased during the monsoon period.Conclusions:There was a high prevalence of P. vivax infection in hospital admissions of sickle cell patients, but the data did not support an etiological role in the bone pain crisis. A trial of malarial prophylaxis might determine its effect on the clinical features and outcome of sickle cell disease.