Background: Renal disease is a common end organ complication of sickle cell disease(SCD). Risk factors of sickle cell nephropathy include age, genotype, and anemia. We have investigated and discovered Lower Hemoglobin Oxygen Saturation levels associated with microalbuminuria. To further investigate this, we investigated a patient’s history of asthma as a risk factor of renal disease. Asthma has been linked to increased mortality in adult and children with SCD from the National Cooperative SCD Study Group. In our ongoing International CASIRE Renal Cohort study, we investigated the clinical history of asthma and laboratory correlates of albuminuria and proteinuria as measured by Urine Protein/Creatinine and Urine Albumin/Creatinine . Methods: 538pediatric and adult SCD (3-59 y/o) patients were recruited at baseline from 6 Centers (USA: Univ of Michigan, Case Medical Center/Rainbow Babies, Albert Einstein-Montefiore Medical Center, Univ of Connecticut; Italy: Univ. of Padova, Univ of Naples;). Clinical history and laboratory studies, including Pain crisis patterns, SBP, DBP, BMI, CBC, Serum Crt, Urine ph, Urine SG were collected. For this report, we concentrated on patient’s comorbidities and sickle cell medical history, specifically pain crisis patterns, acute chest history and asthma. Urine Microalbumin/Crt(UMA) (mg/gm) was obtained in 172 patients and we categorized patients into No Albuminuria: (No UMA)<30mg/gm and Albuminuria(UMAlbum): Microalbuminuria(MicroUMA) 30-299mg/gm and Macroalbuminuria (MacroUMA)>300mg/gm.334 subjects answered the question of medical history of asthma and of those 172 had Urine Microalbumin (UMA) levels. 75% of SCD-Asthma group (N=56) and 78% of SCD-NoAsthma group (N=204) had severe SCD (SS or SBeta Zero). Children (<18y/o) comprised 58% of the SCD-Asthma group (N=43) and 62% of the SCD-NoAsthma group (N=161). Mean age was 16 y/o in both SCD–Asthma and SCD-NoAsthma Groups. Results: No Albuminuria (NoUMAlbum) was reported in 80% (138/172) while Albuminuria(UMAlbum) was recorded in 20% (34/172) of the Cohort. Severe SCD pts represented 91% (n=33) of the Albuminuria pts. Adult UMA levels were higher (mean=61) than Peds UMA levels (mean=22) (p=0.025). Patients with History of Asthma had higher mean UMA levels ( 94 vs 21, p=0.005). Further, a history of asthma was associated with higher mean UMA levels (122 vs 23, p=0.003) within the Severe Genotype group (p=0.002), within all Pediatric SCD patients ( 60 vs 17, p=0.002), and within Severe Pediatric SCD patients ( 68 vs 19, p=0.004) (One Way Anova). Within the Medical history, BMI in the underweight range and a history of priapism were associated with elevated UMA levels. Conclusions: Age and Severe Genotype was associated with Albuminuria. A history of asthma was strongly associated with renal disease in Pediatric SCD patients in addition to a very strong association within Pediatric Severe Genotype patients. Optimal control of asthma could possibly mitigate the risk of kidney disease with SCD patients. A more in-dept analysis of patient’s history of asthma would provide stronger evidence of these findings. Abstract source

Background: Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a multi-national Phase 3 trial to assess the efficacy of prasugrel for the prevention of vaso-occlusive crisis (VOC) as a composite endpoint of painful crisis or acute chest syndrome in children and adolescents aged 2-18 years with sickle cell anemia (SCA). Despite a trend toward fewer VOCs in the prasugrel-treated oldest age group (12-18 years), DOVE did not meet its primary endpoint. This was the first multinational prospective study of diary-reported pain rate and intensity in children and adolescents with SCA. Aim of current study: This sub-study evaluated VOC events (as defined by DOVE), analgesic use, and the rate, intensity, and perception of pain by geographical region and age group. Data: During the DOVE study, participants who were 4 years or older used daily diaries to report pain rate and intensity, and analgesic use. Rates of pain and analgesic use were calculated for each patient by summing the number of days with any pain or analgesic use reported divided by the number of non-missing diary entries from randomization to 9 months. Mean pain intensity was calculated similarly, but days in which participants reported pain of “0” were not included. Pain rate and intensity were evaluated only for participants 7 years or older. Type of analgesic use (opioid vs non-opioid) was also evaluated in all participants. Treatment arms (prasugrel-treated and untreated patients) were combined for the current analysis, as justified by the lack of a statistically significant treatment effect. Data were analyzed by univariable and multivariable methods. Results: There was no association between baseline hematology labs or lactic dehydrogenase levels and pain rate or intensity. In multivariable analysis, older participants (aged ≥12 years) reported more frequent pain than younger participants (p=0.0320). Hydroxyurea (HU) use at baseline did not affect pain rate or pain intensity. The regions of the Americas and West Europe showed higher pain rate and intensity scores than Africa and the Middle East. (Table 1) Opioid use was much higher in the Americas compared with other regions p=0.0002. (Table 2) Conclusions: Pain rates were higher in older children, demonstrating a worsening of pain during the lifespan, which is consistent with previous literature. Pain rate and intensity were similar irrespective of HU treatment; whether this finding reflects increased baseline pain in participants on HU or other causality is unclear. Regional differences in pain rate and intensity were seen. Pain intensity and opioid use were significantly higher in the Americas than in other regions. In contrast, the lowest reported pain rates and intensities were found in Africa. These findings suggest cultural and/or regional differences in SCA pain perception and reporting that require further exploration. The relationship between pain intensity and analgesic treatment practices also needs further study. Abstract source

Background: We undertook a large multisite observational study collecting prospective data on health care utilization of patients with sickle cell disease (SCD). No prospective examination of symptom burden has been undertaken in SCD since the Cooperative Study of Sickle Cell Disease, and none in the modern era, since the widespread adoption of hydroxyurea therapy. The ESCAPED trial aims to compare patient centered outcomes following management of acute painful vaso-occlusive (VOC) events in the emergency department or in the infusion center. Here, we examine acute care utilization patterns in the first 223 subjects who have completed at least 6 months of follow-up and test determinants of utilization. Methods: This is an ongoing, prospective cohort study that is recruiting across four sites (Baltimore, Cleveland, Milwaukee, and Baton Rouge). 500 adults with SCD who live in proximity to one of the study sites are being recruited and followed for 18 months. Data from visits for all acute, uncomplicated VOC are collected by chart review and patient interview. To ensure that acute visits are not missed, subjects are contacted on a monthly basis and where available statewide health information exchanges are queried. We tested for associations between subject characteristics upon enrollment and the number of acute visits during follow up using Poisson regression. Abstract source

Introduction: Acute vaso-occlusive crisis (VOC) is the hallmark clinical complication of sickle cell disease (SCD). VOC involves several mechanisms, including rigid erythrocytes, adhesive blood cells, activated coagulation, activated and dysregulated endothelium, inflammation, and ischemia-reperfusion injury. Surprisingly few data document clinical and laboratory markers that change from steady state to VOC and during the hospital stay, and that predict subsequent rehospitalization. We characterized such markers in this study. Methods: Data were collected as part of a clinical trial of nitric oxide as potential treatment for VOC (DeNOVO). Participants, age >= 10 years requiring hospitalization for VOC, were recruited from 11 academic medical centers at the time of VOC. Length of hospital stay (LOS), change in visual analogue scale (VAS) pain score, and hospital readmission within 30 days were study outcomes. Steady state laboratory values were available in a subgroup of patients for comparison. Differences between admission and steady state laboratory measures and changes in clinical and laboratory parameters from hospital admission to discharge were analyzed by Wilcoxon signed-rank test. Multivariate linear and logistic regression analyses were used to identify the independent predictors of LOS and 30-day readmission risk. Results: 150 recruited patients had a median (interquartile range; IQR) age of 24 (17-33) years; 50% were female, and 91% had HbSS genotype. The median VAS score at time of admission was 7.7 cm which subsided to 3.3 cm at time of discharge (P <0.001). Serum lactate dehydrogenase concentrations (LDH) and neutrophils counts increased from steady state to the time of the VOC (P =< 0.001) and then decreased during the hospital stay (P =< 0.01) (Figure). The median (IQR) LOS was 3.5 (1.9-6.0) days. Longer LOS was predicted by higher admission VAS and serum alkaline phosphatase level, as well as higher increase in respiratory rate during hospital stay (P =< 0.006) (Table). The rate of 30-day hospital/ED readmission was 24%. Longer LOS was associated with lower risk of readmission (OR = 0.65, 95% CI: 0.50-0.86 per day). Other risk factors for readmission were higher serum creatinine at discharge (OR = 5.54, 95% CI: 1.12-27.51 per mg/dL), greater increase in serum alanine aminotransferase (OR = 1.03, 95%CI: 1.01-1.06 per unit increase) and greater cumulative opioid doses (OR = 1.25, 95%CI: 1.11-1.49 per 100 mg) during the index hospitalization. Conclusion: VOC is associated with neutrophilia and increased LDH, consistent with inflammation and hemolysis and/or tissue injury, although of insufficient magnitude to be used as diagnostic criteria. The magnitude of pain and marker of apparent bone involvement predict longer LOS. SCD patients with VOC carry a high burden of readmission risk, which is characterized by higher opioid utilization and earlier discharge from the index hospitalization. These concepts can shape models, especially to reduce readmission rate, to be evaluated in prospective clinical trials. Abstract source

Background: Sickle cell disease (SCD) is associated with vasculopathy in multiple vital organs, which ultimately leads to complications such as stroke, proliferative retinopathy, chronic kidney disease and pulmonary hypertension. Existing studies focus on single organ specific vasculopathy without an emphasis on shared mechanisms and simultaneous progression of vasculopathy in multiple organs. We conducted this retrospective cohort study to determine the onset and progression, as well as sequence of involvement of vasculopathy in the central nervous system (CNS), eye, kidney and lungs of adults with SCD. Methods: Our institutional practice is to perform annual magnetic resonance imaging with magnetic resonance angiography (MRI/MRA, for CNS vasculopathy and silent cerebral infarcts), echocardiography (for tricuspid regurgitant jet velocity > 2.5 m/sec, a surrogate of pulmonary hypertension), retinal examination, and measurement of urinary albumin:creatinine ratio, and serum creatinine in all adults with SCD. All patients were followed until death or last clinical encounter. Data were summarized as counts and proportions. Multivariable logistic regression was used to identify associations of number of organs affected with mortality. Results: We identified 280 adults with SCD followed for a median period of 66 months (interquartile range [IQR] 15.7 to 112 months). Median age was 31.1 (IQR 25.4 to 39.7) years and 49.6% were female. Over half (51.8%) were on hydroxyurea therapy. The prevalence of vasculopathy in different organs was: CNS, 37.8%; retinopathy 26.1%, proteinuria, 20.7% (nephropathy 5.71%); and pulmonary hypertension, 15.36%. There was no evidence of vasculopathy in 103 (36.8%) individuals. Of the remaining 177 (63.2%) adults, vasculopathy was present in one, two, three and all four end organs in100, 55, 18, and 4 individuals respectively. Median age of onset was earliest for CNS vasculopathy [25.42 (IQR 19.31, 38.85)] years followed by retinopathy [28.41 (IQR 23.04, 35.79)] years, proteinuria [31.25 (IQR 25.6, 46.0)] years, and pulmonary hypertension [33.08 (IQR 23.83, 47.17)] years (Figure 1). Mortality rate was 1.69 per 100 patient-years. Patients with vasculopathy affecting 3 or 4 organs had a significantly higher mortality rate than those with 0-2 organs affected by vasculopathy [odds ratio 5.50 (95%CI 4.49-20.35), p=0.007], adjusted for phenotype, age, sex, hydroxyurea therapy, and smoking status. Conclusion: Vasculopathy in SCD occurs in multiple organs simultaneously, with a predisposition to affect the CNS first. These data strongly support that multiple vasculopathy is common, and when present in at least three organs, is associated with earlier mortality. Abstract source

Background: Chronic pain, along with the other physical, emotional, and cognitive manifestations of Sickle Cell Disease (SCD) increases the risk of developing psychological disorders. Studies with limited sample size have suggested that depression occurs at a significantly higher proportion in SCD patients than control groups. In this study we assessed the burden of mood and alcohol dependence disorders in SCD adult patients and their effect on healthcare utilization using a nationwide sample. Methods: Inpatient and outpatient records in the Truven Health MarketScan®Database were used to calculate the prevalence of mental health disorders and hospital utilization in adult SCD patients who sought medical care during 2007 - 2012. The prevalence of mental health disorders were compared to a nationwide sample of African Americans from the Collaborative Psychiatric Epidemiology Surveys (CPES, 2001 - 2003) database. Results: Among 12,394 SCD patients with outpatient claims, the prevalence of mood disorders were 28% and 21% in females and males vs. 6% and 4% in 4,842 participants from the general African American population (all P <0.001). SCD was associated with 4 and 2.5 times higher risk of alcohol use disorders in females and males (all P <0.001). Both types of diagnoses peak at older age (50-59 years) in SCD patients vs. the younger age group (19-29) in general African Americans. Among 44,000 hospital admissions with SCD diagnosis, 47% of patients with a mood disorder were readmitted within 30 days after discharge (OR = 1.48, P <0.001). Mood disorders were associated with 0.5 days longer hospital stay (P <0.001). Neither mood nor alcohol related disorders were associated with higher cost of inpatient care. Conclusion: The high burden of mental health disorders in SCD patients justify the need to include regular screening for mental health disorders for all SCD patients and the provision of early psychological intervention to remit or mitigate symptoms and prevent higher healthcare utilization. Abstract source

Background: Children with severe sickle cell disease (SCD) experience organ damage, poor quality of life, and a risk of premature mortality. Allogeneic bone marrow transplantation (BMT) halts disease progression when stable donor erythropoiesis is established. Myeloablative conditioning (MAC) followed by HLA matched sibling donor BMT is effective, but most patients with SCD lack a matched sibling donor and long term side effects from MAC (e.g., infertility) can be barriers to patient acceptance of BMT. The SCURT trial was designed as a prospective, multicenter phase II trial to evaluate outcomes after HLA matched unrelated donor (MUD) BMT with reduced intensity conditioning (RIC). We hypothesized that an intensely immunosuppressive RIC regimen would be sufficient for donor engraftment and could limit toxicity. The primary endpoint was one year event free survival (EFS) (alive and disease free) ≥75%. All patients were evaluable for the primary endpoint for the purpose of this report. Methods: Children between 3 and 19.75 years of age who had >=1of the following complications stroke, high transcranial doppler velocity, recurrent acute chest syndrome, or significant vaso-occlusive pain crises were eligible. An independent review committee confirmed eligibility. The preparative regimen consisted of alemtuzumab (48 mg) (day -22 to -19), fludarabine (150 mg/m2) (day -8 to -4), and melphalan (140mg/m2) (day -3). Donors and recipients were matched at the HLA allele-level at HLA-A, -B, -C and -DRB1 loci. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus or cyclosporine, methotrexate (7.5 mg/m2) on days +1, +3 and +6, and methylprednisolone (1 mg/kg/day) from day +7, tapered after day +28. Results: Thirty patients were enrolled between 2008 and 2014. One patient was excluded from analysis for a major eligibility violation at the DSMB's recommendation. Twenty-nine patients (16 M, 13F), 5.9-19.3 years old (median 14.0 years) from 19 centers were evaluable with median follow up of 25.2 months (range, 12-61.5 months). All patients recovered neutrophils (median 12 days) and platelets >50x109/L (median 24 days). Graft rejection (GR) in 3 patients (10%) occurred before day +100, and was followed by autologous hematopoietic recovery. No late GR has been observed. The primary endpoint was met with1-year EFS of 76% (Figure 1A). The 1-year probability of overall survival (OS) was 86% (Figure 1B). The cumulative incidence (CINC) of grade II-IV and III-IV acute GVHD at day 180 were 31% and 17% respectively (Figure 2A). The CINC of chronic GVHD at 1-year was 62%. Chronic GVHD was extensive in 38% (Figure 2B). GVHD when present was noted by 12 months post-BMT. There were 7 deaths, all in patients >14 years at time of BMT. One death occurred after a second transplant for graft rejection. The other 6 deaths occurred between 143 and 960 days post BMT, from GVHD. Non-fatal toxicities included posterior reversible encephalopathy syndrome (PRES) associated with hypertension and seizures in 35%. All cases were observed in the first 6 months post-BMT; all patients recovered with no obvious sequelae. No patient developed veno-occlusive disease, idiopathic pneumonia syndrome or cerebral hemorrhage. Infections were common, and occurred in 76% of patients. CMV and EBV reactivation each occurred in 23% of recipients. Surviving patients report performance scores of 100% (n=14), 90% (n=5), and 80% (n=3) at 2 years or at the time of last assessment. At last follow up, 13 patients had successfully discontinued immunosuppressive therapy. Conclusion: In summary, the RIC regimen employed in this trial of MUD BMT in children with severe SCD resulted in low rates of regimen-related organ toxicity (other than a high rate of PRES) and 1-year EFS of 76%, associated with regression of SCD manifestations. . The risk of graft rejection/disease recurrence was similar to that observed after conventional HLA-identical sibling donor BMT. Chronic GVHD occurred in 62% of patients and was the leading cause of toxicity and mortality. Future trials should focus on effective GVHD prophylaxis after URD BMT. Secondary outcome analyses including health-related quality of life and neurocognitive performance are ongoing. Abstract source

Introduction: Neurological injury is a common complication of sickle cell anemia (SCA). SCA is the most common cause of stroke in children between 1-14 years of age, while silent cerebral infarct is the most common neurologic injury in this population. Young children are particularly vulnerable to the adverse impact of strokes, and are at risk of cognitive and developmental deficits; thus, we sought to examine brain volume changes in children with SCA. The Silent Cerebral Infarct Transfusion (SIT) Trial was a multicenter trial designed to determine the efficacy of blood transfusion therapy for prevention of recurrent silent cerebral infarcts in participants with SCA. This intervention trial followed 196 children with SCA aged 5-14 years randomized to receive blood transfusion therapy or observation for 36 months (DeBaun et al. N Engl J Med. 2014; 371(8):699-710). As a planned secondary analysis, we used the SIT Trial brain imaging archive to determine longitudinal brain volume change in children with SCA. We performed a multivariable analysis using demographic and clinical variables to identify predictors of brain volume change. Abstract source

Background: In well-resourced countries, early mortality in sickle cell disease (SCD) is no longer a major feature, thus the burden of SCD mortality has shifted to adults. Recent data on patients with SCD in USA confirmed continuing improvement in adult survival, attributed to better preventative care. Health economics may play a key role in clinical outcome in SCD; we hypothesise that survival would be longer in a system which is not insurance based. King's College Hospital, London, UK has a large SCD cohort in a well-resourced setting within a national health service framework. Methods: 712 adult (>=18 years) SCD patients were observed over 10 years (2004-13 inclusive) to identify mortality outcome (total 5268 patient-years of observation with median 8 years of observation per patient, over median 9 total hospital visits). Demographic data, sickle and alpha genotype were documented. Laboratory data were also collected (list in table): outpatient laboratory values were averaged over the 10 year period to create a steady state value for each patient. Mean number of hospital admissions with a sickle pain crisis was calculated (total admissions/number of observed years per patient). IBM SPSS Statistics 22 was used for Kaplan Meier survival analysis and then regression analysis was undertaken, based on the Cox proportional hazards model, to identify variables which were associated with mortality, and produce hazard ratios for putative predictors (demographic, laboratory and admission data). Results: 43 patients (6.0%) died during the study at a median age of 42 years (IQR: 31-48). Kaplan Meier analysis showed an estimated median survival of 77 years (95% CI: 68-85) for all sickle genotypes. Sub-analysis by sickle genotype showed: HbSS/HbSβ0 thalassaemia together (33 deaths in 450 patients) with estimated median survival 67 years; and HbSC (8 deaths in 229 patients) with significantly higher estimated median survival 82 years (p<0.001), see figure 1. For both genotypes, there was no gender difference on sub-analysis. For HbSS/HbSβ0, there was a significant difference by hospitalisation rate with survival: median survival in those with =<0.5 admissions/year was 67 years, significantly higher than 60 years (CI: 43-77) for high admission rates (p=0.001), see figure 2. Cox regression analysis was conducted for HbSS/HbSβ0 patients (demographic, laboratory and admission data), see table. Risk of death is increased: 2.5-fold if ferritin is high (>1000ug/L), 6% for every extra 10umol/L total bilirubin, 20% for every extra 100 IU/L LDH, 18% for every extra 1 x109/L WBC (all steady state values). Hospitalisation rates were analysed two ways: using the continuous variable, risk of death is increased by 37% for every admission accrued in an individual's mean admission/year statistic; and using a dichotomous variable (high versus low admissions), those with high admission rates have a hazard ratio over 3-fold that of those with low admission rates. Conclusions: These data indicate that adult survival in SCD in our institution is high; estimated median survival of 67 years for HbSS/Sβ0 and 82 years for HbSC. This is markedly longer than those recently quoted from the USA, which may be due to disparities in health economics. Cox regression sub-analysis for the HbSS/Sβ0 group reveals multiple predictors of increased mortality risk including classical laboratory markers of SCD severity - iron loading (likely correlated with disease severity via transfusion rate), inflammatory and haemolytic parameters - as well as confirming hospitalisation rate as a simple but strong predictor of survival in SCD. Abstract source

Background: Sickle cell trait (SCT) and hemoglobin C trait are two of the most common inherited hemoglobin mutations in the world due to their malarial protective effects. APOL1 renal risk variants, which confer resistance to trypanosomal infection, are prevalent in African-ancestry populations and are associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD). While an increased risk of CKD in SCT carriers has been demonstrated; there are conflicting data on SCT and the risk of ESRD, and the association between hemoglobin C trait and kidney disease remains unknown. Furthermore, whether co-inheritance of hemoglobin S or C and APOL1 gene risk variants contributes to the risk of CKD has not been established. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 12,514 African-Americans age ≥ 45 years from the contiguous United States between 2003-2007. All participants consenting to genetic research were genotyped for hemoglobin S and hemoglobin C traits. Individuals with hemoglobin SS, SC, or CC genotypes were excluded from analysis. APOL1 high-risk genotypes were defined as the presence of two renal risk variants, G1/G1, G2/G2, or G1/G2. Prevalent CKD was defined as a baseline eGFR < 60mL/min/1.73 m2 and/or the presence of albuminuria ≥ 30mg/g based on spot urine albumin/creatinine ratio (ACR) measurements. Logistic regression was used to calculate odds ratios (OR) of prevalent CKD for hemoglobin S/C, and Cox regression was used to estimate risk of incident ESRD. All analyses were adjusted for age, sex, smoking, hypertension, diabetes, APOL1 high-risk genotype status, and baseline eGFR (for incident ESRD). A genetic interaction analysis of hemoglobin S/C variants and APOL1 high-risk genotypes on prevalent CKD was also performed. Results: A total of 10,481 African American participants, 7.5% with SCT and 2.5% with hemoglobin C trait, had available genetic data for analysis. As shown in table 1, prevalent CKD was significantly more common in SCT carriers than non-carriers, with an OR for CKD of 1.86 [95% CI 1.57-2.20]). In addition, individuals with SCT had a 1.5-fold increased hazard of incident ESRD compared to non-carriers, although this was not statistically significant. Hemoglobin C trait was not associated with prevalent CKD or incident ESRD, but the numbers were small. On genetic interaction analysis, co-inheritance of hemoglobin C and APOL1 high-risk genotypes significantly increased the risk of prevalent CKD (p-interaction=0.003), while co-inheritance of SCT and APOL1 high-risk genotypes did not appear to interact to increase CKD risk. Conclusions: In this large cohort of over 10,000 African Americans, SCT was associated with an increased risk of prevalent CKD and demonstrated a trend of association with incident ESRD. Hemoglobin C trait was not associated with prevalent CKD but may interact with APOL1 high-risk genotypes to potentiate the risk of CKD. Future studies are needed to further examine these gene-gene interactions and to establish the relationship between hemoglobin S/C traits and ESRD. Abstract source