Frequency Of Vaso-occlusive Crises Research Articles

Implication of HMOX1 and CCR5 genotypes on clinical phenotype of Egyptian patients with sickle cell anemia.

Sickle cell disease (SCD) is a relatively common inherited hemolytic anemia among individuals of African descent. Genetic factors might clarify clinical diversity of the disease and variations in treatment response. Some researchers investigated heme oxygenase-1 (HMOX1) or chemokine receptor 5 (CCR5Δ32) genotypes among SCD patients and their correlation with fetal hemoglobin (HbF) and disease severity. However, there are no such records among Arab nations. We aimed to estimate the prevalence of the HMOX1-413 A>T (rs2071746) and CCR5Δ32 (rs333) polymorphisms, and to assess their effect on SCD phenotype and HbF level among Egyptian patients. Polymerase chain reaction assay was used to determine these polymorphisms among 100 SCD patients and 100 healthy controls. Though not statistically significant, the frequency of individual carrying HMOX-1 polymorphic AT and TT genotypes in both patient and control groups was 92% and 85% respectively. Regarding CCR5Δ32 polymorphisms, all SCD patients harbored the wild genotype (100%), while the heteromutant genotype was encountered in 2% of our controls. Patients harboring mutant HMOX-1 had a less frequent vaso-occlusive crisis (VOC)/lifetime, less VOC in the last year, less incidence of stroke, less frequency of hospitalization, and responded more frequently to hydroxyurea with statistically significant differences (p = 0.028, 0.007, 0.046, 0.007, and 0.011 respectively). No significant associations with HbF level or other hematologic parameters were encountered among our cohort. Our study results suggest a protective effect of mutant HMOX-1 genotypes in ameliorating the phenotypic severity of the disease. HMOX1-413 A>T (rs2071746) polymorphisms might prove to be a prognostic marker among Egyptian SCD, but not CCR5Δ32 (rs333) polymorphisms.

Plasma level of antioxidants is related to frequency of vaso-occlusive crises in children with sickle cell anaemia in steady state in Nigeria

IntroductionSickle cell anaemia (SCA) is associated with deficiency of plasma antioxidants. Frequency of vaso-occlusive crises (VOC) is an index of disease severity. This study determined the relationship between plasma antioxidants in children with SCA and frequency of VOC. MethodIt was a cross-sectional comparative study comprising 80 children each with SCA and HbAA. Those with SCA were grouped into three based on frequency of pain episodes. Antioxidant trace elements (zinc, copper, selenium, and manganese), vitamins A, C and E and antioxidant enzymes (superoxide dismutase and glutathione dismutase) were quantified using atomic absorption spectrophotometry, HPLC and ELISA respectively. ResultsChildren with SCA had lower plasma concentrations of zinc, selenium, manganese, vitamins A, C, E, and superoxide dismutase (SOD) and glutathione peroxidase (GPx), but higher plasma concentration of copper compared to HbAA. Mean plasma concentrations of manganese, vitamin A, vitamin C, vitamin E, SOD and GPx were significantly lower in SCA children with severe disease compared to those with mild and moderate disease (F = 10.629, p < 0.001), (F = 5.636, p = 0.005), (F = 10.438, p < 0.001), (F = 6.424, p = 0.003), (F = 7.006, p = 0.002) and (F = 4.934, p = 0.010) respectively. Also, significant negative correlation existed between frequency of VOC and plasma concentration of Manganese (r = −0.428, p < 0.001), Vitamins A (r = −0.309, p = 0.005), Vitamin C (r = −0.456, p < 0.001), Vitamin E (r = −0.354, p = 0.001), superoxide dismutase (r = −0.320, p = 0.004) and glutathione peroxidase (r = −0.333, p = 0.003). ConclusionDeficiency of plasma antioxidants exists in SCA and plasma levels of some antioxidants have inverse relationship to frequency of VOC.

Therapeutic phlebotomy during major sickle cell disease in Togo.

To determine the influence of therapeutic phlebotomy on the reduction of vaso-occlusive crises (VOCs) and of hospital admissions of patients with sickle cell disease and to describe how they experience this practice. Descriptive cross-sectional study of 27patients with sickle cell disease who underwent phlebotomies. We estimated the number of VOCs, hemoglobin levels, and patient response. Among 27sickle cell patients (24SC and 3SS) who underwent phlebotomies, there were 22men (81.5%) men and 5 (18.5%) women, with an average age of 34.6 ±10.9years (range: 21-56years). Before the phlebotomies, 23 (85.2%) had showed signs of hyperviscosity, they had a mean of 5.3 ± 1.02 (range: 3-8) VOCs annually, and their mean hemoglobin level was 14.3 ±1.5g/dl (range: 10.4 g/dl-16.8 g/dl). The mean number of phlebotomies was 4.9±4.11 (range: 1-13). After this treatment, 21 (91.3%) reported that their signs of hyperviscosity disappeared, and the mean number of VOCs annually decreased to 0.9 ±0.07 (range: 0-2). The mean change in hemoglobin was 1.9 ±0.8 g/dl (range: 0.9-3.2 g/dl). Nine patients (6SC and 3SS), 7 under anti-anemic treatment, initially refused phlebotomy, mainly because they did not understand how it could be useful to reduce the amount of blood in patients with a potentially anemic disease. Phlebotomy has resulted in a decrease in the frequency of VOCs and hospitalizations. It is essential to further popularize it and increase patients' aware of its value in combatting sickle cell disease and thus improve their willingness for and adherence to this treatment.

CHRONIC KIDNEY DISEASE AMONGST SICKLE CELL ANAEMIA PATIENT AT THE UNIVERSITY OF MAIDUGURI TEACHING HOSPITAL, NORTH EASTERN NIGERIA: A STUDY OF PREVALENCE AND RISK FACTORS

BackgroundInvolvement of the kidneys in patients with sickle cell anaemia is a well recognised chronic complication. This study seeks to determine the prevalence of chronic kidney disease in patients with homozygous sickle cell disease (HbSS) and to identify risk factors associated with its development.MethodologyThe subjects consisted of adolescents and adults with HbSS recruited sequentially from the adult haematology outpatient clinic and Daycare ward of the unit. Clinical variables including age at diagnosis of SCA, the frequency of vaso-occlusive crisis and transfusion therapy, as well as laboratory data including haematological profile and renal function tests were obtained. The glomerular filtration rate was estimated (eGFR) using the ‘modification of diet in renal disease’ (MDRD) formula.ResultsTwo hundred and eighty-four HbSS patients were recruited. The prevalence of CKD amongst them was 38.9%. Further stratification of the patients based on eGFR showed that sixty-nine (26.8%) had hyperfiltration; 35 (13.6%) stage 1 CKD; 53 (20.6%) stage 2 CKD; 33 (12.8%) stage 3a CKD; 28 (10.9%) stage 3b CKD; 30 (11.7%) stage 4 CKD and 9 (3.5%) had end stage renal disease. There was significant association between eGFR and clinical parameters such as age (r −0.353, p=0.000), SBP (r −0.148, p= 0.021), DBP (r −0.213, p=0.001) and total number of blood received (r −0.276, p=0.000); and laboratory parameters such as PCV (r 0.371, p=0.000); urea ( r 0.527, p=000); creatinine (r 0.625, p=0.000) and uric acid ( r −0.419, p=0.000).ConclusionsThe present study has revealed a high prevalence of CKD amongst patients with SCA in our region. Clinical and laboratory predictors of CKD using eGFR were identified to include age, SBP, number of units of blood transfusion, PCV, urea, creatinine and uric acid levels.

Serum visfatin in sickle cell diseases: association to frequency of vaso-occlusive crises

Serum visfatin in sickle cell diseases: association to frequency of vaso-occlusive crises

Patient Satisfaction of Care in the Treatment of Vaso-Occlusive Crises: A Comparison of Emergency Department and Infusion Centers in the Escaped Study

IntroductionPatients with sickle cell disease (SCD) suffer from frequent vaso-occlusive crises (VOC), the leading cause of hospitalization and emergency department (ED) visits for these patients. Patients and healthcare providers often report dissatisfaction with the quality of SCD pain management in the ED. Satisfaction has been defined as whether a patient's expectations about a health encounter were met. Infusion centers (IC) are alternatives to ED care for patients with VOC. The aim of this study is to describe adult patients' satisfaction with care for the treatment of uncomplicated VOC in EDs and ICs.MethodsAs part of a prospective cohort study (the ESCAPED study) comparing outcomes between ED and IC care for uncomplicated VOC, we conducted a descriptive analysis of patient satisfaction from the first acute visit of adult patients (>18 years) who were recruited from 4 sites (Baltimore, Baton Rouge, Cleveland, Milwaukee) from April 2015 to December 2016. Demographic and clinical variables were collected via medical record review. Participants were provided with a survey about their satisfaction of care within 72 hours after their acute visit to the ED or IC. The survey tool included questions about overall satisfaction with quality of care and with pain treatment received, satisfaction with pain management, communication with clinicians including physicians and nurses, interpersonal aspects of care, clinician competence, involvement of family and friends, and access to care. Responses were scored on a 7-point Likert scale from very strongly agree to very strongly disagree, except for “access to care” items, which were binary and categorical. We dichotomized Likert scale responses by grouping positive responses (very strongly agree, strongly agree, and agree) as being satisfied, and negative responses (very strongly disagree, strongly disagree, disagree, and uncertain) as being dissatisfied. Descriptive statistics were computed using Mann-Whitney U test for continuous variables and chi-squared test for categorical variables. All hypothesis testings were 2-sided and p values were not adjusted for multiple comparisons.ResultsWe enrolled 483 patients in ESCAPED and followed them for 18 months. We excluded 115 patients who did not have VOC visits during their observation period. Of the 368 patients with visits, 212 patients (58%) responded to the survey after their first acute visit: 89 (42%) had received care at an ED and 123 (58%) received care at an IC. Patients who received care at an IC were older, more likely to be married or with a significant other, and less likely to live alone. More patients who had a history of kidney disease received care at an IC than in an ED. Patients with higher numbers of ED visits in the previous year were more likely to seek care in an ED and those with higher numbers of IC visits in the previous year were more likely to seek care at an IC.The majority of patients (55%) in the ED responded to the survey by phone whereas the majority of patients (54%) in the IC responded to the survey in-person. Overall, patients who received care in an IC were more satisfied with the quality of care (95% vs. 73%, p< 0.001) and with their pain treatment (93% vs. 66%, p< 0.001) than patients who received care in an ED. (Table) Adults who received care at an IC were more satisfied with the pain management, communication with clinicians, interpersonal aspects of care, and clinician competence than adults who received care at an ED. The majority of patients in both groups (59%) came for care unaccompanied; ED-treated patients were more likely than IC-treated patients to agree that a companion helped improve the quality of care they received.ConclusionsPatients who received care in an IC were more satisfied with their care and with the quality of their pain management than patients who received care from an ED. Increasing access to IC models of care can improve delivery of patient-centered care for VOC. [Display omitted] DisclosuresBrooks:PCORI: Research Funding. Wang:PCORI: Research Funding. Seufert:PCORI: Research Funding. Haywood:PCORI: Research Funding. Varadhan:PCORI: Research Funding. Saheed:PCORI: Research Funding. Segal:PCORI: Research Funding. Field:Incyte: Research Funding; Ironwood: Consultancy, Research Funding; Prolong: Research Funding. Frymark:PCORI: Research Funding. Little:Doris Duke Charitable Foundations: Research Funding; NHLBI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; PCORI: Research Funding. Griffin:PCORI: Research Funding. Arnold:PCORI: Research Funding. Shows:PCORI: Research Funding. Piehet:PCORI: Research Funding. Proudford:PCORI: Research Funding. Robertson:PCORI: Research Funding. Wallace:PCORI: Research Funding. Kincaid:PCORI: Research Funding. Green:PCORI: Research Funding. Burgess:PCORI: Research Funding. Lanzkron:Selexys: Research Funding; Pfizer: Consultancy, Research Funding; GBT: Consultancy, Research Funding; Prolong: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Ironwood: Research Funding.

A Five Fold Decrease in Admissions for Uncomplicated Vaso-Occlusive Crisis and Other Benefits from Care in Infusion Clinics: Results from the Escaped Trial

Background: Patients with sickle cell disease (SCD) suffer from frequent vaso-occlusive crises (VOC), the leading cause of hospitalization and ED visits for these patients. Infusion centers (IC) are alternatives to ED care and may provide patients with a better care experience. We previously demonstrated in a single center that the use of such centers provides more rapid pain control and can decrease the risk of a hospital admission. For the management of VOC the NHLBI's guidelines recommend that patients receive analgesic therapy within 60 minutes of registration and that pain be reassessed every 15-30 minutes until it is controlled. In the ESCAPED study, we aimed to learn whether the ED or IC more rapidly provides analgesia to patients who present with an uncomplicated VOC.Methods: The ESCAPED study is a prospective cohort study that recruited subjects at four sites (Baltimore, Cleveland, Milwaukee and Baton Rouge). The Baltimore and Milwaukee sites have dedicated ICs that treat only adults with SCD; the Cleveland and Baton Rouge sites have ICs that treat a diverse group of patients requiring infusion services. Patients were enrolled during regular outpatient visits between 4/2015 and 12/2016. Uncomplicated crisis was defined as an acute episode of pain with no known other cause and required treatment with parenteral pain medications. Upon study entry, participants completed surveys to collect demographic data; chart abstraction was done for information on comorbidities. Data was extracted after the acute visits for the primary endpoint: time to first dose of pain medication. We also extracted data on reassessment of pain after the first dose of parenteral pain medication and admission or discharge status. Patients' comorbidities were updated through chart abstraction after each visit. Each participant was followed for 18 months and data from visits for acute, uncomplicated VOC were collected. All acute visits were recorded and complete data was collected for each patient from the first visit each month to each site of care for uncomplicated crisis. Time-varying propensity scores estimated by a random effects model was used to balance covariates in the two arms. The treatment effects were estimated using a sub-classification approach and standard errors were computed by nonparametric bootstrapping at the individual level.Results: 483 subjects were enrolled and 444 completed 18 months of follow up (29 withdrew, 10 died). The median follow-up was 8.2 months (IQR, 5.7-12.0) for the 39 subjects who did not complete the study. There were 4851 acute visits for uncomplicated VOC of which 2910 had the complete data collected. 1445 visits to an ED and 1465 visits to an IC. The mean number of visits per patient was 10.0 (SD, 15.5) and median number was 4 (IQR, 1-12.5). 115 subjects had no acute visits during the study period. In the adjusted analyses, the mean time to first dose of parenteral pain medications was 125 minutes in an ED setting and 63 minutes in an IC setting (95% CI, 54-69). Patients seen in an IC were significantly more likely to have their pain reassessed 30 minutes after their first dose of pain medication than patients treated in an ED (OR, 2.5; 95% CI, 2.1-3.0) and visits to the ED were significantly more likely to end in the patient being admitted than visits to the IC (OR, 5.9; 95% CI, 4.7-7.3).Conclusions: With adjustment for differences between patients treated in the ED and IC, we demonstrated that those treated in an IC have significantly better treatment experiences than subjects treated in an ED: a 50% reduction in time to first dose of pain medication and an almost 6-fold decrease in hospital admission. Increasing access to infusion clinics is essential to improving the quality of care of uncomplicated VOC in adults with SCD. DisclosuresLanzkron:GBT: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Prolong: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Selexys: Research Funding; Ironwood: Research Funding. Little:Doris Duke Charitable Foundations: Research Funding; PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; NHLBI: Research Funding. Field:Incyte: Research Funding; Ironwood: Consultancy, Research Funding; Prolong: Research Funding. Haywood:PCORI: Research Funding. Varadhan:PCORI: Research Funding. Saheed:PCORI: Research Funding. Proudford:PCORI: Research Funding. Robertson:PCORI: Research Funding. Kincaid:PCORI: Research Funding. Burgess:PCORI: Research Funding. Green:PCORI: Research Funding. Wang:PCORI: Research Funding. Seufert:PCORI: Research Funding. Brooks:PCORI: Research Funding. Piehet:PCORI: Research Funding. Griffin:PCORI: Research Funding. Arnold:PCORI: Research Funding. Frymark:PCORI: Research Funding. Huang:PCORI: Research Funding. Wallace:PCORI: Research Funding. Segal:PCORI: Research Funding.

Role of Automated Red Cell Exchange in Acute and Chronic Complications of Sickle Cell Disease

Background. Automated red cell exchange transfusion (ARCET) is commonly used in patients with sickle cell disease, but objective data on its impact on acute and chronic complications are limited.Methods. Fifty-two sickle cell disease patients at the University of Illinois at Chicago underwent exchange transfusion from January 2011 to January 2016. Six patients were excluded due to incomplete data leaving 46 patients available for analysis. We collected data from the year before, year after and the year of ARCET to study the impact of red cell exchange on clinical, biological and hematological parameters.Results. There were 435 procedures with average of 9.45 per patient (range 4-14). The mean age of our cohort was 58.2 years. There were 22 (47.8%) males and 24 (52.2%) females. Genotypes include 42 (91.3%) HbSS, 1 (2.2%) HbSC, 1 (2.2%) HbSBeta+thalassemia and 2 (4.3%) HbSBeta0thalassemia. The most common indication for ARCET in our cohort was prior stroke in 32 patients (69.6%) and prevention of stroke in 7 patients (15.2%), followed by frequent vaso-occlusive crisis (VOC) 8 patients (17.4%), multiple acute chest syndrome 6 patients (13%), pulmonary hypertension 6 patients (13%) and chronic kidney disease 5 patients (8.9%). Iron overload, sickle hepatopathy, cardiomyopathy and seizure were some of the other indications. Twenty-five patients (54.3%) had more than one indication to undergo the ARCET. Thirty-one patients (67.4%) are still continuing the treatment. Thirty patients (65.2%) were on hydroxyurea (HU) prior to ARCET and 8 patients (17.4%) were still on HU while on ARCET. The mean frequency of ARCET was every 6 weeks. The mean pre and post ARCET values for hemoglobin(Hb), hematocrit (Hct), Hemoglobin S %(HbS), white cell count (wbc) and platelets(plt) are shown in Table 1. Paired t-test and Wilcoxon signed-rank test were used to analyze the clinical and hematological parameters. Analysis shows increase in mean Hb and Hct post ARCET and decrease in mean wbc, plt and HbS % post ARCET and the difference is statistically significant. (Table 3). Post ARCET body mass index (BMI) and weight are increased and the difference is statistically significant with p value 0.002 for BMI and 0.003 for weight. (Table 3). Ten (21.7%) patients showed decrease in the ferritin level post exchange. Thirty patients (65%) had VORTEX port whereas 29 patients (63%) had central venous access for procedures prior to Vortex placement (17/29, 59%). Nine patients (20%) had peripheral access mostly power port (for access) with one peripheral vein for return (6/9 67%). There were 10 access related complications and there were 3 port replacements due to septum damage and infection. There were 10 procedure related complications and 10 transfusion reactions as described in Table 2. ED admissions were decreased in 13(28.3%) patients from mean 7.69 to 2.92 admissions. The annual inpatient admissions showed a decrease in 18(39.2%) patients from mean 4.6 days pre ARCET to 1.6 admissions post ARCET. The acute care admissions showed an increase due to program expansion of our acute care center during this study period.Discussion. Our study shows that red cell exchange is an effective treatment modality for patients with sickle cell disease. It contributes to improvement in weight, increase in Hb and Hct and decrease in wbc, plt, HbS% and iron overload. It also decreases inpatient and ED admissions. The procedure is safe and tolerable with minimal complications. Long term studies are needed study the efficacy of this treatment modality and its contribution to improvement of quality of life and life expectancy in sickle cell disease patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Content Validation of Sickle Cell Pain Diaries for Caregivers: Results from Interviews with Caregivers

Background:Sickle Cell Disease (SCD) is a genetic, progressive, vascular disease that affects approximately 100,000 children and adults in the US. Vaso-occlusive crises (VOCs), also referred to as pain crises, are a primary complication of SCD. VOCs are caused by several factors, including inflamed, damaged vasculature and increased cellular adherence to the endothelium and other cells, resulting in occlusion of the microvascular systems. VOCs have been associated with increased morbidity and mortality.Healthcare visit data partially reflect VOC and SCD outcomes for children and provide understanding of healthcare resource utilization (HCRU), but miss the breadth and depth of the burden of SCD, and fail to capture daily variations of pain and other quality of life (QoL) concepts. This is particularly problematic for children, who may experience less frequent VOCs and may have lower HCRU, but will likely experience progressive non-VOC SCD-related symptoms and impacts as they age. Further, evaluating HCRU data underestimates the burden of SCD; patients who avoid seeking care outside the home are not represented.The Sickle Cell Pain Diary - Caregiver Report (SCPD-C) is a daily observer-reported outcome (ObsRO) measure for use with caregivers of patients with SCD under 12. Two diary versions were developed for SCD caregivers: one for school age children (SCPD-CS) and one for non-school age children (SCPD-CN). The diaries were designed to capture the frequency and severity of pain during and outside of a VOC and to examine the impact of SCD-related pain on other QoL concepts. The objective of this study was to investigate the content validity of the SCPD-CS and SCPD-CN.Methods:Two rounds of 90-minute in-depth, hybrid concept elicitation and cognitive debriefing (CD) interviews and one round of 60-minute CD interviews (N=22) were conducted in person (n=8) and by phone (n=14) with caregivers of SCD patients aged ≤11. Interviewers used a semi-structured guide to explore concepts relevant to caregivers' observations of VOC in children, and to test the diaries.The CD portion of the interviews required caregivers to state their thoughts while reading the diary aloud; interviewers elicited feedback on the diary instructions, recall period, items, and response choices. All interviews were recorded, transcribed, coded and analyzed.Results:Round 1 interviews (N=6), confirmed the relevance of the SCPD-C for most caregivers; however, several items were reported as not relevant for patients aged ≤3 years. Therefore the SCPD-C was split into the SCPD-CS for school age children and SCPD-CN for non-school age children. Other changes resulting from round 1 included: adding 8 items, removing 1, and wording edits for clarity and consistency.In round 2 interviews (N=3), only the SCPD-CS was tested and 2 items were added for electronic programming purposes. Round 3 (N=13) tested both the revised SCPD-CS and the SCPD-CN. Caregivers confirmed the relevance and comprehensibility of both diaries; no new items were added. Minor wording revisions were made to improve readability. Final changes to the diaries included adding skip logic to ensure transition to an electronic format. Saturation analyses revealed that no additional interviews were needed.Conclusions:This study provided evidence that supports the content validity of the SCPD-CS (formerly SCPD-C) and SCPD-CN, observer-reported daily diaries focused on capturing daily variations of pain in SCD. While we intended to evaluate the content validity of a single caregiver diary (SCPD-C) for SCD patients aged ≤11 years, we found that two versions were required to accurately capture caregivers' perspectives relative to their child's age and school attendance status. Evidence gathered during caregiver interviews indicated that the SCPD-CS and SCPD-CN are valuable measures of VOC-related pain frequency and severity and the impact of this pain on other QoL concepts including fatigue and emotional health. In addition, the diaries capture the QoL of patients outside of HCRU, providing a more holistic view of the impact of VOCs and SCD. Future work includes development of scoring algorithms and user's manuals, and conducting psychometric validation. Use of the diaries in clinical trials with caregivers of patients who experience VOCs is anticipated, to capture the QoL impacts of new interventions designed to reduce the frequency and intensity of VOCs DisclosuresBailey:Novartis: Employment. Stebbins:Optum: Employment; Novartis: Research Funding. D'Alessio:Novartis: Employment. Mitchell:Optum: Employment; Novartis: Research Funding. Saucier:Optum: Employment; Novartis: Research Funding. White:Optum: Employment; Akcea: Research Funding.

Content Validation of the Sickle Cell Pain Diary-Self Report

Background:Sickle Cell Disease (SCD) is a genetic, progressive, vascular disease that affects approximately 100,000 children and adults in the US. Vaso-occlusive crises (VOCs), also referred to as pain crises, are a primary complication of SCD. VOCs are thought to be caused by several factors, including inflamed, damaged vasculature and increased cellular adherence to the endothelium and other cells, resulting in occlusion of the microvascular system. VOCs have been associated with increased morbidity and mortality.Healthcare visit data partially reflect VOC and SCD outcomes and provide an understanding of healthcare resource utilization (HCRU). However, evaluating only HCRU data misses the breadth and depth of the patient experience and burden of SCD as it fails to capture daily variations of pain and other important quality of life (QoL) concepts. Additionally, patients who avoid seeking care outside the home are not represented in HCRU data.The Sickle Cell Pain Diary- Self Report (SCPD-S) was developed as a daily patient-reported outcome (PRO) measure primarily intended to capture the frequency and severity of SCD-related pain during and outside of a VOC and secondarily to examine the impact of the pain on other patient-relevant QoL concepts. The objective of this study was to investigate the content validity of the SCPD-S.Methods:A draft diary was developed from the literature. In line with FDA guidance for PRO development, the content validation of the SCPD-S included four consecutive steps: (1) literature review to identify important concepts to measure and mapping of concepts to draft diary; (2) expert review to improve wording and layout; (3) round 1 (N=13) of qualitative interviews with patients; and (4) round 2 (N=6) of qualitative interviews with patients. Revisions made to the diary after each step were tested in the following step.In total, 18 in-depth, hybrid concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted in English in person (n=13) and by phone (n=5) with SCD patients in the US aged ≥12 years. A semi-structured guide was used to explore concepts relevant to patients' experience with VOCs and to test the draft diary. The CD portion of the interviews required patients to state their thoughts while reading the diary aloud, after which interviewers probed on areas that seemed confusing and asked questions specific to the diary instructions, recall period, items, and response choices. All interviews were recorded, transcribed, coded and analyzed.Results:All four steps of this content validation study resulted in changes to the SCPD-S. The literature review, expert review, and round 1 patient interviews resulted in expansion of the SCPD-S from 8 to 19 items covering concepts highlighted by patients as important. For example, impact of VOCs on school/work, activities of daily living, social and recreational activities, sleep, and emotional wellbeing were added. Five items from the original diary were significantly revised, as were all response choices. Round 2 interviews confirmed the comprehensiveness of the revised diary, comprehensibility of the wording, and appropriateness of the recall period and response choices. Final changes to the diary included adding skip logic to ensure transition to an electronic format. Saturation analyses revealed that no additional interviews were needed.Conclusions:This study provided evidence that supports the content validity of the SCPD-S, a self-report SCD daily diary focused on capturing daily variations of pain in SCD. Evidence gathered during patient interviews indicated that the SCPD-S is a valuable, fit for purpose measure of VOC-related pain frequency and severity as well as the impact of this pain on other QoL concepts including fatigue and emotional health. In addition, the diary captures the QoL of patients who may not seek care outside the home providing a more holistic view of the overall impact of VOCs and SCD. The numerous changes to the SCPD-S as a result of the study findings highlight the importance of the content validation process in establishing a PRO measure. Future work on the SCPD-S includes development of a scoring algorithm and user's manual, and conducting psychometric validation. Use of the SCPD-S is anticipated in future clinical trials enrolling patients who experience VOCs as a way to help capture the QoL impacts of new interventions designed to reduce the frequency and intensity of VOCs. DisclosuresBailey:Novartis: Employment. Stebbins:Optum: Employment; Novartis: Research Funding. D'Alessio:Novartis: Employment. Raymond:Novartis: Research Funding; Optum: Employment. White:Akcea: Research Funding; Optum: Employment.

Established Prevention of Vaso-Occlusive Crises with Crizanlizumab Is Further Improved in Patients Who Follow the Standard Treatment Regimen: Post-Hoc Analysis of the Phase II Sustain Study

Background: In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo in patients with sickle cell disease (SCD), crizanlizumab 5.0 mg/kg significantly reduced the frequency of vaso-occlusive crises (VOCs) leading to healthcare utilization versus placebo (Ataga KI et al. N Engl J Med 2017;376:429-39). The overall incidences of adverse events and serious adverse events were similar among the patients treated with crizanlizumab and placebo.Aims: This post-hoc analysis from SUSTAIN evaluated key VOC-related endpoints in crizanlizumab 5.0 mg/kg and placebo groups in the per protocol (PP) population, as a way to assess the effect in patients who are able to follow the standard treatment regimen; data from the intention-to-treat (ITT) population will also be shown for context.Methods: The SUSTAIN study was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361) that enrolled patients aged 16-65 years with SCD who had experienced 2-10 VOC events in the previous 12 months. Patients were randomized 1:1:1 to receive crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo 14 times intravenously over 52 weeks; here we focus on the 5.0 mg/kg dose of crizanlizumab versus placebo. The number and time of VOCs leading to healthcare utilization (e.g., hospital admission, emergency department visit) from randomization to end of treatment were measured for each individual patient. Analyses were conducted on the ITT population (i.e., all patients randomized) and PP population (i.e., all patients randomized who received at least 12/14 planned doses of treatment, and completed the study without major protocol violations that impacted the efficacy assessments).Results: In the crizanlizumab 5.0 mg/kg and placebo groups, there were 67 and 65 patients in the ITT population, and 40 and 41 patients in the PP population, respectively; the main reasons for exclusion from the PP population were associated with violations of the visit schedule. As shown previously (Ataga KI et al. N Engl J Med 2017;376:429-39), the median annual rate of VOCs was 1.63 in the crizanlizumab 5.0 mg/kg group versus 2.98 in the placebo group (stratified Wilcoxon Rank-Sum test, P=0.01; Table) in the ITT population. The median time to first on-treatment VOC was 4.07 versus 1.38 months (stratified log-rank test, P=0.001), respectively, in the crizanlizumab 5.0 mg/kg and placebo groups. Overall, 24/67 (35.8%) and 11/65 (16.9%) patients in the crizanlizumab 5.0 mg/kg and placebo groups (stratified Cochran-Mantel-Haenszel test, P=0.013), respectively, did not experience any VOCs during treatment. In the PP population, the median annual rate of VOCs was 1.04 with crizanlizumab 5.0 mg/kg versus 2.18 with placebo (P=0.02; Table). The median time to first on-treatment VOC was 6.55 months with crizanlizumab 5.0 mg/kg and 1.58 months in the placebo group (P<0.001). Overall, 15/40 (37.5%) and 5/41 (12.2%) patients in the crizanlizumab 5.0 mg/kg and placebo groups, respectively, did not experience any VOCs during treatment (P=0.008). The effect of treatment with crizanlizumab 5.0 mg/kg over placebo, as assessed by the three selected endpoints, is visible on the Figure, i.e., reduced frequency of VOCs, delayed first VOC, and increased number of patients with no VOCs during treatment.Conclusions: This post-hoc analysis of SUSTAIN shows that crizanlizumab 5.0 mg/kg provided benefit over placebo: nearly halving the median annual rate of VOCs, doubling the time to first VOC, and doubling the number of patients with no VOCs during treatment in the ITT population. The effect was even more pronounced in the PP population. This suggests that the superior VOC-related treatment outcomes of crizanlizumab 5.0 mg/kg versus placebo are further improved in patients who are able to follow the standard crizanlizumab treatment regimen. [Display omitted] DisclosuresKanter:NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Sancilio: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kutlar:Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding; Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member. Bruederle:Novartis: Employment. Shi:Novartis: Employment, Other: Stock owner of Novartis. Campigotto:Novartis: Employment. Ataga:Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Sickle cell disease: a case report of renal amyloidosis

BackgroundThe development of proteinuria and reduced glomerular filtration rate is associated with higher mortality among patients with sickle cell disease (SCD). AA amyloidosis, also associated with increased mortality, in SCD is rare. We present a case of a woman with homozygous sickle cell disease with nephrotic syndrome and antibodies to double stranded DNA without clinical features of systemic lupus erythematosus. Kidney biopsy reveals AA amyloidosis and is the first report of concomitant AA amyloidosis with antibodies to double stranded DNA in SCD.Case presentationA 40-year-old Central African woman with homozygous sickle cell disease and history of vaso-occlusive pain crises undergoes kidney biopsy for nephrotic-range proteinuria. Kidney biopsy reveals AA type amyloidosis, which is a rare manifestation of SCD in the kidney. Her anemia worsens with an ACE inhibitor, initiated to reduce proteinuria and limit GFR decline, so it was discontinued. Hydroxyurea, shown to decrease the frequency of vaso-occlusive crises and lower proteinuria, was subsequently initiated but then discontinued due to worsening anemia. Unfortunately, her glomerular filtration rate worsens.ConclusionsAA amyloidosis and antibodies to double stranded DNA can occur in sickle cell disease. ACE inhibition and hydroxyurea decrease proteinuria so they may limit progression of chronic kidney disease. Hydroxyurea also decreases frequency of vaso-occlusive pain crises so it might be helpful in limiting progression of renal AA amyloidosis. However, further studies are needed to determine optimal treatment strategies for AA amyloidosis in sickle cell disease.

PRM222 - STUDY OF THE SEVERITY OF VASO-OCCLUSIVE CRISIS FOR PATIENT SUFFERING FROM SICKLE CELL DISEASE IN FRANCE USING A MACHINE LEARNING APPROACH ON THE FRENCH MEDICAL INFORMATION SYSTEM DATABASE

The PMSI (medical information system database) is the French national administrative database containing medical information and patients’ features for millions of hospital stays. Most medical studies only use descriptive methods to analyze patient cohorts. The objective of this study is to assess the capability of an innovative Machine Learning algorithm to discover hidden values in health data and to bring a better understanding of diseases. We applied this approach to predict the severity of Vaso-Occlusive Crisis (VOC) for patients suffering from Sickle-Cell Disease (SCD). The severity is expressed by the frequency of VOC and the average time between two VOC. We only selected hospital stays with an SCD related ICD-10 code. Patients hospitalized with a VOC code in 2014 were extracted and followed up for two years. 20 groups of comorbidities, 7 features related to the patient’s medical history and 8 features about the patient’s life have been identified. Data were analyzed with an Enhanced Decision Tree technique, to explain the severity of VOC with non-linear combinations of these 35 variables. 5 630 patients were included in the study. The enhanced decision tree was able to gather patients into distinct groups based on patient and disease features. 20 distinct groups were identified. The most discriminating variables for the severity of VOC were the features related to patients’ history and the number of received transfusions during the follow-up, whereas the comorbidities, the age or the gender were not discriminating. This exploratory study shows that Enhanced Decision Trees are relevant to identify patient profiles from healthcare databases and have predictive capabilities. It helps identifying leverages to prevent the severity of VOC, and so to adapt the treatment given to patients according to the risk of having a VOC in the next months.

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4+CD28null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4+CD28null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4+CD28null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4+CD28null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4+CD28null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4+CD28null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4+CD28null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

Prophylaxis oral aspartame improves anaemia and decreases frequency and severity of vaso-occlusive painful crisis among sickle cell disease patients and noninferior to hydroxyurea

Background: Sickle cell disease (HbSS) causes much of the morbidity and mortality due to its chronic anaemia and vaso-occlusive painful crisis. Hydroxyurea is now using to treat HbSS. Aspartame appears to have antisickling properties. The objective of this study was to asses the effects of prophylaxis oral Aspartame among HbSS patients on anaemia and vaso-occlusive painful crisis.Methods: 208 cases of HbSS patients with history of vaso-occlusive crisis (VOC) and/or anaemia were selected for the study and divided into study group (n = 104) and control group (n = 104). 31 and 38 patients were on Hydroxyurea in study group and control group respectively. Baseline hemoglobin was estimated in all cases and oral Aspartame was given in a dose of 4 mg/kg/day in three divided doses. Monthly hemoglobin levels were measured in all cases for six months. Data were collected and compared with control data by using SPSS software version 25.Results: Mean baseline hemoglobin was 6.99 gm% and increased to 8.43 gm% (P &lt;0.05) after receiving Aspartame prophylaxis. Aspartame add on to Hydroxyurea also had increased in haemoglobin levels. Incidence of VOC was 7.26% in control group. In Hydroxyurea group 3.58% had VOC. In study group 1.2% and in add on to Hydroxyurea group had 1.125 of milder degree of VOC (P &lt;0.05).Conclusions: Aspartame appears to have antisickling properties and improves anaemia and decreases frequency and severity of VOC among HbSS patients and is non-inferior to Hydroxyurea.

Effect of homocysteine and folic acid on vaso-occlusive crisis in children with sickle cell disease

Introduction Vaso-occlusion is a determinant for most manifestations of sickle cell anemia (SCA). Elevated concentration of homocysteine contributes to thrombosis, a frequent event in SCA. Folic acid deficiency leads to increase in plasma homocysteine. The aim of study was to test whether children with SCA have elevated serum homocysteine with diminished folate level and to determine whether hyperhomocysteinemia has a correlation with the frequency of vaso-occlusive crisis. Patients and methods A case–control study was carried over a period of 1 year (January to December 2014) in the hematology clinic, Abo El-Reesh Hospital, Cairo University. A total of 50 patients with SCA were included together with 30 age-matched and sex-matched healthy children recruited from Menoufia Hospital. Venous blood samples were obtained from both groups to measure serum homocysteine and folic acid levels. Results The mean±SD of age of the patients and controls were 6.20±2.55 and 6.03±2.64 years, respectively. Homocysteine level was significantly higher in the patients group compared with control group, with a mean±SD of 44.68±9.096 and 18.81±3.76 µmol/l, respectively (P>0.01). Folic acid level was lower in the patients group than control group, with 12.02±2.76 and 14.68±2.99 ng/ml, respectively (P Conclusion Patients with sickle cell disease have high serum homocysteine with low folate levels. This hyperhomocysteinemia is positively correlated with the frequency of vaso-occlusive crisis.

Candidate Gene Associations with Vaso-Occlusive Crisis in Children with Sickle Cell Anemia Enrolled in the Multinational DOVE Trial

Introduction: Sickle cell disease (SCD) is complex, with marked inter-individual variability in disease severity. The clinical heterogeneity of SCD is largely influenced by genetic factors, including several well-established modifiers of fetal hemoglobin (HbF) levels within the beta globin locus, BCL11A, and HBS1L-MYB genes. However, little is known about genetic factors that may influence variability in treatment response, particularly in clinical trials assessing potential therapeutic agents for SCD. The DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) study was a multinational, phase 3, randomized, double-blinded, placebo-controlled trial evaluating the efficacy and safety of the antiplatelet agent prasugrel for the reduction of vaso-occlusive crisis (VOC) in children with sickle cell anemia (NCT01794000). Although the primary endpoint of reduction of rate of VOC did not reach statistical significance in the DOVE trial in the ITT population, a treatment effect of prasugrel was suggested in certain subgroups. The objective of this study was to evaluate candidate genetic variants with SCD severity and to assess impact of these variants on response to prasugrel, as measured by the frequency of VOC (composite of painful crisis and acute chest syndrome events) during the study period of up to 24 months.Methods: De-identified dried blood spot samples were collected for genetic analyses as per informed consent and study protocol. Genomic DNA was extracted from a 3 mm Whatman FTA card punch using Qiagen QIAamp DNA kit. A total of 313 (92%) DOVE patients (Hb SS or Hb S/β0 thalassemia) were genotyped using the TaqMan assay. After quality control, 253 patients and 28 variants were considered for genetic evaluation. These variants have been reported to be associated with SCD and/or its related comorbidities. All variants were analyzed for VOC in the prasugrel and placebo groups separately and for treatment by variant interactions in the overall study population. Variants were also assessed in the overall study population for associations with a hemolytic score, derived from 5 biomarkers of hemolysis and baseline hematologic markers including leukocyte, neutrophil, and platelet counts, and red cell mean corpuscular volume. All analyses were conducted using additive multivariate regression framework as the main model and were adjusted for age, race, geographic region, and hydroxyurea (HU) use at baseline. In addition, genotypic, dominant, and recessive models were evaluated as supportive analyses.Results: Two variants, rs7482144, located in the 5'- HBG2 gene promoter (-158 Xmn1) on chr 11 and rs1427407, located in the BCL11A gene on chr 2, were associated with VOC and a treatment interaction effect of prasugrel. HBG2 rs7482144, was associated with a significant decrease in frequency of VOC in prasugrel-treated patients relative to placebo (adjusted p=0.0065). The BCL11A rs1427407 variant was associated with an increase in VOC in prasugrel-treated patients relative to placebo (adjusted p=0.0205).No genetic associations were found with baseline composite hemolytic score in the overall population. However, significant associations with KLF-1, HBG2, and HBE variants were observed with individual hematologic markers. The KLF-1 variant (rs112631212) was associated with lower leukocyte (p<0.0001) and neutrophil (p=0.0002) counts in the subgroup of participants on HU; whereas the HBG2 (rs2070972; p=0.0116) and HBE (rs3834466 and rs7130110; p=0.0274 and p=0.0340 respectively) variants were associated with elevated platelet counts in the overall group.Conclusions: Given the study sample size, this study highlights the significance of HBG2 and BCL11A variants for the frequency of VOC in prasugrel-treated patients versus placebo. These variants have been reported in association with HbF/F-cells, an ameliorating factor for VOC that is only partly explained by endogenous levels of HbF. Our findings suggest that these variants may have contributed to the treatment-related effects of prasugrel on VOC outcomes in the DOVE trial. Identifying such genetic variants that are associated with differential response to treatment may help guide selection of patients for clinical trials based on predicted risk of VOC. DisclosuresHoppe:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership, Other: Former employee and minor shareholder of Eli Lilly and Company. Foster:Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Heath:Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Pillai:Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Pallav:Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company.

Correlates of Pulmonary Function in Children with Sickle Cell Disease and Elevated Fetal Hemoglobin

Objective: The current study was carried out to compare pulmonary function tests (PFTs) in pediatric Kuwaiti sickle cell disease (SCD) patients to age-matched normal controls and to investigate the association of PFTs with selected clinical and laboratory parameters. Subjects andMethods: There were 38 patients with SCD and 36 controls in the study. The patients were recruited from the Pediatric Hematology Clinics of Mubarak Al-Kabeer and Al-Amiri Hospitals, Kuwait, and were studied in steady state. The controls were healthy, non-sickle cell siblings of the patients. Forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), total lung capacity, and other PFT parameters were obtained using a constant-volume, variable-pressure, body plethysmograph. Hemoglobin, fetal hemoglobin, serum bilirubin, and lactate dehydrogenase were determined using standard methods. Results: The mean ages of the patients and controls were 10.5 ± 3.2 and 10.5 ± 3.5 years, respectively. The FEV₁% predicted of 84.1 ± 15.4% among the patients was significantly lower than the 92.1 ± 11.8% in the controls (p = 0.003). The FVC% predicted was also significantly lower (p = 0.022) in the patients than in the controls, although the values were generally within the normal range. There was no association of FEV₁ with pain phenotype, acute chest syndrome (ACS), or blood transfusions. Also, there was no significant correlation with reticulocytes, bilirubin, or lactate dehydrogenase. Conclusions: In this study, changes in PFT, especially FEV₁, developed early in the SCD patients. There was no demonstrable association with frequent vaso-occlusive crisis, ACS, and other variables. Hence, there is a need for follow-up studies with serial PFTs to identify vulnerable patients, who might need intervention to prevent early mortality.

Enhancing Effect of Hydroxyurea on Hb F in Sickle Cell Disease: Ten-Year Egyptian Experience

Patients with sickle cell disease experience hemolytic anemia and vaso-occlusions that result in pain, organ injury, and premature mortality. Several prospective studies have verified the efficacy and tolerability of hydroxyurea (HU), and demonstrated its efficacy in reducing painful vaso-occlusive crises (VOCs) in addition to its ability to increase Hb F levels. We aimed to evaluate the long-term effects of HU therapy on Hb F and assess its long term efficacy and safety in sickle cell disease patients. A retrospective study on 60 sickle cell disease patients was conducted. We studied the laboratory changes, frequency of VOCs per year, frequency of hospital admisions per year and number of transfusions per year, both before and after HU therapy. The follow-up period was 4 to 120 months. Hb F levels after HU therapy positively correlated with the duration of HU therapy, baseline Hb F levels and baseline total hemoglobin (Hb) (r = 0.4, p = 0.04; r = 0.45, p = 0.001; r = 0.5, p = 0.019, respectively) and inversely correlated with baseline total leucocyte count (r = –0.33, p = 0.034). Hydroxyurea therapy was associated with an increase in the total Hb and mean corpuscular volume (MCV) (p = 0.009, p = 0.000; respectively) and with a decrease in total leucocyte count, platelet count and reticulocyte count (p = 0.00, p = 0.03, p = 0.02, respectively). Moreover, a significant reduction in the frequency of VOCs, transfusion frequency and hospital admissions per year after HU therapy was shown in the studied subjects. Hydroxyurea induced an increase in Hb F level, which was maintained over time and was associated with clinical efficacy and acceptable safety.

Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review.

Sickle-cell disease (SCD) is characterized by frequent and painful vaso-occlusive crises (VOCs). Various treatments have been evaluated over the years. However, a clear overview is lacking. The objective of this study was to systematically review all pharmacotherapeutical strategies in the prevention of VOCs beyond hydroxyurea. We performed a systematic literature search (MEDLINE, Embase, CENTRAL). Eligible studies were controlled clinical trials evaluating pharmacotherapeutical interventions targeting the reduction of VOCs in patients with SCD. Primary outcomes were the number or duration of SCD-related pain days, VOCs, or hospital admissions for VOCs. Secondary outcomes included time to first VOC or hospital admission for a VOC. A standardized data extraction sheet was used. The methodological quality of studies was assessed using Cochrane's risk-of-bias tool. A total of 36 studies were included in this review, covering 26 different prophylactic interventions. The most promising interventions for reducing the frequency of either VOCs or hospitalizations were the oral antioxidants l-glutamine and ω-3 fatty acids and the IV antiadhesive agent crizanlizumab. Twenty-three studies did not show any beneficial effect of the intervention under investigation, and 6 studies were either too small or methodologically inadequate to draw conclusions. Because of the heterogeneity of interventions, no meta-analysis was performed. In conclusion, this review identified 3 promising pharmacotherapeutical strategies in the prevention of VOCs in SCD. Importantly, this study highlights the discrepancy between the significant burden of SCD worldwide and the low number of adequate trials performed. This review was registered at PROSPERO (CRD42015025250).