Despite advances in the survival of pediatric patients with sickle cell disease (SCD), affected individuals continue to experience progressive end-organ damage, recurrent painful vaso-occlusive episodes (VOEs) and a shortened lifespan, highlighting the need for additional therapies. Recent animal and human studies suggest that antibiotic exposure may actually ameliorate the severity of SCD by altering the gastrointestinal microbiome. Specifically, depletion of intestinal microbiota by administration of broad-spectrum antibiotics significantly reduces the number of circulating pro-inflammatory, aged neutrophils and improves inflammation-related organ damage or endotoxin-induced septic shock in mouse models of SCD. Further, routine administration of penicillin propylaxis to SCD patients up to 5 years of age has also been associated with a reduced percentage and absolute number of aged neutrophils. A recent murine study showed the dependence of stress-induced VOEs and inflammation on the gut microbiota, mediated by aged neutrophil expansion. These observations suggest that in addition to infection prevention, there may be a role for extended antibiotic “prophylaxis” to reduce SCD severity by modulating the gut microbiome to decrease inflammation. Abstract source

Hydroxyurea is an efficacious treatment for sickle cell disease (SCD), but adoption is low among individuals with SCD. The objective of this study was to examine barriers to patients’ adherence to hydroxyurea use regimens by using the intentional and unintentional medication nonadherence framework. We interviewed individuals with SCD age 15 to 49.9 years who were participants in the Sickle Cell Disease Implementation Consortium (SCDIC) Needs Assessment. The intentional and unintentional medication nonadherence framework explains barriers to using hydroxyurea and adds granularity to the understanding of medication adherence barriers unique to the SCD population. In total, 90 semi-structured interviews were completed across 5 of the 8 SCDIC sites. Among interviewed participants, 57.8% (n = 52) were currently taking hydroxyurea, 28.9% (n = 26) were former hydroxyurea users at the time of the interview, and 13.3% (n = 12) had never used hydroxyurea but were familiar with the medication. Using a constructivist grounded theory approach, we discovered important themes that contributed to nonadherence to hydroxyurea, which were categorized under unintentional (eg, Forgetfulness, External Influencers) and intentional (Negative Perceptions of Hydroxyurea, Aversion to Taking Any Medications) nonadherence types. Participants more frequently endorsed adherence barriers that fell into the unintentional nonadherence type (70%) vs intentional nonadherence type (30%). Results from this study will help SCD health care providers understand patient choices and decisions as being either unintentional or intentional, guide tailored clinical discussions regarding hydroxyurea therapy, and develop specific, more nuanced interventions to address nonadherence factors. Abstract source

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death underlies the majority of young adult mortality in SCD. To better understand the clinical importance of multi‐level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S’) and diastole (E’), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty‐eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional‐hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end‐organ failure. On Cox proportional‐hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S’ results in a 91% increase and 1 cm/s decrease in E’ results in a 43% increase in mortality. In conclusion, Elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers. Abstract source

This consensus study report was commissioned by the Office of Minority Health at the Office of the Assistant Secretary for Health at the U.S. Department of Health and Human Services to provide a comprehensive approach to the management and potential interventions for sickle cell disease (SCD), a genetic condition affecting approximately 100,000 people in the United States and millions worldwide. The report sets forth a substantial agenda beginning with the important need for information across the life span to characterize the trajectory of SCD and the antecedents of later complications.   Chapter: 1 - Introduction Chapter: 2 - Societal and Structural Contributors to Disease Impact Chapter: 3 - Screening, Registries, and Surveillance Chapter: 4 - Complications of Sickle Cell Disease and Current Management Approaches Chapter: 5 - Health Care Organization and Use Chapter: 6 - Delivering High-Quality Sickle Cell Disease Care with a Prepared Workforce Chapter: 7 - Developing and Delivering the Next Generation of Therapies Chapter: 8 - Community Engagement and Patient Advocacy Chapter: 9 - Strategic Plan and Blueprint for Sickle Cell Disease Action   Abstract source

Objectives: Individuals with sickle cell disease (SCD) experience significant health problems that may result in unpredictable pain episodes and frequent healthcare utilization. Disparities in clinical care may contribute to health-related stigma and racial bias for this majority African-American/Black population. There is less known about the influence of health-related stigma and racial bias on the health-related quality of life (HRQOL) of children with SCD. In the present study, we assessed these relationships and identified differences across demographic factors (i.e. age, gender). Design: Data was collected from African American children with SCD aged 8–16 years (57% male, 63% HbSS). Children completed the Childhood Stigma Scale (adapted for SCD), the Child Perceptions of Racism in Children and Youth scale, and the Pediatric Quality of Life Inventory Sickle Cell Disease Module. Caregivers provided demographic information. Results: In the first regression model, health-related stigma (p = .007) predicted HRQOL, but neither age nor gender were significant predictors. In the second regression model, age (p = .03) predicted HRQOL, but neither gender nor racial bias were significant predictors. Of interest, there was a significant interaction between age, gender, and racial bias (p = .02). Specifically, older girls who reported high levels of perceived racial bias had poorer HRQOL. Conclusions: Our study highlights the need for increased awareness about the effects of health-related stigma and racial bias on HRQOL for children with SCD, particularly for older girls who endorse racial bias. Our findings will guide future stigma and bias reduction interventions that may meet the needs of older girls with SCD. Abstract source

Study objective: Individuals living with sickle cell disease (SCD) often require urgent care; however, some patients hesitate to present to the emergency department (ED), which may increase the risk of serious clinical complications. Our study aims to examine psychosocial, clinical, and demographic factors associated with delaying ED care. Methods: This was a cross-sectional study of 267 adults with SCD from the national INSIGHTS Study. The binary outcome variable asked whether, in the past 12 months, participants had delayed going to an ED when they thought they needed care. Logistic regression was performed with clinical, demographic, and psychosocial measures. Results: Approximately 67% of the participants reported delaying ED care. Individuals who delayed care were more likely to have reported higher stigma experiences (odds ratio [OR]=1.09; 95% confidence interval [CI] 1.03 to 1.16), more frequent pain episodes (OR=1.15; 95% CI 1.01 to 1.32), lower health care satisfaction (OR= 0.74; 95% CI 0.59 to 0.94), and more frequent ED visits (OR=6.07; 95% CI 1.18 to 31.19). Disease severity and demographics, including sex, age, and health insurance status, were not significantly associated with delay in care. Conclusion: Psychosocial factors, including disease stigma and previous negative health care experiences, are associated with delay of ED care in this SCD cohort. There is a need to further investigate the influence of psychosocial factors on the health care–seeking behaviors of SCD patients, as well as the downstream consequences of these behaviors on morbidity and mortality. The resulting knowledge can contribute to efforts to improve health care experiences and patient-provider relationships in the SCD community. Abstract source

Study objective: We determine the association between use of specific cephalosporins and macrolides and hospital length of stay in patients with sickle cell disease (SCD) who are admitted with acute chest syndrome, and determine treatment risk factors for acute chest syndrome–related 30-day readmission. Methods: Patients admitted to 48 US hospitals within the Pediatric Health Information System between January 2008 and December 2016 with associated International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10 diagnoses of SCD and acute chest syndrome were included. Primary outcomes were hospital length of stay and acute chest syndrome–related and all-cause 30-day readmission. Data were analyzed with t tests, ANOVA, and bivariable and multivariable linear and logistic regressions. Results: In 21,126 visits (representing 8,856 patients), median age was 11.2 years (interquartile range 6.1 to 16.5 years), 53.5% were male patients, and 77.2% had hemoglobin SS genotype. Median length of stay was 4 days (interquartile range 2 to 6 days; mean 4.76 days [SD 4.62 days]). Ceftriaxone alone (length of stay 4.75 days [SD 4.66 days]; P<.001) or the combination of ceftriaxone and azithromycin (length of stay 4.84 days [SD 4.74 days]; P<.001) was associated with the shortest length of stay and a reduced risk of acute chest syndrome–related readmission (ceftriaxone odds ratio [OR] 0.31; 95% confidence interval [CI] 0.27 to 0.35; ceftriaxone+azithromycin OR 0.20; 95% CI 0.17 to 0.24). Albuterol (OR 0.97; 95% CI 0.96 to 0.98) and RBC transfusion (OR 0.60; 95% CI 0.43 to 0.83) were also associated with decreased rates of acute chest syndrome–related 30-day readmission. All-cause 30-day readmission rate was 16.7% (95% CI 16.2% to 17.3%). Conclusion: Guideline-compliant therapy for acute chest syndrome could preferentially include ceftriaxone and azithromycin. All-cause 30-day readmission for acute chest syndrome is lower than that reported for all-cause readmissions for SCD and more consistent with rates of readmission for pneumonia in the general population. Abstract source

Study objective: This was a prospective, pre-post, 13-year observational study documenting the multiyear implementation of an observation unit sickle cell pathway for patients with uncomplicated vaso-occlusive events. Methods: The sickle cell pathway begins with rapid triage to identify patients with uncomplicated vaso-occlusive events for immediate transfer to the observation unit and initiation of patient-controlled analgesia followed by repeated evaluations of pain and identification of other complications. Data were abstracted from the electronic medical record or observation unit database. The sickle cell pathway was initiated in April 2006. Major revisions of it were carried out in June 2009 (physician evaluation occurs in sickle cell pathway and only patient-controlled analgesia administration of medications) and October 2010 (multidisciplinary management and individual dosing). Results: Annual ED visits ranged between 287 and 528. The preimplementation hospital admission rate was 33% (123/368), 3-day return rate 16% (60/368), and 30-day return rate 67% (248/368). Refinements to the sickle cell pathway have resulted in a decrease in admission rate to 20% (258/1276); 3-day return rate, to 3.6% (46/1,276); and 30-day return rate, to 41% (525/1,276) for the past 3 years. Conclusion: The use of a sickle cell pathway for the treatment of uncomplicated vaso-occlusive events has been effective in providing rapid treatment and reducing hospital admissions. However, it was not only the intervention and its refinement that made the sickle cell pathway successful. With the Consolidated Framework for Implementation Research, it was discerned that outer setting factors of organizational commitment to the care of patients with SCD, inner setting factors of learning climate and leadership engagement, individuals, and process contributed to the success of the sickle cell pathway. Abstract source

Study objective: The National Heart, Lung, and Blood Institute evidence-based guidelines for timeliness of opioid administration for sickle cell disease (SCD) pain crises recommend an initial opioid within 1 hour of arrival, with subsequent dosing every 30 minutes until pain is controlled. No multisite studies have evaluated guideline adherence, to our knowledge. Our objective was to determine guideline adherence across a multicenter network. Methods: We conducted a multiyear cross-sectional analysis of children with SCD who presented between January 1, 2016, and December 31, 2018, to 7 emergency departments (EDs) within the Pediatric Emergency Care Applied Research Network. Visits for uncomplicated pain crisis were included, defined with an International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 code for SCD crisis and receipt of an opioid, excluding visits with other SCD complications or temperature exceeding 38.5°C (101.3°F). Times were extracted from the electronic record. Guideline adherence was assessed across sites and calendar years. Results: A total of 4,578 visits were included. The median time to first opioid receipt was 62 minutes (interquartile range 42 to 93 minutes); between the first and second opioid receipt, 60 minutes (interquartile range 39 to 93 minutes). Overall, 48% of visits (95% confidence interval 47% to 50%) were guideline adherent for first opioid. Of 3,538 visits with a second opioid, 15% (95% confidence interval 14% to 16%) were guideline adherent. Site variation in adherence existed for time to first opioid (range 22% to 70%) and time between first and second opioid (range 2% to 36%; both P<.001). There was no change in timeliness to first dose or time between doses across years (P>.05 for both). Conclusion: Guideline adherence for timeliness of SCD treatment is poor, with half of visits adherent for time to first opioid and one seventh adherent for second dose. Dissemination and implementation research/quality improvement efforts are critical to improve care across EDs. Abstract source

Study objective: We provide an updated assessment of trends in sickle cell disease (SCD)–related mortality, a significant source of mortality in the United States among black persons, using 1979 to 2017 US mortality data. Methods: SCD-related deaths were identified with International Classification of Diseases codes. Because SCD-related death is rare in other races, the analysis focused on black decedents. Age-specific and average annual SCD-related death rates were calculated. Causes of death codes were categorized into 20 groups relevant to SCD outcomes. SCD-related deaths were compared with non–SCD-related deaths after matching on race, sex, age group, and year of death. Results: There were 25,665 SCD-related deaths reported among blacks in the United States from 1979 through 2017. During that period, the annual SCD-related death rate declined in children and increased in adults, and the median age at death increased from 28 to 43 years. Acute causes of death, such as infection and cerebrovascular complications, were more common in younger age groups. Chronic complications were more common in adults. SCD-related deaths were more likely to be related to acute cardiac, pulmonary, and cerebrovascular complications; acute infections; and chronic cardiac and pulmonary complications and renal disorders; and less likely to be related to drug overdose and chronic infections than non–SCD-related deaths. Conclusion: These data indicate SCD-related deaths are now more likely to be related to chronic complications of the disease than to acute complications. More research regarding prevention and treatment of chronic complications of SCD is necessary because persons with SCD are living longer. Abstract source