Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity.

Importance: Sickle cell disease (SCD) and cystic fibrosis (CF) are severe autosomal recessive disorders associated with intermittent disease exacerbations that require hospitalizations, progressive chronic organ injury, and substantial premature mortality. Research funding is a limited resource and may contribute to health care disparities, especially for rare diseases that disproportionally affect economically disadvantaged groups. Objective: To compare disease-specific funding between SCD and CF and the association between funding and research productivity. Design, Setting, and Participants: This cross-sectional study examined federal and foundation funding, publications indexed in PubMed, clinical trials registered in ClinicalTrials.gov, and new drug approvals from January 1, 2008, to December 31, 2018, in an estimated US population of approximately 90 000 individuals with SCD and approximately 30 000 individuals with CF. Main Outcomes and Measures: Federal and foundation funding, publications indexed in PubMed, clinical trial registrations, and new drug approvals. Results: From 2008 through 2018, federal funding was greater per person with CF compared with SCD (mean [SD], $2807 [$175] vs $812 [$147]; P < .001). Foundation expenditures were greater for CF than for SCD (mean [SD], $7690 [$3974] vs $102 [$13.7]; P < .001). Significantly more research articles (mean [SD], 1594 [225] vs 926 [157]; P < .001) and US Food and Drug Administration drug approvals (4 vs 1) were found for CF compared with SCD, but the total number of clinical trials was similar (mean [SD], 27.3 [6.9] vs 23.8 [6.3]; P = .22). Conclusions and Relevance: The findings show that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD. Increased federal and foundation funding is needed for SCD and other diseases that disproportionately affect economically disadvantaged groups to address health care disparities.

Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review.

Background: Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes. Purpose: To evaluate associations between SCT and clinical outcomes in children and adults. Data Sources: English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles. Study Selection: Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality. Data Extraction: A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus. Data Synthesis: Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low. Limitation: Publication bias was possible, and high-quality evidence was scant. Conclusion: Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT. Primary Funding Source: National Human Genome Research Institute.

Chronic Opioid Therapy and Central Sensitization in Sickle Cell Disease.

Chronic opioid therapy (COT) for chronic non-cancer pain is frequently debated, and its effectiveness is unproven in sickle cell disease (SCD). The authors conducted a descriptive study among 83 adult SCD patients and compared the severity of disease and pain symptoms among those who were prescribed COT (n=29) with those who were not using COT. All patients completed baseline laboratory pain assessment and questionnaires between January 2010 and June 2014. Thereafter, participants recorded daily pain, crises, function, and healthcare utilization for 90 days using electronic diaries. Analyses were conducted shortly after the final diary data collection period. Patients on COT did not differ on age, sex, or measures of disease severity. However, patients on COT exhibited greater levels of clinical pain (particularly non-crisis); central sensitization; and depression and increased diary measures of pain severity, function, and healthcare utilization on crisis and non-crisis diary days, as well as a greater proportion of days in crisis. Including depressive symptoms in multivariate models did not change the associations between COT and pain, interference, central sensitization, or utilization. Additionally, participants not on COT displayed the expected positive relationship between central sensitization and clinical pain, whereas those on COT demonstrated no such relationship, despite having both higher central sensitization and higher clinical pain. Overall, the results point out a high symptom burden in SCD patients on COT, including those on high-dose COT, and suggest that nociceptive processing in SCD patients on COT differs from those who are not.

An Evaluation of Central Sensitization in Patients With Sickle Cell Disease.

UNLABELLED: Central sensitization (CS), nociceptive hyperexcitability known to amplify and maintain clinical pain, has been identified as a leading culprit responsible for maintaining pain in several chronic pain conditions. Recent evidence suggests that it may explain differences in the symptom experience of individuals with sickle cell disease (SCD). Quantitative sensory testing (QST) can be used to examine CS and identify individuals who may have a heightened CS profile. The present study categorized patients with SCD on the basis of QST responses into a high or low CS phenotype and compared these groups according to measures of clinical pain, vaso-occlusive crises, psychosocial factors, and sleep continuity. Eighty-three adult patients with SCD completed QST, questionnaires, and daily sleep and pain diaries over a 3-month period, weekly phone calls for 3 months, and monthly phone calls for 12 months. Patients were divided into CS groups (ie, no/low CS [n = 17] vs high CS [n = 21]), on the basis of thermal and mechanical temporal summation and aftersensations, which were norm-referenced to 47 healthy control subjects. High CS subjects reported more clinical pain, vaso-occlusive crises, catastrophizing, and negative mood, and poorer sleep continuity (Ps < .05) over the 18-month follow-up period. Future analyses should investigate whether psychosocial disturbances and sleep mediate the relationship between CS and pain outcomes. PERSPECTIVE: In general, SCD patients with greater CS had more clinical pain, more crises, worse sleep, and more psychosocial disturbances compared with the low CS group.

Quantitative sensory testing and pain-evoked cytokine reactivity: comparison of patients with sickle cell disease to healthy matched controls.

Sickle cell disease (SCD) is an inherited blood disorder associated with significant morbidity, which includes severe episodic pain, and, often, chronic pain. Compared to healthy individuals, patients with SCD report enhanced sensitivity to thermal detection and pain thresholds and have altered inflammatory profiles, yet no studies to date have examined biomarker reactivity after laboratory-induced pain. We sought to examine this relationship in patients with SCD compared to healthy control participants. We completed quantitative sensory testing in 83 patients with SCD and sequential blood sampling in 27 of them, whom we matched (sex, age, race, body mass index, and education) to 27 healthy controls. Surprisingly, few quantitative sensory testing differences emerged between groups. Heat pain tolerance, pressure pain threshold at the trapezius, thumb, and quadriceps, and thermal temporal summation at 45°C differed between groups in the expected direction, whereas conditioned pain modulation and pain ratings to hot water hand immersion were counterintuitive, possibly because of tailoring the water temperature to a perceptual level; patients with SCD received milder temperatures. In the matched subsample, group differences and group-by-time interactions were observed in biomarkers including tumor necrosis factor alpha, interleukin-1ß, interleukin-4, and neuropeptide Y. These findings highlight the utility of laboratory pain testing methods for understanding individual differences in inflammatory cytokines. Our findings suggest amplified pain-evoked proinflammatory cytokine reactivity among patients with SCD relative to carefully matched controls. Future research is warranted to evaluate the impact of enhanced pain-related cytokine response and whether it is predictive of clinical characteristics and the frequency/severity of pain crises in patients with SCD.

Sickle cell trait diagnosis: clinical and social implications.

The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT.

The five key things you need to know to manage adult patients with sickle cell disease.

The lack of a strong evidence base to guide the management of adults with sickle cell disease (SCD) makes it difficult for patients to receive high quality care outside of specialty centers. As there is a dearth of providers with sickle cell expertise, the purpose of this article is to identify some of the key things every provider who manages the care of adults with SCD should know. Managing adults with SCD requires excellent clinical skills, as it can affect every organ and cause life-threatening complications but it also requires a willingness to manage patients who often have psychosocial issues that are complex and impact care and care delivery in very significant ways. We have chosen topics for which there is a limited evidence base but which have significant clinical consequences if left unrecognized or poorly managed. The topics that will be addressed include chronic pain, neurocognitive dysfunction, renal disease, venous thromboembolism, and avoiding the inappropriate use of red cell transfusions.

Sickle cell disease in the United States: looking back and forward at 100 years of progress in management and survival.

The past 100 years since James Herrick's first description of sickle cell disease in the United States have been characterized by the gradual development of management strategies. We review the progress in sickle cell disease management in the United States over the past 100 years, with emphasis on the diverse forces surrounding advances in disease management. Mortality and survival data are presented chronologically, with an attempt to highlight improvements in survival associated with specific advancements for pediatric and adult care. Finally, the future course for sickle cell disease management is explored, given the continued work in advancing the field.

Hydroxyurea for the treatment of sickle cell disease.

OBJECTIVES: To synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea (HU) when used for treatment of sickle cell disease (SCD); and to review the evidence regarding barriers to its use. DATA SOURCES: Articles cited in MEDLlNE, EMBASE, TOXLine, and CINAHL through June 30, 2007. REVIEW METHODS: Paired reviewers reviewed each title, abstract, and article to assess eligibility. They abstracted data sequentially and then independently graded the evidence. RESULTS: In one small, randomized trial of HU in children with SCD; the yearly hospitalization rate was lower with HU than placebo (1.1 versus 2.8, p=0.002). The absolute increase in fetal hemoglobin (Hb F%) was 10.7 percent. Twenty observational studies of HU in children reported similar increases in Hb F%, while hemoglobin concentration increased by roughly 1 g/dl. One large randomized trial tested the efficacy of HU in adults with SCD and found that after 2 years of treatment, Hb F% increased by 3.2 percent and hemoglobin increased by 0.6 g/dl, The median number of painful crises was 44 percent (p<0.001) lower among patients treated with HU. The 12 observational studies of HU enrolling adults with SCD supported these findings. Panelists from the Center for the Evaluation of Risks to Human Reproduction reviewed the literature for potential toxicities of HU. They concluded that HU does not cause a growth delay in children 5-15 years old. There were no data on the effects on subsequent generations following exposure of developing germ cells to HU in utero. Some evidence supported impaired spermatogenesis with use of HU. Although we identified six patients taking HU who developed leukemia, the evidence did not support causality. Similarly, the evidence suggested no association between HU and leg ulcers in patients with SCD, although there was in patients with other illnesses. The literature supported neutropenia, skin rashes and nail changes associated with use of HU, but was sparse regarding skin neoplasms or other secondary malignancies in SCD. Only two studies investigated barriers to use of HU. Perceived efficacy and perceived safety of HU had the largest influence on patients' (or parents' ) choice to use HU. Providers reported barriers to be patient concerns about side effects; and their own concerns about HU in older patients, patient compliance, lack of contraception, side effects and carcinogenic potential, doubts about effectiveness, and concern about costs. CONCLUSIONS: HU is efficacious in children and adults with SCD; with an increase in Hb F%, and reduction in hospitalizations and pain crises. However, few studies have measured the effectiveness of HU for SCD in usual practice. The paucity of long-term studies limits conclusions about toxicities and about mortality. Future studies of interventions to overcome the barriers to use of HU in patients with SCD are necessary.

Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease.

BACKGROUND: Hydroxyurea is the only approved drug for treatment of sickle cell disease. OBJECTIVE: To synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea when used in adults with sickle cell disease. DATA SOURCES: MEDLINE, EMBASE, TOXLine, and CINAHL were searched through 30 June 2007. STUDY SELECTION: Randomized trials, observational studies, and case reports evaluating efficacy and toxicity of hydroxyurea in adults with sickle cell disease, and toxicity studies of hydroxyurea in other conditions that were published in English. DATA EXTRACTION: Paired reviewers abstracted data on study design, patient characteristics, and outcomes sequentially and did quality assessments independently. DATA SYNTHESIS: In the single randomized trial, the hemoglobin level was higher in hydroxyurea recipients than placebo recipients after 2 years (difference, 6 g/L), as was fetal hemoglobin (absolute difference, 3.2%). The median number of painful crises was 44% lower than in the placebo group. The 12 observational studies that enrolled adults reported a relative increase in fetal hemoglobin of 4% to 20% and a relative reduction in crisis rates by 68% to 84%. Hospital admissions declined by 18% to 32%. The evidence suggests that hydroxyurea may impair spermatogenesis. Limited evidence indicates that hydroxyurea treatment in adults with sickle cell disease is not associated with leukemia. Likewise, limited evidence suggests that hydroxyurea and leg ulcers are not associated in patients with sickle cell disease, and evidence is insufficient to estimate the risk for skin neoplasms, although these outcomes can be attributed to hydroxyurea in other conditions. LIMITATION: Only English-language articles were included, and some studies were of lower quality. CONCLUSION: Hydroxyurea has demonstrated efficacy in adults with sickle cell disease. The paucity of long-term studies limits conclusions about toxicity.