Disparities in pediatric hospital use during transition to adult healthcare for young adults with childhood-onset chronic conditions.

BACKGROUND: Young adults (YA) with childhood-onset chronic conditions-particularly YA with cystic fibrosis (CF), congenital heart disease (CHD), and sickle cell disease (SCD)-continue to have pediatric hospital admissions. Factors associated with this continued pediatric hospital use remain underexplored. OBJECTIVE: To determine if pediatric hospital use by YA differed (1) across condition and (2) within each condition by sociodemographic factors. METHODS: Conducted a cross-sectional analysis of admissions for YA 22-35 years with CF, CHD, and SCD from 2016 to 2020 in the National Inpatient Sample. Admissions for YA with CF, CHD, and SCD were identified by international classification of diseases, 10th revision-clinical modification diagnosis codes. To determine if conditions or sociodemographic factors were associated with YA pediatric hospital use, we used multivariable logistic regression with separate models for the different objectives. RESULTS: YA with SCD had lower odds of pediatric hospital use compared to YA with CF. Relationships between sociodemographic factors and pediatric hospital use varied. Black YA with both CF and CHD had lower odds of pediatric hospital use than white YA with CF and CHD. For YA with SCD, despite 17,810 (6.5%) having rural residence, zero (0) had pediatric hospital use; whereas YA with CF living in a rural area had greater odds of pediatric hospital use compared to urban residents. CONCLUSION: YA with SCD used pediatric hospitals less than YA with either CF or CHD. Coupled with our findings that Black YA with CF and CHD had less pediatric hospital use, these data may reflect systematic racial differences within pediatric to adult healthcare transition programs.

Current Evidence and Rationale to Guide Perioperative Management, Including Transfusion Decisions, in Patients With Sickle Cell Disease.

Sickle cell disease (SCD) is a collection of inherited hemoglobin disorders that results in chronic hemolytic anemia, vaso-occlusion, pain, and end organ damage. Surgery in the SCD population requires careful planning, as perioperative stressors can lead to increased sickling and risk of inducing or further exacerbating vaso-occlusive episodes (VOEs). Additionally, the underlying hypercoagulability and immunocompromised state due to SCD places patients at increased risk of both venous thromboembolism and infection. Judicious fluid administration, temperature regulation, thorough preoperative and postoperative analgesic planning, and preoperative transfusion are all crucial components of decreasing risks of surgery in patients with SCD.

An evaluation of cardiopulmonary endurance and muscular strength in adults living with sickle cell disease.

There have been limited investigations into exercise in sickle cell disease (SCD). In the general population, health is reflected in general physical fitness. It is unclear if the same associations are seen in people with SCD. Here, we report a cross-sectional assessment of two important measures of physical fitness, muscle strength and cardiorespiratory endurance, in adults with SCD. A total of 29 adults with SCD (aged 24-62 years; 72% female) completed cardiopulmonary and muscular strength testing using a cycle ergometer and an isokinetic dynamometer. Adults with SCD had lower median values for cardiorespiratory endurance (the median [interquartile range, IQR] peak oxygen uptake [VO2 ] 16.1 [6.3] vs. 42.65 [11.3] ml/kg/min, p < 0.001) and knee strength (median [IQR] flexor torque 26.91[22.5] vs. 55.6 [22.7] Nm, p < 0.001) compared to controls and predicted values. Interestingly, there was a very positive association between muscular strength and peak VO2 values for adults with SCD (r = 0.53, p = 0.003) suggesting these values may be useful in determining cardiopulmonary health.

Low rates of transfusion-transmitted infection screening in chronically transfused adults with sickle cell disease.

BACKGROUND: Adults with sickle cell disease (SCD) on chronic transfusion therapy are exposed to a large volume of blood products, thus increasing their risk of transfusion-associated human immunodeficiency virus (HIV), hepatitis C (HCV), and hepatitis B (HBV). METHODS: We performed a systematic chart review of chronically transfused SCD subjects at the Johns Hopkins Sickle Cell Center for Adults between October 2014 and September 2019 to determine our Center's adherence to the 2014 National Heart, Lung and Blood Institute (NHLBI) SCD guidelines for annual screening for Transfusion Transmitted infections (TTI) and assessed HBV immunity and HBV vaccination rates. RESULTS: The study included 85 subjects with a median age of 34 years (23-63); 52% were female. No subject received annual screening; 68 subjects (80%) were screened for HIV, 60 subjects (71%) for HCV and 53 subjects (62%) for HBV infections at least once in the study period. Of those screened, one patient was newly diagnosed with HCV infection, and none with HIV or HBV infection. Among 31 subjects tested for anti-Hepatitis B surface antibody, 16 subjects (52%) tested negative. Nineteen (20%) subjects had HBV vaccination documented. CONCLUSIONS: Low adherence to the NHLBI TTI screening guidelines, especially for HBV, highlights the resource intensiveness of this patient population. The low rates of anti-Hepatitis B surface antibody positivity highlight the need to confirm vaccination, provide boosters as indicated, and investigate the adults with SCD's immune response to HBV vaccination.

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.

2019 sickle cell disease guidelines by the American Society of Hematology: methodology, challenges, and innovations.

The American Society of Hematology (ASH) convened 5 guideline panels to develop clinical practice recommendations addressing 5 management areas of highest importance to individuals living with sickle cell disease: pain, cerebrovascular complications, pulmonary and kidney complications, transfusion, and hematopoietic stem cell transplant. Panels were multidisciplinary and consisted of patient representatives, content experts, and methodologists. The Mayo Clinic Evidence-Based Practice Center conducted systematic reviews based on a priori selected questions. In this exposition, we describe the process used by ASH, including the GRADE approach (Grades of Recommendations, Assessment, Development and Evaluation) for rating certainty of the evidence and the GRADE Evidence to Decision Framework. We also describe several unique challenges faced by the guideline panels and the specific innovations and solutions used to address them, including a curriculum to train patients to engage in guideline development, dealing with the opioid crisis, and working with indirect and noncomparative evidence.

National trends in hydroxyurea and opioid prescribing for sickle cell disease by office-based physicians in the United States, 1997-2017.

PURPOSE: To identify trends in physician drug prescribing practices for sickle cell disease (SCD). METHODS: We used data from the National Disease and Therapeutic Index to evaluate medications prescribed to children (definition: aged 19 years or younger) and adults (20 years or older) with SCD by office-based physicians in the United States during 1997 to 2017. Prescriptions were evaluated in 3-year intervals. RESULTS: The proportion of SCD visits that included new/continued hydroxyurea prescriptions increased from less than or equal to 8% before 2009 to 33% in 2015 to 2017. The increase was significant in visits by children (2.5% in 1997-1999 to 47% in 2015-2017; P = .003 by Spearman's rank-order correlation) but not in adults (6.9% to 11%; P = .12). Opioids, started/continued in 13% (lowest 3-year average) to 35% (highest) of visits by children and 55% to 81% of visits by adults, remained the most frequently prescribed medications for SCD overall. There were no significant changes over time in opioid prescribing for adults (P = .64) or children (P = .38). Hematologists/oncologists accounted for a higher proportion of visits by children (67.2% over 1997-2017) than adults (25.2%), while emergency medicine visits were higher in adults (14.0%) than children (2.6%). CONCLUSIONS: This study suggests a robust increase in hydroxyurea prescribing for children with SCD. The BABY HUG trial, which demonstrated safety and efficacy of starting hydroxyurea in infancy and informed current SCD guidelines recommending broader use in children, may have contributed to this increase. However, hydroxyurea prescribing for adults remains infrequent and considerably lower than opioids. Barriers in access to specialist care persist for adults with SCD.

Clinical and Ophthalmic Factors Associated With the Severity of Sickle Cell Retinopathy.

PURPOSE: To identify associations between severity of sickle cell retinopathy (SCR) and other clinical, laboratory, or treatment factors relevant to sickle cell disease (SCD). DESIGN: Retrospective cohort study. METHODS: We investigated clinical, laboratory, and demographic associations with the severity of SCR in 296 patients seen at both our SCD specialty clinic and our retina clinic. Multivariate multinomial logistic regression was used to estimate the association between each clinical variable and severity of SCR. RESULTS: Multivariate analysis showed that in patients with sickle cell anemia (SCA) genotypes, older age (95% confidence interval [CI], 1.04-1.15; P < .001) and male sex (95% CI, 0.13-0.87; P = .02) were associated with proliferative sickle cell retinopathy (PSR). In patients with genotypic variants, visual symptoms (95% CI, 1.36-21.62; P = .02) were associated with PSR. Laser photocoagulation and vitrectomy surgery, the standard interventions for PSR, were associated with older age (95% CI, 1.05-1.13; P < .001), visual symptoms (95% CI, 1.48-7.40; P = .004), higher hemoglobin level (95% CI, 1.14-1.65; P = .001), and no chronic transfusion (95% CI, 0.16-1.09; P = .08) across the whole cohort. CONCLUSIONS: These findings may inform clinicians of the symptoms, systemic findings, and disease-modifying therapies most frequently associated with SCR in SCD patients. Visual symptoms such as blurred vision or floaters were associated with progression of SCR and may be criteria for referral for retinal examination. Chronic transfusion therapy may be protective against the need for retinal laser photocoagulation or vitrectomy. Prospective studies are necessary to further explore risk factors for SCR and to identify which individuals with SCD are at risk for incident or progression of retinopathy.

Risks associated with fertility preservation for women with sickle cell anemia.

OBJECTIVE: To highlight the risk of complications among women with sickle cell anemia (SCA) receiving fertility preservation treatment (FPT) before hematopoietic stem cell transplant (HSCT). DESIGN: Single-center case series. SETTING: Academic fertility center. PATIENT(S): Women aged 15-32 years with SCA undergoing FPT before HSCT. INTERVENTION(S): Retrospective, systematic review. MAIN OUTCOME MEASURE(S): FPT modality, SCA complications during FPT. RESULT(S): Over an 8-year period (2009-2017), seven women with SCA ages 15-32 years (mean 28.5 years) underwent FPT with embryo cryopreservation (n = 1), oocyte cryopreservation (n = 4), and ovarian tissue cryopreservation (n = 2). The five women subjects who underwent oocyte or embryo cryopreservation were treated with an antagonist controlled ovarian hyperstimulation protocol and individualized gonadotropin dosing. The trigger medications included leuprolide acetate (n = 2), and human chorionic gonadotropin (n = 3). Most patients (n = 5) received a disease-modifying therapy for SCA (hydroxyurea or chronic transfusions) before FPT. Three patients experienced periprocedural SCA complications that included life-threatening respiratory failure, painful crisis requiring interruption of a stimulation cycle, and severe postharvest painful crisis. CONCLUSION(S): Women with SCA may choose to undergo diverse FPT strategies before HSCT and are at risk for serious SCA-related complications. Evidence-based strategies to mitigate SCA-related morbidity and to optimize fertility preservation outcomes are needed.

A prospective quality improvement initiative in adult hemophagocytic lymphohistiocytosis to improve testing and a framework to facilitate trigger identification and mitigate hemorrhage from retrospective analysis.

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal, hyperinflammatory syndrome in adults triggered by an underlying illness in most cases. As such, suspicion of HLH dictates further investigation to identify the HLH trigger and determine treatment. HLH is clinically challenging due to diverse presentations and underlying triggers, provider unfamiliarity, and bleeding complications. Clinically, we observed diagnostic error from incorrect testing and cognitive biases (interleukin-2 confused with soluble interleukin-2 receptor and natural killer cell quantification confused with functional assays).This study reports our single institutional experience with adult HLH with the aim to reduce erroneous testing with a quality improvement (QI) project, and to facilitate trigger discovery and mitigate hemorrhage. Provider education on HLH testing was the prospective intervention, followed by mistaken test removal. HLH triggers and diagnostic utility were determined by retrospective chart review. Risk factors for hemorrhage were determined by multivariable analysis.Erroneous HLH testing was reduced from 74% to 24% of patients (P < .001) by the QI intervention. These changes were projected to save $11,700 yearly. The majority (64%) of patients evaluated for HLH were on non-hematology/oncology services, highlighting the need for vigilance in hematology consultation. Sixty-three patients met classic HLH-2004 criteria for HLH. Malignancy (38%), infection (27%), Epstein-Barr virus (EBV) (14%), or autoimmune disease (8%) triggered most HLH cases. HLH triggers were most commonly identified by serologic testing (27%) and bone marrow biopsy (19%). Biopsy of other affected organs based on PET-CT imaging after unsuccessful initial diagnostic measures was helpful, and focal fluorodeoxyglucose uptake was predictive of an underlying malignancy (likelihood ratio 8.3, P = .004). Major hemorrhage occurred in 41% of patients. On multivariable analysis the odds ratios (OR) for major hemorrhage were increased for patients with intensive care unit level care (OR 10.47, P = .005), and disseminated intravascular coagulation in the first week of admission (OR 10.53, P = .04).These data are incorporated into a framework to encourage early HLH recognition with the HScore, facilitate trigger identification, identify those at risk for hemorrhage, and minimize low-yield or erroneous testing.

Transition to adulthood and adult health care for patients with sickle cell disease or cystic fibrosis: Current practices and research priorities.

INTRODUCTION: A growing population of adults living with severe, chronic childhood-onset health conditions has created a need for specialized health care delivered by providers who have expertise both in adult medicine and in those conditions. Optimal care of these patients requires systematic approaches to healthcare transition (HCT). Guidelines for HCT exist, but gaps in care occur, and there are limited data on outcomes of HCT processes. METHODS: The Single Disease Workgroup of the Lifespan Domain Task Force of the National Center for Advancing Translational Sciences Clinical and Translational Science Award programs convened a group to review the current state of HCT and to identify gaps in research and practice. Using cystic fibrosis and sickle cell disease as models, key themes were developed. A literature search identified general and disease-specific articles. We summarized key findings. RESULTS: We identified literature characterizing patient, parent and healthcare provider perspectives, recommendations for transition care, and barriers to effective transition. CONCLUSIONS: With increased survival of patients with severe childhood onset diseases, ongoing study of effective transition practices is essential as survival increases for severe childhood onset diseases. We propose pragmatic methods to enhance transition research to improve health and key outcomes.

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.

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.

Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia.

Chronic leg ulcers are frequent and debilitating complications of sickle cell anemia. Inadequate blood supply has been postulated to be an important factor in their occurrence and delayed healing. Little is known about their microcirculatory and histopathological changes. We evaluated the microcirculation of lower extremity ulcers with laser speckle contrast imaging and infrared thermography and obtained clinical and laboratory characteristics in 18 adults with sickle cell anemia and chronic leg ulcers. Skin biopsies were obtained in four subjects. Subjects had markers of severe disease, anemia, high degree of hemolysis, inflammation, and thrombophilia. The highest blood flow was present in the ulcer bed, progressively less in the immediate periwound area, and an unaffected control skin area in the same extremity. Microscopic examination showed evidence of venostasis, inflammation, and vasculopathy. Blood vessels were increased in number, had activated endothelium and evidence of thrombosis/recanalization. High blood flow may be due to chronic inflammation, cutaneous vasodilatation, venostasis, and in situ thrombosis. These changes in skin microcirculation are similar to chronic venous ulcers in the non-sickle cell disease (SCD) population, thus suggesting that leg ulcers may be another end-organ complication with endothelial dysfunction that appears in patients with SCD at a younger age and with higher frequency than in the general population.

Sickle cell disease and venous thromboembolism: what the anticoagulation expert needs to know.

Venous thromboembolism (VTE) is common in patients with sickle cell disease (SCD). The etiology of increased risk of VTE in SCD patients is multifactorial and is related to both traditional factors and SCD-specific factors. Traditional risk factors such as central venous catheters, frequent hospitalization, orthopedic surgeries for avascular necrosis, and pregnancy may lead to increased incidence of VTE in the SCD population. In addition, SCD itself appears to be a hypercoagulable state, and many SCD-specific factors such as thrombophilic defects, genotype and splenectomy may modify the risk of VTE. SCD complications such as acute chest syndrome and pulmonary hypertension may also be related to VTE. Anticoagulation experts should be aware of these factors to help inform prophylaxis and treatment decisions.

HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease.

Allogeneic marrow transplantation can cure sickle cell disease; however, HLA-matched donors are difficult to find, and the toxicities of myeloablative conditioning are prohibitive for most adults with this disease. We developed a nonmyeloablative bone marrow transplantation platform using related, including HLA-haploidentical, donors for patients with sickle cell disease. The regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, and graft-versus-host disease prophylaxis with posttransplantation high-dose cyclophosphamide, mycophenolate mofetil, and tacrolimus or sirolimus. After screening 19 patients, we transplanted 17, 14 from HLA-haploidentical and 3 from HLA-matched related donors. Eleven patients engrafted durably. With a median follow-up of 711 days (minimal follow up 224 days), 10 patients are asymptomatic, and 6 patients are off immunosupression. Only 1 patient developed skin-only acute graft-versus-host disease that resolved without any therapy; no mortality was seen. Nonmyeloablative conditioning with posttransplantation high-dose cyclophosphamide expands the donor pool, making marrow transplantation feasible for most patients with sickle cell disease, and is associated with a low risk of complications, even with haploidentical related donors. Graft failure, 43% in haploidentical pairs, remains a major obstacle but may be acceptable in a fraction of patients if the majority can be cured without serious toxicities.