Silent cerebral infarction during immune TTP remission: prevalence, predictors, and impact on cognition.

Immune thrombotic thrombocytopenic purpura (iTTP) survivors have increased risk of cardiovascular disease, including strokes, and report persistent cognitive difficulties during remission. We conducted this prospective study involving iTTP survivors during clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neurodeficits. We also tested the hypothesis that SCI is associated with cognitive impairment, assessed using the National Institutes of Health ToolBox Cognition Battery. For cognitive assessments, we used fully corrected T scores adjusted for age, sex, race, and education. Based on the diagnostic and statistical manual 5 criteria, we defined mild and major cognitive impairment as T scores with a 1 or 2 standard deviation (SD) and >2 SD below the mean on at least 1 test, respectively. Forty-two patients were enrolled, with 36 completing MRIs. SCI was present in 50% of the patients (18), of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs 27.7%; P = .026), including major cognitive impairment (50% vs 5.6%; P = .010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment (odds ratio [OR] 10.5 [95% confidence interval (95% CI), 1.45-76.63]; P = .020) and major cognitive impairment (OR 7.98 [95% CI, 1.11-57.27]; P = .039) after adjusting for history of stroke and Beck depression inventory scores. MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these silent infarcts are neither silent nor innocuous.

Mental health, pain and likelihood of opioid misuse among adults with sickle cell disease.

Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.

Short-term air pollution levels and sickle cell disease hospital encounters in South Carolina: A case-crossover analysis.

BACKGROUND: Sickle cell disease (SCD) is a genetic disorder and symptoms may be sensitive to environmental stressors. Although it has been hypothesized that exposure to outdoor air pollution could trigger acute SCD events, evidence is limited. METHODS: We obtained SCD administrative data on hospital encounters in South Carolina from 2002 to 2019. We estimated outdoor air pollutant (particulate matter<2.5 µm (PM2.5), ozone (O3), and PM2.5 elemental carbon (EC) concentrations at residential zip codes using spatio-temporal models. Using a random bi-directional, fixed-interval case-crossover study design, we investigated the relationship between air pollution exposure over 1-, 3-, 5-, 9-, and14-day periods with SCD hospital encounters. RESULTS: We studied 8410 patients with 144,129 hospital encounters. We did not observe associations among all patients with SCD and adults for PM2.5, O3, and EC. We observed positive associations among children for 9- and 14-day EC (OR: 1.05 (95% confidence interval (CI): 1.02, 1.08) and OR: 1.05 (95% CI: 1.02, 1.09), respectively) and 9- and 14-day O3 (OR: 1.04 (95%CI: 1.00, 1.08)) for both. CONCLUSIONS: Our findings suggest that short-term (within two-weeks) levels of EC and O3 and may be associated with SCD hospital encounters among children. Two-pollutant model results suggest that EC is more likely responsible for effects on SCD than O3. More research is needed to confirm our findings.

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.

Implementation of national blood conservation recommendations at an adult sickle cell center.

BACKGROUND: Due to the national blood supply crisis caused by the COVID-19 pandemic, the American Society of Hematology proposed guidance to decrease blood utilization for sickle cell patients on chronic transfusion therapy (CTT). Little evidence exists to support the efficacy and safety of these blood conservation strategies. STUDY DESIGN AND METHODS: Through retrospective analysis, we sought to describe outcomes following implementation of these recommendations in 58 adult sickle cell patients on chronic exchange transfusions. The strategies employed included: relaxing the goal fraction of cells remaining (FCR) to 30%-50%, utilizing depletion exchanges in select patients, and transitioning select patients to monthly simple transfusions. We compared hemoglobin S%, hemoglobin values, and other laboratory parameters, acute care visits, and red blood cell usage during the first year of the COVID-19 pandemic to the year prior using Wilcoxon signed rank test. RESULTS: Of 53 patients who remained on chronic exchanges during the pandemic, use of depletion exchange increased (15%-23%) and FCR increased (34.9 [SD 4.7] vs. 37.6 [SD 4.5], p < .05). These changes resulted in 854 units conserved without clinically significant changes to pre-exchange laboratory parameters, including hemoglobin S%, or number of acute care presentations. In contrast, five patients who transitioned to predominantly simple transfusions, experienced difficulty maintaining hemoglobin S% less than 30 and worsening anemia. DISCUSSION: Our data suggest that in a blood shortage crisis, optimizing the exchange procedure itself may be the safest means of conserving blood in a population of adult patients with sickle cell disease.

Converting adults with sickle cell disease from full agonist opioids to buprenorphine: A reliable method with safety and early evidence of reduced acute care utilization.

Buprenorphine, a novel opioid with complex pharmacology, is effective for treating pain and is qualitatively safer than high-dose full agonist opioid therapy; but transitioning to buprenorphine can be technically complex and carries some risk of precipitated withdrawal. We report our clinic's experience converting 36 patients with sickle cell disease (SCD) from full agonist opioids to buprenorphine using a method developed in the past 10 years. Thirty of these patients were induced using a standard outpatient protocol and six were induced during medical admissions. Typically, patients were on high-dose chronic opioid therapy (COT) with inadequate response, and often with very high acute care utilization. Unlike prior case series, the method of induction, dosing, and management of withdrawal are detailed, as are post-induction adverse events. There were seven adverse events in the first 3 days following standard induction, and two of which were judged to be definitely related to the induction but none with any lasting sequelae. At 6 months follow-up, five participants had discontinued buprenorphine (16.67%), and overall acute care visits dropped from a mean of 10.50 (SD 11.35) in the 6 months pre-induction to 2.89 (SD 3.40) in the 6 months post-induction. In an appropriately interdisciplinary care setting, buprenorphine shows promise as a safe alternative to COT with early evidence of benefit for high-utilizing patients with SCD.

A Preliminary Investigation of the Underlying Mechanism Associating Daily Sleep Continuity Disturbance and Prescription Opioid Use Among Individuals With Sickle Cell Disease.

BACKGROUND: There are emerging data indicating that sleep disturbance may be linked with an increase in opioid use. The majority of sickle cell disease (SCD) patients experience sleep disturbances, which can elevate pain severity and pain catastrophizing, both of which are important predictors of opioid consumption. PURPOSE: We conducted a preliminary investigation on the association between previous night sleep disturbance and short-acting opioid use, as well as the potential mediating roles of pain severity and pain catastrophizing. Because sex is associated with sleep disturbance, pain-related experiences, and opioid use, we also explored the potential moderating role of sex. METHODS: Participants were 45 SCD patients who were prescribed opioids. For 3 months, sleep diaries were collected immediately upon participants' awakening. Daily pain severity, pain catastrophizing, and prescription opioid use measures were collected before bedtime. RESULTS: Multilevel structural equation modeling revealed that wake time after sleep onset (WASO) during the previous night (Time 1) predicted greater short-acting opioid use during the next day (Time 2). Pain severity and pain catastrophizing measured during the next day (Time 2) also mediated the association between the two. Sex moderation analysis showed that the positive association between WASO and pain severity was largely driven by women. CONCLUSION: These findings provide some preliminary evidence as to the mechanism linking sleep continuity disturbance and opioid requirement in SCD patients. Future studies should replicate and extend these findings with clearer temporal information and employing more refined measures of sleep continuity and prescription opioid use in a larger sample.

A case-control analysis of hyperhemolysis syndrome in adults and laboratory correlates of complement involvement.

BACKGROUND: Hyperhemolysis syndrome (HS) is a poorly understood, severe hemolytic anemia provoked by transfusion. Both host and donor RBCs are destroyed in HS; thus, transfusion paradoxically worsens anemia. Risk factors and mechanism of HS are unknown. STUDY DESIGN AND METHODS: A retrospective case-control analysis was performed on adults with HS. Patients with HS were matched 1:1 with matched, transfused controls, and HS risk factors were analyzed with multivariable logistic regression. HS samples were analyzed for complement deposition by flow cytometry, and an in vitro model of bystander hemolysis was developed. RESULTS: Forty-one patients with 54 episodes of HS were identified in a 26-year period from 1992 to 2018. Of the HS episodes, only 18.5% were associated with a new alloantibody, and such patients were more tolerant of additional transfusion in the acute episode (p = 0.005). Thirteen percent of episodes were fatal, and HS recurred in 52.6%. Alloimmunization (odds ratio [OR], 17.3), non-B blood type (OR, 9.8), D antigen (OR, 9.1), and infection (OR, 5.5) were associated with HS on multivariable analysis. Hyperbilirubinemia was predictive of fatal HS (OR, 33.6). Increased complement was observed on RBCs during HS episodes, and the in vitro model of bystander hemolysis recapitulated complement decoration of sickled RBCs. CONCLUSIONS: HS is associated with significant morbidity, mortality, and recurrence. Risk factors such as known alloimmunization, blood group, and infection predispose to HS. Bystander complement activation may drive HS. These factors may help physicians refine risk-benefit assessments for transfusion and guide further therapeutic development.

Examination of the Patient and Hospitalization Characteristics of 30-Day SCD Readmissions.

OBJECTIVES: Sickle cell disease (SCD) is associated with a high level of emergency department and hospital utilization, as well as a high rate of hospital readmissions. At Johns Hopkins Hospital, as at other institutions, SCD accounts for a large proportion of readmissions. Our study examined patient and hospitalization factors involved in readmissions at Johns Hopkins Hospital. METHODS: Patients at the Johns Hopkins Sickle Cell Center for Adults with a readmission in fiscal year 2011 were compared with an age- and sex-matched sample of clinic patients for comorbidities, complications, and prior utilization. Hospitalizations that were followed by readmissions were compared with those that were not as to admitting service, length of stay, and average daily opioid dose. RESULTS: Patients with readmissions had more complications and comorbidities and much higher prior utilization than typical clinic patients, whereas hospitalizations that were followed by readmissions had a longer length of stay but similar opioid doses. CONCLUSIONS: For patients with SCD with a high volume of hospital use, readmissions may be a natural consequence of a high-admission frequency associated with greater disease severity and higher comorbidity.

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.

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.

Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.

IMPORTANCE: Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. OBJECTIVE: To support and expand the number of health professionals able and willing to provide care for persons with SCD. EVIDENCE REVIEW: Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. FINDINGS: Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. CONCLUSIONS AND RELEVANCE: Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

Terminology for Retinal Findings in Sickle Cell Disease Research: A Scoping Review.

OBJECTIVE: To review the current sickle cell disease (SCD) literature to assess how "retinopathy" has been defined and to identify ocular outcomes that have been measured and described. DESIGN: A systematic scoping review of SCD literature was completed regarding ocular manifestations of SCD and vision outcomes across all medical specialties. SUBJECTS: Participants with SCD and control patients were included in our data extraction. METHODS: We reviewed English-language literature from 2000 to 2021 for eligible studies by searching PubMed, Google Scholar, Embase, and the Cochrane library using terms to encompass SCD and ocular findings. MAIN OUTCOME MEASURES: Data collection included study information, patient characteristics, vision-related findings (inclusion criteria and/or study outcomes), and retinopathy characteristics (definition, when, how and by whom diagnosed). RESULTS: We identified 4006 unique citations and 111 were included in the analysis. Ophthalmologists were senior authors of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The studies had been conducted primarily in North America (54/111; 48.6%) or Europe (23/111; 20.7%); designs were cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%), and case-control (4/111; 3.6%). Among studies reporting any retinopathy, it was commonly defined as a combination of nonproliferative sickle cell retinopathy and proliferative sickle cell retinopathy (PSR; 52/87; 59.8%), infrequently as PSR only (6/87; 6.9%), or not defined at all (23/87; 26.4%). The Goldberg classification was used to grade retinopathy in almost half of the studies (41/87; 47.1%). Investigators reporting diagnostic methods used clinical fundus examination (56/111; 50.4%), OCT (24/111; 21.6%), fluorescein angiography (20/111; 18.0%), ultrawidefield fundus photographs (15/111; 13.5%), and OCT angiography (10/111; 9.0%), or did not report methods (28/111; 25.2%). CONCLUSIONS: There are inconsistencies in documentation of methods and outcomes in studies of SCD ophthalmic findings. Particularly concerning is the lack of documentation of ophthalmic examination methods, qualifications of examiners, and clarity and specificity of sickle cell retinopathy definitions. With the increase in SCD treatment research and novel systemic therapies available, it is important to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Depressive and Insomnia Symptoms Sequentially Mediate the Association Between Racism-Based Discrimination in Healthcare Settings and Clinical Pain Among Adults With Sickle Cell Disease.

Racism-based discrimination in healthcare settings has been associated with clinical pain in adults living with sickle cell disease; however, no studies have examined depressive and insomnia symptoms as mechanisms that may drive this relationship. This secondary data analysis examined associations between depressive and insomnia symptoms, racism-based discrimination, and clinical pain. Seventy-one adults with sickle cell disease (70% female, Mage = 38.79) provided baseline reports of racism-based discrimination, depressive symptoms, insomnia symptoms, and pain (severity, interference, catastrophizing), and they completed daily diaries of pain severity and interference over 3 months. In a sequential mediation model, baseline depressive (1st) and insomnia symptoms (2nd) significantly mediated the association between racism-based discrimination and baseline pain interference, average daily diary pain severity, and average daily diary pain interference. Although the mediation model with baseline pain severity as the outcome was significant, the total and direct effects were not. Results indicate that discrimination in healthcare settings contributes to depression, which may act on pain through sleep disturbance. Findings support the need for systemic and structural changes to eliminate discrimination in healthcare settings and behavioral mood and sleep interventions to reduce the impact of discrimination on clinical pain. PERSPECTIVE: The relationship between discrimination in healthcare settings and pain in adults with sickle cell disease may be driven by depression and sleep disturbance, modifiable risk factors and potential treatment targets. Results suggest that systemic, structural, and institutional changes must be implemented to promote better patient care and health outcomes.

Nonmydriatic Ultra-Widefield Fundus Photography in a Hematology Clinic Shows Utility for Screening of Sickle Cell Retinopathy.

PURPOSE: To determine the feasibility and accuracy of nonmydriatic ultra-widefield (UWF) fundus photographs taken in a hematology clinic setting for screening of sickle cell retinopathy (SCR) DESIGN: Prospective cohort study. METHODS: This single-site study took place at the Johns Hopkins Sickle Cell Center for Adults and the Wilmer Eye Institute. The study population was 90 eyes of 46 consecutive adults with sickle cell disease (SCD). Bilateral nonmydriatic fundus photos taken by clinic personnel during the participants' routine hematology appointment were graded by 2 masked retina specialists at the Wilmer Eye Institute for the presence of nonproliferative SCR (NPSR) and proliferative sickle retinopathy (PSR). A third retina specialist adjudicated in cases of grader disagreement. All participants underwent the standard dilated fundus examination (DFE) within 2 years of acquisition of UWF photographs. The main outcome measure was the sensitivity and specificity of nonmydriatic UWF images for the detection of NPSR and PSR RESULTS: PSR was noted in 19 of 90 eyes that underwent DFE and in 9 of 67 gradable UWF images. Interrater agreement between the 2 graders was moderate, with κ = 0.65 (range 0.43-0.87) for PSR. For gradable UWF photos, the sensitivity and specificity of detecting SCR using the nonmydriatic photos compared with the DFE were 85.2% and 62.5% for NPSR, respectively, and 69.2% and 100% for detection of PSR, respectively. One participant required ophthalmic therapy in both eyes for active sea-fan neovascularization. CONCLUSIONS: UWF imaging shows utility in screening for SCR and may help identify patients with PSR who require a DFE and who may benefit from treatment.

Mortality and Access to Kidney Transplantation in Patients with Sickle Cell Disease-Associated Kidney Failure.

BACKGROUND AND OBJECTIVES: Patients with sickle cell disease-associated kidney failure have high mortality, which might be lowered by kidney transplantation. However, because they show higher post-transplant mortality compared with patients with other kidney failure etiologies, kidney transplantation remains controversial in this population, potentially limiting their chance of receiving transplantation. We aimed to quantify the decrease in mortality associated with transplantation in this population and determine the chance of receiving transplantation with sickle cell disease as the cause of kidney failure as compared with other etiologies of kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a national registry, we studied all adults with kidney failure who began maintenance dialysis or were added to the kidney transplant waiting list in 1998-2017. To quantify the decrease in mortality associated with transplantation, we measured the absolute risk difference and hazard ratio for mortality in matched pairs of transplant recipients versus waitlisted candidates in the sickle cell and control groups. To compare the chance of receiving transplantation, we estimated hazard ratios for receiving transplantation in the sickle cell and control groups, treating death as a competing risk. RESULTS: Compared with their matched waitlisted candidates, 189 transplant recipients with sickle cell disease and 220,251 control recipients showed significantly lower mortality. The absolute risk difference at 10 years post-transplant was 20.3 (98.75% confidence interval, 0.9 to 39.8) and 19.8 (98.75% confidence interval, 19.2 to 20.4) percentage points in the sickle cell and control groups, respectively. The hazard ratio was also similar in the sickle cell (0.57; 95% confidence interval, 0.36 to 0.91) and control (0.54; 95% confidence interval, 0.53 to 0.55) groups (interaction P=0.8). Nonetheless, the sickle cell group was less likely to receive transplantation than the controls (subdistribution hazard ratio, 0.73; 95% confidence interval, 0.61 to 0.87). Similar disparities were found among waitlisted candidates (subdistribution hazard ratio, 0.62; 95% confidence interval, 0.53 to 0.72). CONCLUSIONS: Patients with sickle cell disease-associated kidney failure exhibited similar decreases in mortality associated with kidney transplantation as compared with those with other kidney failure etiologies. Nonetheless, the sickle cell population was less likely to receive transplantation, even after waitlist registration.

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.

Identifying Clinical and Research Priorities in Sickle Cell Lung Disease. An Official American Thoracic Society Workshop Report.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality.Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus.Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation.Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.