BACKGROUND:In this planned ancillary analysis of our completed clinical trial, we hypothesized that among older children with sickle cell anemia (SCA) and severe acute malnutrition, those with higher levels of food insecurity would have lower end-of-trial body mass index (BMI) z-scores compared to their peers with SCA and lower levels of food insecurity. PROCEDURE:Data from 108 children who completed the feasibility trial for managing severe acute malnutrition in older children with SCA in Nigeria were analyzed. Children aged 5-12 years old with severe acute malnutrition (BMI z-score of <-3.0) were randomly allocated to receive either supplemental ready-to-use therapeutic food (RUTF) alone or RUTF with moderate-dose hydroxyurea (20 mg/kg/day). Caregivers completed the United States Household Food Security Survey Module to measure food security. We focused on the childhood section for its accuracy in assessing food security in older children. Higher scores (0-8) indicate greater food insecurity. We constructed multivariable linear regression models to estimate the association between childhood food insecurity and BMI z-scores at baseline and endpoint. RESULTS:Most participants were food insecure, with 55% (n = 59) and 34% (n = 37) having low and very low food security, respectively. Higher scores on the continuous food security measure, indicating lower food security, were associated with lower BMI z-scores at both study entry (β = -0.05, p = 0.047) and after malnutrition treatment (β = -0.07, p = 0.016). CONCLUSIONS:Among severely malnourished children with SCA, lower childhood food security scores are associated with an adverse treatment response, reflected by a lower BMI z-score at the trial's end. URL AND TRIAL IDENTIFICATION NUMBER:NCT03634488, https://clinicaltrials.gov/study/NCT03634488.

Stroke in children with sickle cell disease (SCD) is associated with significant morbidity and mortality. Transcranial Doppler (TCD) velocities, specifically time-averaged maximum mean velocity (TAMMV), are critical for stroke risk stratification. Variability in TCD velocity measurements across different machines and ultrasonographers complicates clinical decision-making. Using a phantom Doppler flow machine generating a fixed flow, we evaluated four non-imaging and one imaging TCD machine against a reference TAMMV of 191 cm/s. All machines demonstrated high precision but varied accuracy, with mean velocities ranging from 169 to 189 cm/s. All non-imaging machines underestimated the TAMMV (p < 0.001). The imaging TCD machine also underestimated the velocity, even after a standard adjustment of adding 15 cm/s to the velocity (p < 0.001). Based on the results of the local non-imaging TCD machines accuracy, the northern Nigerian pediatricians agreed on the following threshold for primary stroke prevention for all non-imaging TCD machines: two independent ultrasonographers' velocities for any velocity ≥ 180 cm/sec and < 220 cm/sec or one TCD velocity > 200 cm/sec.

Background: While mobile health (mHealth) apps have been made for various diseases, including sickle cell disease (SCD), most focus on a single purpose. SCD is a chronic disease that requires knowledge of the disease, self-management, and adherence to treatment plans. While mHealth apps have been made with single features for SCD, there is limited understanding of using an mHealth app with a more comprehensive set of features that could engage adults with SCD, depending on what features they prefer and need to engage and empower them in living with their disease. Objective: We evaluated the usage of an mHealth app with various features, including pain tracking, quizzes for patient-facing guidelines, pain and asthma action plans, and goal setting. Methods: Adults with SCD were enrolled at 2 sickle cell centers between 2018 and 2022 as part of a 6-month feasibility randomized controlled trial with participants completing surveys at baseline and 6 months. Participants were randomized into receiving either an mHealth app and booklet with patient-facing guidelines or a booklet with the guidelines alone. The mHealth app comprised web pages with patient-facing guideline material and a Research Electronic Data Capture (REDCap) project. The REDCap project included a personal profile, a pain tracker, goal setting, quizzes about the guidelines, and pain or asthma action plans. The REDCap project also included the ability to send daily text messages at a time they chose, which contained a message they could create and a link to their profile. Outcomes included SCD-specific knowledge and acute health care utilization (emergency room visits and hospitalizations). We evaluated the usage of these different features and relationships with baseline variables, each other, and study outcomes. Results: Approximately 75% (50/67) of the enrolled and randomized participants completed all the study components, and 100% (26/26) of the participants who were randomized to the mHealth app arm and completed the study used the mHealth app. Further, 15/30 (50%) participants used multiple features. Baseline sickle cell knowledge and female gender were associated with more usage of pain diary (P=.04) and mission (P=.046) features, respectively. While not significant, mission completion was associated with lower hospitalizations (P=.06). Conclusions: Adults with SCD engaged differently with an mHealth app with multiple features. As this study was not focused on one part of our app, engagement with features in this app was entirely patient-driven, which may demonstrate the expected real-world use of an mHealth app in this population. A multipurpose app can help engage participants in self-management strategies through different features and potentially improve outcomes.

BackgroundRelated human leukocyte antigen (HLA)-haploidentical bone marrow transplantation (BMT) with posttransplant cyclophosphamide may be curative for sickle cell disease. However, graft failure, severe graft-versus-host disease (GVHD), infections, and mortality remain a concern. We evaluated a novel conditioning regimen followed by related HLA-haploidentical BMT in adults with sickle cell disease.MethodsIn a phase 2, open-label, single-arm, multicenter study, 54 eligible participants from 19 U.S. centers were enrolled. Of these, 42 (78%) received transplantation with conditioning including antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation. GVHD prophylaxis included posttransplant cyclophosphamide, mycophenolate mofetil, and sirolimus. The primary outcome was event-free survival at 2 years, while secondary outcomes included overall survival and other transplant-related end points.ResultsThe median age at enrollment was 22.8 years (range, 15.5 to 43.2), and the median follow-up period was 37.2 months (range, 20.4 to 56.4). The 2-year event-free and overall survival rates were 88.0% (95% confidence interval [CI], 73.5 to 94.8%) and 95.0% (95% CI, 81.5 to 98.7%), respectively. Two participants experienced primary and another secondary graft failure. The incidence of grade-3-to-4 acute GVHD at day 100 was 4.8% (95% CI, 0.9 to 14.4%), while the 2-year chronic GVHD rate was 22.4% (95% CI, 10.9 to 36.4%). Two of the four reported deaths were due to early infectious complications.ConclusionsHLA-haploidentical BMT is an accessible and potentially curative therapy for adults with sickle cell disease. Adverse events were those anticipated from this procedure, including GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; BMT CTN 1507; ClinicalTrials.gov number, NCT03263559) In this phase 2, open-label, single-arm study, adults with sickle cell disease were treated with a modified conditioning regimen involving thymoglobulin, thiotepa, cyclophosphamide, and fludarabine followed by haploidentical bone marrow transplantation and graft-versus-host disease prophylaxis. The primary outcome was 2-year posttransplant event-free survival. After a median follow-up period of 37.2 months, the 2-year event-free and overall survival rates were 88.0% (95% CI, 73.5 to 94.8%) and 95.0% (95% CI, 81.5 to 98.7%), respectively.

ABSTRACT:Pregnant women with sickle cell disease (SCD) are at higher risk of SCD-related morbidity and mortality than after pregnancy. Existing data from health care use suggest increased acute vaso-occlusive pain events during pregnancy, particularly in the third trimester and puerperium (6 weeks after childbirth). Many acute vaso-occlusive pain events are managed at home and may not capture the full scope of pregnancy-related morbidity. To date, to our knowledge, no studies have examined daily self-reported acute vaso-occlusive pain events during pregnancy and after pregnancy to assess their occurrence at home. Based on self-report using an electronic diary (eDiary) mobile application, we tested the primary hypothesis that self-reported acute SCD pain events during pregnancy (third trimester to puerperium) are greater than after pregnancy (beginning of 6, to end of 9 months, after childbirth).In a tertiary care hospital in Ghana, we approached 42 pregnant women with SCD at ≤16 weeks gestation to participate in the prospective study; 40 of 42 (95.2%) pregnant women with SCD agreed to participate; only 33 participants completed 71.5% of expected eDiary mobile application entries during and after pregnancy. The eDiary data revealed a 1.85-fold higher self-reported acute SCD pain incidence rate during pregnancy than after pregnancy (0.74 vs 0.40 events per person-month; P < .001). Based on the eDiary mobile application, we demonstrated a higher rate of self-reported acute SCD pain during pregnancy than after pregnancy. Preconception counseling for women with SCD should address the expected increase above their baseline in acute vaso-occlusive pain events, particularly in the third trimester and puerperium.

Globally, an estimated 300 million individuals have sickle cell trait (SCT), the carrier state for sickle cell disease. While sickle cell disease (SCD) is associated with increased morbidity and shortened lifespan, SCT has a lifespan comparable to that of the general population. However, “sickle cell crisis” has been used as a cause of death for decedents with SCT in reports of exertion-related death in athletes, military personnel, and individuals in police custody. To appraise this practice, the American Society of Hematology (ASH) convened an expert panel of hematologists and forensic pathologists to conduct a systematic review of the literature relating to the occurrence of sickle cell pain crises and exertion-related mortality in people with SCT. Multiple bibliographic databases were searched with controlled vocabulary and keywords related to “sickle cell trait,” “vaso-occlusive pain,” and “death,” yielding 18 of 1,474 citations. Independent pairs of reviewers selected studies and extracted data. We found no studies comparing uncomplicated acute pain crises in individuals with SCT and SCD. Additionally, no study was identified to support the occurrence of acute vaso-occlusive pain crises in individuals with SCT. Further, this systematic review did not identify any evidence to support an association between SCT and sudden-unexplained death in the absence of exertion-related rhabdomyolysis. We conclude that there are no data to support the diagnosis of acute vaso-occlusive sickle cell crisis as a cause of death in SCT, nor does the available evidence support the use of SCT as a cause of exertion-related death without rhabdomyolysis.

BACKGROUND:Guidelines recommend that hydroxyurea be offered to children with sickle cell disease (SCD) as early as 9 months of age using shared decision-making. To help clinicians implement shared decision-making with parents, we developed the Hydroxyurea Shared Decision-Making (H-SDM) toolkit. We evaluated its effectiveness on parent decisional uncertainty, perceptions of shared decision-making, hydroxyurea knowledge, and the likelihood of being offered and prescribed hydroxyurea. PROCEDURE:Sites began in the usual care condition (clinician pocket guide) before crossing over to the H-SDM toolkit condition between 2018 and 2022. Caregivers of children with SCD (birth to 5 years) eligible for hydroxyurea completed assessments at baseline, immediately after discussing hydroxyurea with their clinician, and 3-7 months later. RESULTS:Participants included 176 caregivers (93.2% female, 89% Black); most toolkit participants were enrolled during the pandemic (n = 81). There were no statistically significant differences between conditions on parent decisional uncertainty, perceptions of shared decision-making, or hydroxyurea knowledge (p-values >0.05). However, there was a clinically important difference in certainty, with higher decisional uncertainty in the usual care group. A greater proportion of participants enrolled during usual care were offered (80.7%) and prescribed hydroxyurea (48.2%), compared to 58.7% offered and 39.7% prescribed during the toolkit condition (p-values ≤0.01). CONCLUSIONS:Findings suggest the toolkit may help parents feel more confident in deciding about hydroxyurea. Given the significant impacts of the COVID-19 pandemic on study implementation, the impact on hydroxyurea uptake requires additional exploration. Ultimately, the H-SDM toolkit may be most beneficial for clinics that do not routinely use a shared decision-making process for those considering hydroxyurea.

Advances in conditioning regimens have made non-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) a viable curative option for adults with sickle cell disease (SCD). However, prospective studies comparing pre- and post-transplant patient-reported health outcomes are scarce. Therefore, in a prospective, mixed-methods cohort study in adults with SCD undergoing HSCT, we tested the hypothesis that physical, mental, and social health improves after HSCT relative to baseline. We compared 9 Patient-Reported Outcomes Measurement Information System (PROMIS®) measures at 6, 12, and 18 months post-transplant to baseline and general population values. Semi-structured interviews were conducted pre- and post-transplant that were thematically analyzed (MAXQDA). Seventeen patients (7 females, 10 males; median age 26 years) underwent matched sibling (9) or haploidentical donor (8) transplantation. Compared to baseline, pain interference (p = 0.008), physical function (p < 0.001), fatigue (p = 0.001), anxiety (p = 0.016), anger (p = 0.037), and the ability to (p < 0.001) and satisfaction with (p < 0.001) social roles and activities improved at 18 months. Compared to reference values, physical function, sleep disturbance, fatigue, anxiety, and the ability to and satisfaction with social roles and activities T-scores were significantly worse at baseline but comparable or better after 18 months. Thematic analysis of the interviews revealed high satisfaction with improved physical and social abilities alongside complex mental health challenges, including processing the psychological aftermath of SCD, dealing with transplant-related toxicity, adjustment challenges, and identity conflicts. In conclusion, while physical, mental, and social health improves after HSCT, the effects on mental health can be complex and warrant psychosocial support early in the process of curative therapies.

Painimation, a novel digital pain assessment tool, allows patients to communicate their pain quality, intensity, and location using abstract animations (painimations) and a paintable body image. This study determined the construct validity of painimations and body image measures by testing correlations with validated pain outcomes in adults with sickle cell disease (SCD). Analyses used baseline data from a multisite randomized trial of 359 adults with SCD and chronic pain. Participants completed questionnaires on demographics, pain severity, frequency and interference, catastrophizing, opioid use, mood and quality of life, plus the Painimation app. Participants were categorized by selected painimations, and were split into groups based on the proportion of painted body image. Potential confounding was evaluated by age, gender, race, education, disability, site, depression, and anxiety. The 'shooting' painimation was strongly associated with daily pain intensity, pain interference, frequency, and severity. 'Electrifying' was associated with daily pain and opioid misuse, while greater body area in pain correlated with worse outcomes across all pain measures. Both painimations and body image measures correlated with validated pain outcomes, quality of life and mental health measures. This demonstrates animations and body image data can assess SCD pain severity, potentially with more accuracy than a 0-10 scale. Future research will explore whether Painimation can differentiate biological and psychosocial pain components. Perspective: This article presents the preliminary construct validity of Painimation in SCD by examining the associations of "painimations" and body area image data with daily e-diary and traditional self-report pain outcomes.

ABSTRACT:Recurrent ischemic priapism is a common complication of sickle cell anemia (SCA) and is associated with devastating physical and psychosocial consequences. All previous trials for priapism prevention have failed to demonstrate clear efficacy. We conducted a randomized, controlled, double-blind phase 2 feasibility trial comparing fixed moderate-dose hydroxyurea plus placebo (usual-care arm) with fixed moderate-dose hydroxyurea plus tadalafil (experimental arm) in 64 males (aged 18-40 years) with at least 3 episodes of SCA-related priapism in the past 12 months. Priapism data were obtained via daily text messages to the participants. The trial's primary outcome measures were 100% recruitment, 98.4% retention, and 93.5% adherence rates. Over a median of 10 months (interquartile range, 3-12), 2.5 and 3.02 priapism events per participant-month were recorded in the usual-care and the experimental arms, with an incidence rate ratio of 0.8 (95% confidence interval [CI], 0.3-1.9; P = .654). The rates of serious adverse events (P = .999) and hospitalization (P = .289) were similar in the 2 arms. Sperm concentration, motility, and normal morphology significantly decreased on hydroxyurea therapy but recovered to prehydroxyurea levels 3 months after therapy cessation. Post hoc, single-arm, pre-post analysis showed a 58.3% priapism incidence rate reduction in the usual-care arm (5.9-2.5 events per month; difference, 3.4; 95% CI, 1.1-5.8; P = .005) and a 66.3% priapism reduction in the experimental arm (8.9-3.02 events per month; difference, 5.9; 95% CI, 3.4-8.5; P < .001) compared with the prerandomization rates. A randomized controlled trial for priapism prevention is feasible in men with SCA. This trial was registered at www.clinicaltrials.gov as #NCT05142254.

Sickle cell disease (SCD) is the most common inherited blood disease. Disease-modifying therapy and supportive care have improved the survival of children with SCD in the United States and Europe. Yet, adults with SCD continue to have high risks of morbidity and early death. Recently, 2 US Food and Drug Administration-approved genetic therapies offer the potential for a short-term decrease in acute vaso-occlusive pain events if not cure. Allogeneic hematopoietic cell transplantation (allo-HCT) is also curative but, until recently, was constrained by limited donor availability and the risks of graft-versus-host disease, graft rejection, and death. Importantly, recent advances have attenuated these barriers. Here, we discuss the current state of therapies with curative intent for SCD. Both genetic therapy and allo-HCT offer the potential for cure for most with SCD. However, the cost (similar to 5 times higher), the current need for myeloablation, and associated late-health effects may make genetic therapies less favorable choices than allo-HCT.

Background Children with sickle cell anemia (SCA) are at high risk for stroke. Protocols for stroke prevention including blood transfusions, screening for abnormal non-imaging transcranial Doppler (TCD) measurements, and hydroxyurea therapy are difficult to implement in low-resource environments like Nigeria. This study aimed to examine the contextual factors around TCD screening in a community hospital in Nigeria using qualitative interviews and focus groups. Methods We conducted a descriptive qualitative study in a community hospital in Kaduna, Nigeria, using focus groups and interviews. Interview guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR) framework and the Theory of Planned Behavior. Transcripts were coded and analyzed using an iterative deductive (CFIR)/Inductive (transcribed quotes) qualitative methodology. Results We conducted two focus groups and five interviews with health care workers (nurses and doctors) and hospital administrators, respectively. Themes identified key elements of the inner setting (clinic characteristics, resource availability, implementation climate, and tension for change), characteristics of individuals (normative, control, and behavioral beliefs), and the implementation process (engage, implement, and adopt), as well as factors that were influenced by external context, caregiver needs, team function, and intervention characteristics. Task shifting, which is already being used, was viewed by providers and administrators as a necessary strategy to implement TCD screening in a clinic environment that is overstressed and under-resourced, a community stressed by poverty, and a nation with an underperforming health system. Conclusion Task shifting provides a viable option to improve health care by making more efficient use of already available human resources while rapidly expanding the human resource pool and building capacity for TCD screening of children with SCD that is more sustainable. Trial registration NCT05434000.

In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year KaplanMeier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Oral iron supplementation in iron deficient children with sickle cell anemia and normal transcranial Doppler ultrasound (TCD) velocities does not reduce arterial flow in the middle cerebral artery.

Background and ObjectivesPreviously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones. MethodsAdults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors. ResultsOf 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model. DiscussionWhen compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.