Outcomes In Sickle Cell Disease Research Articles

Infections in sickle cell disease.

Sickle cell disease (SCD) is one of the commonest severe inherited disorders in the world. Infection accounts for a significant amount of the morbidity and mortality, particularly in sub- Saharan Africa, but is relatively poorly studied and characterized. Patients with SCD have significant immunodeficiency and are more likely to suffer severe and life-threatening complications of infection, and additionally infections can trigger complications of SCD itself. Those with more severe forms of SCD have functional asplenia from a very early age, which accounts for much of the morbidity in young children, particularly invasive infections from encapsulated bacteria including Streptococcus Pneumoniae, Haemophilus Influenzae, Salmonella Typhi and meningococcal disease. Additionally, there are other defects in immune function in SCD, associated with anemia, tissue infarction and impaired adaptive immunity. Complications of infections in SCD include acute chest syndrome (ACS), acute painful episodes, osteomyelitis, meningitis, urinary tract infections, overwhelming sepsis and death. Viral infections cause significant morbidity, particularly severe anemia associated with Parvovirus, and to a lesser extent other infections such as influenza and COVID19. The relationship between malaria and SCD is complicated and discussed in this review. Unlike many of the genetic risk factors for poor outcomes in SCD, it is theoretically possible to modify the risks associated with infections with established public health measures. These include the provision of vaccinations, prophylactic antibiotics and access to clean water and mosquito avoidance, although current financial restraints and political priorities have made this difficult.

Pediatric Sickle Cell Disease Patients' Hematological Changes during Vaso-Occlusive Crises (VOCS) Versus Steady State

Background: The primary acute outcome of sickle cell disease (SCD) is a vaso-occlusive crisis (VOC) with extreme pain. More than three vaso-occlusive crisis (VOC) hospitalizations in a year increase the risk of early death. The objective of the study was to evaluate the hematological alterations in complete blood count (hemoglobin, red blood cell indices, white blood cell count, and platelets) and C-reactive protein levels during vaso-occlusive crises in patients with sickle cell anemia (HbSS) compared to a stable symptomatic state. Methodology: This study is a prospective descriptive study conducted in a hospital setting. During the period from February to June 2015, a Sudan Sickle Cell Anemia Center (SSCAC) in North Kordofan State, Sudan, treated a total of 100 patients with sickle cell anemia. Out of these patients, 74 had a vaso-occlusive crisis and 26 had a steady-state condition. All patients had measurements of their complete blood count (CBC) and C-reactive protein (CRP) levels. We calculated the average values of CBC and CRP level counts during vaso-occlusive crises and compared them to the values during steady state using independent t-tests. We analyzed the collected data using the Statistical Tool for Social Sciences (SPSS) software tool, specifically version 13. Results: The statistical analysis of the patient sample during vaso-occlusive crisis and steady state revealed that the concentration of hemoglobin (Hb) was 6.55 g/dl ± 1.3 and 9.8 g/dl ± 2.4, respectively, with a p-value of 0.000. The packed cell volume (PCV) was 20.4% ± 3.9 and 30.7% ± 7.1, respectively, with a p-value of 0.000. The red blood cell (RBC) count was 2.5×106/µl ± 0.57 and 3.9×106/µl ± 1.1, respectively, with a p-value of 0.000. A lot more white blood cells (WBC) were present in vasoocclusive than in steady state, with numbers 19.36 x 109/l ± 10.645 and 76.76 x 109/l ± 20.19, respectively, and a P-value of ≤0.000. There was a notable statistical disparity in the platelet count, with values of (357.108109/l ± 162.838) and (290.4610×9/l ± 124.40), with a P value of 0.05. In vaso-occlusive crises, the amounts of hemoglobin, packed cell volume (PCV), and red blood cells (RBCs) are lower than they are in the steady-state phase. Conversely, white blood cell (WBC) and platelet levels are much greater in patients experiencing vaso-occlusive crises compared to those in a steady state. The levels of C-reactive protein (CRP) were significantly different between patients experiencing vaso-occlusive crises and those in a stable condition.

Health Related Quality of Life and Psychosocial Profile of Patients with Sickle Cell Disease and Their Caregivers

Abstract Background Sickle cell disease (SCD) is a chronic, debilitating disorder can negatively affect health-related quality-of-life (HRQoL) outcomes in SCD. Aim of the Study Primary objective was to assess the prevalence of impaired psychosocial profile and poor HRQoL among SCD patients and their caregivers in comparison to age and sex matched controls, while secondary objective was to determine the association of such impairment if any with parameters of disease severity. Methods An observational, case control study recruited sixty-five children and adolescent with confirmed SCD, conducted at Paediatric Haematology Oncology clinic, Ain Shams University, Egyptfrom1st of August 2020 to 28th of February 2021. Demographic and clinical data were collected, and thorough clinical and psychiatric assessments were conducted. Quality-of-life (QoL) of both children and their caregivers were performed compared to 65 matched healthy control. Results sixty five children and adolescents with confirmed SCD were included; there were 34 (52.3%) boys and 31 (47.7%) girls and their mean age was 11.40 ± 3.55. Most patients 44(67.7%) had sickle HbSβ+-thalassemia, the most frequent manifestations were vasoooclusive crises in 24 (36.9%) patients, The most common causes for hospital admission were pain crisis in 14 (33.3%) patients and vasoocclusive crisis in 14 (33.3%). Results indicated that patients with SCD and their caregivers had depression and anxiety symptoms scores more than reported in control group.Sickle children had significantly less self-esteem and quality of life than control children, least scores in s ick le c hild re n Q O L wer e in co mmunica t io n do ma in. These were s ignific a nt ne ga t ive consequences, advanced age, duration of illness, number and duration of hospitalizations, disease severity score and occurrence of complications were associated with psychological disorders. Conclusion The QOoL of children suffered from SCD and their caregivers is adversely affected necessitate implementation of interventions which focus on reducing depressive symptoms, enhancing self-esteem and QoL.

Patient-specific factors that could influence gene therapy outcomes in sickle cell disease

Patient-specific factors that could influence gene therapy outcomes in sickle cell disease

Endari treatment ameliorates sickle cell-related disruption in intestinal barrier functions and is associated with prolonged survival in sickle cell mice

ABSTRACT Background Endari (L-glutamine) is a conditional amino acid that reduces the frequency of vaso-occlusive crisis (VOC) in sickle cell disease (SCD). Aim To investigate whether Endari could ameliorate intestinal barrier function and improve survival outcomes in SCD. Methods We treated female Townes SCD mice with Endari and evaluated their intestinal barrier functions by measuring the recovery of orally administered fluorescein isothiocyanate (FITC)-conjugated dextran 4 kDa in serum, and serum intestinal fatty acid binding proteins (iFABP) and lipopolysaccharide (LPS) concentrations by ELISA. We also explored the impact the Endari has on the survival of the SCD mice that underwent repeated experimentally-induced VOC. Results Compared to SCD mice treated with water only, Endari-treated mice showed improved intestinal barrier functions, with decrease in the barrier permeability and reduction in the translocation of lipopolysaccharides from the intestinal lumen into the circulation. These changes occurred after only 4 weeks of Endari treatment. Improved intestinal barrier function was also associated with prolonged survival in Endari-treated SCD mice after repeated experimentally-induced VOC. Conclusion Our findings provide the evidence supporting the beneficial effects of Enadri in improving intestinal barrier function and associated survival outcomes in SCD.

Chronic kidney disease and outcomes in hospitalized sickle cell disease patients: A National Inpatient Sample analysis.

To examine the association between chronic kidney disease (CKD) and outcomes in sickle cell disease (SCD) patients. Patients ≥18 years with SCD in the National Inpatient Sample database between 2016 and 2018 were identified using ICD-10-CM diagnosis codes. A 1:1 propensity-score matched analysis was performed to compare in-hospital outcomes of patients with and without CKD. Of the 366 240 SCD admissions, 19 365 (5.3%) had CKD. The CKD group had higher odds of in-hospital mortality (odds ratio [OR] 2.59, 95% confidence interval [CI]: 1.63-4.12, p = <.01), blood transfusion (OR 1.67, 95% CI: 1.47-1.90, p < .01), mechanical ventilation (OR 2.20, 95% CI: 1.56-3.12, p = <.01), sepsis (OR 1.75, 95% CI: 1.46-2.10, p < .01), incurred higher costs ($53 255 vs. $47 294, p < .001), but had lower odds of acute chest syndrome (OR 0.71, 95% CI: 0.54-0.95, p = 0.02) and pulmonary embolism (OR 0.45, 95% CI: 0.31-0.67, p < .01). CKD was associated with higher mortality, higher costs, blood transfusion, sepsis, and mechanical ventilation in SCD patients. Further studies are needed to explore the reasons for the reduced odds of pulmonary embolism and acute chest syndrome.

Cost-effectiveness of l-glutamine versus crizanlizumab for adults with sickle cell disease: model focused on reducing pain episode costs from Qatar's healthcare perspective.

Treatment options for preventing vaso-occlusive crises among sickle cell disease patients are on the rise, especially if hydroxyurea treatment has failed. This economic analysis is conducted to assess the comparative clinical effectiveness, safety, and acquisition cost of l-glutamine and crizanlizumab for older adolescents and adults (⩾16 years old) with sickle cell disease in Qatar, with an emphasis on treatment costs and acute pain crises. We conduct a decision-tree model, where we compare the clinical and economic outcomes of two novel Food and drug administration (FDA)-approved medications which are available in Qatar; l-glutamine and crizanlizumab over a time horizon of 1 year in a hypothetical cohort of adult sickle cell disease patients from a Qatar healthcare perspective. The main outcome is incremental cost per sickle cell disease-related acute pain crises averted. Model clinical parameters were derived from individual drug randomized trials, published literature, whereas cost parameters from Qatar healthcare payer system (2020-2021). A sensitivity analysis was carried out, and the study results were robust around model inputs. Costs were converted to 2020 US dollars. Study results showed that both treatment modalities' costs were the main driver of this analysis, with an average annual cost of the treatments per patient being $189,014 for crizanlizumab (5 mg/kg), $143,798 for crizanlizumab (2.5 mg/kg), and $74,323 for l-glutamine. The probability of no first-time sickle cell disease-related vaso-occlusive crises averted was 0.001/year for glutamine, 0.26/year for crizanlizumab (5 mg/kg), and 0.34/year for crizanlizumab (2.5 mg/kg). Lower dose crizanlizumab (2.5 mg/kg) dominated the higher one (5 mg/kg). The incremental cost-effectiveness ratio of crizanlizumab (2.5 mg/kg), when compared to l-glutamine was $81,265 per sickle cell disease-related vaso-occlusive crises averted. When comparing crizanlizumab (5 mg/kg) and l-glutamine, crizanlizumab (5 mg/kg) showed higher efficacy, yet the crizanlizumab incremental cost-effectiveness ratio was at $459,620 than l-glutamine. Crizanlizumab (2.5 mg/kg) may be a cost-effective intervention, yet it is not the approved dose for preventing vaso-occlusive crises in adolescents and adults with sickle cell disease. Crizanlizumab (5 mg/kg) was more cost-effective than the approved l-glutamine per sickle cell disease vaso-occlusive crisis prevented. Of note, we primarily focused on modeling acute vaso-occlusive pain, which limited our ability to consider other key outcomes in sickle cell disease.

Real-world observational study on the long-term effect of L-glutamine treatment on renal parameters of adult and pediatric patients with sickle cell disease.

Sickle cell disease (SCD) is a rare genetic blood condition affecting millions worldwide. Oxidative stress is a key player in the pathogenesis of SCD and its comorbid consequences. Renal function impairment is a common complication of SCD in both pediatric and adult patients with serious consequences leading to increased risk of mortality. In this observational real-world study, we are reporting the long-term (120 weeks) renal function in 10 patients treated with L-glutamine. Ten patients (4 pediatric and 6 adults), with confirmed diagnoses of SCD (HbSS genotype), were enrolled, these included four patients from Qatar with Arab Indian haplotype and six patients from French Guiana with African haplotype. All patients were treated with L-glutamine oral powder (~0.3 g/kg body weight, Endari®) twice daily for 120 weeks. Clinical events and laboratory parameters (renal function, hemoglobin, reticulocytes, and lactate dehydrogenase [LDH]) were measured at baseline, 48, and 120 weeks. The study showed that with L-glutamine treatment there were improvements in renal and hematological parameters with no vaso-occlusive crisis at both 48-and 120-week follow-up time points in all 10 patients. Improvements were seen in the albumin creatinine ratio (ACR) from baseline to 48 weeks (mean [Standard deviation SD] ACR: -4.19 [9.81] mg/g) and 120 weeks (mean [SD] ACR: -12.31 [21.09] mg/g). Mean (SD) increase in hemoglobin concentrations from baseline to 48 weeks and 120 weeks was 0.72 (1) g/dL and 1.41 (0.79) g/dL, respectively. Mean (SD) reticulocyte counts and LDH levels decreased from baseline to 48 weeks (mean [SD] change from baseline to 48 weeks, reticulocyte counts: -40.30 [101.58] × 109 cells/L; LDH levels: -259 [154.93] U/L) and 120 weeks (mean [SD] change from baseline to 120 weeks, reticulocyte counts: -58.30 [128.38] × 109 cells/L; LDH levels: -344.80 [274.63] U/L). This is one of the first studies that assessed the long-term renal outcomes in SCD using L-glutamine. L-glutamine improved the renal function in patients with SCD along with improvements in clinical outcomes and hemolysis, from 48 weeks and sustained through 120 weeks of treatment.

P42 Enhancing the Understanding of Phenotypic Outcomes in Sickle Cell Disease (SCD) Through a Comparison Between Data Collected Through App-Based Home-Reported Outcomes (HROs) Versus Qualitative Methodologies

P42 Enhancing the Understanding of Phenotypic Outcomes in Sickle Cell Disease (SCD) Through a Comparison Between Data Collected Through App-Based Home-Reported Outcomes (HROs) Versus Qualitative Methodologies

Myeloid Neoplasia in Patients with Hereditary Hemoglobinopathies and Hemolytic Anemias (HHAs)

Background: Studies have shown an increased incidence of myeloid neoplasia (MN) in patients with sickle cell disease (SCD). It is hypothesized that increased erythropoietic stress may influence acquisition of molecular drivers of MN in SCD. However, present understanding of MN presentation and outcomes in SCD and other hereditary hemoglobinopathies and hemolytic anemias (HHAs) is limited to case reports. Systematic evaluation of MNs in patients with HHAs will better contextualize the risk of MN in this population relative to non-HHA controls. Methods: Patients with HHAs were identified from the Mass General Brigham Research Patient Data Repository using ICD-10 codes. Evaluated HHAs included sickle cell disease (SCD), sickle cell trait (SCT), thalassemia major, thalassemia trait, other hemoglobinopathy traits, and hereditary spherocytosis or elliptocytosis. A final HHA-MN cohort included patients with laboratory confirmed HHA diagnoses as well as incident myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), Ph+ chronic myelogenous leukemia (Ph+ CML), Ph negative myeloproliferative neoplasms (Ph- MPNs) or acute myeloid leukemia (AML). A control cohort of non-HHA MN patients was obtained from the Dana-Farber Hematologic Malignancies Data Repository. Clinical, molecular, and survival data were summarized and compared between HHA-MN and controls. Results: The HHA-MN cohort included 62 patients with HHAs and incident MN (Table 1). HHAs included SCD (n = 6, 9.7%), SCT (n = 9, 14.5%), thalassemia trait (n = 36, 58.1%), thalassemia major (n = 2, 3.2%), hereditary spherocytosis or elliptocytosis (n = 4, 6.5%), and other hemoglobinopathy traits (n = 5, 8.1%). MN was diagnosed at a median age of 61 years [IQR: 48, 70] in the HHA-MN cohort and incident MNs included AML (n = 12, 19.4%), MDS/CMML (n = 22, 35.4%), Ph+ CML (n = 6, 9.7%), and Ph- MPNs (n = 22, 35.4%). A control population of 3388 MN patients without HHA included cases of AML (n = 754, 22.2%), MDS/CMML (n= 1272, 37.5%), Ph+ CML (n = 354, 10.4%), and Ph- MPNs (n = 1008, 29.7%). Compared to HHA patients, control patients were older at MN diagnosis (median age 65 years [IQR: 56, 73], p = 0.0071), driven by significantly younger ages at AML diagnosis for HHA-MN patients (median age 50 years [IQR: 33, 63] vs 65 years [IQR: 57, 73], p =0.0044). AML was the most common MN in SCD (n = 4, 66.7%) whereas incident MDS/CMML was the predominant MN among individuals with thalassemia trait (n = 12, 33.3%) or hereditary spherocytosis and elliptocytosis (n = 2, 50%). Diagnostic cytogenetic data were available for 45 patients in the HHA-MN cohort (72.6% of cohort). Complex karyotype, defined as 3 or more chromosomal aberrations, was observed in 3 of 11 (27.3%) AML, 3 of 19 (15.8%) MDS/CMML and 1 of 17 (5.9%) Ph- MPN cases. Of the 33 HHA-MN patients with available diagnostic next generation sequencing, 60.6% had 2 or more pathogenic mutations at MN diagnosis. Including 2 cases of TP53-mutant AML in patients with SCD, the majority (90%) of AML and 38.9% of MDS/CMML diagnosed in HHA-MN patients were intermediate to adverse risk by ELN criteria or intermediate to very high risk by IPSS-R, respectively. High risk disease was also common in our control MN cohort, where 88.3% of AML cases were intermediate or adverse risk by ELN criteria and 55.9% of MDS/CMML cases were intermediate to very high risk by IPSS-R. Survival varied by subtype of HHA and MN (Figure 1). Survival was lowest for SCD (33.3% at 60-months) and highest for thalassemia traits (67.1% at 60 months). In HHA patients compared to controls, 60-month survival was 65.0% overall (vs 56.4%), 14.3% for AML (vs 23.8%), 51.0% for MDS/CMML (vs 43.9%), 90.5% in Ph- MPN (vs 80.6%), and 100% in Ph+ CML (vs 89.4%). Within the limitations of our sample size, survival differences were not statistically significant. Conclusion: In this retrospective analysis, we observe younger age of diagnosis of myeloid malignancy for patients with HHAs compared to non-HHA controls. Inferior survival in SCD and thalassemia major is largely explained by a higher proportion of AML diagnoses in patients with SCD. AML and MDS/CMML diagnosed in HHA patients tended to be intermediate or high-risk disease, with survival similar to the non-HHA control population that was also enriched for higher risk patients. Validation of our findings in an expanded cohort of HHA patients is currently underway.

Comfort Therapy with Companionship Improves Learning Memory and Reduces Hyperalgesia in Sickle Mice

Chronic and unpredictable acute pain coexist with cognitive dysfunction in sickle cell disease (SCD). Managing chronic pain is crucial, though efforts are complicated by both physiological and affective contributors to pain. The affective state, which is severely impacted by the environment including stigma and social isolation, plays a substantial role in pain perception and may further exacerbate psychological factors. Therefore, we examined if companionship and social isolation influence cognitive function and pain in SCD. In the present study, we examined the effects of social isolation on hyperalgesia, learning memory, and anxiety in humanized transgenic homozygous BERK mouse model of SCD. At ~3.5 months of age, BERK male mice were paired with age-matched female BERK companions (1 male + 1 female/cage; called companion group) and another group of BERK males were placed into isolation (one male/cage; called isolation group) for ~14 months. Isolation and companion groups were maintained in general housing conditions in the same room. Both groups were assessed for body weight, hyperalgesia and cognitive behaviors. Mechanical hyperalgesia was assessed by counting paw withdrawal frequency (PWF) following 10 applications of a 1.0 g von Frey monofilament (Semmes Weinstein, Stoelting, Wood Dale, IL, USA) to the plantar surface of the hind paw. Cold hyperalgesia was assessed following placement of mice onto a 4°C cold plate chamber (Stoelting) and by measuring PWF over a 2-minute period. Musculoskeletal hyperalgesia was measured by testing grip force of each mouse's peak forepaw grip to a computerized grip force meter (SA Maier, Milwaukee, WI, USA) and normalizing by body weight. The cognitive behavioral assessment consisted of an open field test to assess anxiety-related behaviors, which measured time spent and number of crosses through a central region. Working memory was assessed using novel object recognition and novel placement recognition tests to measure discrimination of novel objects and location. Data are shown as mean ± SEM and comparisons between companionship and isolation groups were performed using unpaired, two-tailed T-tests to determine statistical significance (P&amp;lt;0.05) We observed a significant increase in the body weights of males housed with females ( Companion group) compared to males in isolation (p&amp;lt;0.05). It is likely that males living with a companion were eating more compared to those under isolation. Isolated male sickle mice experience greater hyperalgesia than male mice housed with a female companion. Isolation induces greater PWF to mechanical (P&amp;lt;0.05) and cold (P&amp;lt;0.005) stimuli, indicating exacerbated hypersensitivity to mechanical and cold stimuli. Spontaneous, non-evoked musculoskeletal hyperalgesia was not significantly altered by isolation (P&amp;gt;0.05). Isolation also appeared to impact working and learning memory. Novel object recognition and novel object placement tests revealed reduced discrimination ratios in isolated mice (~25%, P&amp;lt;0.05 and ~25%, P&amp;lt;0.05), which are suggestive of impaired learning and memory function compared to mice with companionship. Open field test showed no significant difference (P&amp;gt;0.05) between isolation and companionship groups in time spent and number of crosses in the open field center area, indicating no detectable differences in anxiety-like behaviors. According to cognitive tests, mice in companionship showed greater novel object and place detection and greater cognitive ability compared to those in isolation. For the first time we show the causal role of social isolation on hyperalgesia and memory in a humanized mouse model of SCD. “ Comfort therapy” with companionship can ameliorate the perception of pain through the higher brain centres. It is also likely that mice in companionship eat more as evinced by a significant increase in their weight, which may provide additional comfort and meet the increased nutritional/calorie demands of SCD due to altered metabolism. Our observations suggest that “ comfort therapy” with improved living conditions and reducing isolation and loneliness may improve pain-related outcomes in SCD.

Clinical Outcomes of Acute Chest Syndrome in Patients with Sickle Cell Disease and Pulmonary Hypertension

Introduction: Sickle-cell disease (SCD) is an inherited hemoglobinopathy frequently complicated by vaso-occlusive episodes (VOE) and acute chest syndrome (ACS). Likely due to chronic hemolysis and inflammation, roughly 10% of patients with SCD develop pulmonary hypertension (PH) (Gordeuk et al., 2016). Early signs of PH in patients with SCD often present as elevated pulmonary pressures and right ventricular (RV) dysfunction, which could be exacerbated by VOE or ACS (Dessap et al., 2007). Multiple studies have shown that ACS and PH are individually established causes of increased mortality in patients with SCD, but less is known about the relationship between concurrent ACS and PH and the effects on clinical outcomes. The diagnostic criteria for PH were recently updated, and the impact of those changes on outcomes in SCD remain unknown. We sought to evaluate clinical outcomes in patients with SCD who met PH diagnostic criteria when hospitalized for ACS. Methods: We retrospectively collected clinical information from the electronic medical record (EMR) for all ACS admissions from 2017-2021 at the University of Chicago. Patients were assessed if they met PH diagnostic criteria based on available right heart catheterization (RHC) and transthoracic echocardiography (TTE) reports prior to the ACS admission date. PH was defined as having a mean pulmonary artery pressure &amp;gt;20 mmHg on RHC, tricuspid regurgitation velocity (TRV) &amp;gt;3.4 m/s, or TRV 2.9-3.4 m/s with two additional concerning TTE findings. ACS was defined as a new pulmonary opacity on imaging and at least one diagnostic symptom such as fever, chest pain, or hypoxemia. Depending on frequencies, chi-square or Fisher's exact tests were used to assess associations between PH and clinical outcomes: intensive care unit (ICU) transfer within 8 days of ACS diagnosis, 28-day readmission, and 28-day mortality. Two-sample t-test was used to assess the association between length of stay (LOS) and PH. Results: There were 231 ACS admissions from 2017-21, but 1 admission was excluded from analysis due to lack of past medical history within the EMR. In total, 10 out of 230 ACS admissions (4%) met PH diagnostic criteria prior to admission, comprised of 8 out of 127 patients (6%). There were no significant associations between PH and clinical outcomes except for LOS (14.5 days for PH vs 9.1 days for no PH, p=0.04). Conclusions: If a patient with SCD and PH was admitted for ACS, their LOS was 5 days longer than a patient without PH. An increased LOS may be due to a higher degree of complications such as elevated pain scores, prolonged oxygen requirements, or greater hemodynamic compromise. Future directions of the study will assess for causes of an increased LOS in the setting of PH. Only 6% of this cohort of patients with ACS admissions had PH, and this was likely under identified due to lack of adequate work-up (RHC or TTE). Diagnosis of PH prior to ACS admission may help with future prognostication and clinical decision-making regarding early intervention. The study highlights the increased healthcare requirements accompanying PH and a continued need to study PH, specifically in patients with SCD who may be at high risk for adverse clinical outcomes during an ACS episode.

Comparison of Devices That Measure Sickle Red Cell Deformability

Background With the emergence of novel pharmacologic and gene-based therapies, identifying the rheological and biophysical RBC abnormalities of sickle cell disease (SCD) not captured by clinical laboratory techniques is crucial. Ektacytometry (LORRCA), the current standard to assess RBC function, does not reflect mechanical stress that RBCs experience in capillary microvasculature in the body. The device is costly, requires a nitrogen gas tank, and its use is difficult to translate outside of large-scale laboratory settings. In comparison, the Microfluidic Impedance Red Cell Assay (MIRCA) is a low-cost, portable device that mimics capillary microvasculature with micropillar arrays spaced 3-12 µm apart. Thus, MIRCA measures mechanical deformability, which is more physiologic, mimicking RBCs squeezing through microvasculature. An impedance analyzer calculates the MIRCA Occlusion Index (OI), representing the % occlusion of the chip. Here we compare the MIRCA to the LORRCA, assessing the correlations of OI and Elongation Index maximum (EI) to conventional laboratory tests and SCD related complications. Methods Peripheral blood from 53 adult (n = 28) and pediatric (n = 25) individuals (HbSS = 35, HbSB0 = 6, HbSC = 5, HbSB0 = 1, and HbAA controls = 6) were obtained under an Emory University IRB approved protocol. Patients transfused &amp;lt; 90 days prior were excluded. Hospitalizations / emergency department (ED) visits for pain within 12 months of sample collection were determined by chart review. Samples were collected in EDTA, stored at 4°C up to 48 hours, centrifuged at 500g, washed, and resuspended to a 20% hematocrit to run on MIRCA, an oxygen gradient ektacytometer (LORRCA), and an ADVIA hematology analyzer. Polydimethylsiloxane (PDMS) fabricated MIRCA chips were bonded to a standard glass slide with pairs of gold-sputtered electrodes adjacent to each array. Chips were prepared by perfusing ethanol, 1X phosphate-buffered saline (PBS), and 3% bovine-serum albumin (BSA) in 1X PBS via syringe pump and were incubated overnight at 4°C prior to use. Baseline impedance was taken for a 2-minute perfusion of 1X PBS, then OIs were calculated from impedance values 10 minutes after sample introduction normalized to baseline. The data was analyzed using the Mann-Whitney U test, Spearman correlation, and linear regression. OriginPro (Northampton, MA, USA) and Stata 18 (College Station, TX, USA) were used for the analyses and a p &amp;lt; 0.05 was considered significant. Results The correlation coefficients for OI and EI with laboratory tests (Table 1) and to each other (Figure 1) were comparable (p &amp;lt; 0.05). HbSS/SB0 had higher OIs than HbSC/SB+ (median = 13.7% vs 6.8%, p &amp;lt; 0.01) and HbAA (median = 4.6%, p &amp;lt; 0.01). Patients with ≥ 1 vaso-occlusive events (VOE) in the past year had higher OIs and lower EIs compared to those without a VOE (median = 15.3% vs 9.6%, p &amp;lt;0.01; median = 0.4 vs 0.5, p = 0.02, respectively). Patients that received acute medical care (admission or ED visit) had higher OIs and lower EIs compared to those that did not (median = 15.7% vs 9.8%, p &amp;lt; 0.01; median = 0.4 vs 0.5, p = 0.02, respectively). In multiple linear regression, HbSS/SB0 (p &amp;lt; 0.01), adults (p = 0.01), and DRBC (p &amp;lt; 0.01) were associated with OI while HbSS/SB0 (p = 0.01), DRBC (p &amp;lt; 0.01), hemoglobin % (p = 0.04), absolute neutrophil count (p = 0.02), and VOE+ (p = 0.02) were associated with EI. The models explained 55.2% and 66.8% variability of OI and EI, respectively. Lower Akaike's information criterion (AIC, 186 vs -80) and Bayesian information criterion (BIC, 192 vs -71) of the EI model suggest a higher correlation to conventional laboratory values and clinical features compared to OI; OI may possibly be a unique biomarker that both laboratory tests and LORRCA fail to fully characterize. Conclusion MIRCA OI and LORRCA EI normoxic deformability are correlated to each other, and both show statistically comparable correlations to many parameters associated with SCD severity. Both OI and EI are significantly associated with SCD outcomes like VOE and acute care. Due to lower device size, cost, and relative ease-of-use, MIRCA may be more convenient for routine clinical use and for use in low resource settings where LORRCA costs and requirements hamper implementation. As the addition of chemical hypoxia to MIRCA is now underway, future work will examine OI under hypoxia and its associations with SCD-relevant outcomes like pain events, stroke and acute chest syndrome.

Dietary Behaviors and Social Determinants of Health Among Adults Living with Sickle Cell Disease

Background: Social determinants of health (SDoH) may impact outcomes in sickle cell disease (SCD), and recent literature reports that particular SDoH, such as food insecurity and housing insecurity, may impact diet choices for individuals with SCD. Notably, health outcomes in SCD are linked to diet choices through increased protein and caloric needs, and through nutrients, such as polyphenols, omega fatty acids and micronutrients, which are involved in SCD pathophysiology. The connection between SDoH and diet quality may occur through multiple pathways including access to food, affordability, chronic pain and psychosocial factors at the individual and family level. Importantly, the impact of this connection may relate to outcomes such as pain frequency, hospitalizations, and SCD pathophysiologic biomarkers, such as inflammation. Study Design and Methods: The Diet and SCD Study (NCT: 05170412) is an observational mixed-methods study initiated in 2021 at the National Institutes of Health Clinical Center (NIH CC) in Bethesda MD with a target sample of 75 adults living with SCD in the United States. The purpose of the study is to evaluate associations between SDoH (food insecurity, neighborhood food access, education, employment, healthcare access), dietary intake, and population health related outcomes among adults living with SCD. Study inclusion criteria consists of adults (≥18 years of age) residing within the United States at the time of screening who have a confirmed diagnosis of sickle cell disease with any genotype, and are not hospitalized at the time of enrollment. To ensure participation from adults in diverse regions of the United States, the study has a hybrid design of in-person and telehealth procedures. In-person protocol visits are conducted at the NIH CC. The CC clinical visit includes a clinical assessment, anthropometric measurements, phlebotomy, as well as monitored/proctored electronic surveys that collect SDoH and disease severity variables. The telehealth protocol visit includes a virtual clinical assessment, phlebotomy at a local laboratory center, as well as the same monitored/proctored electronic surveys completed by CC clinical visit participants. A dietary behavior semi-structured interview is conducted at both the CC clinical visit and telehealth protocol visit to garner participants' personal stories related to food choices and diet. Laboratory variables include SCD disease specific markers, amino acid levels, and measurement of inflammatory cytokine markers. All participants undergo two unannounced phone-administered 24-hour dietary recall interviews with trained NIH nutrition staff to measure recent dietary intake. Data from 24-hour recall interviews are used to determine fluid, caloric, macro and micronutrient, and polyphenol intake. Usual dietary intake of foods of potentially related to SCD pathophysiology (cruciferous vegetables and thiocyanate-rich foods) is measured through self-administered electronic 12-month food frequency questionnaires. Primary objectives are to evaluate social determinants of health related to food security and access relevant to disease severity among adults living with sickle cell disease in the U.S. Secondary outcomes are to evaluate the association of dietary quality, specific dietary nutrient intake and serum levels, including amino acids and polyphenols, with disease severity. Tertiary outcomes include evaluating inflammatory and glucometabolic biomarkers with measures of social determinants of health. When completed, the Diet and SCD study will provide important information on the associations between SDoH, dietary quality, inflammatory biomarkers and disease severity for adults living with SCD and provide initial data for future cohort and intervention studies.

Effects of Air Pollution on Respiratory Events and Pain Crises Among Children with Sickle Cell Disease in New York City

Introduction: Sickle cell disease (SCD) has the highest U.S. disease burden among Black and Hispanic populations, who more commonly live in urban areas with poor ambient air quality. The effect of air pollution exposure and social environmental factors on health outcomes in SCD have not been extensively studied, especially among children, and may further contribute to health disparities. Objectives: This study aims to examine the associations between air pollution exposure and acute respiratory and pain events and to determine whether neighborhood-level social disadvantage would modify their associations. Methods: We collected retrospective data on unscheduled outpatient visits, emergency department (ED) visits, and hospital admissions for respiratory events (i.e., respiratory tract infections, asthma exacerbation, acute chest syndrome) and vaso-occlusive pain crises requiring hospitalization (VOCs) for children with SCD in a tertiary care center in New York City (NYC) from 2015-2018. A total of 114 children with SCD (Table 1) were included in this study and had between 1-4 annual repeated measures of annual average air pollutants (i.e., black carbon (BC), fine particulate matter (PM 2.5), and nitrogen dioxide (NO 2)) with a total of 425 visits. Using home addresses, modeled data from the NYC Community Air Survey data were used to estimate street-level, annual average exposure to air pollution. The area deprivation index (ADI), a composite index of neighborhood-level social disadvantage, was dichotomized at the upper tertile (higher vs lower). Multivariable Poisson regression in generalized estimating equation (GEE) models were used to estimate relative risks (RR), after adjusting for potential covariates. Results: Overall, there were no significant associations between air pollution levels and acute respiratory and pain events among children with SCD. When stratified by ADI, increased exposure to PM 2.5 and NO 2, but not BC, was significantly associated with more frequent respiratory outpatient and ED visits among children residing in higher ADI neighborhoods (RR (95%CI)= 1.13 (1.00, 1.28) and 1.43 (1.01, 2.02) for PM 2.5 and NO 2, respectively, p&amp;lt;0.05 for all), but not among those in lower ADI neighborhoods (P-value for interaction=0.2 and 0.02 for PM 2.5 and NO 2, respectively) (Figure 1). Associations of air pollution with hospital admissions and VOCs were not observed for neither high ADI nor low ADI neighborhoods (p-value&amp;gt;0.05). Conclusions: Exposure to air pollutants increased respiratory complications among children living in deprived neighborhoods.

Birth-Related Risk Factors Impact Cognitive and Academic Outcomes in Children with Sickle Cell Disease

Pre- and peri-natal-related risk factors are associated with slowed neurocognitive development and increased risk of learning difficulties in the general population. A recent study reported expressive language deficits were associated with preterm birth in young children with sickle cell disease (SCD) (Bills et al., 2021); however, no studies to date have examined the long-term impact of low birth weight in children and adolescents with SCD. In this cohort study, we examined associations between low birth weight (&amp;lt;2500g) and cognitive and academic outcomes, including formal school support services (i.e., 504 Plan or Individual Education Program), in children with SCD. Gestational age and neonatal intensive care unit (NICU) admission were investigated as covariates. Participants were children ages 8-18 years old with SCD enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP), an observational cohort study of clinical outcomes in SCD. Participants received targeted neurocognitive evaluations as standard of care every 3-4 years. Performance-based neurocognitive measures were used to assess cognitive and academic abilities, including the Wechsler Abbreviated Scale of Intelligence, Second Edition; Wechsler Intelligence Scale for Children, Fourth and Fifth Editions; Wechsler Adult Intelligence Scale, Fourth Edition; Delis Kaplan Executive Function System; Conners Continuous Performance Test, Second and Third Editions; and Woodcock-Johnson Tests of Achievement, Third and Fourth Editions. Multivariable generalized linear regression examined associations between birth-related risk factors (i.e., birth weight, gestational age, and NICU admission) and cognitive outcomes, academic achievement, and need for school support services after adjusting for age, sex, hydroxyurea treatment, sickle genotype, and socioeconomic status. P-values &amp;lt;0.05 were considered significant. False discovery rate-adjusted p-values or q-values were calculated across the outcomes and all birth-related risk factors to correct for multiple corrections. Of the 326 participants in SCCRIP who completed neurocognitive evaluations, 282 children had normal birth weight (HbSS/HbSβ 0thalassemia=56%) and 44 children were born with low birth weight (HbSS/HbSβ 0=45%). Birth weight groups (&amp;lt;2500g and &amp;gt;2500g) were matched for demographic and disease characteristics (Table 1). The mean age at time of cognitive evaluation was 11.16 (SD= 3.27) years and half of participants were male (51%). Low birth weight was associated with worse word reading (p=0.011; Table 2). Across all participants, admission in the NICU was associated with lower verbal reasoning (p=0.022), processing speed (p=0.017), working memory (p=0.044), word reading (p=0.021), and math fluency (p=0.05). Similarly, across all participants, earlier gestational age was associated with lower verbal fluency (p=0.011). Low birth weight and gestational age predicted need for school support services (p=0.003 and p=0.007, respectively). History of birth-related risk factors should be considered a comorbidity for neurodevelopmental differences in SCD. Specifically, children with SCD who are born with low birth weight or admitted to the NICU are at increased risk for difficulties with processing speed, working memory, language, and academics. The need for formal school support services in SCD is associated with gestational age and birth weight.

Allotransplantation and Gene Therapy Equity for Children with Sickle Cell Disease: Distributional Cost-Effectiveness of Allotransplantation Vs Gene Therapy Vs Standard-of-Care in Pediatric Patients with Sickle Cell Disease in the United States

Introduction: Patients with sickle cell disease (SCD) have reduced quality-adjusted life expectancy due to substantial mortality risks and decreased quality-of-life for every year lived with the disease. Allotransplantation was the first treatment with curative potential, but it carries concomitant risks of transplant-related mortality and graft-versus-host disease (GVHD). Once approved, gene therapy would be the second treatment with the possibility of lifelong cure but unlike allotransplantation, it may do so without the concomitant risks. Prior research has shown that even if gene therapy is conventionally cost-ineffective versus the standard-of-care (SOC), it can be a justifiable treatment option for a historically marginalized patient population in the United States, as demonstrated by equity-weighted cost-effectiveness. For allotransplantation and gene therapy, neither conventional nor distributional (i.e., equity-weighted) cost-effectiveness is known. Accordingly, we conducted the first conventional and distributional cost-effectiveness analyses of allotransplantation therapy for pediatric patients with SCD in the United States. Methods: We built a Markov model of pediatric patients with sickle cell disease to examine the cost-effectiveness of allotransplantation vs gene therapy vs SOC and determine equity weight thresholds. Sex-, age-, and disease-severity-specific annual costs and transition probabilities across disease severities for SOC were informed by 11 years of data from US commercially insured patients with SCD (2007-2017; Optum). Disease severity was defined based on annual number of hospitalizations for vaso-occlusive crises, as defined in clinical trials. SOC included hydroxyurea, opioid therapy, antibiotics, vaccinations, and blood transfusions. Allotransplantation- and GVHD-specific transition probabilities and costs were informed by prior literature and health resource utilization data, originally reported from the Center for International Blood and Marrow Transplant Research and the Pediatric Health Information System. Quality-adjusted life-years (QALYs) were informed by published lifetime simulations of patients living with SCD and matched controls, derived initially from a polynomial fit linking Euroqual-5 Dimensions to the visual analog scale for pain in patients with SCD in several studies. Age-, sex- and disease-specific background mortality probabilities were employed. Conventional cost-effectiveness was quantified using an incremental cost-effectiveness ratio (ICER), at a willingness-to-pay threshold of $100,000/QALY. Given expert clinical experience with optimizing allotransplantation outcomes in SCD, we employed a maximum patient starting age of 12 and assumed that gene therapy cost $2.45 million and was 100% effective. To account for health inequities in SCD, we then conducted a distributional cost-effectiveness analysis (DCEA), which applies an inequality aversion parameter (i.e., how much weight one puts on reducing disparities), to the distribution of outcomes across relevant sub-groups for allotransplantation to be favored over SOC and justify funding per DCEA standards. These were compared to prior estimates for commonly used equity weights in the United States (range 0.5-3.0). Results: In the base-case, allotransplantation, gene therapy, and SOC accrued 22.1, 25.5, 15.7 discounted lifetime QALYs at costs of $1.9, $2.8, $1.0 million, respectively, with all therapies on the cost-effectiveness frontier (Table 1). The ICERs and equity weight thresholds were $138,000/QALY and 0.5, and $253,000/QALY and 4.5, for allotransplantation (vs SOC) and gene therapy (vs allotransplantation), respectively. Conclusion: Similar to findings for gene therapy versus SOC in the first published DCEA in sickle cell disease, allotransplantation also appears to be an equitable therapeutic option for pediatric patients with sickle cell disease, regardless of conventional cost-ineffectiveness and as compared to SOC. The consideration of patient-population-specific equity offers an important opportunity to derive transparent benchmarks for intertwined equity- and value-informed decision making. Quantitative consideration of equity in the context of conventional cost-ineffectiveness can be an important tipping point in justification of funding.

Non-Invasive Screening for Sickle Cell Disease Using Only a Smartphone Application

Introduction Pediatric mortality due to Sickle Cell Disease (SCD) remains high and often occurs prior to diagnosis in most black and brown low- and middle-income countries (LMICs), due to the high prevalence of SCD and limited resources in these countries.To that end, we developed a low-cost non-invasive screening tool that can be widely available at the point of need. Our screening tool utilizes the power of both image analysis and predictive algorithms as a novel approach to SCD screening and diagnostics. In this new app, we have combined the quantitative analysis of fingernail pallor, an adaptation of our previously described smartphone app for estimating blood hemoglobin levels using smartphone images of the nail beds, with qualitative symptom and medical history data to compute an SCD Likelihood Score (SLS) that provides an individual's pre-diagnostic test potential for disease, a key metric in the disease screening and diagnostic process. Methods 417 subjects ages 0.5-20 years old were enrolled from Children's Healthcare of Atlanta (CHOA) hematology/oncology clinic; of these patients, 219 patients had SCD, and 198 did not. Pediatric patients were screened because they best simulated the target populations aimed for the app's use. Our analysis was restricted to the presence of specific pain, past stroke history and/or symptoms, splenic crises, neurodevelopment disorder, family history of SCD, due to their specificity to SCD and their ability to be answered without the need for resource-intensive diagnostics. The SLS was calculated by determining the presence of these medical history items and the patient's anemia status informed by the patient's most recent CBC. For each symptom a weighted score was generated by finding the difference between the percentage of subjects with SCD and those without SCD, who experienced the symptom. The presence of symptoms was binarized with 1 indicating the presence of a symptom and 0 indicating the absence of a symptom. The binary value of the symptom was then multiplied by the symptom's respective weighted value. These values were totaled and normalized to give the overall clinical profile-weighted score with the same weight as the anemia status. A receiver operating characteristic analysis was conducted to select a threshold for the SLS that provided the most accurate diagnosis in our training dataset. We incorporated this SLS model into our lab's previously described smartphone app predictive algorithm . Results A clinical assessment of the screening app was conducted at CHOA and enrolled 68 participants from both in-patient and out-patient settings. Patient hemoglobin measurements were obtained using our previously described hemoglobin screening app and patients (and their parents for those needing their assistance) were asked to provide responses to the symptom survey. Of the five medical history items queried, family history and a history of splenic crisis when present was found to contribute to 30% and 41%, respectively, of the overall clinical profile score. Whereas the presence of a history of pain, stroke history, and learning difficulties made up smaller portions of this portion of the SLS. The app performed with a sensitivity of 100% and a specificity of 75% in screening for SCD in patients &amp;lt;5 years of age, the target demographic for early screening. Conclusion This SCD screening application has the potential to expand and improve SCD outcomes in LMICs where access to the gold standard or any accurate diagnostic tools is limited. The app's non-invasive and easy-to-use nature and the ubiquity of smartphones globally make this screening tool a practical and feasible mode of screening. Early disease screening is paramount to survival for children with SCD and if this tool proves to be accurate in these settings, can be lifesaving for the hundreds of thousands of infants with SCD born in LMICs per year. Non-invasive modalities such as our SCD screening application can enable resource allocation and cost reduction by identifying those patients who do and do not have a high likelihood of disease, thus reserving tests for those who are high risk.

Current challenges and new approaches to implementing optimal management of sickle cell disease in sub-Saharan Africa

Sickle cell disease (SCD) is the most common life-threatening monogenic disorder in the world. The disease is highly prevalent in malaria endemic areas with over 75% of patients residing in Sub-Saharan Africa (SSA). It is estimated that, without proper care, up to 90% of children with SCD will not celebrate their fifth birthday. Early identification and enrolment into comprehensive care has been shown to reduce the morbidity and mortality related with SCD complications. However, due to resource constraints, the SSA is yet to implement universal newborn screening programs for SCD. Furthermore, care for patients with SCD in the region is hampered by the shortage of qualified healthcare workers, lack of guidelines for the clinical management of SCD, limited infrastructure for inpatient and outpatient care, and limited access to blood and disease modifying drugs such as Hydroxyurea which contribute to poor clinical outcomes. Curative options such as bone marrow transplant and gene therapy are expensive and not available in many SSA countries. In addressing these challenges, various initiatives are ongoing in SSA which aim to enhance awareness on SCD, improve patient identification and retention to care, harmonize the standards of care for SCD, improve the skills of healthcare workers and conduct research on pertinent areas in SCD in the SSA context. Fortifying these measures is paramount to improving the outcomes of SCD in SSA.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26–42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PerspectiveThis study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.