Acute Chest Syndrome Research Articles

Introduction of asingle-nucleotide variant, rs16851030, into the ADORA1 gene increased cellular susceptibility to hypoxia.

Aim: Rs16851030, a single-nucleotide variant located in the 3'-untranslated region of the ADORA1 gene, has been proposed as a potential marker of caffeine sensitivity in apnea of prematurity. Besides, it is associated with aspirin-induced asthma and the development of acute chest syndrome. However, its functional significance is still unconfirmed. This study aimed to elucidate the functional impact of rs16851030 by using CRISPR/Cas9 approach to induce the DNA variant and attendant physiological changes.Methods: Rs16851030 was introduced into HEK293 cells via homology-directed repair (HDR). Edited cells were fluorescence-enriched, sorted, isolated, and expanded into single-cell-derived clones. The edit was confirmed by Sanger sequencing. RNA sequencing was used to analyze affected pathways.Results: Rs16851030-mutant cells showed increased susceptibility to hypoxia, a condition related to apnea of prematurity. After 24h of hypoxia, the viability of mutant clones 1 and 2 was low compared with wild-type cells (75.45% and 74.47% vs. 96.34%). RNA sequencing revealed transcriptomic changes linked to this increased vulnerability.Conclusion: Rs16851030 impairs cellular resistance to hypoxia, suggesting its role in conditions like apnea of prematurity. Further research should investigate the molecular mechanisms and transcriptomic alterations caused by rs16851030 under hypoxic conditions.

Prevent Acute Chest Syndrome checklist (PACScheck): A quality improvement initiative to reduce acute chest syndrome.

Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). The Prevent Acute Chest Syndrome checklist (PACScheck) was created to drive appropriate ordering of opioids, incentive spirometry (IS), intravenous fluids (IVF), evaluation of oxygen desaturation, and bronchodilator use. Decrease the development of ACS by 5% in a hospitalized pediatric SCD population. A multidisciplinary team conducted a quality improvement (QI) project between April 2020 and August 2021 on an inpatient pediatric hematology unit. At-risk hospitalizations were patients with SCD who did not have ACS upon hospital admission. PACScheck was implemented and weekly run charts assessed documentation. Process control (p) charts, geometric control (g) charts, and chi-square tests assessed checklist process measures pre- and post-PACScheck. G chart assessed the number of encounters between ACS events. A total of 483 at-risk hospitalizations were identified in the 12 months prior and 363 during the study period. A g chart demonstrated that fewer encounters developed ACS during PACScheck. A p chart demonstrated that IS documentation increased during PACScheck. A run chart of PACScheck documentation demonstrated a median of 100% documentation at least once per hospitalization during the last six months of the intervention. Development of ACS can be reduced by implementing a best-practices checklist (PACScheck) on an inpatient pediatric hematology unit with a multidisciplinary team.

Hydroxyurea Pharmacokinetic Evaluation in Patients with Sickle Cell Disease

Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management of SCD patients, helping to reduce vaso-occlusive crises, acute chest syndrome, the need for blood transfusions, hospitalizations and mortality. There is considerable variability among individuals in HU pharmacokinetic (Pk) parameters that can influence treatment efficacy and toxicity. The objective of this work is part of a clinical study aimed at investigating HU Pk and determining the optimal sampling time to estimate the Area Under the Curve (AUC) in SCD patients. Methods: HU plasma concentration in 80 patients at various time points (2, 4, 6, 24 h) following a 48-h drug washout was quantified using High-Pressure Liquid Chromatography (HPLC) coupled with an ultraviolet (UV) detection method previously described in the literature and adapted to new conditions with partial modifications. Results: The mean HU administered dose was 19.5 ± 5.1 mg/kg (range: 7.7–37.5 mg/kg). The median AUC quantified in plasma patients was 101.3 mg/L/h (Interquartile Range (IQR): 72.5–355.9) and it was not influenced by the weight-based dose. However, there was a strong positive correlation between AUC and Body Mass Index (BMI) as well as dose per Body Surface Area (BSA). Along with a three-point approach for AUC determination present in the literature, we show results obtained from a four-point sampling strategy, which is more useful and effective for better optimizing dose escalation to the maximum tolerated dose (MTD). Moreover, we observed that most patients achieved the maximum HU plasma concentration two hours after drug administration, regardless of age differences. Conclusions: HU treatment, which represents a milestone in the treatment of SCD due to its ability to reduce disease complications and improve patients’ quality of life, requires careful monitoring to optimize the individual dose for saving potential side effects and/or adverse events.

Respiratory phenotype and health care utilization patterns by adults with sickle cell disease

AbstractAdults with sickle cell disease (SCD) and asthma have increased mortality and health care utilization; however, there are individuals with respiratory symptoms (including cough and wheeze) without asthma. These individuals may have similar patterns of increased mortality and health care utilization. To characterize the association between respiratory phenotype and health care utilization by adults with SCD. Cross-sectional study of adults with SCD presenting for emergency and inpatient hospital care from 2012 to 2014 in Florida, Iowa, and New York using state-level health care utilization databases. Outcomes of interest include all-cause, SCD-related, painful episode, and acute chest syndrome–related care. Respiratory phenotype was defined as SCD + asthma, SCD + respiratory symptoms, and SCD + none. We built multivariable logistic regression and negative binomial regression models to evaluate the association adjusting for demographics, social determinant of health proxies, year of care, and state. Of 29 952 identified individuals, 3.4% had intermittent respiratory symptoms, and a larger proportion (15.6%) had asthma. There was a high rate of inpatient hospitalizations (43%) and ED visits (60%). Individuals with asthma had a higher annual risk of inpatient hospitalizations (48% vs 37%) but lower annual risk of an ED visit (62% vs 86%) than individuals with intermittent respiratory symptoms. The pattern of increased health care utilization among individuals with intermittent respiratory symptoms was consistent across each utilization type. In this large cohort of adults with SCD, we identified some with intermittent respiratory symptoms who had significantly increased health care utilization. This warrants further evaluation to understand potential etiologies and interventions.

Incremental eligibility criteria for the BMT CTN 1507 haploidentical trial for children with sickle cell disease

AbstractThe Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507 leadership and the data safety monitoring board (DSMB) established incremental entry criteria for children aged 5 to 14.99 years with sickle cell disease (SCD) enrolling in a phase 2 trial of HLA-haploidentical hematopoietic stem cell transplantation. First, the enrollment was limited to overt stroke in the first 10 participants (stage 4). Subsequently, the DSMB reviewed the interim results and expanded the eligibility to include children with silent cerebral infarcts or abnormal transcranial Doppler velocities with magnetic resonance angiography–defined cerebral vasculopathy (stage 3). A third cohort was enrolled after the DSMB reviewed the clinical outcomes in these cumulative initial enrollments (n = 18). Additions to the entry criteria included nonneurologic morbidities (stage 2). Eligibility criteria included the following: (1) life-threatening acute chest syndrome requiring exchange transfusion; (2) right heart catheterization confirmed pulmonary hypertension; (3) persistent systemic hypertension despite maximum medical therapy; (4) acute pain despite maximum medical therapy in the absence of psychosocial factors and unmanaged asthma after adjudication; or (5) 2 major priapism episodes in 12 months or 3 in 24 months. Children with SCD who did not meet the criteria for stages 4, 3, and 2 were not eligible. To our knowledge, for the first time, we introduce a staged strategy for eligibility in a curative therapy trial for children with SCD concordant with 45 Code of Federal Regulations § 46.405(b). The research governance–mandated eligibility strategy used within the BMT CTN 1507 phase 2 study may apply to future pediatric SCD curative therapy trials. This trial was registered at www.ClinicalTrials.gov as #NCT032635590.

Physician perspectives about the diagnosis and management of acute chest syndrome.

Acute chest syndrome (ACS) is the leading cause of mortality, accounting for 25% of all deaths among individuals with sickle cell disease (SCD). There is a lack of evidence-based laboratory and clinical risk stratification guidelines for the diagnosis and management of ACS. To better understand physician practices for the management of ACS in the United States, we created an ACS Working Group including hematology and transfusion medicine physicians from four different SCD treatment centers in the United States. The working group created a physician survey that included physician demographics and ACS diagnostic criteria that they had to rate. The survey also included three case scenarios to assess physician attitudes about the management of ACS. Management options included supportive and preventive strategies in addition to transfusion therapy options. Out of 455 physicians who received the survey, 195 responded (response rate = 43%). The respondents were primarily hematology/oncology physicians. The responses showed wide variability among physicians in how diagnostic criteria for ACS are used and how physicians risk-stratify ACS patients in their practice. The responses also reflected variability in the use of transfusions for ACS. Based on our results, we conclude that ACS is diagnosed and managed inconsistently among expert physicians, especially in their transfusion practices due to a lack of consensus on risk stratification criteria. Our data suggest an urgent need for well-designed prospective studies to provide evidence-based guidelines and minimize management variability among physicians who care for individuals with SCD and ACS.

Characteristics and outcomes of children and young adults with sickle cell disease supported with extracorporeal membrane oxygenation (ECMO): An updated analysis of the ELSO registry.

Sickle cell disease (SCD) is a global hemoglobinopathy; approximately 300 000 individuals are diagnosed annually. Acute chest syndrome (ACS), a common complication, leads to significant hospitalization and mortality, particularly in cases of severe respiratory distress. ECMO outcomes in this specific population are poorly described. This retrospective observational study, utilizing data from the Extracorporeal Life Support Organization (ELSO) registry, focuses on children and young adults (<40 years) with SCD undergoing ECMO from 1998 to 2022. We observed a growing trend in ECMO cases over the last 15 years, with 210 SCD patients identified in the registry (five neonates, 95 children, 110 adults). ECMO was predominantly initiated for pulmonary support (62%), and most of the primary diagnoses were related to SCD (reported as "SCD" or "acute chest syndrome"). The global survival rate was 55.8% (59% for children and 52.7% for adults). None of the children supported for extracorporeal cardiopulmonary resuscitation survived, and only 2/18 (11%) of adults cannulated for ECPR survived. Complication rates, including acute renal failure (33.8%) neurological events (13%), thrombotic (23.3%), or bleeding events (22.9%) were not noticeably different from reported outcomes in the ELSO registry. Our findings suggest that ECMO outcomes in SCD patients align with general ECMO trends and may not be limited by suspected unfavorable results in children and young adults. Despite limitations, our study contributes valuable insights into using ECMO in SCD, emphasizing the need for further research and understanding in this underexplored domain.

Newborn Screening for Sickle Cell Disease in Catalonia between 2015 and 2022-Epidemiology and Impact on Clinical Events.

In 2015, Catalonia introduced sickle cell disease (SCD) screening in its newborn screening (NBS) program along with standard-of-care treatments like penicillin, hydroxyurea, and anti-pneumococcal vaccination. Few studies have assessed the clinical impact of introducing NBS programs on SCD patients. We analyzed the incidence of SCD and related hemoglobinopathies in Catalonia and the change in clinical events occurring after introducing NBS. Screening 506,996 newborns from 2015 to 2022, we conducted a retrospective multicenter study including 100 screened (SG) and 95 unscreened (UG) SCD patients and analyzed SCD-related clinical events over the first six years of life. We diagnosed 160 cases of SCD, with an incidence of 1 in 3169 newborns. The SG had a significantly lower median age at diagnosis (0.1 y vs. 1.68 y, p < 0.0001), and initiated penicillin prophylaxis (0.12 y vs. 1.86 y, p < 0.0001) and hydroxyurea treatment earlier (1.42 y vs. 4.5 y, p < 0.0001). The SG experienced fewer median SCD-related clinical events (vaso-occlusive crisis, acute chest syndrome, infections of probable bacterial origin, acute anemia requiring transfusion, acute splenic sequestration, and pathological transcranial Doppler echography) per year of follow-up (0.19 vs. 0.77, p < 0.0001), a reduced number of annual emergency department visits (0.37 vs. 0.76, p < 0.0001), and fewer hospitalizations (0.33 vs. 0.72, p < 0.0001). SCD screening in Catalonia's NBS program has effectively reduced morbidity and improved affected children's quality of life.

Atypical bacteria in pediatric sickle cell patients with acute chest syndrome

Abstract The purpose of this study was to quantify the frequency of Mycoplasma pneumoniae or Chlamydia pneumoniae in a large contemporary real-world data set. This was a retrospective database analysis utilizing data collected from the TriNetX Global Collaborative Network, which provided access to electronic medical records for patients from 78 different healthcare organizations. Data were collected using ICD-10 codes and laboratory test order codes from TriNetX. Inclusion criteria are patients less than or equal to 18 years old with SCD with an ICD-10 code for ACS or pneumonia. Patients were included in the primary outcome analysis if they had a laboratory code for a rapid diagnostic test for M. pneumoniae and/or C. pneumoniae performed by either nasal swab or respiratory culture. There were 6762 pediatric sickle cell patients with an ICD-10 code for ACS or pneumonia identified. Of these patients, only 16.3% were tested for M. pneumoniae and 17.1% were tested for C. pneumoniae. The patients who were tested for these atypical organisms were further investigated for positivity on rapid diagnostic testing, and the positivity rate in these patients was 1.1% for M. pneumoniae and less than or equal to 0.87% for C. pneumoniae. Pediatric patients with ACS who were tested for M. pnuemoniae and C. pnuemoniae had low rates of positivity for these organisms. Most of these patients did not have recorded microbiologic testing, showing evidence of a large underutilization of diagnostic tools available that could assist with de-escalation of antibiotics.

Secretory Phospholipase A2 as a Promising Biomarker for Predicting Acute Chest Syndrome in Children With Sickle Cell Disease: A Systematic Review and Meta-Analysis.

Acute chest syndrome (ACS) is a severe and potentially life-threatening complication of sickle cell disease (SCD). Early identification of patients at risk for ACS is crucial for timely intervention. There is a potential association between ACS and elevated levels of secretory phospholipase A2 (sPLA2), an enzyme involved in the breakdown of phospholipids. sPLA2 has emerged as a promising biomarker for predicting ACS. This systematic review and meta-analysis aimed to assess the diagnostic value of PLA2 in predicting ACS among children with SCD. A comprehensive search was conducted across multiple databases, including MEDLINE, Embase, Cochrane Library, PubMed, and Web of Science. Studies assessing the relationship between sPLA2 levels and ACS in SCD patients were included. Pooled sensitivity, specificity, likelihood ratios, and the area under the receiver operating characteristic curve (AUC) were calculated to assess sPLA2's diagnostic accuracy. There is a potential association between significant association between elevated sPLA2 levels and increased ACS risk in SCD patients. The pooled sensitivity of sPLA2 for predicting ACS was 0.766 (95% CI: 0.620-0.877), with a pooled specificity of 0.736 (95% CI: 0.680-0.787). The AUC of the summary receiver operating characteristic (SROC) curve was 0.84, indicating good discriminatory ability. sPLA2 emerges as a promising biomarker for predicting ACS in SCD patients, potentially guiding risk stratification and early intervention strategies to enhance patient outcomes. Nonetheless, further prospective studies are warranted to validate its clinical utility and standardize sPLA2 assay protocols.

Lung ultrasound score to predict development of acute chest syndrome in children with sickle cell disease

This study aims to identify lung ultrasound (LUS) findings associated with acute chest syndrome (ACS) at the time of admission and 24-48 h later, to compare these to chest radiography (CXR) findings and to establish a score to predict the development of this pulmonary complication in sickle cell disease (SCD) children METHODS: A prospective observational study of SCD children presenting signs or symptoms of ACS evaluated by LUS and CXR at admission and 24-48 h later. A score was conceived to predict the evolution of ACS during hospitalization based on ultrasonographic findings. Seventy-eight children were evaluated; 61 (78.2 %) developed ACS. A score greater than one at admission showed sensitivity, specificity, accuracy, and positive predictive value (PPV) of 75.4 %, 88.2 %, 78.2 %, and 95.8 %, respectively to predict ACS, while only 32 (52.5 %) CXR showed alterations. The development of ACS during hospitalization was unlikely for a score of zero and very likely for a score greater than one at admission. Regarding follow-up exams, a score greater than one showed sensitivity, specificity, accuracy, and PPV of 98.4 %, 76.5 %, 93.6 %, and 92.8 %, respectively to predict the development of ACS. ACS development was very unlikely for a score of zero and very likely for a score greater than zero in the follow-up. LUS is an effective tool to assess risk for the development of ACS in SCD children with clinical suspicion.

Patterns of acute chest pain at two tertiary centres in Accra, Ghana.

To assess the clinical presentation and evaluation of acute life-threatening chest pain in Accra, Ghana. This was a cross-sectional study at the emergency departments of two leading tertiary hospitals in Accra. The study was conducted at the Korle-Bu Teaching Hospital and the 37 Military Hospital in Accra. The study participants comprised adult patients aged 18 years and above who presented with acute chest pain at the emergency departments between April and June 2018. Acute coronary syndrome is the leading life-threatening cause of chest pain with poor pre- and in-hospital care. 232 patients with chest pain were enrolled as respondents aged 18 to 94 years. The prevalence of life-threatening conditions causing chest pain was 31.9% of those who presented with acute chest pain. These included acute coronary syndrome (82.4%), pulmonary embolism (14.9%), and acute chest syndrome (2.7%). A few (6.6%) with life-threatening conditions such as acute coronary syndrome were transported by ambulances, and 44.3% reported to the facility within 2 to 9 days after the onset of chest pain. None of the patients with pulmonary embolism and acute chest syndrome had computer tomography pulmonary angiogram (CTPA) and echocardiogram done, respectively. Our study found that life-threatening conditions amongst patients presenting with acute chest pains are common; however, there is a need to improve pre-hospital care and in-hospital assessment of these cases. The study was partly funded by the Medtronic Foundation.

Identification of genetic variants associated with clinical features of sickle cell disease

Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the β-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10–10) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10–8) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10–8) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10–8), 15q26.1 (rs62020555, P = 2.04 × 10–9) and 15q26.3 (rs117797325, P = 4.63 × 10–8). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD.

Standardization of coding definitions for sickle cell disease complications: A systematic literature review.

Sickle cell disease (SCD) affects all organ systems and is characterized by numerous acute and chronic complications and comorbidities. Standardized codes are needed for complications/comorbidities used in real-world evidence (RWE) studies that rely on administrative and medical coding. This systematic literature review was conducted to produce a comprehensive list of complications/comorbidities associated with SCD, along with their diagnosis codes used in RWE studies. A search in MEDLINE and Embase identified studies published from 2016 to 2023. Studies were included if they were conducted in US SCD populations and reported complications/comorbidities and respective International Classification of Diseases, Clinical Modification (ICD-CM) codes. All identified complications/comorbidities and codes were reviewed by a certified medical coding expert and hematologist. Of 1851 identified studies, 39 studies were included. The most reported complications/comorbidities were stroke, acute chest syndrome, pulmonary embolism, venous thromboembolism, and vaso-occlusive crisis. Most of the studies used ICD-9-CM codes (n = 21), while some studies used ICD-10-CM codes (n = 3) or both (n = 15), depending on the study period. Most codes reported in literature were heterogeneous across complications/comorbidities. The medical coding expert and hematologist recommended modifications for several conditions. While many studies we identified did not report their codes and were excluded from this review, the studies with codes exhibited diverse coding definitions. By providing a standardized set of diagnosis codes that were reported by studies and reviewed by a coding expert and hematologist, our review can serve as a foundation for accurately identifying complications/comorbidities in future research, and may reduce heterogeneity, enhance transparency, and improve reproducibility. Future efforts focused on validating these code lists are needed.

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

The disease burden of sickle cell disease (SCD) is highest among U.S. Black and Hispanic populations, who are often disproportionately represented in communities with poor air quality. There is limited data on the effects of air pollution exposure and social environmental factors on health outcomes in children with SCD. The objective of our study was to examine the associations between air pollution exposure and acute respiratory and vaso-occlusive pain crises (VOCs), and further study the associations stratifying by asthma status and neighborhood disadvantages. We conducted a retrospective study collecting data on outpatient sick and ED visits, and hospital admissions for respiratory events (i.e., respiratory tract infections, asthma exacerbation, acute chest syndrome), and hospitalizations for VOCs among children with SCD in a tertiary care center in New York City (NYC) from 2015-2018. Modeled data from the NYC Community Air Survey data using home addresses estimated street-level, annual-average exposure to air pollution (i.e., black carbon (BC), fine particulate matter (PM2.5), and nitrogen dioxide (NO2)). The area deprivation index (ADI): continuous national ranking percentile (1-100) was used, representing a composite index for neighborhood-level social disadvantage. We further dichotomized study participants at the upper tertile (high vs. low ADI). Multivariable Poisson regression in generalized estimating equation (GEE) models were used to estimate relative risks (RR), after adjusting for potential covariates. A total of 114 children with SCD were included in this study and had between 1-4 annual repeated measures of annual average air pollutants over a total of 425 visits. Overall, there were no significant associations between air pollution levels and acute respiratory and VOCs among children with SCD and when stratified by asthma status. We found significant interactions between air pollution levels and the continuous ADI variable on respiratory outpatient and frequent respiratory outpatient/ED visits (p<0.1). When stratified by high ADI, increased exposure to PM2.5 was significantly associated with more frequent respiratory outpatient/ED visits among children residing in higher ADI neighborhoods (RR (95% CI)= 1.13 (1.01, 1.27), p<0.05), but not among those in lower ADI neighborhoods. Increased exposure to NO2 was associated with more outpatient respiratory events for children in high ADI neighborhoods (RR (95%CI= 2.74 (1.24, 6.08), p<0.05), compared with low ADI neighborhoods. Air pollution exposures increased respiratory complications among children with SCD living in deprived neighborhoods.

REVISION HIP ARTHROPLASTY IN PATIENTS WITH SEVERE SICKLE-CELL DISEASE: CHALLENGES AND EARLY OUTCOMES

Total hip arthroplasty (THA) has proved to be an effective treatment modality for sickle-cell hip arthropathy (mosaic-like dense bone due to infarcts). However, mode of failure, survival rates and challenges associated with revision hip arthroplasty in sickle-cell disease patients are mostly unknown.We retrospectively evaluated prospectively collected data from all patients with sickle-cell disease who underwent revision hip arthroplasty from 2016. Patient, surgery, medical and surgical complications related data were collected. The pinnacle and reclaim revision system with gription augments (JJ) was used in all patients. Pre-op and post-op clinical outcome data (both objective and subjective, HOOS Jr and OHS) were recorded. Cumulative success rates were recorded with re-revision surgery as an end point.We performed fifteen revision THAs on 13 patients (mean follow up of 6.6 years). The mean age of the patients was 48 years (range, 30–59). At final follow-up, a statistically significant improvement of mean OHS and HOOS JR scores eas found in all patients. reported (OHS: 34.0 and HOOS JR: 77.7). Cumulative success rate was 100% for re-revision for all reasons at 6 years. Five intensive care unit (ITU) admissions, two vaso-occlusive sickle cell crises, one transfusion-related complication and one acute chest syndrome (ACS) were recorded. On admission, the mean percentage of HbS was 75.25% (64.6–86.4%).Revision arthroplasty in sickle-cell disease patients poses increased risks, with medical and surgical challenges. However, with careful preparation, planning and a multi-disciplinary team approach, revision arthroplasty can result in excellent clinical outcomes and excellent functional scores in the majority of patients in the short and mid-term.

CureSCi Metadata Catalog-finding and harmonizing studies for secondary analysis of hydroxyurea use for sickle cell disease.

Sickle cell disease (SCD) is a rare group of inherited red blood cell disorders that affect hemoglobin, resulting in serious multi-system complications. The limited number of patients available to participate in research studies can inhibit investigating sophisticated relationships. Secondary analysis is a research method that involves using existing data to answer new research questions. Data harmonization enables secondary analysis by combining data across studies, especially helpful for rare disease research where individual studies may be small. The National Heart, Lung, and Blood Institute Cure Sickle Cell Initiative (CureSCi) Metadata Catalog is a web-based tool to identify SCD study datasets for conducting data harmonization and secondary analysis. We present a proof-of-concept secondary analysis to explore factors associated with discontinuation of hydroxyurea, a safe and effective first line SCD therapy, to illustrate the utility of the CureSCi Metadata Catalog to expedite and enable more robust SCD research. We performed secondary analysis of SCD studies using a multi-step workflow: develop research questions, identify study datasets, identify variables of interest, harmonize variables, and establish an analysis method. A harmonized dataset consisting of eight predictor variables across five studies was created. Secondary analysis involved a generalized linear model was employed to identify factors that significantly impact hydroxyurea discontinuation. The CureSCi Metadata Catalog provided a platform to efficiently find relevant studies and design a harmonization strategy to prepare data for secondary analysis. Multivariate analysis of the harmonized identified that patients who are older, are female, had a history of blood transfusion therapy, had episodes of acute chest syndrome, and had the SC sickle cell genotype are more likely to stop hydroxyurea treatment. This secondary analysis provides a template for how the CureSCi Metadata Catalog expedites dataset discovery of sickle cell studies for identifying relationships between variables or validating existing findings.

Gene Therapies for Sickle Cell Disease.

Background: Sickle cell disease (SCD) is a prevalent autosomal recessive hemoglobinopathy affecting millions worldwide, particularly individuals of African ancestry. Sickle cell disease is a lifelong condition associated with a negative impact on quality of life and mortality, causing complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, long-term anemia, and end-organ damage. Currently, there are 4 U.S. Food and Drug Administration (FDA)-approved drugs, including hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, which work to alleviate symptoms and prevent complications associated with SCD, albeit without addressing the underlying cause of SCD. Allogeneic hematopoietic stem cell transplant (HSCT) has shown promise as a curative approach to SCD but is limited by donor availability and associated complications. This paper aims to review the efficacy and safety of exagamglogene autotemcel and lovotibeglogene autotemcel for managing patients with SCD, including their place in therapy, cost, and accessibility in clinical care. Data Sources: The authors searched PubMed and Medline from 2017 to 2024, for primary literature on both exagamglogene autotemcel and lovotibeglogene autotemcel. Results: The authors identified relevant studies and summarized the data on the two gene therapies. Conclusion: Exagamglogene autotemcel and lovotibeglogene autotemcel are two management strategies that address the underlying cause of SCD and provide curative potential for patients with SCD.

Venoarterial Extracorporeal Membrane Oxygenation Therapy in Patients with Sickle Cell Disease: Case Series and Review for Intensive Care Physicians.

Sickle cell disease (SCD) is associated with substantial morbidity and early mortality in afflicted adults. Cardiopulmonary complications that occur at increased frequency in SCD such as pulmonary embolism, pulmonary arterial hypertension, and acute chest syndrome can acutely worsen right ventricular function and lead to cardiogenic shock. Mechanical circulatory support including venoarterial extracorporeal membrane oxygenation (VA ECMO) is being increasingly utilized to treat hemodynamic collapse in various patient populations. However, a paucity of literature exists to guide the use of mechanical circulatory support in adults with SCD where disease-related sequela and unique hematologic aspects of this disorder may complicate extracorporeal therapy and must be understood. Here, we review the literature and describe three cases of adult patients with SCD who developed cardiogenic shock from acute decompensated right heart failure and were treated clinically with VA ECMO. Using an in vitro ECMO system, we investigate a potential increased risk of systemic fat emboli in patients with SCD who may be experiencing vaso-occlusive events with bone marrow involvement given the high-volume shunting of blood from venous to arterial systems with VA ECMO. The purpose of this study is to describe available extracorporeal life support experiences, review potential complications, and discuss the special considerations needed to further our understanding of the utility of VA ECMO in those with SCD.

Prevalence, patterns, and factors associated with abnormal lung function among children with sickle cell disease in Uganda: a cross-sectional study

BackgroundPulmonary complications are common among children with sickle cell disease (SCD). However, there is little literature on associated lung function abnormalities in Uganda. We aimed to determine the prevalence, patterns, and factors associated with abnormal lung function among children with SCD in a tertiary care hospital in Uganda.MethodA cross-sectional study was conducted among children aged 6 to 18 years at the SCD clinic (SCC) of Mulago National Super-Specialized Hospital between January 2020 and April 2021. Data on sociodemographic and clinical characteristics was collected using a standardized questionnaire. Laboratory investigations, including a complete blood count and serum lactate dehydrogenase (LDH), were done. Spirometry was performed following the ATS/ERS standards. Multivariable modified Poisson regression analysis was performed to determine factors associated with abnormal lung function.ResultsA total of 332 participants were enrolled. The mean age was 11.7 ± 3.4 years, and 184 (55.4%) were female. Overall, 126 (37.9%) participants had abnormal lung function: 67/126 (53.2%) restrictive, 57/126 (45.2%) obstructive, and 2/126 (1.6%) mixed-ventilatory patterns. Factors associated with abnormal lung function were; serum LDH level > 600UL (aIRR: 1.89 95% CI: 1.2 — 7.4, p = 0.049), a history of acute chest syndrome (aIRR: 1.55, 95% CI: 1.06–2.25, p = 0.024), wasting (aIRR: 1.33, 95%CI: 1.02 — 1.72, p = 0.032), and use of charcoal for household cooking (aIRR: 1.49, 95% CI: 1.03–2.15, p = 0.035).ConclusionMore than one-third of children with SCD in Uganda have lung function abnormalities. Strategies to improve nutrition, reduce exposure to charcoal smoke, and monitoring serum LDH levels may be important in preventing or managing abnormal lung function in this population. The identification of reversible and irreversible airway obstruction in children with sickle cell disease also highlights the need for targeted interventions to address these specific patterns of abnormal lung function.