Episodes Of Acute Chest Syndrome Research Articles

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.

Assessment of fatigue in adult patients with sickle cell disease: Useof the functional assessment of chronic illness therapy-Fatigue (FACIT-fatigue) questionnaire.

Few studies have used validated scales to assess the intensity and determinants of fatigue, a major symptom of sickle cell disease (SCD). We aimed to assess the level of basal fatigue in adult patients with SCD, using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire. We prospectively included 102 stable adult outpatients with SCD over 2 months, who answered the FACIT-Fatigue (ranging from 0 (worst imaginable fatigue) to 52 (no fatigue)) and reported on the intensity of fatigue and its impact on quality of life. The cut-off for significant fatigue was <34. The median [IQR] FACIT-Fatigue score was 29 [22-37], indicating moderate-to-severe fatigue. In a multivariate analysis, the FACIT-Fatigue score was significantly associated with female sex, high body mass index, high level of stress, poor sleep quality, and number of previous episodes of acute chest syndrome, but not with the genotype or the haemoglobin level. Most adult patients with SCD experience significant and sometimes intense fatigue; this is probably due to several factors, including disease activity. Fatigue should be evaluated systematically during consultations and in patient education programmes and as an end-point in therapeutic trials.

Pulmonary function assessments and clinical correlates in children with sickle cell disease in Cape Town, South Africa

Objectives: Among children with sickle cell disease (SCD) in Africa, there are varied reports on pulmonary function assessments. Restrictive pulmonary function is common in children with SCD in Africa; however, reports from Africa are few. We aimed to describe pulmonary function and its clinical correlates in children with SCD in Cape Town, South Africa. Materials and Methods: A prospective cross-sectional study was carried out over seven months from October 2018 to April 2019 in children 6–16 years with SCD. Children with hemoglobin (Hb) genotypes, homozygous for the BS globin mutation, and sickle-beta0-thalassemia Hb were included in the study. Children were excluded if they had acute complications. Medical record review clinical, laboratory, and pulmonary function assessments were done. Data were entered into Excel and exported to Stata Version 16.0 statistical software for analysis. Results: A total of 25 participants were recruited, mean (standard deviation) age of 10 ± (3.0) years. Thirteen (53%) children were under ten years and 15 (60%) were male. The median/interquartile range age at diagnosis was 1.7 [0.8–3.0] years. SCD-related complications were common. A review of the medical records showed a third of the patients (32%) had at least one previous episode of acute chest syndrome, 20 (80%) had a history of vaso-occlusive crisis, and 15 (76%) had required at least one blood transfusion. Spirometry was performed on 19 (76%) of the participants 9 (47%) had abnormal lung function. The most common spirometry abnormality was a restrictive pattern (forced vital capacity (FVC) &lt; lower limit of normal (LLN)). No participant had a positive bronchodilator response. Older age was associated with a decrease in forced expiratory volume in the first second (FEV1) Z-score (−0.16, 95% confidence interval [CI] −0.31, −0.01; P = 0.04). Children on hydroxyurea similarly had reduced FEV1 Z-score (−1.5, 95%CI −2.88, −0.12; P = 0.04) and reduced FVC Z-score (−2.21, 95%CI −3.64, −0.79; P &lt; 0.001). Conclusion: Lung function abnormalities were common among children with SCD, with restrictive abnormality predominating. Asthma and obstructive airway abnormalities were uncommon in children with SCD in South Africa.

Safety and Efficacy of Adenotonsillectomy in Sickle Cell Disease Patients with Obstructive Sleep Apnea – A Scoping Review

Abstract This scoping review aimed to determine the safety and efficacy of adenotonsillectomy in patients with sickle cell disease (SCD) and obstructive sleep apnea (OSA). Six databases were searched from inception till December 2022 to identify relevant articles, and five articles were selected. Standardized mean difference and 95% confidence interval were used as the effect sizes of the pooled data. Adenotonsillectomy was associated with a significant decrease in the apnea–hypopnea index and a significant increase in nadir O2 and SpO2. However, no differences were detected in the mean annual rates of acute chest syndrome and pain episodes. Adenotonsillectomy appears to improve the health status of SCD patients with OSA and was associated with a wide safety margin. Nevertheless, we recommend larger sample sizes with extended follow-up periods to confirm our findings.

Factors Associated with Overt Stroke in Children and Adolescents with Sickle Cell Disease: A Retrospective Cohort Study

Sickle cell disease (SCD) is associated with a high occurrence of complications due to vaso-occlusive phenomenon such as stroke. This retrospective cohort study aimed to examine the clinical and laboratory characteristics of 120 children and adolescents with SCD and analyze the factors associated with overt stroke incidence. All relevant data were obtained from patient medical records. Survival analysis was used to compare the demographic, clinical, and laboratory characteristics between patients with and those without overt stroke. The patients were 52.5% female with a mean (SD) age of 11.2 (4.3) years. The incidence of overt stroke in this cohort was nine out of 956.7 patient-years, resulting in an incidence density of 0.94 cases/100 patient-years. Reports of greater than or equal to two previous attacks of dactylitis and greater than or equal to three episodes of acute chest syndrome (ACS)/pneumonia were associated with overt stroke and an increase in reticulocyte count and red blood cell distribution width (RDW). In conclusion, a history of a high number of dactylitis, ACS/pneumonia, increased RDW, and reticulocytosis was associated with overt stroke occurrence in children and adolescents with SCD. Future studies with a higher stroke incidence in the evaluated sample are necessary to confirm this hypothesis.

Decreased risk of underdosing with continuous infusion versus intermittent administration of cefotaxime in patients with sickle cell disease and acute chest syndrome.

Underdosing of antibiotics is common in patients with sickle cell disease (SCD). We hypothesized that in critically-ill patients with SCD receiving cefotaxime during acute chest syndrome, the continuous infusion may outperform the intermittent administration in achieving pharmacokinetic/pharmacodynamic targets. Prospective before-after study. Intensive-care unit of a French teaching hospital and sickle cell disease referral center. Sixty consecutive episodes of severe acute chest syndrome in 58 adult patients with sickle cell disease. Patients were treated with intermittent administration during the first period (April 2016 -April 2018) and with continuous infusion during the second period (May 2018 -August 2019). We included 60 episodes of acute chest syndrome in 58 patients (29 [25-34] years, 37/58 (64%) males). Daily dose of cefotaxime was similar between groups (59 [48-88] vs. 61 [57-64] mg/kg/day, p = 0.84). Most patients (>75%) presented a glomerular hyperfiltration with no difference between groups (p = 0.25). More patients had a cefotaxime trough level ≥2 mg/L with continuous infusion than intermittent administration: 28 (93%) vs. 5 (16%), p<0.001. The median residual concentration was higher in the continuous infusion than intermittent administration group: 10.5 [7.4-13.3] vs. 0 [0-0] mg/L, p<0.001. No infection relapse was observed in the entire cohort. Hospital length of stay was similar between groups. As compared to intermittent administration, continuous infusion of cefotaxime maximizes the pharmacokinetic/pharmacodynamic parameters in patients with SCD. The clinical outcome did not differ between the two administration methods; however, the study was underpowered to detect such a difference.

Resolvin-D1 (RvD1) and Its Association with Markers of Inflammation, Endothelial Activation, Hemolysis and Clinical Correlates in Children with Sickle Cell Disease (SCD)

Introduction: Sickle Cell Disease (SCD) is an inflammatory and vaso-occlusive pathology. Multiple lipid mediators: resolvins, protectins and maresins, collectively known as Specialized Pro-resolving Mediators (SPMs), that are biosynthesized from Omega-3-PolyUnsaturated Fatty Acids (O3PUFAs), docosahexaenoic acid and eicosapentaenoic acid, appear to play a role in the resolution of inflammation. In a recent study, we have documented the presence of SPMs including Resolvin-D1 (RvD1), 17R-RvD3, and their pathway markers in plasma from both children with SCD and age-and race-matched controls with a significant increase in RvD1 levels noted in plasma from children with SCD. In an SCD mouse model exposed to hypoxia/reoxygenation, a previous study has shown that oral administration of 17R-RvD1, the longer acting isomer of RvD1, promotes resolution of SCD-associated inflammation and tissue damage. Objectives: We assessed whether there were any associations in children with SCD between baseline plasma levels of RvD1 and either markers of inflammation, endothelial activation and hemolysis or SCD-related clinical correlates. Methods: Multiplex assays were employed to assess endothelial activation markers (soluble adhesion molecules VCAM-1, ICAM-1 and E-selectin), and inflammatory cytokines (IL-1β, IL-4, IL-6, IL-10, TNF-α and CRP) in plasma. A 3-year retrospective review of individual SCD patient records was performed, and the number of painful episodes of vaso-occlusion or VOC, including those complicated by the occurrence of acute chest syndrome (ACS) were recorded. Total cumulative painful episodes over a 3-year period were included in the analysis. Spearman Rank Correlation was employed to assess the association between two variables. Results: Consistent with the published results, levels of endothelial activation markers (soluble VCAM-1 and soluble E-selectin), cytokines (IL-4, IL-6 and TNF-α), CRP and LDH were increased in SCD plasma compared to controls (Table-1). No significant associations were found in SCD between RvD1 or other lipid mediators and markers of endothelial activation or inflammation (Table-2). However, there were two significant associations noted between 5-HEPE and IL-1β, and between 12-HETE and IL-6. Plasma levels of the hemolytic marker LDH positively correlated with PGE2, TxB2, 7-HDHA, 5-HEPE and 5-HETE (Table-2). Review of medical history revealed 33 of 45 subjects (73%) had at least one VOC episode, and 17 (38%) had at least one ACS episode in the past 3 years. Subjects who had at least one ACS episode in the past 3 years also reported at least one VOC episode during the same period. There was no statistically significant difference in the RvD1 level by VOC [median RvD1 (ng/ml) of 0.056 in VOC -ve sub-group (n=12) vs 0.084 in VOC +ve sub-group (n=33), p=0.748] or ACS history [median RvD1 (ng/ml) of 0.060 in ACS -ve sub-group (n=28) vs 0.104 in ACS +ve sub-group (n=17), p=0.256]. There was no statistically significant association between levels of RvD1 and the total number of VOC/ACS in the past 3 years (correlation coefficient = -0.06, p=0.694). Summary and Conclusions: Because of the documented pro-resolving and anti-inflammatory effects of orally administered 17R-RvD1 in a mouse model of SCD, and elevated basal plasma levels of RvD1 in children with SCD, we investigated whether endogenous RvD1 provides protection against inflammation and clinical complications in SCD children. Other lipid mediators, which were synthesized from O3PUFAs and arachidonic acid, present in increased levels in SCD plasma and potentially involved in modulation of inflammation were also included in the analysis. Unlike in SCD mouse model in which exogenous RvD1 exerted anti-inflammatory effect in ex-vivo experiments and orally administered 17R-RvD1 promoted resolution of inflammation and down-regulated adhesion molecule expression and cytokine production, endogenous RvD1 did not show any significant association with markers of inflammation and endothelial activation or clinical correlates in a small group of SCD children under healthy condition. No significant findings were noted with other lipid mediators. Whether these lipid mediators modulate inflammation during crisis, pre- or post-crisis clinical conditions and whether their production is different during these clinical conditions compared to steady state healthy condition require further investigation.

Sickle Cell Disease-Eligibility for Curative Treatment in Indian Tribal Population-Urgent Need to Stop and Think

Introduction: Sickle cell disease (SCD) is one of the most common hemoglobinopathies, with nearly 40000 children born annually to the tribal population of India. Hematopoietic stem cell transplantation is currently the only curative option available. Patients eligible for transplantation according to the ASH and other guidelines are those with multiple episodes of veno-occlusive crisis, despite disease-modifying treatment, recurrent episodes of acute chest syndrome, osteonecrosis, patients who experienced overt stroke, or abnormal transcranial Doppler ultrasound, requiring frequent admissions to the hospital. Although HSCT is the sole curative treatment, only a fraction of eligible patients receive it in resource-limited settings. To understand the requirements for bone marrow transplantation, we analyzed the number of eligible patients using clinical data. Methods: A cross-sectional prospective research design was used that involved clinical examination and personal interviews with patients and caregivers, with the completion of questionnaires on clinical characteristics and treatment options. Two hundred fifty individuals with S ,invited to outreach clinics, were analyzed Results: Among the 251 surveyed children, 122 (48.6%) were male and 129(51.4%) were female. Among them, 160 (63.7%) children had recurrent episodes of VOC in the past 1 year, despite 116 (72.5%) receiving regular hydroxyurea. Among them, 98 (62%) required multiple admissions for VOC. Episodes of fever were observed in 51 % of the patients. The requirement for admission to a healthcare facility was recorded in 57 % of the patients. Nearly 13 % of the patients required more than three transfusions in the preceding year. Conclusions: There is an urgent need to organize SCD care pathways, as the whooping number of patients (64%) falls within the criteria of eligibility for HSCT, a curative option. The transplant community, along with healthcare providers and non-governmental organizations, should decide on a strategy to offer this important modality of curable alternatives.

Neighborhood Disadvantage Increases Risk of Adverse Clinical Events in Children with Sickle Cell Disease

Background: Hydroxyurea is the most widely used pharmacologic agent to treat patients with sickle cell disease (SCD). Hydroxyurea treatment has well established effects of inducing expression of fetal hemoglobin (HbF) and a beneficial impact on clinical outcomes such as reduced number of vaso-occlusive (VOC) events, transfusions, and hospitalizations. In non-SCD populations, living in socio-economic disadvantage is a well-established factor for poor health outcomes. However, there is a paucity of data to describe how social stressors impact children with SCD. We hypothesized that socio-economic disadvantage impacts risk of adverse clinical outcomes in pediatric SCD patients even while on hydroxyurea therapy. Methods: We performed a retrospective chart review on 121 pediatric patients with severe SCD genotypes (homozygous HbS and sickle-beta 0 thalassemia) seen at Texas Children's Hospital (TCH) between 2010-2021. All patients were treated with hydroxyurea for a minimum of five years. Adherence to hydroxyurea was assessed through lab markers including absolute neutrophil count and reticulocyte counts. Patients not adherent were excluded from analysis. We examined the incidence of all clinical events for a total of 1026 patient years, including the number of office visits, ER visits, hospitalizations, transfusions, VOC, acute chest syndrome episodes (ACS), acute splenic sequestration (ASS), and febrile illness. We collected laboratory data including absolute neutrophil count, hemoglobin level, and HbF levels for each patient per year they were on hydroxyurea. We used the area deprivation index (ADI) to determine a score of neighborhood disadvantage amongst our cohort of patients. The ADI is a factor-based index which uses 17 US Census variables including poverty, education, and employment. We used individual residential addresses during our observation period to assign a geocode specific to each individual and obtain an ADI score. The ADI scores are ranked from 1-10, with higher ADI rankings reflecting a higher level of disadvantage. Results: All individuals with SCD had a robust response to hydroxyurea within their first year of initiating the drug (&amp;gt;20% HbF). We stratified our cohort based on their ADI scores into low ADI (1-3; n=42); medium ADI (4-6; n=42); and high ADI groups (7-10; n=37), where high ADI is the group with highest levels of disadvantage. All three groups had a similar average duration of hydroxyurea treatment. There were no significant differences in age, sex, or reason given for starting hydroxyurea between the ADI groups. When we examined hydroxyurea response, there was no significant difference in HbF levels at 1 year (23.8 vs. 24.06 %HbF in the low vs. high ADI groups) or after 5 years (19.6 vs. 18.6 % HbF in the low and high ADI groups). Individuals with high ADI did started hydroxyurea at a younger age (2.9 years vs. 4.9 years, p=0.02). We found that any individual living in an area with higher ADI had an increased incidence of adverse clinical events. We calculated the incidence of each clinical event per 100 patient years in our 3 ADI groups and used a conditional maximum likelihood estimate of rate ratio method to compare incidences (Table 1). We found that among individuals living in an area with a higher ADI (more deprived region), there was increased frequency of ER visits, hospitalizations, transfusions, VOC, and ASS. In particular, patients with the highest ADI had a 3 and 5 times higher rate of VOC and ASS, respectively (Table 1). Discussion: While we did not observe an association between ADI and HbF expression, our results show that higher neighborhood disadvantage is associated with poorer clinical outcomes among hydroxyurea-adherent pediatric patients with SCD who maintained a robust response to the drug (&amp;gt;20% HbF). All individuals in our study had a similar number of routine office visits at our clinic but any patient living in an area of high ADI had significantly more ER visits and hospitalizations for VOC and ASS events. While hydroxyurea is shown to reduce hospitalizations and VOC events in pediatric sickle cell patients, we show that neighborhood disadvantage can influence clinical outcomes even among patients who respond to hydroxyurea. More analysis remains in order to better characterize this association, and to understand additional strategies that can be used to reduce clinical events in pediatric patients of lower socioeconomic status.

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.

A Working Definition of Acute Chest Syndrome without the Requirement of Chest X-Rays

Introduction:Sickle Cell Disease (SCD) is a rare genetic disease in high-income countries where most of the cited literature used to guide clinical management emanate from. One of the most serious and potentially fatal complications of SCD is acute chest syndrome (ACS) which requires immediate medical attention. Approximately 50% of individuals with SCD will eventually develop ACS ( Blood 84, 643-649 (1994)). Despite the high frequency of ACS and its associated risk of death, no consensus diagnosis has been established that applies to children and adults living in low-middle income countries, where 95% of the children born with SCD are found. To create a uniform definition of ACS in both low, middle, and high-income countries, we propose using a new ACS definition that does not require a chest X-ray. Additionally, the new ACS definition should have a quantifiable and reproducible physical examination and clinical findings to allow for the reproducibility of the definition in all settings. This definition was developed over several years at Korle Bu Teaching Hospital, Accra Ghana, in pregnant women with SCD. Before we started the multidisciplinary team care in pregnant women with SCD, ACS was the most common cause of maternal death. Subsequently, based on the new ACS definition that did not require a chest X-ray, we developed strategies to prevent, aid early diagnosis, and treat ACS resulting in an 89% relative risk reduction of death. We refer to this new definition as the Korle Bu Teaching Hospital (KBTH)-ACS definition. In this study, we compare the ACS definition in the top 20 cited ACS articles as of July 2023 with our proposed KBTH-ACS definition. Methods:Using Google Scholar, we identified the top 20 cited articles with ACS in children or adults with SCD as primary or secondary outcomes. Each article was reviewed for the presence of the following criteria: chest x-ray, vitals, hemoglobin oxygen saturation, and lung physical exam findings. We compared the definition of ACS in the top 20 cited ACS articles to the KBTH-ACS definition that included the following features: “abnormal findings on lung auscultation and the presence of at least 2 of the following criteria: 1) temperature ≥ 38.0°C, 2) increased respiratory rate greater than the 90th percentile for age, positive chest pain or pulmonary auscultatory findings, 3) hemoglobin oxygen saturation decrease by ≥3% from a documented steady-state value on room air, and 4) a new radiodensity on chest roentgenogram. A diagnosis of pneumonia was considered an ACS episode.”. Results:The 20 most cited ACS articles required radiographical criteria to diagnose ACS. Fourteen of twenty articles included fever in their ACS definition. However, only 4 articles specified any temperature and all specified ≥ 38.5 ºC. A total of 17 articles mentioned the presence of lung or respiratory findings, but only 12 articles specifically identified the pulmonary findings. Among the 12 articles that specified lung findings, 5 included increased respiratory rate (tachypnea) without a specific definition, 2 included abnormal auscultatory findings, and 3 included hypoxemia/hypoxia in their definition. However. One study defined hypoxemia/hypoxia as “transcutaneous oxygen saturation &amp;lt;85% despite supplemental oxygen.”. Another article included “SpO2 of ≥ 3% compared to baseline steady-state values.”. In addition, among the twelve studies that specified respiratory findings, the following were present or absent features: chest pain (n=12), wheezing (n=3), coughing(n=3), and respiratory distress without a formal definition (n=3). No article included pneumonia in the ACS definition nor defined a threshold for tachypnea that was age-adjusted. None of the articles would allow for a direct comparison with the KBTH-ACS definition. Conclusion: All the 20 most cited ACS articles required a chest X-ray with various clinical and physical examination findings. Many of the ACS definitions in these studies were based on clinical impressions that were not quantifiable or reproducible. We propose using the KBTH-ACS definition in future ACS studies to improve generalizability, reproducibility, and genotype and phenotype studies designed to elucidate the genetic variation of lung disease in children and adults with SCD.

Unique Changes in the Incidence of Acute Chest Syndrome in Children With Sickle Cell Disease Unravel the Role of Respiratory Pathogens: A Time Series Analysis

Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Although respiratory pathogens are frequently detected in children with ACS, their respective role in triggering the disease is still unclear. We hypothesized that the incidence of ACS followed the unprecedented population-level changes in respiratory pathogen dynamics after COVID-19-related nonpharmaceutical interventions (NPIs). What is the respective role of respiratory pathogens in ACS epidemiology? This study was an interrupted time series analysis of patient records from a national hospital-based surveillance system. All childrenaged < 18 years with SCD hospitalized for ACS in France between January 2015 and May 2022 were included. The monthly incidence of ACS per 1,000 children with SCD over time was analyzed by using a quasi-Poisson regression model. The circulation of 12 respiratory pathogens in the general pediatric population over the same period was included in the model to assess the fraction of ACS potentially attributable to each respiratory pathogen. Among the 55,941 hospitalizations of children with SCD, 2,306 episodes of ACS were included (median [interquartile range] age, 9 [5-13] years). A significant decrease was observed in ACS incidence after NPI implementation in March 2020 (-29.5%; 95%CI, -46.8 to -12.2; P= .001) and a significant increase after lifting of the NPIs in April 2021 (24.4%; 95%CI, 7.2 to 41.6; P= .007). Using population-level incidence of several respiratory pathogens, Streptococcus pneumoniae accounted for 30.9%(95%CI, 4.9 to 56.9; P= .02) of ACS incidence over the study period and influenza 6.8%(95%CI, 2.3 to 11.3; P= .004); other respiratory pathogens had only a minor role. NPIs were associated with significant changes in ACS incidence concomitantly with major changes in the circulation of several respiratory pathogens in the general population. This unique epidemiologic situation allowed determination of the contribution of these respiratory pathogens, in particular S pneumoniae and influenza, to the burden of childhood ACS, highlighting the potential benefit of vaccine prevention in this vulnerable population.

Is Hydroxyurea Treatment Changing the Life of Children with Sickle Cell Disease?

Background: Sickle cell disease (SCD) is a prevalent hemoglobinopathy involving sickled hemoglobin that causes multiorgan disease due to chronic recurrent vaso-occlusion and hemolysis. Fetal hemoglobin (HbF) being present showed reduction in disease severity, owing to which hydroxyurea has gained significant recognition. The latter’s exact mechanism of action is yet unknown, but it has been demonstrated that the resulting rise in HbF raises hemoglobin levels and lessens the incidence of acute chest syndrome and vaso-occlusive crises. In the United Arab Emirates, our study is the first to assess the effects of hydroxyurea therapy in pediatric SCD patients. Methods: We conducted a retrospective cross-sectional study on 100 patients aged 2–13 years who were diagnosed with SCD, under regular outpatient follow-up with pediatric hematology clinic and receiving hydroxyurea therapy for at least 2 years. Basic hematologic parameters, frequency of SCD complications, and need for blood transfusions were studied. Results: Our analysis has shown a statistically significant (p < 0.05) correlation between hydroxyurea therapy and improved baseline hemoglobin and HbF levels; it decreased the incidence of painful crises and acute chest syndrome episodes; reduced the demand for blood transfusions; and recorded no side effects (pancytopenia or liver function disturbance). Conclusions: This study is the first of its kind in the UAE, and our findings support those of international data. The use of hydroxyurea therapy in SCD significantly improved hematologic and clinical parameters, thus markedly improving the patient’s quality of life. The side-effect profile is also limited, which further supports the fact that hydroxyurea is a relatively safe drug.

Outcomes before and after providing interdisciplinary hematology and pulmonary care for children with sickle cell disease.

People with sickle cell disease (pwSCD) are at risk of developing lung conditions that complicate their SCD but often face health care access barriers. An interdisciplinary clinic providing pulmonary care for pwSCD was created in 2014 at the Nationwide Children's Hospital (NCH) to address access barriers that may prevent optimized treatment. We hypothesize that pwSCD and pulmonary disease would have fewer hospitalizations for acute chest syndrome (ACS), asthma, and vaso-occlusive episodes in the 2 years after their initial SCD-pulmonary clinic visit compared with the 2 years before. From 2014 to 2020, 119 pwSCD were evaluated in the SCD-pulmonary clinic and followed up at the NCH for at least 2 years before and after this initial visit. Acute care outcomes, pulmonary function, polysomnography, echocardiogram, laboratory, and medication prescribing data were collected and analyzed using the Wilcoxon signed ranked and McNemar tests. The median number of acute care visits for ACS (P< .001) and asthma (P= .006) were significantly lower during the 2 years after pwSCD's initial SCD-pulmonary clinic evaluation compared with the 2 years before. Asthma and allergic rhinitis were more frequently diagnosed and prescriptions for hydroxyurea (P= .005) and inhaled corticosteroids (P= .005) were more common in the post-SCD-pulmonary clinic period. The median number of prescribed systemic corticosteroids was lower in the 2 years after SCD-pulmonary clinic evaluation (P<.0001). Lactate dehydrogenase and white blood cell counts also significantly decreased. Implementing a multidisciplinary SCD-pulmonary clinic is feasible and may allow improved management of pulmonary problems and lead to improvements in the usage of health and acute care.

The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD.

The lung microenvironment plays a crucial role in maintaining lung homeostasis as well as the initiation and resolution of both acute and chronic lung injury. Acute chest syndrome (ACS) is a complication of sickle cell disease (SCD) like acute lung injury. Both the endothelial cells and peripheral blood mononuclear cells are known to secrete proinflammatory cytokines elevated during ACS episodes. However, in SCD, the lung microenvironment that may favor excessive production of proinflammatory cytokines and the contribution of other lung resident cells, such as alveolar macrophages and alveolar type 2 epithelial (AT-2) cells, to ACS pathogenesis is not completely understood. Here, we sought to understand the pulmonary microenvironment and the proinflammatory profile of lung alveolar macrophages (LAMs) and AT-2 cells at steady state in Townes sickle cell (SS) mice compared to control mice (AA). In addition, we examined lung function and micromechanics molecules essential for pulmonary epithelial barrier function in these mice. Our results showed that bronchoalveolar lavage (BAL) fluid in SS mice had elevated protein levels of pro-inflammatory cytokines interleukin (IL)-1β and IL-12 (p ⩽ 0.05) compared to AA controls. We showed for the first time, significantly increased protein levels of inflammatory mediators (Human antigen R (HuR), Toll-like receptor 4 (TLR4), MyD88, and PU.1) in AT-2 cells (1.4 to 2.2-fold) and LAM (17-21%) isolated from SS mice compared to AA control mice at steady state. There were also low levels of anti-inflammatory transcription factors (Nrf2 and PPARy) in SS mice compared to AA controls (p ⩽ 0.05). Finally, we found impaired lung function and a dysregulated composition of surfactant proteins (B and C). Our results demonstrate that SS mice at steady state had a compromised lung microenvironment with elevated expression of proinflammatory cytokines by AT-2 cells and LAM, as well as dysregulated expression of surfactant proteins necessary for maintaining the alveolar barrier integrity and lung function.

Description of a Colocated Comprehensive Care Model for People With Sickle Cell and Comorbid Pulmonary Disease.

Comorbid pulmonary complications in people with sickle cell disease (pwSCD) are associated with high rates of morbidity and mortality, and poor access to care contributes to poor outcomes among this particularly high-risk pwSCD. Our purpose was to describe the population served and the resources required for hematology, pulmonary, nursing, respiratory therapy, social work, genetics, psychology, and school liaison providers to see these patients in an integrated clinic. We abstracted demographic, medication, clinical, and diagnostics data of the pwSCD seen at least once in this clinic from February 1, 2014 to December 10, 2020 from the electronic medical record and identified 145 unique pwSCD. Abnormal lung function and bronchodilator responsiveness were detected in 31% and 42% of participants respectively. Sleep abnormalities were found in over two-thirds of those screened and 65% had ≥1 previous acute chest syndrome episode. This clinic also allowed for direct provider communication and required relatively limited resources to serve a large number of severely affected pwSCD. Given the degree of abnormal respiratory variables detected and the limited resources required to implement this model, studies are warranted to evaluate whether it has the potential to improve outcomes in high-risk populations.

A systematic review comparing allogeneic hematopoietic stem cell transplant to gene therapy in sickle cell disease

ABSTRACTIntroductionAllogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials.ObjectiveTo compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions.MethodsPhase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed.ResultsIn total, 56 studies (HSCT, n = 53; GT, n = 3) representing 1,198 patients met inclusion criteria (HSCT, n = 1,158; GT, n = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported.DiscussionReporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.

Asthma in Children with Sickle Cell Disease

Sickle Cell Disease is a life-threatening hereditary blood disorder which affects millions of people worldwide. Pulmonary complications are important causes of morbidity and mortality in patients with sickle cell disease. Asthma is a recognised comorbidity of sickle cell disease and may occur in between 15 and 28% of children with sickle cell disease. It has been associated with increased episodes of acute chest syndrome and all cause mortality. Obstructive lung disease, however, is common in children with sickle cell disease, independent of an asthma diagnosis. This review explores the pathophysiology, diagnosis and therapeutic opportunities for asthma in sickle cell disease patients. The diagnostic challenges and inconsistencies in current clinical approaches are highlighted. Convergence of inflammatory pathways in sickle cell disease and asthma occurs, but there is also a heightened level of inflammation unique to sickle cell disease. Thus, wheezing may not be due to asthma but be a manifestation of sickle cell disease per se and the result of the increased pulmonary vascular volume. As a consequence, anti-asthma therapy may not be appropriate for all wheezy children with sickle cell disease and commencing treatment on the basis of a physician’s diagnosis alone is inappropriate. Data from paediatric cohorts suggest use of spirometry, aeroallergen sensitisation tests, impulse oscillometry and dedicated interdisciplinary pulmonary clinics could improve diagnosis accuracy. Corticosteroids and bronchodilators are well-established treatments for asthma; observational studies suggest they may provide benefit for some children with sickle cell disease, but therapies such as hydroxyurea may improve respiratory outcomes in others. It is, therefore, essential children are thoroughly investigated and followed-up and a personalised approach taken to their care. Prospective randomised studies are required to establish the effectiveness of asthma therapies in children with sickle cell disease.

Acute pain episodes, acute chest syndrome, and pulmonary thromboembolism in pregnancy

Pregnancy in women with sickle cell disease (SCD) is a life-threatening condition. In both high- and low-income countries, there is an 11-fold increased risk of maternal death and a 4-fold increased risk of perinatal death. We highlight the epidemiology of SCD-specific and obstetric complications commonly seen during pregnancy in SCD and propose definitions for acute pain and acute chest syndrome (ACS) episodes during pregnancy. We conducted a systematic review of the recent obstetric and hematology literature using full research articles published within the last 5 years that reported outcomes in pregnant women with SCD. The prevalence of acute pain episodes during pregnancy ranged between 4% and 75%. The prevalence of ACS episodes during pregnancy ranged between 4% and 13%. The estimated prevalence of pulmonary thromboembolism in women with SCD during pregnancy is approximately 0.5 to 1%. ACS is the most common cause of death and is often preceded by acute pain episodes. The most crucial time to develop these complications in pregnancy is during the third trimester and postpartum period. In a pooled analysis from studies in low- and middle-income settings, maternal death in women with SCD is approximately 2393 and 4300 deaths per 100 000 live births with and without multidisciplinary care, respectively. In comparison, in the US and northern Europe, the general maternal mortality rate is approximately 23.8 and 8 deaths per 100 000 live births, respectively. A multidisciplinary SCD obstetrics care approach reduces maternal and perinatal morbidity and mortality in low- and middle-income countries.

Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.

Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. This is an update of a previously published Cochrane Review. The aim of the review is to determine whether the use of inhaled, short-acting bronchodilators for acute chest syndrome reduces morbidity and mortality in people with sickle cell disease and to assess whether this treatment causes adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2004) and Embase (1981 to 2004) and ongoing trial registries (28 September 2022). Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 25 July 2022. Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.