Acute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) associated with significant morbidity and mortality, necessitating optimized prevention and management strategies for improved patient outcomes. This review does not evaluate red blood cell exchange, as no randomized controlled trials meeting our inclusion criteria reported outcomes for this intervention. A thorough literature review identified interventions for ACS in SCD patients. Seventeen randomized controlled trials (RCTs) underwent assessment using the Cochrane Risk of Bias 2 tool, and a frequentist network meta-analysis was conducted to compare interventions. The use of hydroxyurea and simple transfusion was associated with a lower proportion of patients who developed ACS during the study period compared with standard care (RR: 0.42, 95% CI [0.20-0.86]; RR: 0.31, 95% CI [0.12-0.75], respectively). Intravenous dexamethasone was associated with a lower risk of persistent fever, reduced need for blood transfusion, and shorter durations of both opioid and oxygen therapy, as well as a shorter in-hospital stay (p < 0.01 for all comparisons). When compared with standard care, hydroxyurea was associated with reduced requirement for blood transfusion (RR: 0.17, 95% CI [0.04, 0.73]), with a similar association observed for intravenous dexamethasone (RR: 0.19, 95% CI [0.05, 0.77]). No significant associations were identified between any treatment and rates of hospitalization or readmission. This study offers insights into ACS treatment efficacy and safety in SCD patients. Hydroxyurea and transfusion strategies demonstrated the strongest evidence for reducing acute chest syndrome risk. Corticosteroids were associated with improved inpatient outcomes in predominantly pediatric populations, but concerns regarding potential rebound pain and rehospitalization warrant cautious interpretation. Larger trials are required before routine steroid use can be broadly recommended.

SCD is a prevalent genetic disorder marked by chronic complications that impact quality of life and survival. Affecting approximately 100 000 individuals in the United States and millions globally, SCD results from a mutation in the β-globin gene, leading to sickle-shaped red blood cells and subsequent vaso-occlusive episodes, hemolysis, and multiorgan damage. Despite advancements such as newborn screening and disease-modifying therapies, individuals with SCD continue to face significant long-term challenges. This review focuses on the major long-term complications of SCD, including chronic pain, mental health diagnoses, neurological deficits, infection, alloimmunization, cardiopulmonary complications, and reproductive health concerns. Pain, often a hallmark of SCD, significantly affects quality of life and requires an individualized approach to management. Depression and anxiety are prevalent and impact both psychosocial well-being and disease outcomes. Neurological complications, including stroke and cognitive deficits, pose substantial risks and require ongoing monitoring. Reproductive health concerns, such as fertility and pregnancy complications, demand careful management. Alloimmunization, a potential consequence of transfusion exposure transfusion exposure, complicates future transfusion therapy and increases the risk of delayed hemolytic transfusion reactions. Cardiopulmonary complications, including pulmonary hypertension and restrictive lung disease secondary to recurrent acute chest syndrome, are associated with increased morbidity and warrant early recognition and monitoring. This review aims to bridge the knowledge gap for general pediatricians by providing comprehensive insights into these long-term complications and offering strategies for effective management. Understanding these aspects is essential for improving patient outcomes and ensuring that pediatricians can provide informed, empathetic, and proactive care for children with SCD.

Hydroxyurea (HU) reduces complications of sickle cell anemia (SCA), but the response is variable. L-glutamine, an antioxidant that improves redox balance, is implicated in a distinct pathophysiological pathway and may provide additional clinical benefit when added to HU. We evaluated HU plus L-glutamine versus HU alone in pediatric/adolescent SCA. In a 6-month, double-blind, placebo-controlled trial, 53 patients with HbSS or HbS/β0-thalassemia were randomized to the HU + L-glutamine (n=27) or the HU + placebo (n=26) group while continuing HU at ~20 mg/kg/day. The primary endpoint was vaso-occlusive crisis (VOC) frequency; secondary endpoints included acute chest syndrome (ACS), hospitalizations, and hematological parameters. Analyses were performed for intention-totreat with baseline-adjusted models for key outcomes. Over 6 months, the HU + L-glutamine group experienced significantly fewer VOCs (1.00±0.73 vs. 1.65±0.80; p=0.003) and ACS episodes (0.19 vs. 0.77; p=0.006). Hospitalizations declined by 40% (p=0.04). Hemoglobin (Hb) rose more in the combination arm (+0.78 vs. +0.32 g/dL; p=0.028), with larger reductions in reticulocytes (p=0.04) and greater fetal Hb increases (+6.2% vs. +1.6%; p<0.001). Adherence exceeded 80% in both arms and no serious adverse events occurred. Adding L-glutamine to HU significantly reduced VOCs, ACS, and hospitalizations while improving Hb and hemolysis markers, without added toxicity. The combination’s efficacy likely reflects synergistic effects on oxidative stress and sickle cell pathophysiology. This well-tolerated combination may improve SCA control, but larger confirmatory trials are needed.

Adult patients with sickle cell disease may present to the emergency department with a broad spectrum of acute clinical manifestations. These acute complications can be life-threatening and require a structured, time-sensitive emergency management approach. Although vaso-occlusive pain crises represent the most frequent cause of presentation, other severe complications-including cerebrovascular events, acute chest syndrome, priapism, and hepatobiliary disorders-may also require immediate medical evaluation. Prompt diagnostic assessment and initiation of appropriate therapy are essential to prevent clinical deterioration and the development of secondary complications.

Sickle cell disease (SCD) is a complex thrombo-inflammatory disorder in which haemolysis, platelet activation, thrombocytosis, inflammation and endothelial activation operate as an intricate network creating a perpetual cycle of cellular injury and vascular dysfunction that drives vaso-occlusive crises, tissue ischaemia and progressive end-organ damage. Thrombocytosis is common in SCD, especially in response to acute chest syndrome, vaso-occlusive crises and chronic haemolysis. Increased platelet activity contributes to the proinflammatory and prothrombotic environment. Activated platelets release platelet-derived microparticles (PMPs) containing phospholipids and inflammatory mediators, which enhance thrombin generation, entrap leucocytes and promote cellular adhesions leading to endothelial dysfunction and vaso-occlusion within the microvasculature. This review provides insights into the mechanisms underlying thrombocytosis and PMP formation in SCD and discusses therapeutic strategies targeting platelet activation to mitigate inflammation and vascular complications.

BackgroundVaso-occlusive crises (VOC) are the most frequent complications among people living with sickle cell disease. VOC lead to frequent hospitalisations, reduce quality of life and contribute to long-term sequelae such as stroke, acute chest syndrome, and renal impairment. There are limited contemporary data on the incidence and risk factors for VOC among children with sickle cell anaemia (SCA) after the introduction of hydroxyurea in Uganda.MethodsA prospective cohort study conducted among children living with SCA enrolled in the Uganda Sickle Pan-African Research Consortium Registry, at the Mulago Hospital Sickle Cell Clinic. Participants aged 6 months to 18 years enrolled and followed for six months to assess the occurrence of VOC. Cox proportional hazards regression was used to evaluate associations between clinical and laboratory variables and time to VOC.ResultsA total of 438 participants were enrolled, with a median age of 9 years (IQR: 5–13). Most participants (80.1%) reported hydroxyurea use. The mean baseline haemoglobin concentration was 7.7 g/dL (SD: 1.2), and the median foetal haemoglobin (HbF) level was 12.3% (IQR: 7.2–18.2). in the preceding year, history of VOC was reported by 88.8%, and 30.1% had received at least one blood transfusion. The incidence of VOC was 102.3 (95% CI: 88.2–118.8) per 100 person-years, with 13% experiencing more than one episode during follow-up. After adjusting for sex and prior VOC history, previous blood transfusion was independently associated with increased VOC risk (aHR: 1.11; 95% CI: 1.02–1.22;p = 0.020).ConclusionVOC remains a common and clinically significant complication among Ugandan children living with SCA. Prior blood transfusion was identified as a potential predictor of VOC, underscoring the need for optimised clinical management, including timely and appropriately dosed hydroxyurea therapy, to mitigate risk in this population.

Children with sickle cell disease (SCD) frequently experience chronic inflammation, increased metabolic demands, and recurrent acute complications. Asthma is a recognised comorbidity associated with increased morbidity in SCD. However, the contribution of nutritional status, particularly body mass index (BMI), to clinical severity among children with SCD and confirmed asthma remains poorly documented, especially in tropical settings. The objective of this study was to describe the nutritional status of children with SCD and spirometry-confirmed asthma and to assess the association between BMI-for-age z-scores and clinical severity. We conducted a multicentre observational study including children aged 5-17 years with SCD and spirometry-confirmed asthma. Nutritional status was assessed using WHO 2007 BMI-for-age z-scores calculated from measured weight and height. Undernutrition was defined as a BMI-for-age z-score < - 2. Clinical severity was defined as the occurrence of at least two hospitalisations for vaso-occlusive crises and/or acute chest syndrome in the preceding 12 months. Associations between nutritional indicators and clinical severity were evaluated using bivariate and multivariable logistic regression models adjusted for relevant clinical covariates. A total of 138 children were included (median age 8.0 years). Overall, 17.4% presented undernutrition, while 12.3% were overweight or obese. In bivariate analyses, undernutrition was more frequent among children with severe disease than among those with non-severe disease (24.5% vs. 13.5%). When BMI-for-age z-score was analysed as a continuous variable, lower values were associated with increased odds of severe disease (OR per 1-SD decrease = 1.34; 95% CI 1.01-1.78). After multivariable adjustment, the association between BMI-for-age z-score and severity was attenuated and did not reach statistical significance (adjusted OR 1.29; 95% CI 0.96-1.74; p = 0.09). These findings highlight the contribution of clinical and inflammatory factors to disease severity in children with sickle cell disease and confirmed asthma, including prior ACS, which showed a borderline association. Clinical severity appeared to be more closely related to respiratory burden than to nutritional status alone. Lower BMI-for-age z-scores reflected global systemic vulnerability rather than an independent risk factor. Routine nutritional assessment may therefore support risk stratification and help identify children who could benefit from targeted multidisciplinary care.

ABSTRACT Background Sickle cell disease (SCD) is a monogenic hemoglobinopathy characterized by recurrent vaso-occlusive crises (VOCs) that affect any organ and progress to multi-organ failure. Acute chest syndrome (ACS) is a major complication and leading cause of death. This study explored whole-blood circRNA signatures as candidate molecular markers for VOC and ACS and examined their functional relevance through miRNA mapping and pathway enrichment. Research design and methods A publicly available total RNA-seq dataset (GSE139912) was analyzed for circRNA expression at baseline (n = 12), VOC (n = 10), and ACS (n = 11). Results Significant circRNA dysregulation was identified in ACS vs. baseline and VOC vs. baseline. An exploratory panel of the top 20 upregulated and 16 downregulated circRNAs in ACS was summarized as a composite circRNA score. The unchanged score increased stepwise across clinical states, with mean differences of 1.60 for VOC vs. baseline and 1.08 for ACS vs. VOC. Standardized effect sizes were Cohen’s d = 2.89 and 1.61, respectively. VOC showed intermediate scores between baseline and ACS. Enrichment analyses suggested immune and inflammatory involvement, including interleukin signaling and PI3K/AKT/MAPK-related cascades. Conclusions These findings support circRNA expression as a source of candidate biomarkers for ACS and VOC, although validation in independent multicenter cohorts is required.

Erythrocytaphoresis or RBC exchange (RBCX) is a key intervention in the management of sickle cell anemia for both chronic prophylaxis and emergent clinical care during sickle cell disease (SCD) emergencies. RBCX removes sickled RBCs while replacing them with donor RBCs and reducing hemoglobin S (HbS) levels. Unlike simple transfusion, it minimizes iron overload and avoids fluid overload, making it a mainstay for the management of acute stroke, acute chest syndrome, and other settings where fluid overload can complicate disease morbidity. Chronic RBCX has shown benefit in not only improving oxygenation and reducing hospitalization rates but also improving overall quality of life in SCD patients. Advances in apheresis technology and personalized transfusion have brought new opportunities for enhancement in safety, efficacy, and feasibility of this therapeutic modality. In this review, we explore the clinical efficacy and role of chronic RBC exchange and its long-term outcomes in managing complications of SCD.

Curative treatment for severe sickle cell disease: allogeneic hematopoietic cell transplant or gene therapy.

To determine whether adults with sickle cell disease (SCD) without glaucoma exhibit subclinical structural optic neuropathy (SON) on optical coherence tomography (OCT) and to identify genetic, clinical, and biologic correlates of optic nerve thinning. Monocentric, retrospective cross-sectional study of 185 eyes from 96 adults with SCD (116 eyes/59 HbSS; 69 eyes/37 HbSC) and 40 eyes from 20 controls. Spectral-domain OCT measured Bruch's membrane opening-minimum rim width (BMO-MRW), peripapillary retinal nerve fibre layer (RNFL), and macular ganglion cell complex (GCC). SON was defined as concordant thinning across all three parameters. Patient-clustered models with Holm adjustment compared groups; multivariable clustered logistic regression identified risk factors. Compared with controls, SCD eyes showed thinner BMO-MRW, RNFL, and GCC (all p < 0.001). Within SCD, HbSC exhibited greater thinning than HbSS, especially in temporal and superonasal BMO-MRW sectors and RNFL average, inferotemporal, and superotemporal sectors. Proliferative SCR showed more pronounced loss than non-proliferative disease, including lower BMO-MRW, temporal RNFL thinning, and global GCC reduction. Haemoglobin correlated positively with BMO-MRW in HbSS (ρ = 0.41, p = 0.001), haematocrit tended toward a negative association with RNFL in HbSC (ρ = -0.29, p = 0.06), and reticulocytes were inversely associated with GCC in HbSS (ρ = -0.25, p = 0.038) and HbSC (ρ = -0.31, p = 0.038). Older age, recent acute chest syndrome, and ≥1 vaso-occlusive crisis within 2 years independently increased SON odds, whereas higher haemoglobin was protective. Adults with SCD show OCT-detectable subclinical SON linked to genotype, retinopathy stage, anaemia severity, and vaso-occlusive burden; combined BMO-MRW, RNFL, and GCC may aid risk-stratified surveillance.

Abstract BACKGROUND Sickle cell anemia is a globally prevalent hematological disorder. Acute chest syndrome (ACS), asthma, pulmonary hypertension and venous thromboembolism are examples of pulmonary complications in sickle cell disease. While several studies have explored the relationship between asthma, airway hyperresponsiveness, and acute chest syndrome, no study has yet demonstrated the association between bronchodilator response (BDR) and ACS. Methods This study explored the relationship between BDR and ACS, and their recurrences in children and adolescents with sickle cell disease (SCD). This retrospective chart review included patients from Arkansas Children’s Hospital from 2017 to July 2025, during which we assessed BDR using pulmonary function tests (PFTs). We calculated both ERS/ATS 2022 criteria (positive if change &amp;gt;10% in FEV1), and Pre 2021 ERS/ATS criteria (positive if ≥ 12% and ≥200ml increase in FEV1 after SABA use) for each patient. We analyzed the association between BDR and ACS using the Chi-square test, and identified factors contributing to ACS using univariate and multivariate logistic regression, with statistical significance at P &amp;lt; 0.05. Results Between January 2017 and July 2025, 53 patients with SCD underwent PFTs and BDR assessments. The median age was 14 years, with 56.6% male and 43.4% female. ACS was observed in 71.7% of patients, while 84.9% experienced a SCC. For BDR, the P-values using the pre-2021 ERS/ATS criteria were 0.72 for ACS and 0.40 for recurrent ACS, while the 2022 criteria yielded P-values of 0.86 and 0.63, respectively. Patients with negative BDR had ACS recurrence rates of 38% (pre-2021) and 40% (2022), with a P-value of 0.632. The P-values for BMI percentile were 0.21 and 0.03 (adjusted for age, asthma, allergy, and White Cell Count) for ACS. For history of prior chest syndrome, the P-values were 0.04 and 0.05 (adjusted similarly) for ACS. Conclusion Our study did not find a significant association between BDR and ACS and recurrences. We observed that ACS recurrence is lower in patients with a negative BDR than in those with a positive BDR, though this finding was non-significant statistically. BMI and H/O prior ACS were significant predictors of ACS. The findings are limited by the sample size, the retrospective study design, and the fact that PFT and BDR are conducted only in sickle cell patients after episodes of ACS or other respiratory issues. This highlights the need for a follow-up study with a prospective design and a larger sample size to strengthen the validity of the research findings. This abstract is funded by: NA

Inflammatory markers in sickle cell disease during vaso-occlusive crisis.

Asthma is a frequent comorbidity in children with sickle cell disease and has been associated with an increased risk of acute complications, particularly vaso-occlusive crises and acute chest syndrome. However, determinants of clinical severity among children with sickle cell disease and confirmed asthma remain poorly characterized, especially in tropical settings. This study aimed to identify factors associated with clinical severity in this population. We conducted an observational study among children with sickle cell disease followed in French Guiana. The analysis was restricted to children with confirmed asthma. Clinical severity was defined as the occurrence of at least two hospitalizations during the 12 months preceding evaluation for vaso-occlusive crises and/or acute chest syndrome. Factors associated with severity were assessed using univariate and multivariate logistic regression analyses. A total of 138 children with sickle cell disease and confirmed asthma were included, of whom 102 (73.9%) presented a severe clinical form. In multivariate analysis, no variable was independently associated with clinical severity. However, a trend toward an increased risk of severe disease was observed among children living in rural areas (adjusted OR = 1.94; 95% CI: 0.77-4.86), while a trend toward a protective effect was observed for Strongyloides stercoralis infection (adjusted OR = 0.18; 95% CI: 0.02-1.51). Allergic sensitization, although frequent (64.5%), was not associated with clinical severity after adjustment (adjusted OR = 0.66; 95% CI: 0.31-1.44). Among children with sickle cell disease and confirmed asthma, more than one third experience severe clinical disease. No independent predictors of severity were identified. Observed trends should be interpreted cautiously and considered exploratory. These findings support a stratified approach to sickle cell-associated asthma to identify high-risk children and prevent avoidable acute complications.

SummaryIndividuals with sickle cell anaemia (SCA) exhibit significant clinical heterogeneity influenced by several factors, especially fetal haemoglobin (HbF) levels. Variations in adult HbF levels are partly explained by the co‐inheritance of genetic variants that regulate globin expression. In this study, we investigated the association of BCL11A rs4671393, rs1427407, rs11886868 and HBS1L‐MYB rs9399137 polymorphisms with HbF levels and clinical complications in a cohort of 409 adult Brazilian SCA patients. Our findings reveal that variant alleles of all four single‐nucleotide polymorphisms (SNPs) were significantly associated with higher HbF levels. Moreover, homozygosity for the major alleles was independently associated with higher risk and cumulative incidence of stroke, avascular necrosis, leg ulcers, priapism and acute chest syndrome. Haplotype analysis with BCL11A variants was also associated with HbF and the patient's phenotype. A genetic risk score (GRS) combining the risk genotypes was significantly associated with lower HbF levels (p < 0.0001) and increased complication risk (p < 0.0001). A model integrating the GRS with clinical variables demonstrated superior discriminatory performance (area under the curve (AUC): 0.72) compared to models based solely on clinical factors. In summary, this study underscores the clinical relevance of HbF‐related genetic variants and supports their integration into risk stratification and personalized management strategies for SCA.

Sequential inflammatory stages characterizing early tuberculosis (TB) disease and reports of differentially culturable M. tuberculosis have compounded existing gaps in the detection of paucibacillary TB disease, threatening global elimination goals. Here we report unanticipated results we encountered while conducting early development work for an ultrasensitive molecular TB assay that has been validated in various cohorts of patients with suspected TB disease. Detection of M. tuberculosis DNA (TB-DNA) was confirmed by an alternate molecular target and sequencing. Over a six-year period, we conducted three separate clinical studies (N = 297) that tested two sets of anonymized respiratory samples from patients hospitalized in two Boston hospitals, and a longitudinal observational study to determine clinical associations and outcomes. We found an unexpectedly high prevalence of TB-DNA in US-born patients and a potential association with acute chest syndrome in patients with sickle cell disease. These results are preliminary and will require further study in prospective studies that include clinical, radiological, immunological, and microbiological correlation.

Sickle cell disease (SCD) is characterized by a chronic inflammatory state that leads to various complications. In this investigation, we quantified circulating levels of select inflammatory biomarkers including white blood cell count (WBC), C-reactive protein (CRP), and pro-inflammatory cytokines (Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Tumor Necrosis Factor-α (TNF-α)) in a cohort of 66 patients with SCD during the steady-state. These were compared to levels in a control group, and we analyzed the association between changes in these biomarkers and the risk of SCD-related complications using odds ratios. Thus we found elevated levels of those inflammatory biomarkers when compared to controls. High WBC count was significantly more common in SCD patients with a history of recurrent infections and with cholelithiasis, but significantly less common in patients who presented with repetitive vaso-occlusive crisis (VOC). The odds of high CRP were significantly higher in the patients who presented with acute splenic sequestration (ASS), but significantly less common in those with cholelithiasis, heart murmur, osteonecrosis of femoral heads and nephropathy. High levels of IL1 were less common in patients with repetitive VOC and acute chest syndrome. High levels of IL8 were significantly more common in patients with recurrent infections and with heart murmur, but significantly less commun in patients with ASS. High TNFα levels were significantly most common in patients who developed cholelithiasis. Consequently, the assessment of inflammatory biomarker profiles during the steady-state phenotype may serve as a prognostic indicator for the development of SCD-related complications.

Targeting PAR1 biased signaling with parmodulin reduces thromboinflammation and acute lung injury in sickle cell disease.

Sickle cell disease.

Purpose: To report the rates of loss to follow-up of pediatric patients with sickle disease. Methods: This retrospective cohort analysis included patients with sickle cell disease who were referred from Boston Children's Hospital hematology division and had an ophthalmic examination from January 2014 to 2024. Loss to follow-up was defined as failure to attend an appointment within 6 months of the scheduled date. After adjusting for covariates, the prevalence of sickle cell retinopathy, maculopathy, and systemic conditions (eg, stroke, acute chest syndrome, vaso-occlusive crisis, asthma, hospitalization) was tabulated and compared between the loss to follow-up and non-loss to follow-up groups. Results: Among the 255 included patients with sickle cell disease, 165 (65%) had at least 1 loss to follow-up event, with 66 (26%) having attended only 1 visit. Of the patients (n = 99) who did follow-up eventually, the median duration of loss to follow-up was 17.2 months/523.5 days (interquartile range, 335.5-655), and the mean duration was 25.1 months/754 days (SD, 611.7). In the entire cohort, sickle cell retinopathy was present in 61 eyes (24%), while the rate of coexisting major systemic comorbidities was 13%. No statistically significant differences in demographics, retinal findings, or systemic outcomes existed between the 2 groups. Conclusions: More than half of the pediatric patients with sickle cell disease were lost to follow-up, many with retinopathy and maculopathy. It is important to monitor this patient population to prevent disease progression and visual impairment.