Abstract Background Acute Chest Syndrome (ACS) remains one of the most serious pulmonary complications of sickle cell disease (SCD), leading to frequent hospitalization, ICU admission, and early mortality. Hydroxyurea (HU) is the backbone of disease-modifying therapy (DMT) and is known to reduce vaso-occlusive crises and ACS in both adults and children. The pulmonary effects of newer agents, including crizanlizumab (anti–P-selectin) and voxelotor (HbS polymerization inhibitor), are less well defined. We sought to quantify the impact of these therapies on ACS incidence and severity. Methods We systematically searched PubMed, Embase, and Cochrane CENTRAL (January 2015–August 2024) following PRISMA 2020 guidelines. Eligible studies were randomized trials and observational cohorts reporting ACS-related outcomes with HU, crizanlizumab, or voxelotor versus standard care or no DMT. The primary outcome was ACS incidence; secondary outcomes included ACS recurrence, ICU admission, mechanical ventilation, transfusion/exchange requirement, and ACS-related mortality. Random-effects meta-analysis was used to estimate pooled odds ratios (OR) with 95% confidence intervals (CI). Results Fourteen studies, including 2,042 patients (HU n = 1,216; crizanlizumab n = 492; voxelotor n = 334), met inclusion. Median follow-up was 20 months (range 12–60). • Hydroxyurea was associated with a 48% lower odds of ACS versus standard care (pooled OR 0.52; 95% CI 0.40–0.68; p 0.001), consistent with landmark adult and pediatric HU trials showing ∼40–50% ACS reduction. • Crizanlizumab showed a directional but non-significant reduction in ACS (OR 0.82; 95% CI 0.54–1.25; p = 0.36). ACS events were infrequent and served primarily as secondary endpoints in the source trials, limiting power. • Voxelotor had no clear effect on ACS incidence (OR 0.94; 95% CI 0.68–1.31; p = 0.72), in line with HOPE data, which showed that pulmonary events were not significantly altered despite hematologic improvement. • Combination therapy (HU plus a novel agent; n = 174) showed a non-significant trend toward fewer recurrent ACS events (OR 0.74; 95% CI 0.41–1.32; p = 0.29); these exploratory data come from small, largely observational cohorts. Conclusions Our findings reinforce HU as the only DMT with consistently demonstrated ACS risk reduction across multiple trials and real-world cohorts. Crizanlizumab and voxelotor do not yet have robust ACS-specific evidence; any apparent benefit in our pooled estimates should be considered hypothesis-generating, given low event rates and secondary endpoint status. Future trials of novel SCD therapies should be explicitly powered for ACS and other pulmonary outcomes to support decision-making. This abstract is funded by: None
Sharma et al. (Fri,) studied this question.