Supportive care, prevention, and emerging therapies for acute chest syndrome in sickle cell disease

INTRODUCTION: Acute chest syndrome (ACS) is the leading cause of death and a major cause of hospitalization in sickle cell disease (SCD). Despite advances in care, ACS remains a life-threatening complication with no FDA-approved targeted therapy for established disease. This review examines the current evidence base for supportive care, preventive strategies, and emerging therapies. AREAS COVERED: We conducted a comprehensive literature search of PubMed, clinical trial registries, and major hematology conferences through December 2025. This review synthesizes data on supportive measures (fluid management, analgesia, antibiotics, oxygen/respiratory support, and transfusion), preventive interventions (incentive spirometry and nocturnal bilevel positive airway pressure), disease-modifying therapies (hydroxyurea, L-glutamine), investigational agents (therapeutic anticoagulation, inhaled nitric oxide, and pyruvate kinase activators), and recently approved gene therapies (exagamglogene autotemcel, lovotibeglogene autotemcel). Pathophysiology, biomarkers, and barriers to implementation in resource-limited settings are also addressed. EXPERT OPINION: Supportive care has reduced ACS mortality but remains reactive and non-curative. Hydroxyurea remains first-line prevention, while L-glutamine offers a complementary option. Gene therapies represent a paradigm shift toward durable or potentially curative prevention of ACS. With expanding access to these therapies, ACS may become a rare complication of SCD, although significant barriers related to cost, infrastructure, and global equity must be overcome.