Acute chest syndrome (ACS) in sickle cell disease (SCD): pathogenesis and pharmacotherapies in early clinical development.

Introduction: Sickle cell disease (SCD) is a monogenic disorder caused by a point mutation in the HBB gene, leading to the production of sickle hemoglobin (HbS). Under hypoxic or acidic conditions, HbS polymerizes within erythrocytes, leading to a series of downstream events resulting in tissue ischemia. Acute chest syndrome (ACS) is a severe and often life-threatening complication of SCD and the leading cause of intensive care unit admission and mortality in children.

Areas covered: This review covers the latest understanding of ACS pathology involving infectious triggers, pulmonary fat embolism, endothelial activation, hypercoagulability, and sterile inflammation. We discuss the role of neutrophil extracellular traps, inflammasomes, and platelet - leukocyte aggregates in pulmonary microvasculature causing tissue infarction, ventilation perfusion mismatch, and respiratory failure. We explore the emergence of targeted therapies in preventing and treating ACS.

Expert opinion: Although understanding of ACS pathogenesis has improved, current treatments are mainly supportive, with hydroxyurea as the primary preventive therapy. Newer treatments focus on specific mechanisms such as heme scavenging, P-selectin inhibition, toll-like receptor blockade, nitric oxide pathway modulation, and anti-thrombotic strategies. Given ACS's complex nature, a multi-drug targeted approach is likely needed. Scaling up hydroxyurea use remains essential to improving outcomes for millions affected globally by this life-threatening condition.