The acute chest syndrome (ACS) is the leading cause of death and hospitalization in patients with sickle cell disease (SCD). The study analyzed 671 episodes of ACS in 538 patients to determine its causes, outcomes, and treatment responses. ACS was defined by new pulmonary infiltrates consistent with alveolar consolidation. Patients were often admitted for pain, with ACS diagnosed later. Common findings included hypoxia, decreased hemoglobin, and multilobar pneumonia. The mean hospital stay was 10.5 days, with 13% requiring mechanical ventilation and 3% dying. Older patients and those with neurological symptoms had more severe courses. Treatment included phenotypically matched transfusions, bronchodilators, and bronchoscopy. Transfusions improved oxygenation, with a 1% alloimmunization rate. Bronchodilators improved clinical outcomes in 20% of patients. Mechanical ventilation led to 81% recovery. Specific causes were identified in 38% of episodes, including pulmonary fat embolism and 27 infectious pathogens. Infection contributed to 56% of deaths, with the most common causes being pulmonary emboli and infectious bronchopneumonia. The study found that ACS is commonly caused by fat embolism and infection, especially community-acquired pneumonia. Older patients and those with neurological symptoms often progress to respiratory failure. Transfusions and bronchodilators improve oxygenation, and aggressive treatment leads to recovery in most patients with respiratory failure. The study highlights the importance of early diagnosis and treatment, as well as the need for further research into the pathophysiology and optimal management of ACS in SCD.The acute chest syndrome (ACS) is the leading cause of death and hospitalization in patients with sickle cell disease (SCD). The study analyzed 671 episodes of ACS in 538 patients to determine its causes, outcomes, and treatment responses. ACS was defined by new pulmonary infiltrates consistent with alveolar consolidation. Patients were often admitted for pain, with ACS diagnosed later. Common findings included hypoxia, decreased hemoglobin, and multilobar pneumonia. The mean hospital stay was 10.5 days, with 13% requiring mechanical ventilation and 3% dying. Older patients and those with neurological symptoms had more severe courses. Treatment included phenotypically matched transfusions, bronchodilators, and bronchoscopy. Transfusions improved oxygenation, with a 1% alloimmunization rate. Bronchodilators improved clinical outcomes in 20% of patients. Mechanical ventilation led to 81% recovery. Specific causes were identified in 38% of episodes, including pulmonary fat embolism and 27 infectious pathogens. Infection contributed to 56% of deaths, with the most common causes being pulmonary emboli and infectious bronchopneumonia. The study found that ACS is commonly caused by fat embolism and infection, especially community-acquired pneumonia. Older patients and those with neurological symptoms often progress to respiratory failure. Transfusions and bronchodilators improve oxygenation, and aggressive treatment leads to recovery in most patients with respiratory failure. The study highlights the importance of early diagnosis and treatment, as well as the need for further research into the pathophysiology and optimal management of ACS in SCD.