The National Acute Chest Syndrome Study Group reported12 on 671 episodes of ACS that were treated in 30 centers. Half of the patients were admitted to the hospital for a reason other than ACS, mostly VOC. Clinical findings of patients with ACS developed in a mean of 2.5 days after hospital admission. A specific cause (eg, pulmonary infection or fat embolism) for the ACS was found in 38% of all episodes and in 70% of episodes with complete data. Pulmonary infection, caused by 27 different organisms, was present in 36% of episodes, with Chlamydia, Mycoplasma, and viruses being the three most common pathogens. Fat emboli, with or without infection, were present in 8.8% of patients, pulmonary infarction was inferred in 16% of patients, and in 46% of patients the cause was unknown. Pleural effusions were present in 36% of patients at the time of diagnosis, and in 55% during the hospitalization. Bilobar involvement was typical. Thirteen percent of patients required mechanical ventilation, 11% had neurologic symptoms, and 9% of those > 20 years of age died. Children, in contrast to adults, were more likely to present with fever, cough, and wheeze, with upper and middle lobe opacities present on chest radiographs. Adults had more chest pain, limb pain, and dyspnea, with fever and cough occurring in only about 60% of patients. These differences may reflect differences in the relative frequencies of etiology, with children presenting with ACS due to pulmonary infection and adults more commonly presenting with VOC complicated by subsequent fat emboli and ACS. In this sense, pain is a prodrome of the ACS, indicating the need to monitor for and try to prevent its development in those admitted to the hospital for VOC.