PurposeFew studies address the association ofChlamydia pneumoniaeinfection with pulmonary disease and outcome in patients with underlying pathology such as sickle cell disease (SCD). SCD patients are susceptible to the pulmonary disorder known as acute chest syndrome (ACS), where the etiology remains ill defined. The purpose of this study was to analyze the clinical course and outcome ofC. pneumoniae-associated ACS among SCD patients as part of the National Acute Chest Syndrome Study.Patients and MethodsThis was a longitudinal study of SCD patients presenting with ACS to multiple U.S. medical centers. Two hundred ninety-six SCD patients who developed ACS were tested by PCR forC. pneumoniaeand by standard techniques for other respiratory pathogens. These infections were evaluated for association with ACS, clinical course, and complications.ResultsForty-one (14%) patients with first episodes of ACS were PCR positive forC. pneumoniae.Compared with other infections,C. pneumoniae-infected patients were older, were more likely to present with chest pain, and had higher hemoglobin levels at diagnosis. Both groups had similar rates of respiratory failure and prolonged hospitalization. Of the 89 patients with single-pathogen infections, 27 (30%) were due toC. pneumoniae, 21% toMycoplasma pneumoniae, 10% to RSV, 4% toStaphylococcus aureus, and 3% toStreptococcus pneumoniae.ConclusionsC. pneumoniaewas the most prevalent pathogen in this study of ACS and was responsible for significant morbidity. Additional research is required to develop effective treatment guidelines for ACS.