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Dual respiratory viral infections are frequently associated with lower respiratory tract illness in infants. This study aimed to determine the impact of a dual respiratory viral infection on specific aspects of the infant's immune response and the clinical course of illness.A prospective study was performed with 772 infants hospitalized from October 2000 through July 2004. Sensitive polymerase chain reaction methodology revealed the presence of a single respiratory virus in 443 (57%) of 772 cases, whereas dual infections were identified in 153 (20%) of cases. From 250 infants with confirmed respiratory viral infection, fresh heparinized blood was analyzed for interferon-γ (IFN-γ) responses by flow cytometry. Of these, 191 patients had a single infection with respiratory syncytial virus (RSV), rhinoviruses, adenoviruses or influenza viruses; and 59 patients had a dual infection with RSV and rhinoviruses, RSV and adenoviruses, influenza viruses and rhinoviruses or adenoviruses and rhinoviruses. The clinical features and peripheral lymphocyte IFN-γ responses were compared among infants with single or dual infections.It was found that dual infections with non-RSV respiratory viruses induced peripheral blood mononuclear cell IFN-γ responses that mimic those of single infections, whereas coinfection with RSV was associated with reduced IFN-γ responses and a more severe clinical course of lower respiratory tract disease.The results indicate that the clinical characteristics and the IFN-γ response differ significantly in single and dual respiratory viral infection, depending on the nature of the simultaneously detected viruses. In dual infections, RSV involvement was associated with a decreased IFN-γ response in peripheral blood mononuclear cell and an increase in severity of illness.