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BACKGROUND--Cryptogenic fibrosing alveolitis (synonymous with idiopathic pulmonary fibrosis) is a clinically heterogeneous condition in which the precipitating factor is unclear. Both environmental and infective factors have been implicated. An association between Epstein-Barr virus (EBV) and cryptogenic fibrosing alveolitis was suggested over a decade ago by a study based on EBV serology, but the significance of this has been unclear. METHODS--Lung tissue obtained surgically from patients (n = 20) with cryptogenic fibrosing alveolitis was investigated for evidence of EBV replication and compared with lung tissue from 21 control patients. Fourteen of the 20 patients had received no specific therapy for cryptogenic fibrosing alveolitis at the time of biopsy. Monoclonal antibodies directed against the EBV viral antigens, EBV viral capsid antigen (VCA) and gp 340/220 antigen, which are expressed during the lytic phase of the EBV life cycle, were studied. RESULTS--Fourteen (70%) of the 20 patients with cryptogenic fibrosing alveolitis were positive for both EBV VCA and gp 340/220 compared with two (9%) of the 21 controls. In the patients with cryptogenic fibrosing alveolitis viral replication was localised to pulmonary epithelial cells using epithelial cell markers, and immunohistochemical analysis confirmed the staining to be within type II alveolar cells. CONCLUSIONS--This is the first report of in vivo EBV replication within epithelial cells of the lower respiratory tract in an immunocompetent human host. Furthermore, this suggests that EBV may be an immune trigger or contribute to lung injury in cryptogenic fibrosing alveolitis, thus offering a potential new avenue of treatment.