Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Background: Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed. Methods: Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. Results: A higher frequency of virus positive cases was found in IPF patients than in controls (p=0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p=0.01), poorer performance in the six minute walking test (6MWT; p=0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p=0.002 and p=0.004) and higher TGF-beta expression (p=0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p=0.03), poorer performance in the 6MWT (p=0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. Conclusion: Herpesviral infections may contribute to the development of PH in IPF patients.