Herpesvirus DNA Is Consistently Detected in Lungs of Patients with Idiopathic Pulmonary Fibrosis

Abstract

On the basis of earlier reports associating Epstein-Barr Virus (EBV) with half of the cases of idiopathic pulmonary fibrosis (IPF), we hypothesized that chronic infection with EBV or a closely related herpesvirus would be detected in all cases of IPF. We tested lung specimens from 33 IPF patients (8 patients with familial IPF and 25 patients with sporadic IPF) and 25 patients with other diseases as controls for the presence of eight herpesviruses using PCR-based techniques. One or more of four herpesviruses (cytomegalovirus [CMV], EBV, human herpesvirus 7 [HHV-7], and HHV-8) were detected in 32 of 33 (97%) subjects with IPF and in 9 of 25 (36%) controls (P < 0.0001). CMV, EBV, and HHV-8 were found more frequently in IPF patients than in controls (P < 0.05, P < 0.001, and P < 0.01 respectively). Two or more herpesviruses were detected in 19 of 33 (57%) IPF patients and in 2 of 25 (8%) controls (P < 0.001). Two or more herpesviruses and HHV-8 were found more frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05 for both comparisons), and CMV was found less frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05). Immunohistochemistry for EBV or HHV-8 antigen showed viral antigen primarily in airway epithelial cells. These data support the concept that a herpesvirus could be a source of chronic antigenic stimulation in IPF.

The role of infection in the pathogenesis of idiopathic pulmonary fibrosis

“…Whilst EBV has been the most frequently studied of the HHVs, TANG et al [18] looked more broadly at a range of HHV family members and found evidence of past infection with at least one HHV in 97% of patients with IPF compared to only 36% of healthy controls. Over 50% of the IPF patients in their study had evidence of past infection with at least two HHVs.…”

Toll-like Receptors, Notch Ligands, and Cytokines Drive the Chronicity of Lung Inflammation

“…This suggests an exacerbated response to respiratory illnesses among patients with a cytokine polarization away from a type 1 response (23). In the context of chronic interstitial disease, data from a number of studies provide evidence that products from DNA viruses (cytomegalovirus, Epstein-Barr virus, and herpesvirus) are associated with lung tissue recovered from a significant number of patients with chronic pulmonary disease (13,14). Although there is yet only correlative information regarding a type 2 cytokine environment and recoverable viral components from these clinical specimens, it is of interest to speculate that there may be a causeand-effect relationship between these two findings.…”

“…This virus is closely related to human Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8), two DNA viruses that have been associated with lung tissue recovered from patients with interstitial pulmonary fibrosis (13,14). Wild-type mice infected via the respiratory route with MuHV-68 exhibited a lytic infection of alveolar epithelial cells with a subsequent latent infection of B cells and an elevation of CD8 1 T cells (24).…”

“…The activity of these cytokines may explain why certain chronic lung diseases with a type 2 phenotype are either predisposed to exacerbated viral infections or are associated with the presence of viral products (12)(13)(14). In the context of infectious and immune-mediated chronic lung diseases, studies have identified that both type 2 cytokines and viral products are associated with evolving lung pathology (13,14).…”

“…The activity of these cytokines may explain why certain chronic lung diseases with a type 2 phenotype are either predisposed to exacerbated viral infections or are associated with the presence of viral products (12)(13)(14). In the context of infectious and immune-mediated chronic lung diseases, studies have identified that both type 2 cytokines and viral products are associated with evolving lung pathology (13,14). Thus, the progression and clinical manifestation of chronic alterations found in these enigmatic diseases may be dictated by the cytokine phenotype and the host's response to a subsequent viral pathogen superimposed on the initial etiologic agent, constituting a ''two-hit'' mechanism that results in augmented pathology ( Figure 1).…”