key: cord-1005325-m5xymedi authors: Maher, Toby M. title: Targeting Human Herpesviruses: An Effective Strategy for Treating Idiopathic Pulmonary Fibrosis? date: 2021-03-30 journal: Annals of the American Thoracic Society DOI: 10.1513/annalsats.202105-536ed sha: dbb9105d50ddd7a77ea044c70a797891e4cc06bf doc_id: 1005325 cord_uid: m5xymedi nan Idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and inevitably fatal scarring disorder of the lung, is believed to arise because of an aberrant wound healing response driven by premature senescence of alveolar epithelial stem cells (1) . This premature senescence appears to be the consequence of a combination of genetic susceptibility and a lifetime of excessive alveolar epithelial damage. Epidemiological studies have linked a variety of occupational exposures, all of which have the potential to cause alveolar epithelial injury, to an increased risk for the development of IPF. Direct viral-mediated injury to the lung epithelium, occurring either acutely during primary infection or chronically because of persistence of lytic viruses within the alveolar epithelium, has been proposed as a potential initiating factor in the development of IPF (2) . Although supported by data derived from animal models of fibrosis (3), evidence supporting this hypothesis in human disease has been difficult to obtain. Followup of individuals from the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks suggests that fibrosis may be a sequela of viral infection; however, these reports fail to disentangle the effect of direct viral injury to the lung from the similarly injurious consequences of prolonged mechanical ventilation (4, 5) . During the current pandemic, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported to cause fibrotic lung injury even in individuals who have not required mechanical ventilation (6) . Aside from coronaviruses, the biggest group of viruses implicated in the pathogenesis of IPF are the human herpes viruses (HHVs). These are a large family of ubiquitous DNA viruses, which include herpes-simplex virus 1, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HHV-7 and -8. On the basis of analysis of biopsy and bronchoalveolar lavage specimens, several small studies have reported an increased incidence of past EBV infection in individuals with IPF compared with healthy control subjects (7, 8) . Tang and colleagues used a polymerase chain reaction-based measurement of viral DNA in lung tissue obtained from 33 patients with IPF and 25 healthy control subjects to assess the presence of eight different HHVs (9). One or more of CMV, EBV, or HHV-7 or -8 were found in 97% of subjects with IPF but only 36% of control subjects. However, a more recent study by Yin and colleagues using RNA sequencing to quantify viral RNA expression for 740 viruses in lung tissue samples from 28 subjects with IPF and 20 control subjects failed to find a difference in the prevalence of viral RNA between groups (10). In addition to having a role in the pathogenesis of IPF, it is plausible that viral infection may be an important trigger for acute exacerbations (AEs) of IPF. The seasonal nature of idiopathic AEs speaks to a potential infectious etiology. However, studies looking for evidence of a virus in bronchoalveolar lavage fluid of patients undergoing an AE-IPF have generated mixed data with some, but not all, identifying viruses in samples obtained during AE but not the steady state of disease (11, 12) . Transcriptomic profiling of lung tissue from eight individuals who died of AE-IPF failed to identify signatures associated with a host response to viral infection (13) . All of these studies have been small, and sampling of the lung has often been conducted at a time point distant to the development of the AE. A small open label study of intravenous ganciclovir given for 2 weeks to 14 subjects with IPF with positive EBV serology hinted at a benefit of antiviral treatment (14) . Valganciclovir, an orally available prodrug of ganciclovir, inhibits viral DNA polymerase and is approved for the treatment of CMV infection after solid organ transplant. Data generated in transplant recipients suggest that prophylactic valganciclovir can reduce the risk of CMV and possibly EBV reactivation (15) . In this issue of AnnalsATS, Blackwell and colleagues (pp. 1291-1297) report the Internet address: www:atsjournals:org outcomes of a 3-month, phase 1 randomized placebo-controlled study of valganciclovir conducted in 31 subjects with IPF, all of whom were on a stable dose of pirfenidone and had serological evidence of past infection with either EBV or CMV (16) . The primary endpoint of the study was safety and to this end valganciclovir was well tolerated. Only one subject discontinued treatment prematurely (because of a rash) and aside from this there were no dose adjustments or reductions. There was a statistically, but not clinically, significant reduction in total leukocyte count in the valganciclovir group but no cytopenias were reported. The study was not powered to assess efficacy outcomes; however, there was a numerical reduction in the loss of forced vital capacity (FVC) observed in the valganciclovir group at both 12 and 52 weeks when compared with the placebo group. Blackwell and colleagues are to be congratulated for conducting such a rigorous study. Their data provide considerable reassurance that valganciclovir can be safely administered to patients with IPF and that it can be used in combination with pirfenidone (although, inexplicably, no data were generated in combination with nintedanib). One of the challenges encountered by the authors, and which is common to other proof-of-concept studies in IPF, is that of demonstrating clinical efficacy. Although FVC is the primary endpoint of choice in late-phase trials in IPF, high interindividual variability makes it poorly suited to determining efficacy in shorter and smaller studies; this is also true of other physiological measures. Similarly, the rarity of acute exacerbations makes these impossible to measure in a trial of this size. The authors could have sought an indirect assessment of valganciclovir's effectiveness in IPF by measuring EBV or CMV copies in serum or even bronchoalveolar lavage. But data on such measures have not been presented. Thus, although the trial demonstrates safety, it fails to provide any meaningful insight into the potential effectiveness of valganciclovir as a treatment for IPF. Arguably, given the weakness of the existing literature in supporting a role for viruses in the pathogenesis of IPF, a stronger preclinical rationale for valganciclovir is required before a definitive phase 3 trial can be justified. Evincing a role for EBV or CMV reactivation or chronic persistence in alveolar epithelium in larger prospective IPF cohorts would provide such a rationale. In the meantime, the current coronavirus disease (COVID-19) pandemic may well provide the necessary tools to better understand the role played by viral infection in the pathogenesis and natural history of chronic respiratory diseases including IPF. Author Disclosures are available with the text of this article at www.atsjournals.org. Recent advances in understanding idiopathic pulmonary fibrosis Viral infection increases the risk of idiopathic pulmonary fibrosis: A meta-analysis Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus Advances in imaging of the solitary pulmonary nodule Follow-up chest radiographic findings in patients with MERS-CoV after recovery Pulmonary fibrosis secondary to COVID-19: a call to arms? A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fibrosis The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis Assessment of viral RNA in idiopathic pulmonary fibrosis using RNA-seq Viral infection in acute exacerbation of idiopathic pulmonary fibrosis The role of infection in acute exacerbation of idiopathic pulmonary fibrosis Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis Ganciclovir antiviral therapy in advanced idiopathic pulmonary fibrosis: an open pilot study The efficacy of valganciclovir for prevention of infections with cytomegalovirus and Epstein-Barr virus after kidney transplant in children A phase I randomized, controlled, clinical trial of valganciclovir in idiopathic pulmonary fibrosis