In the context of routine clinical practice, it is not uncommon to see patients, previously diagnosed with idiopathic pulmonary fibrosis (IPF), who present with increasing dyspnea, associated with general malaise, myalgia, and low-grade fever. This has been described ever since the first IPF case studies (1), and the symptoms are suggestive of an infectious etiology. As such, respiratory viruses have long been considered as potential causes or triggers of acute IPF exacerbations. Detection of viruses in nasopharyngeal swabs or sputum samples is nowadays rather straightforward since the advent of polymerase chain reaction (PCR) diagnostic tools. It is well established that acute exacerbations in other chronic lung disease are associated with viral infections: it is estimated that more than half of all chronic obstructive pulmonary disease (COPD) exacerbations may be related to viral pathogens (2), and systematic assessment of the association between viruses and COPD demonstrated that viruses are strongly linked to acute exacerbations of COPD, with the highest detection rates of viruses being in Europe (3). Commonly found viruses in asthma and COPD include respiratory syncytial virus, human rhinovirus, metapneumovirus, parainfluenza, coronavirus, and others (4, 5). In contrast to chronic airway disease, there is relatively little published research related to a possible viral cause for acute exacerbations of IPF (AE-IPF).

In this issue of the Journal, Wootton and colleagues (pp. 1698–1702) provide evidence suggesting that viruses do not play a crucial role in a majority of patients with acute exacerbation of IPF (6). Using standard PCR in bronchoalveolar lavage (BAL) fluid, they found common respiratory viruses in 4 of 43 patients with well-defined AE-IPF. With more sophisticated PCR technology an additional 15 BAL samples revealed the presence of viruses, with significantly more patients with AE-IPF having torque teno virus (TTV) in their BAL compared with stable IPF (12 versus none). However, the careful choice of control groups in this study allowed the authors to demonstrate that TTV was also seen in patients with ARDS, suggesting that its presence is not specific for AE-IPF, but rather may be associated with acute lung injury in general. It is always more difficult to convince peers of the validity of negative over positive data: this is why the authors used deep sequencing technology with a subset of patients with AE-IPF with clinical signs of viral disease but negative PCR and did not find any additional evidence for viral pathogens. Overall, this study confirms another recent report of Huie and colleagues, who found viruses in 5 and bacteria in 3 of 27 cases with AE-IPF (7).

Now, is this truly enough evidence to put the hypothesis of viruses as reason for AE-IPF at rest? There are several issues that have to be considered before we draw this conclusion. One is that the authors may simply have failed to detect the virus in the early phase of an acute infection, and they acknowledge this as limitation of their study. It is positive that sampling of BAL was done within 48 hours of admission, but the median duration between symptom onset and bronchoscopy was 7 days, giving a significant chance that a viral pathogen may already have been eliminated by the host. Our clinical practice suggests that a good number of patients with IPF seem initially rather reluctant to contact their pulmonary specialist, possibly fearing “bad news.” This is quite different from asthma and COPD exacerbations, where the clinical worsening is often more abrupt than in IPF. Patients with IPF are used to self-management of worsening episodes, particularly during the first days of deterioration. Another smaller issue related to sampling is the relatively limited geographic area that was examined in this study, with most patients with AE-IPF coming from one center in Korea and some from another center in Japan. Nevertheless, the investigators around Wootton and colleagues have done as well as possible to detect viruses.

Second, it is unclear if BAL fluid is the correct compartment to look for viruses. IPF is an interstitial disease after all, and the evidence that acute exacerbations are related to alveolar injury is indirect at best. Most of this assumption is based on the fact that lungs of patients who died of AE-IPF have morphologic signs of acute-on-chronic lung injury (8). One small study (n = 8) applying gene array analysis to lung tissue homogenates supported that AE-IPF is characterized by a pattern of enhanced epithelial injury and proliferation, and found no gene expression profiles indicative of a response to viral or bacterial infection (9). However, one cannot ignore recurrent reports confirming presence of viruses in human IPF lungs, particularly Epstein-Barr virus (EBV) and other human herpesviruses (10, 11) and the indirect findings from animal models (12). It cannot be ruled out that AE-IPF may be result of latent herpesvirus infection in the lungs or an acute reactivation of these latent infections. Similar mechanisms have been proposed for COPD, after describing that alveolar epithelial cells of smokers and patients with severe emphysema are more frequently latently infected with adenovirus, as compared with smokers without airflow obstruction (13). Therefore, the issue of the relationship between acute viral infection and the subsequent development of chronic inflammatory disease remains uncertain.

Third, there is solid evidence from experimental research in support of viruses as a possible cause for IPF and/or a co-factor for AE-IPF (14). Infection with murine γherpesvirus 68 leads to the development of lung fibrosis in mice under certain conditions, or can worsen existing experimental fibrosis in animals, similar to acute IPF exacerbations in humans (15). This concept even makes sense on a mechanistic level, as EBV is able to induce epithelial–mesenchymal transition in alveolar epithelial cells, which is currently believed to be a major pathogenetic mechanism in IPF (16).

In summary, the study by Wootton and colleagues suggests that viral pathogens may not have a prominent role in the acute exacerbation of IPF, which is remarkably different from COPD and asthma exacerbations. They used cutting-edge technology and a solid study design, including appropriate controls (stable IPF and non-IPF acute lung injury), demonstrating the high value that these modern molecular tools have in translational medicine and eventually clinical practice (17). Are we yet at a point at which we can say “rest in peace” to the hypothesis of viruses being a major cause for AE-IPF? If so, why are the underlying causes and mechanisms for AE so different between asthma and COPD on the one hand and IPF on the other? Exciting years in research await us and will imminently benefit our patients with IPF!

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