SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

Bacterial and viral coinfection in idiopathic pulmonary fibrosis patients: the prevalence and possible role in disease progression.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia of unknown aetiology with a mean survival rate of less than 3 years. No previous studies have been performed on the role of co-infection (viral and bacterial infection) in the pathogenesis and progression of IPF. In this study, we investigated the role of viral/bacterial infection and coinfection and their possible association with pathogenesis and progression of IPF. METHODS: We investigated the prevalence and impact of bacterial and viral coinfection in IPF patients (n = 67) in the context of pulmonary function (FVC, FEV1 and DLCO), disease status and mortality risk. Using principal component analysis (PCA), we also investigated the relationship between distribution of bacterial and viral co-infection in the IPF cohort. RESULTS: Of the 67 samples, 17.9% samples were positive for viral infection, 10.4% samples were positive for bacterial infection and 59.7% samples were positive coinfection. We demonstrated that IPF patients who were co-infected had a significantly increased risk of mortality compared (p = 0.031) with IPF patients who were non-infected [Hazard ratio: 8.12; 95% CI 1.3-26.9]. CONCLUSION: In this study, we report for the first time that IPF patients who were coinfected with bacterial and viral infection have significantly decreased FVC and DLCO (% predicted). Besides, the results demonstrated the increased AE-IPF, increased incidence of death and risk of mortality in infected/coinfected patients compared to non-infected IPF patients.

The Crucial Role of NLRP3 Inflammasome in Viral Infection-Associated Fibrosing Interstitial Lung Diseases.

Idiopathic pulmonary fibrosis (IPF), one of the most common fibrosing interstitial lung diseases (ILD), is a chronic-age-related respiratory disease that rises from repeated micro-injury of the alveolar epithelium. Environmental influences, intrinsic factors, genetic and epigenetic risk factors that lead to chronic inflammation might be implicated in the development of IPF. The exact triggers that initiate the fibrotic response in IPF remain enigmatic, but there is now increasing evidence supporting the role of chronic exposure of viral infection. During viral infection, activation of the NLRP3 inflammasome by integrating multiple cellular and molecular signaling implicates robust inflammation, fibroblast proliferation, activation of myofibroblast, matrix deposition, and aberrant epithelial-mesenchymal function. Overall, the crosstalk of the NLRP3 inflammasome and viruses can activate immune responses and inflammasome-associated molecules in the development, progression, and exacerbation of IPF.

Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis.

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.

Assessment of viral RNA in idiopathic pulmonary fibrosis using RNA-seq.

BACKGROUND: Numerous publications suggest an association between herpes virus infection and idiopathic pulmonary fibrosis (IPF). These reports have employed immunohistochemistry, in situ hybridization and/or PCR, which are susceptible to specificity artifacts. METHODS: We investigated the possible association between IPF and viral RNA expression using next-generation sequencing, which has the potential to provide a high degree of both sensitivity and specificity. We quantified viral RNA expression for 740 viruses in 28 IPF patient lung biopsy samples and 20 controls. Key RNA-seq results were confirmed using Real-time RT-PCR for select viruses (EBV, HCV, herpesvirus saimiri and HERV-K). RESULTS: We identified sporadic low-level evidence of viral infections in our lung tissue specimens, but did not find a statistical difference for expression of any virus, including EBV, herpesvirus saimiri and HERV-K, between IPF and control lungs. CONCLUSIONS: To the best of our knowledge, this is the first publication that employs RNA-seq to assess whether viral infections are linked to the pathogenesis of IPF. Our results do not address the role of viral infection in acute exacerbations of IPF, however, this analysis patently did not support an association between herpes virus detection and IPF.

IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.

FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice.

Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-ß1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.

Investigation of viral infection in idiopathic pulmonary fibrosis among Iranian patients in Tehran.

AIM OF THE STUDY: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, which can be lethal with chronic complications. Viral infections may be associated with IPF and other fibrotic lung diseases. In the present study, we investigate for the first time in Iran the related viral etiology of IPF in order to detect three respiratory viruses; human adenovirus, enterovirus and bocavirus. MATERIALS AND METHODS: In this cross-sectional study which was supported by Iran University of Medical Sciences, Tehran, Iran. The diagnostic criteria for IPF were based on internationally accepted clinical and imaging criteria in accordance with the 2011 IPF guidelines. 30 nasopharyngeal (NP) swabs or broncho-alveolar lavage (BAL) samples were obtained from the lung of IPF patients that were diagnosed by a sophisticated practitioner from April 2015 to February 2016. Real-time (RT) polymerase chain reaction (PCR) method was performed to detect the three viruses. Fluorescence dye of a labeled probe recorded the results in order to create positive and negative controls. SPSS version 20 software was used to calculate basic descriptive and frequency features. RESULTS: Of 30 specimens, 13 (43.4%) were male and 17 (56.6%) were female with the total mean age ± standard deviation 68.2 ± 12.0. RT-PCR assay results illustrated there was no infection of human adenovirus, enterovirus, and bocavirus detected in these samples. Significant results between IPF incidence and variables were not significant (p > 0.05). CONCLUSION: The causes of IPF in Iranian patients need more research although, based on the results of this study, there was no association between human adenovirus, enterovirus, bocavirus, and IPF.

No Evidence of Herpesvirus Infection in West Highland White Terriers With Canine Idiopathic Pulmonary Fibrosis.

In humans, horses, and rodents, an association between pulmonary fibrotic disorders and gammaherpesvirus infection has been suggested. In dogs, canine idiopathic pulmonary fibrosis (CIPF), a progressive fibrotic lung disease of unknown origin and poorly understood pathophysiology, has been reported to occur in West Highland white terriers (WHWTs). The present study investigated the potential association between CIPF and herpesvirus infection. A PCR assay, using a mixture of degenerate and deoxyinosine-substituted primers targeting highly conserved regions of the DNA polymerase gene (DPOL) of herpesviruses, was applied on both lung and blood samples from WHWTs affected with CIPF and controls. Herpesvirus DPOL sequence could not be amplified from any of 46 lung samples (28 affected WHWTs and 18 control dogs of various breeds) and 38 blood samples (19 CIPF WHWTs and 19 control age-matched WHWTs) included. An association between CIPF and herpesvirus infection is therefore unlikely. Investigation of other causes of the disease is warranted.

Idiopathic pulmonary fibrosis is strongly associated with productive infection by herpesvirus saimiri.

Idiopathic pulmonary fibrosis is a fatal disease without effective therapy or diagnostic test. To investigate a potential role for γ-herpesviruses in this disease, 21 paraffin-embedded lung biopsies from patients diagnosed with idiopathic pulmonary fibrosis and 21 lung biopsies from age-matched controls with pulmonary fibrosis of known etiology were examined for a series of γ-herpesviruses' DNA/RNA and related proteins using in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods. We detected four proteins known to be in the genome of several γ-herpesviruses (cyclin D, thymidylate synthase, dihydrofolate reductase, and interleukin-17) that were strongly co-expressed in the regenerating epithelial cells of each of the 21 idiopathic pulmonary fibrosis cases and not in the benign epithelia of the controls. Among the γ-herpesviruses, only herpesvirus saimiri expresses all four of these 'pirated' mammalian proteins. We found herpesvirus saimiri DNA in the regenerating epithelial cells of 21/21 idiopathic pulmonary fibrosis cases using four separate probe sets but not in the 21 controls. RT-PCR showed that the source of the cyclin D RNA in active idiopathic pulmonary fibrosis was herpesvirus saimiri and not human. We cloned and sequenced part of genome corresponding to the DNA polymerase herpesvirus saimiri gene from an idiopathic pulmonary fibrosis sample and it matched 100% with the published viral sequence. These data are consistent with idiopathic pulmonary fibrosis representing herpesvirus saimiri-induced pulmonary fibrosis. Thus, treatment directed against viral proliferation and/or viral-associated proteins may halt disease progression. Further, demonstration of the viral nucleic acids or proteins may help diagnose the disease.

Mendelian randomization study on the causal effect of herpes simplex virus infection on idiopathic pulmonary fibrosis.

BACKGROUND: Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor). RESEARCH DESIGN AND METHODS: To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study. RESULTS: We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048-1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032-1.692; p = 0.027). CONCLUSIONS: Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.

Right place, right time: the evolving role of herpesvirus infection as a "second hit" in idiopathic pulmonary fibrosis.

Over the course of the past decade, increasing evidence has implicated alveolar epithelial cell injury and dysfunction in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Genetic factors, cigarette smoking, and other environmental exposures have been identified as potential factors leading to a population of vulnerable alveolar epithelial cells. In addition, molecular techniques have demonstrated herpesviruses are commonly detectable in the lungs of patients with IPF, raising suspicion that, in the setting of a vulnerable alveolar epithelium, lytic (or latent) herpesvirus infection may act as a "second hit" leading to the development of pulmonary fibrosis. Intriguingly, in vivo modeling has shown that herpesvirus infection induces or worsens lung fibrosis when combined with immunodeficiency or other injurious stimuli. Here, we discuss potential mechanisms through which herpesvirus infection may contribute to the pathogenesis of IPF. Ultimately, antiviral therapy may hold promise for halting the progression of this deadly disease.

Viral infection in acute exacerbation of idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis is a progressive, uniformly fatal interstitial lung disease. An acute exacerbation of idiopathic pulmonary fibrosis is an episode of acute respiratory worsening without an identifiable etiology. Occult viral infection has been proposed as a possible cause of acute exacerbation. OBJECTIVES: To use unbiased genomics-based discovery methods to define the role of viruses in acute exacerbation of idiopathic pulmonary fibrosis. METHODS: Bronchoalveolar lavage and serum from patients with acute exacerbation of idiopathic pulmonary fibrosis, stable disease, and acute lung injury were tested for viral nucleic acid using multiplex polymerase chain reaction, pan-viral microarray, and high-throughput cDNA sequencing. MEASUREMENTS AND MAIN RESULTS: Four of forty-three patients with acute exacerbation of idiopathic pulmonary fibrosis had evidence of common respiratory viral infection (parainfluenza [n = 1], rhinovirus [n = 2], coronavirus [n = 1]); no viruses were detected in the bronchoalveolar lavage from stable patients. Pan-viral microarrays revealed additional evidence of viral infection (herpes simplex virus [n = 1], Epstein-Barr virus [n = 2], and torque teno virus [TTV] [n = 12]) in patients with acute exacerbation. TTV infection was significantly more common in patients with acute exacerbation than stable controls (P = 0.0003), but present in a similar percentage of acute lung injury controls. Deep sequencing of a subset of acute exacerbation cases confirmed the presence of TTV but did not identify additional viruses. CONCLUSIONS: Viral infection was not detected in most cases of acute exacerbation of idiopathic pulmonary fibrosis. TTV was present in a significant minority of cases, and cases of acute lung injury; the clinical significance of this finding remains to be determined.

ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.

Viral infections and abnormal host response are thought to cause epithelial injury in idiopathic pulmonary fibrosis (IPF). To understand IPF pathogenesis, we have used overexpression cell models and expression microarrays to discover genes networked with ELMO domain containing 2 (ELMOD2) gene genetically implicated in IPF. The identified pathways were confirmed in vitro, and ELMOD2 protein expression was characterized in tissue samples. Here 303 genes were significantly altered after ELMOD2 transfection of human alveolar epithelial A549 cell line. The enriched pathways were interferon induction, viral response, antigen processing and presentation, and I-/nuclear factor-kappaB signaling. ELMOD2 showed immunoreactivity in macrophages and type II alveolar epithelial cells in normal human lung. In A549 cells, forced expression of ELMOD2 increased type I and type III interferon mRNA expression, and ELMOD2-specific siRNA molecules inhibited expression of these antiviral cytokines in response to Toll-like receptor three (TLR3) activation. In human macrophages silencing of ELMOD2 inhibited TLR3-dependent expression of type I and type III interferon genes. Influenza A virus infection decreased ELMOD2 mRNA expression in A549 cells and macrophages suggesting negative regulation in viral infections. In summary, our results show that TLR3 pathway is dependent on ELMOD2.-Pulkkinen, V., Bruce, S., Rintahaka, J., Hodgson, U., Laitinen, T., Alenius, H., Kinnula, V. L., Myllärniemi, M., Matikainen, S., Kere, J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.

Latent herpesvirus infection augments experimental pulmonary fibrosis.

RATIONALE: No effective treatment exists for idiopathic pulmonary fibrosis, and its pathogenesis remains unclear. Accumulating evidence implicates herpesviruses as cofactors (either initiating or exacerbating agents) of fibrotic lung disease, but a role for latent herpesvirus infection has not been studied. OBJECTIVES: To develop a murine model to determine whether latent herpesvirus infection can augment fibrotic responses and to gain insight into potential mechanisms of enhanced fibrogenesis. METHODS: Mice were infected with murine gammaherpesvirus 14 to 70 days before a fibrotic challenge with fluorescein isothiocyanate or bleomycin so that the virus was latent at the time of fibrotic challenge. Measurements were made after viral infection alone or after the establishment of fibrosis. MEASUREMENTS AND MAIN RESULTS: gammaHerpesvirus is latent by 14 days post infection, and infection 14 to 70 days before fibrotic challenge augmented fibrosis. Fibrotic augmentation was not dependent on reactivation of the latent virus to a lytic state. Total cell numbers and fibrocyte numbers were increased in the lungs of latently infected mice administered fibrotic challenge compared with mock-infected mice that received fibrotic challenge. Latent infection up-regulates expression of proinflammatory chemokines, transforming growth factor-beta1, and cysteinyl leukotrienes in alveolar epithelial cells. CONCLUSIONS: Latent gammaherpesvirus infection augments subsequent fibrotic responses in mice. Enhanced fibrosis is associated with the induction of profibrotic factors and the recruitment of fibrocytes. Our data complement existing human and animal data supporting the hypothesis that gammaherpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.

CUX1/Wnt signaling regulates epithelial mesenchymal transition in EBV infected epithelial cells.

Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGFbeta1-mediated lytic phase. EBV lytic reactivation by TGFbeta1 drives a selective alteration in CUX1 variant (a) (NCBI accession number NM_181552) expression, inducing activation of non-canonical Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition (EMT), the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids (ATRA). Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via CUX1 signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.

Viral Infection Increases the Risk of Idiopathic Pulmonary Fibrosis: A Meta-Analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with a poor prognosis. Although many factors have been identified that possibly trigger or aggravate IPF, such as viral infection, the exact cause of IPF remains unclear. Until now, there has been no systematic review to assess the role of viral infection in IPF quantitatively. OBJECTIVE: This meta-analysis aims to present a collective view on the relationship between viral infection and IPF. METHODS: We searched studies reporting the effect of viral infection on IPF in the PubMed, Embase, Cochrane Library, Web of Science, and Wiley Online Library databases. We calculated ORs with 95% CIs to assess the risk of virus in IPF. We also estimated statistical heterogeneity by using I2 and Cochran Q tests and publication bias by using the funnel plot, Begg test, Egger test, and trim-and-fill methods. Regression, sensitivity, and subgroup analyses were performed to assess the effects of confounding factors, such as sex and age. RESULTS: We analyzed 20 case-control studies from 10 countries with 1,287 participants. The pooled OR of all viruses indicated that viral infection could increase the risk of IPF significantly (OR, 3.48; 95% CI, 1.61-7.52; P = .001), but not that of exacerbation of IPF (OR, 0.99; 95% CI, 0.47-2.12; P = .988). All analyzed viruses, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8), were associated with a significant elevation in the risk of IPF, except human herpesvirus 6 (HHV-6). CONCLUSIONS: The presence of persistent or chronic, but not acute, viral infections, including EBV, CMV, HHV-7, and HHV-8, significantly increases the risk of developing IPF, but not exacerbation of IPF. These findings imply that viral infection could be a potential risk factor for IPF.

Acute Hypoxemic Respiratory Failure and Native Lung Idiopathic Pulmonary Fibrosis Exacerbation in Single-lung Transplant Patients with Cytomegalovirus Disease: A Case Series.

BACKGROUND: Our case series describes three patients who have received single-lung transplantations for idiopathic pulmonary fibrosis (IPF) that develop cytomegalovirus (CMV) disease and hypoxemic respiratory failure with radiographic opacification of the native lung and sparing of the allograft. RESULTS: Hypoxemia resolved with treatment and with resolution of CMV viremia. Viral infections causing IPF exacerbations have been described in the literature, however, pulmonary CMV disease in single-lung transplant recipients has typically been observed as pneumonitis of the allograft. CONCLUSIONS: These clinical scenarios are consistent with acute exacerbation of native-lung IPF and subradiographic pneumonitis of the allograft caused by CMV disease.