Discussion
Recent studies have led to the implication of viral or bacterial infections in both the initiation and progression of IPF.[5,11,13,16–19] Previously, viral infection was hypothesized to play a predominant role in the initiation and the progression of IPF.[20] However, more recently a role for bacterial infection has also been implicated in the development of rapidly progressive IPF.[11,13,18] Optimal antiviral and antibacterial immunity are vital in the maintenance of lung homeostasis and health in IPF patients.
In this study, we investigated for the first time, the effect of bacterial, viral and co-infection in disease progression in IPF. Here, we demonstrate that IPF patients who are co-infected with bacterial and viral infection has significantly worsened FVC and DLCO function, a greater AE-IPF and reduced survival compared with uninfected patients. Longitudinal rate of decline in FVC (% predicted) is a well-established marker of disease progression and known predictor of mortality in IPF.[21,22] In this study, these effects were associated with a significantly greater risk of mortality (Hazards Ratio: 8.12; 95% CI 1.3–26.9; p = 0.031) using Kaplan Meier survival curve analysis over a period of 60 months follow-up. These results suggest that the status of co-infection in IPF patients may be a good prognostic factor for accelerated disease progression. Additionally, these results suggest that the use of antiviral and/or antibacterial therapies may be useful in treating disease progression in co-infected IPF patients. Currently, clinical trials are underway to investigate the efficacy of the macrolide-type antibiotic, Azithromycin (AZT; ClinicalTrials.gov Identifier: NCT02173145). The antiviral, Valganciclovir, is currently being investigated as an adjuvant therapy with Pirfenidone, in the AE-IPF in patients with a history of CMV infection (ClinicalTrials.gov Identifier: NCT02871401).
AE-IPF are episodes of acute respiratory worsening of unknown cause which may become fatal.[13] Evidence has also suggested that viral infection is responsible for a percentage of acute exacerbations in IPF, which can lead to a rapid deterioration in health.[19] Many patients describe a viral type prodrome before the initial development of respiratory stress in IPF.[23] Currently, there is a growing body of evidence to suggest that bacterial infection, in addition to viral infection, plays a role in AE-IPF.[13] In 2017, Molyneaux et al. demonstrated that there is increased bacterial burden in BAL fluids of IPF patients experiencing AE-IPF compared with stable patients.[13] In this study, we demonstrated that 82.1% IPF patients who were co-infected with bacteria and virus experienced AE-IPF compared with 10.4% patients with bacterial infection only and 17.9% of virus infected patients only. These results suggest a cumulative effect of bacterial and viral infection in the AE-IPF. In order to confirm this, a larger study cohort would be needed.
Using PCA analysis in this study, we demonstrated the following co-infection patterns in IPF patients NPL and BAL fluid samples: (1) coronavirus, parainfluenza virus and adenovirus, (2) rhinovirus and S. pneumonia, (3) H. influenza, K. pneumonia and P. aeruginosa, (4) RSV, Influenza and S. aureus have similar co-infection patterns. The co-infection pattern of virus and bacteria is of particular interest. Previous studies have shown that viral infection can predispose to bacterial superinfection. Bacterial superinfection of the lung during influenza infection promotes severe disease pathogenesis and leads to increased mortality.[24] Influenza infection can also predispose individuals to S. aureus superinfection,[25] which is a co-infection pattern observed in our IPF samples. The ability of influenza to facilitate bacterial superinfection in IPF patients underlines a mechanism by which bacterial and viral co-infected IPF patients may experience increased disease progression, mortality risk and reduced lung function as observed in this study.
We previously established that toll-like receptor 3 in an important protective factor against rapid disease progression in IPF.[26,27] TLR3 is a member of the toll-like receptor superfamily of pathogen recognition receptors (PRRs).[28] It has previously been shown to bind dsRNA from viruses, bacteria and helminths, respectively, in addition to mRNA released from necrotic cells.[29–32] Recently, our laboratory demonstrated that the TLR3 SNP, Leu412Phe (TLR3 L412F, rs3775291), which results in defective TLR3 function, is associated with a significantly greater risk of mortality and an accelerated rate of decline in FVC of lung function in IPF patients.[26,33] Our recent data demonstrates that 412F-heterozygous IPF patients have reduced responses to viral dsRNA and a number of bacterial agonists.[26] We suggest that bacterial and viral co-infection will have a much more deleterious effect in IPF patients who have defective TLR3 function, and are 412F-heterozygous.
In this study, we used NPL and BAL fluid in our to quantitate bacterial and viral infection in IPF patients. However, IPF is a lung disease which affects the parenchymal tissue. In order to assess the level of co-infection in lung tissue, it would be necessary to perform a video-assisted thoracic surgery (VATS) biopsy on patients. These biopsies are associated with considerable risk for the patient and have appreciable rates of morbidity and mortality. Therefore, analysis of co-infection in parenchymal IPF lung is not a viable option. However, it is promising to note that quantitation of levels co-infection in distal IPF samples, such as NPL and BAL fluid, can give significant results which are linked to accelerated disease progression, increased AE-IPF and increased mortality risk. Our study is not without limitations. The main limitations of this study are its retrospective nature and small sample size. The retrospective nature of this study limiting our ability to control for potential confounding factors. Also, low sample size in studied groups could be effect on power of the statistical tests.
BMC Pulm Med. 2022;22(60) © 2022 BioMed Central, Ltd.
