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Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study

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Summary

Background

The role of the lung microbiome in the pathogenesis of idiopathic pulmonary fibrosis is unknown. We investigated whether unique microbial signatures were associated with progression of idiopathic pulmonary fibrosis.

Methods

Patients (aged 35–80 years) with idiopathic pulmonary fibrosis within 4 years of diagnosis from the Correlating Outcomes with biochemical Markers to Estimate Time-progression (COMET) in idiopathic pulmonary fibrosis study were followed up for a maximum of 80 weeks. Progression-free survival was defined as time to death, acute exacerbation, lung transplant, or decrease in forced vital capacity (FVC) of 10% or greater or decrease in diffusion capacity of the lung (DLCO) of 15% or greater. DNA was isolated from 55 samples of bronchoscopic alveolar lavage. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) to bacteria based on a 3% sequence divergence. Adjusted Cox models were used to identify OTUs that were significantly associated with progression-free survival at a p<0·10. These OTUs were then used in the analysis of the principal components. The association between principal components and microbes with high factor loadings and progression-free survival were assessed with Cox regression analyses. The COMET study is registered with ClinicalTrials.gov, number NCT01071707.

Findings

Mean FVC was 70·1% (SD 17·0) and DLCO 42·3% (14·0) of predicted. Disease progression was significantly associated with increased relative abundance of two OTUs—Streptococcus OTU 1345 (relative risk 1·11, 95% CI 1·04–1·18; p=0·0009) and Staphylococcus OTU 1348 (1·16, 1·03–1·31, p=0·012). Thresholds for relative abundance of each OTU associated with progression-free survival were more than 3·9% for Streptococcus OTU 1345 (10·19, 2·94–35·35; p=0·0002) and more than 1·8% for Staphylococcus OTU 1348 (5·06, 1·71–14·93; p=0·003).

Interpretation

These preliminary data suggest progression of idiopathic pulmonary fibrosis is associated with the presence of specific members within the Staphylococcus and Streptococcus genera. Additional research will be needed to identify the specific bacterial species and to ascertain whether this is a causal association.

Funding

National Institutes of Health.

Introduction

Established risk factors for idiopathic pulmonary fibrosis include male sex and old age. Recently, genetic factors including MUC5B, TOLLIP,1 TERT,2 and TLR3,3 have been implicated in the pathogenesis of idiopathic pulmonary fibrosis.4 Other prognostic biomarkers in idiopathic pulmonary fibrosis have also been identified and include specific gene expression profiles of peripheral blood mononuclear cells,5 downregulation of CD28 on circulating CD4 T cells,6 and peripheral blood protein signatures including MMP7.7 Although infectious agents have not been implicated in disease pathogenesis other than in acute exacerbations, accumulating data indicate a role for bacteria in the pathogenesis of idiopathic pulmonary fibrosis.8 A reduction in the mortality rate was reported in patients with idiopathic pulmonary fibrosis who were treated with co-trimoxazole in a placebo-controlled randomised trial, but an explanation for this effect was not clear.9 The lack of data to corroborate an association between idiopathic pulmonary fibrosis and bacteria might be due to the difficulty in defining the true microbial composition of the lung because more than 70% of the bacterial species inhabiting body surfaces cannot be cultured by use of the available techniques.10 We postulated that a bacterial signature identified through 16 S sequences would be associated with rapid progression of disease. To answer this question, we used samples that had been obtained previously as part of Correlating Outcomes with biochemical Markers to Estimate Time-progression (COMET)-idiopathic pulmonary fibrosis, a prospective observational study to identify and correlate biomarkers with disease progression in patients with idiopathic pulmonary fibrosis.11

Section snippets

Patients

Patients from COMET,11 were included in this analysis. Patients were recruited for the COMET study at nine clinical centres in the USA. Inclusion criteria were diagnosis of idiopathic pulmonary fibrosis and age 35–80 years. Patients were excluded if they had been diagnosed with idiopathic pulmonary fibrosis more than 4 years before screening or if they had a collagen-vascular disorder, forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio of less than 0·60, evidence of

Results

Table 1 shows the baseline characteristics of the patients. Of 71 available patients from COMET, complete data for analysis were available for 55 patients. Appendix p 1 summarises the missing data from the exclusion of 16 patients in this analysis. With the exception of the Shannon diversity index and inverse Simpson index, which were both slightly lower in the excluded group, the baseline characteristics of the patients who were not included in the analysis were not significantly different

Discussion

In this report, we showed an association between progression of idiopathic pulmonary fibrosis and the lung microbiome. Most importantly, we showed that the presence of specific Streptococcus and Staphylococcus OTUs seem to be associated with poorer outcomes than are other OTUs. To our knowledge, this is the first report of an association between the presence of specific microbes and disease progression in patients with idiopathic pulmonary fibrosis. These preliminary data could be used to

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