ArticlesLung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study
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
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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
References (38)
- et al.
Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study
Lancet Respir Med
(2013) - et al.
A double blind randomised placebo controlled pilot study of oral co-trimoxazole in advanced fibrotic lung disease
Pulm Pharmacol Ther
(2008) - et al.
Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis
Nat Genet
(2013) - et al.
The toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis
Am J Respir Crit Care Med
(2013) - et al.
Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis
JAMA
(2013) - et al.
Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis
Sci Transl Med
(2013) - et al.
CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis
PLoS One
(2010) - et al.
MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis
PLoS Med
(2008) - et al.
The role of infection in the pathogenesis of idiopathic pulmonary fibrosis
Eur Respir Rev
(2013) - et al.
Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial
Thorax
(2013)
Significance of the microbiome in obstructive lung disease
Thorax
Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis
Am J Physiol Lung Cell Mol Physiol
Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy
Infect Immun
High-throughput sequencing of PCR products tagged with universal primers using 454 life sciences systems
Curr Protoc Mol Biol
An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management
Am J Respir Crit Care Med
Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis?
Am J Respir Crit Care Med
Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?
Am J Respir Crit Care Med
Acute exacerbations of idiopathic pulmonary fibrosis
Am J Respir Crit Care Med
Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities
Appl Environ Microbiol
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