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


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
National Institutes of Health.
University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: mrking@umich.edu.
MeiLan K
MK
Han
University of Michigan Health System, Ann Arbor, MI, USA.
Yueren
Y
Zhou
University of Michigan Health System, Ann Arbor, MI, USA.
Susan
S
Murray
University of Michigan Health System, Ann Arbor, MI, USA.
Nabihah
N
Tayob
University of Chicago, Chicago, IL, USA.
Imre
I
Noth
University of Michigan Health System, Ann Arbor, MI, USA.
Vibha N
VN
Lama
University of Michigan Health System, Ann Arbor, MI, USA.
Bethany B
BB
Moore
University of Michigan Health System, Ann Arbor, MI, USA.
Eric S
ES
White
University of Michigan Health System, Ann Arbor, MI, USA.
Kevin R
KR
Flaherty
University of Michigan Health System, Ann Arbor, MI, USA.
Gary B
GB
Huffnagle
University of Michigan Health System, Ann Arbor, MI, USA.
Fernando J
FJ
Martinez
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004269:DNA, Bacterial; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000382:microbiology* / Q000503:physiopathology; D008168:Lung / Q000382:microbiology*; D008297:Male; D064307:Microbiota; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D013210:Staphylococcus / Q000235:genetics / Q000302:isolation & purification*; D013291:Streptococcus / Q000235:genetics / Q000302:isolation & purification*; D014797:Vital Capacity
D004269:DNA, Bacterial