The Oral–Lung Microbiome Axis in Connective Tissue Disease-Related Interstitial Lung Disease

Abstract

Connective tissue disease-related interstitial lung disease (CTD-ILD) is a frequent and serious complication of CTD, leading to high morbidity and mortality. Unfortunately, its pathogenesis remains poorly understood; however, one intriguing contributing factor may be the microbiome of the mouth and lungs. The oral microbiome, which is a major source of the lung microbiome through recurrent microaspiration, is altered in ILD patients. Moreover, in recent years, several lines of evidence suggest that changes in the oral and lung microbiota modulate the pulmonary immune response and thus may play a role in the pathogenesis of ILDs, including CTD-ILD. Here, we review the existing data demonstrating oral and lung microbiota dysbiosis and possible contributions to the development of CTD-ILD in rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus. We identify several areas of opportunity for future investigations into the role of the oral and lung microbiota in CTD-ILD.

Keywords

oral microbiome - lung microbiome - interstitial lung disease - connective tissue disease

Publikationsverlauf

Artikel online veröffentlicht:
16. April 2024

• References

• 1 Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med 2016; 375 (24) 2369-2379
• 2 Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol 2023; 23 (01) 9-23
• 3 Wells AU, Denton CP. Interstitial lung disease in connective tissue disease–mechanisms and management. Nat Rev Rheumatol 2014; 10 (12) 728-739
• 4 Sawcer S, Hellenthal G, Pirinen M. et al. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476 (7359): 214-219
• 5 Gravallese EM, Firestein GS. Rheumatoid arthritis—common origins, divergent mechanisms. N Engl J Med 2023; 388 (06) 529-542
• 6 Zhang X, Zhang D, Jia H. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21 (08) 895-905
• 7 Greiling TM, Dehner C, Chen X. et al. Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus. Sci Transl Med 2018; 10 (434) eaan2306
• 8 Brewer RC, Lanz TV, Hale CR. et al. Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Sci Transl Med 2023; 15 (684) eabq8476
• 9 Kohm AP, Fuller KG, Miller SD. Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology. Trends Microbiol 2003; 11 (03) 101-105
• 10 Maeda Y, Kurakawa T, Umemoto E. et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol 2016; 68 (11) 2646-2661
• 11 Wolter M, Grant ET, Boudaud M. et al. Leveraging diet to engineer the gut microbiome. Nat Rev Gastroenterol Hepatol 2021; 18 (12) 885-902
• 12 Han K, Xu J, Xie F, Crowther J, Moon JJ. Engineering strategies to modulate the gut microbiome and immune system. J Immunol 2024; 212 (02) 208-215
• 13 Spagnolo P, Cordier JF, Cottin V. Connective tissue diseases, multimorbidity and the ageing lung. Eur Respir J 2016; 47 (05) 1535-1558
• 14 O'Dwyer DN, Ashley SL, Moore BB. Influences of innate immunity, autophagy, and fibroblast activation in the pathogenesis of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2016; 311 (03) L590-L601
• 15 Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med 2018; 379 (08) 797-798
• 16 O'Dwyer DN, Dickson RP, Moore BB. The lung microbiome, immunity, and the pathogenesis of chronic lung disease. J Immunol 2016; 196 (12) 4839-4847
• 17 O'Dwyer DN, Ashley SL, Gurczynski SJ. et al. Lung microbiota contribute to pulmonary inflammation and disease progression in pulmonary fibrosis. Am J Respir Crit Care Med 2019; 199 (09) 1127-1138
• 18 Invernizzi R, Wu BG, Barnett J. et al. The respiratory microbiome in chronic hypersensitivity pneumonitis is distinct from that of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2021; 203 (03) 339-347
• 19 Molyneaux PL, Cox MJ, Willis-Owen SA. et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014; 190 (08) 906-913
• 20 Invernizzi R, Barnett J, Rawal B. et al. Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent. Eur Respir J 2020; 55 (04) 1901519
• 21 O'Dwyer DN, Kim JS, Ma SF. et al. Commensal oral microbiota, disease severity and mortality in fibrotic lung disease. Am J Respir Crit Care Med 2023; (e-pub ahead of print)
• 22 Gurczynski SJ, Lipinski JH, Strauss J. et al. Horizontal transmission of gut microbiota attenuates mortality in lung fibrosis. JCI Insight 2023; 9 (01) e164572
• 23 Chioma OS, Mallott EK, Chapman A. et al. Gut microbiota modulates lung fibrosis severity following acute lung injury in mice. Commun Biol 2022;5(01):
• 24 Yoon YM, Hrusch CL, Fei N. et al. Gut microbiota modulates bleomycin-induced acute lung injury response in mice. Respir Res 2022; 23 (01) 337
• 25 Baker JL, Mark Welch JL, Kauffman KM, McLean JS, He X. The oral microbiome: diversity, biogeography and human health. Nat Rev Microbiol 2024; 22 (02) 89-104
• 26 Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486 (7402): 207-214
• 27 Kumar PS. From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease. J Physiol 2017; 595 (02) 465-476
• 28 Dutzan N, Kajikawa T, Abusleme L. et al. A dysbiotic microbiome triggers T_H17 cells to mediate oral mucosal immunopathology in mice and humans. Sci Transl Med 2018; 10 (463) eaat0797
• 29 Kitamoto S, Nagao-Kitamoto H, Jiao Y. et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell 2020; 182 (02) 447-462.e14
• 30 Shigdel R, Johannessen A, Lin H. et al. Oral bacterial composition associated with lung function and lung inflammation in a community-based Norwegian population. Respir Res 2023; 24 (01) 183
• 31 Yang L, Dunlap DG, Qin S. et al. Alterations in oral microbiota in HIV are related to decreased pulmonary function. Am J Respir Crit Care Med 2020; 201 (04) 445-457
• 32 Abdel-Aziz MI, Thorsen J, Hashimoto S. et al. U-BIOPRED Study Group. Oropharyngeal microbiota clusters in children with asthma or wheeze associate with allergy, blood transcriptomic immune pathways, and exacerbation risk. Am J Respir Crit Care Med 2023; 208 (02) 142-154
• 33 Hilty M, Burke C, Pedro H. et al. Disordered microbial communities in asthmatic airways. PLoS One 2010; 5 (01) e8578
• 34 Natalini JG, Singh S, Segal LN. The dynamic lung microbiome in health and disease. Nat Rev Microbiol 2023; 21 (04) 222-235
• 35 Charlson ES, Bittinger K, Haas AR. et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011; 184 (08) 957-963
• 36 Bassis CM, Erb-Downward JR, Dickson RP. et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. MBio 2015; 6 (02) e00037
• 37 Dickson RP, Erb-Downward JR, Freeman CM. et al. Bacterial topography of the healthy human lower respiratory tract. MBio 2017; 8 (01) e02287-16
• 38 Dickson RP, Erb-Downward JR, Freeman CM. et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 2015; 12 (06) 821-830
• 39 Dickson RP, Erb-Downward JR, Falkowski NR, Hunter EM, Ashley SL, Huffnagle GB. The lung microbiota of healthy mice are highly variable, cluster by environment, and reflect variation in baseline lung innate immunity. Am J Respir Crit Care Med 2018; 198 (04) 497-508
• 40 Venkataraman A, Bassis CM, Beck JM. et al. Application of a neutral community model to assess structuring of the human lung microbiome. MBio 2015; 6 (01) e02284-14
• 41 Sulaiman I, Wu BG, Li Y. et al. Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism. Eur Respir J 2021; 58 (01) 2003434
• 42 Wu BG, Sulaiman I, Tsay JJ. et al. Episodic aspiration with oral commensals induces a MyD88-dependent, pulmonary T-helper cell type 17 response that mitigates susceptibility to Streptococcus pneumoniae . Am J Respir Crit Care Med 2021; 203 (09) 1099-1111
• 43 Segal LN, Clemente JC, Li Y. et al. Anaerobic bacterial fermentation products increase tuberculosis risk in antiretroviral-drug-treated HIV patients. Cell Host Microbe 2017; 21 (04) 530-537.e4
• 44 Segal LN, Clemente JC, Tsay JC. et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol 2016; 1: 16031
• 45 Gollwitzer ES, Saglani S, Trompette A. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med 2014; 20 (06) 642-647
• 46 Remot A, Descamps D, Noordine ML. et al. Bacteria isolated from lung modulate asthma susceptibility in mice. ISME J 2017; 11 (05) 1061-1074
• 47 Pattaroni C, Watzenboeck ML, Schneidegger S. et al. Early-life formation of the microbial and immunological environment of the human airways. Cell Host Microbe 2018; 24 (06) 857-865.e4
• 48 Yun Y, Srinivas G, Kuenzel S. et al. Environmentally determined differences in the murine lung microbiota and their relation to alveolar architecture. PLoS One 2014; 9 (12) e113466
• 49 Rhoades NS, Davies M, Lewis SA. et al. Functional, transcriptional, and microbial shifts associated with healthy pulmonary aging in rhesus macaques. Cell Rep 2022; 39 (03) 110725
• 50 Pettigrew MM, Tanner W, Harris AD. The lung microbiome and pneumonia. J Infect Dis 2021; 223 (12, Suppl 2): S241-S245
• 51 Dickson RP, Singer BH, Newstead MW. et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol 2016; 1 (10) 16113
• 52 Stanley D, Mason LJ, Mackin KE. et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med 2016; 22 (11) 1277-1284
• 53 Wen SW, Shim R, Ho L. et al. Advanced age promotes colonic dysfunction and gut-derived lung infection after stroke. Aging Cell 2019; 18 (05) e12980
• 54 Yang W, Yuan Q, Li Z. et al. Translocation and dissemination of gut bacteria after severe traumatic brain injury. Microorganisms 2022; 10 (10) 2082
• 55 Dickson RP, Schultz MJ, van der Poll T. et al. Biomarker Analysis in Septic ICU Patients (BASIC) Consortium. Lung microbiota predict clinical outcomes in critically ill patients. Am J Respir Crit Care Med 2020; 201 (05) 555-563
• 56 Ashley SL, Sjoding MW, Popova AP. et al. Lung and gut microbiota are altered by hyperoxia and contribute to oxygen-induced lung injury in mice. Sci Transl Med 2020; 12 (556) eaau9959
• 57 Laiman V, Lo YC, Chen HC. et al. Effects of antibiotics and metals on lung and intestinal microbiome dysbiosis after sub-chronic lower-level exposure of air pollution in ageing rats. Ecotoxicol Environ Saf 2022; 246: 114164
• 58 Smith DJ, Badrick AC, Zakrzewski M. et al. Pyrosequencing reveals transient cystic fibrosis lung microbiome changes with intravenous antibiotics. Eur Respir J 2014; 44 (04) 922-930
• 59 Hahn A, Fanous H, Jensen C. et al. Changes in microbiome diversity following beta-lactam antibiotic treatment are associated with therapeutic versus subtherapeutic antibiotic exposure in cystic fibrosis. Sci Rep 2019; 9 (01) 2534
• 60 McAleer JP, Nguyen NL, Chen K. et al. Pulmonary Th17 antifungal immunity is regulated by the gut microbiome. J Immunol 2016; 197 (01) 97-107
• 61 McAleer JP, Kolls JK. Contributions of the intestinal microbiome in lung immunity. Eur J Immunol 2018; 48 (01) 39-49
• 62 Li N, Dai Z, Wang Z. et al. Gut microbiota dysbiosis contributes to the development of chronic obstructive pulmonary disease. Respir Res 2021; 22 (01) 274
• 63 Yang D, Chen X, Wang J. et al. Dysregulated lung commensal bacteria drive interleukin-17b production to promote pulmonary fibrosis through their outer membrane vesicles. Immunity 2019; 50 (03) 692-706.e7
• 64 Gaeckle NT, Pragman AA, Pendleton KM, Baldomero AK, Criner GJ. The oral-lung axis: the impact of oral health on lung health. Respir Care 2020; 65 (08) 1211-1220
• 65 Dickson RP, Erb-Downward JR, Martinez FJ, Huffnagle GB. The microbiome and the respiratory tract. Annu Rev Physiol 2016; 78: 481-504
• 66 Han MK, Zhou Y, Murray S. et al. COMET Investigators. Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. Lancet Respir Med 2014; 2 (07) 548-556
• 67 Lipinski JH, Moore BB, O'Dwyer DN. The evolving role of the lung microbiome in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2020; 319 (04) L675-L682
• 68 Lipinski JH, Erb-Downward JR, Huffnagle GB. et al. Toll-interacting protein and altered lung microbiota in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2022; 206 (02) 224-227
• 69 Musher DM, Jesudasen SS, Barwatt JW, Cohen DN, Moss BJ, Rodriguez-Barradas MC. Normal respiratory flora as a cause of community-acquired pneumonia. Open Forum Infect Dis 2020; 7 (09) ofaa307
• 70 Baty JJ, Stoner SN, Scoffield JA. Oral commensal Streptococci: gatekeepers of the oral cavity. J Bacteriol 2022; 204 (11) e0025722
• 71 Lindén A, Laan M, Anderson GP. Neutrophils, interleukin-17A and lung disease. Eur Respir J 2005; 25 (01) 159-172
• 72 Wilson MS, Madala SK, Ramalingam TR. et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med 2010; 207 (03) 535-552
• 73 Mi S, Li Z, Yang HZ. et al. Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol 2011; 187 (06) 3003-3014
• 74 Segal LN, Alekseyenko AV, Clemente JC. et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 2013; 1 (01) 19
• 75 O'Dwyer DN, Armstrong ME, Cooke G, Dodd JD, Veale DJ, Donnelly SC. Rheumatoid arthritis (RA) associated interstitial lung disease (ILD). Eur J Intern Med 2013; 24 (07) 597-603
• 76 Courbon G, Rinaudo-Gaujous M, Blasco-Baque V. et al. Porphyromonas gingivalis experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat. Ann Rheum Dis 2019; 78 (05) 594-599
• 77 Jung H, Jung SM, Rim YA. et al. Arthritic role of Porphyromonas gingivalis in collagen-induced arthritis mice. PLoS One 2017; 12 (11) e0188698
• 78 Cheng Z, Do T, Mankia K. et al. Dysbiosis in the oral microbiomes of anti-CCP positive individuals at risk of developing rheumatoid arthritis. Ann Rheum Dis 2021; 80 (02) 162-168
• 79 Kroese JM, Brandt BW, Buijs MJ. et al. Differences in the oral microbiome in patients with early rheumatoid arthritis and individuals at risk of rheumatoid arthritis compared to healthy individuals. Arthritis Rheumatol 2021; 73 (11) 1986-1993
• 80 Lehenaff R, Tamashiro R, Nascimento MM. et al. Subgingival microbiome of deep and shallow periodontal sites in patients with rheumatoid arthritis: a pilot study. BMC Oral Health 2021; 21 (01) 248
• 81 de Pablo P, Dietrich T, McAlindon TE. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J Rheumatol 2008; 35 (01) 70-76
• 82 Lockhart PB, Brennan MT, Thornhill M. et al. Poor oral hygiene as a risk factor for infective endocarditis-related bacteremia. J Am Dent Assoc 2009; 140 (10) 1238-1244
• 83 Sokolove J, Bromberg R, Deane KD. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One 2012; 7 (05) e35296
• 84 Brito-Zerón P, Baldini C, Bootsma H. et al. Sjögren syndrome. Nat Rev Dis Primers 2016; 2: 16047
• 85 van der Meulen TA, Harmsen HJM, Bootsma H. et al. Dysbiosis of the buccal mucosa microbiome in primary Sjögren's syndrome patients. Rheumatology (Oxford) 2018; 57 (12) 2225-2234
• 86 Siddiqui H, Chen T, Aliko A, Mydel PM, Jonsson R, Olsen I. Microbiological and bioinformatics analysis of primary Sjogren's syndrome patients with normal salivation. J Oral Microbiol 2016; 8: 31119
• 87 Bustos-Lobato L, Rus MJ, Saúco C, Simon-Soro A. Oral microbial biomap in the drought environment: Sjogren's syndrome. Mol Oral Microbiol 2023; 38 (05) 400-407
• 88 Singh M, Teles F, Uzel NG, Papas A. Characterizing microbiota from Sjögren's syndrome patients. JDR Clin Trans Res 2021; 6 (03) 324-332
• 89 Pope JE, Denton CP, Johnson SR, Fernandez-Codina A, Hudson M, Nevskaya T. State-of-the-art evidence in the treatment of systemic sclerosis. Nat Rev Rheumatol 2023; 19 (04) 212-226
• 90 Steele R, Hudson M, Lo E, Baron M, Group CSR. Canadian Scleroderma Research Group. Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res (Hoboken) 2012; 64 (04) 519-524
• 91 Suliman YA, Dobrota R, Huscher D. et al. Brief report: pulmonary function tests: high rate of false-negative results in the early detection and screening of scleroderma-related interstitial lung disease. Arthritis Rheumatol 2015; 67 (12) 3256-3261
• 92 Tashkin DP, Elashoff R, Clements PJ. et al. Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354 (25) 2655-2666
• 93 Tashkin DP, Roth MD, Clements PJ. et al. Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016; 4 (09) 708-719
• 94 Distler O, Highland KB, Gahlemann M. et al. SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019; 380 (26) 2518-2528
• 95 Russo E, Bellando-Randone S, Carboni D. et al. The differential crosstalk of the skin-gut microbiome axis as a new emerging actor in systemic sclerosis. Rheumatology (Oxford) 2024; 63 (01) 226-234
• 96 Melchiorre D, Ceccherini MT, Romano E. et al. Oral Lactobacillus species in systemic sclerosis. Microorganisms 2021; 9 (06) 1298
• 97 Schneeberger PHH, Zhang CYK, Santilli J. et al. Lung allograft microbiome association with gastroesophageal reflux, inflammation, and allograft dysfunction. Am J Respir Crit Care Med 2022; 206 (12) 1495-1507
• 98 McGinniss JE, Whiteside SA, Deek RA. et al. The lung allograft microbiome associates with pepsin, inflammation, and primary graft dysfunction. Am J Respir Crit Care Med 2022; 206 (12) 1508-1521
• 99 Clancy RM, Marion MC, Ainsworth HC. et al. Salivary dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus. J Autoimmun 2020; 107: 102354
• 100 Liu F, Ren T, Li X. et al. Distinct microbiomes of gut and saliva in patients with systemic lupus erythematous and clinical associations. Front Immunol 2021; 12: 626217
• 101 Fabbri C, Fuller R, Bonfá E, Guedes LK, D'Alleva PS, Borba EF. Periodontitis treatment improves systemic lupus erythematosus response to immunosuppressive therapy. Clin Rheumatol 2014; 33 (04) 505-509
• 102 Raghu G, Anstrom KJ, King Jr TE, Lasky JA, Martinez FJ. Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366 (21) 1968-1977
• 103 Jee AS, Sheehy R, Hopkins P. et al. Diagnosis and management of connective tissue disease-associated interstitial lung disease in Australia and New Zealand: a position statement from the Thoracic Society of Australia and New Zealand. Respirology 2021; 26 (01) 23-51
• 104 Scher JU, Joshua V, Artacho A. et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome 2016; 4 (01) 60
• 105 Lou Y, Wei Q, Fan B. et al. The composition of the lung microbiome differs between patients with dermatomyositis and rheumatoid arthritis associated with interstitial lung disease. FEBS Open Bio 2022; 12 (01) 258-269
• 106 Quintero-Puerta T, Lira-Lucio JA, Falfán-Valencia R. et al. Lung microbiome alterations in patients with anti-Jo1 antisynthetase syndrome and interstitial lung disease. Front Cell Infect Microbiol 2023; 13: 1321315
• 107 Valenzi E, Yang H, Sembrat JC. et al. Topographic heterogeneity of lung microbiota in end-stage idiopathic pulmonary fibrosis: the Microbiome in Lung Explants-2 (MiLEs-2) study. Thorax 2021; 76 (03) 239-247
• 108 Raghu G, Remy-Jardin M, Ryerson CJ. et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202 (03) e36-e69
• 109 Patolia S, Tamae Kakazu M, Chami HA. et al. Bronchoalveolar lavage lymphocytes in the diagnosis of hypersensitivity pneumonitis among patients with interstitial lung disease. Ann Am Thorac Soc 2020; 17 (11) 1455-1467
• 110 Molyneaux PL, Smith JJ, Saunders P. et al. BAL is safe and well tolerated in individuals with idiopathic pulmonary fibrosis: an analysis of the PROFILE study. Am J Respir Crit Care Med 2021; 203 (01) 136-139
• 111 Galli JA, Panetta NL, Gaeckle N. et al. COMET investigators. Pneumothorax after transbronchial biopsy in pulmonary fibrosis: lessons from the multicenter COMET trial. Lung 2017; 195 (05) 537-543
• 112 Chotirmall SH, Bogaert D, Chalmers JD. et al. Therapeutic targeting of the respiratory microbiome. Am J Respir Crit Care Med 2022; 206 (05) 535-544
• 113 Carney SM, Clemente JC, Cox MJ. et al. Methods in lung microbiome research. Am J Respir Cell Mol Biol 2020; 62 (03) 283-299