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Editor’s Note: Authors are invited to respond to Correspondence that cites their previously published work. Those responses appear after the related letter. In cases where there is no response, the author of the original article declined to respond or did not reply to our invitation.
Potential Mechanisms of Microbial Pathogens in Idiopathic Interstitial Lung Disease To the Editor:
We read with great interest the review by Azadeh et al1 published in this issue of CHEST on the role of infections in idiopathic interstitial lung disease (ILD). Mechanisms enhancing infections in chronic respiratory diseases are poorly understood, and wider discussion of new insights into potential mechanisms contributing to bacterial and viral infection vulnerability would be valuable. A fundamental issue is how these pathogens initially adhere to the airway epithelium. We suggest that our recent work on microbial adhesion sites on the airway epithelium in COPD might aid the understanding of enhanced infectivity in ILD and would be an important area of investigation in this context.
intracellular adhesion molecule-1 (ICAM-1), an adhesin for most human rhinoviruses, as well as NTHI, is upregulated in the airways of patients with COPD.5 Similar to COPD, patients with ILD are frequently smokers or ex-smokers and experience acute exacerbations in which bacterial or viral infections, or both, are implicated, but there is little understanding of the mechanisms involved. It is again possible that PAFr and ICAM-1 might be upregulated on respiratory epithelium to provide key adhesion sites, which could explain at least some of this increased susceptibility. However, little if any work has been done on these microbial adhesins in ILD despite a lot of interest in bacterial/viral colonization. We believe that this deficiency needs to be rectified, as, again, it could have substantial translational therapeutic implications. Thus, lessons that are beginning to be learned in COPD research might be applicable to other lung conditions, including idiopathic ILD. Sukhwinder Singh Sohal, PhD Launceston, Australia Philip M. Hansbro, PhD Shakti Dhar Shukla, PhD Newcastle, NSW, Australia
We recently published our findings that plateletactivating factor receptor (PAFr), which is potentially an important adhesion site for Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHI) is highly expressed on the airway epithelium of smokers, and especially patients with COPD.2,3 The interaction between these pathogens and the epithelium occurs because these bacteria almost uniquely express phosphorylcholine (a molecular mimic of platelet-activating factor [PAF]) on their surface.2 Importantly, we have also found that inhaled corticosteroids tend to increase PAFr expression in patients with COPD, which might explain why patients receiving these treatments are at higher risk of pneumococcal infections.2 In a follow-up study, we also reported high PAFr expression in the small airways and alveolar epithelium of patients with COPD.4 In an in vitro study, we also observed that antagonizing PAFr significantly decreased the adherence of both pneumococci and NTHI to pulmonary epithelium.3 We also reported recently that the
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Mathew Suji Eapen, MSc Eugene Haydn Walters, DM, DSc, FCCP Hobart, Australia AFFILIATIONS: From the Breathe Well Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing (Drs Sohal and Walters and Mr Eapen), University of Tasmania; the School of Health Sciences (Dr Sohal), University of Tasmania, Launceston, Australia; and the Priority Research Centre for Healthy Lungs (Drs Hansbro and Shukla), School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle. FINANCIAL/NONFINANCIAL DISCLOSURES: None declared. FUNDING/SUPPORT: This work was supported by the Clifford Craig Foundation [Grant No. 153 to S. S. S.]. CORRESPONDENCE TO: Dr Sukhwinder Singh Sohal, PhD, School of Health Sciences, University of Tasmania, Locked Bag – 1322, Newnham Dr, Launceston, Tasmania 7248, Australia; e-mail:
[email protected] Copyright Ó 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2017.05.024
Acknowledgments Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
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References 1. Azadeh N, Limper AH, Carmona EM, Ryu JH. The role of infection in interstitial lung diseases: a review. Chest. 2017;152(4):842-852. 2. Shukla SD, Sohal SS, O’Toole RF, Eapen MS, Walters EH. Platelet activating factor receptor: gateway for bacterial chronic airway infection in chronic obstructive pulmonary disease and potential therapeutic target. Expert Rev Respir Med. 2015;9(4): 473-485. 3. Shukla SD, Fairbairn RL, Gell DA, et al. An antagonist of the platelet-activating factor receptor inhibits adherence of both nontypeable Haemophilus influenzae and Streptococcus pneumoniae to cultured human bronchial epithelial cells exposed to cigarette smoke. Int J Chron Obstruct Pulmon Dis. 2016;11: 1647-1655. 4. Shukla SD, Muller HK, Latham R, Sohal SS, Walters EH. Plateletactivating factor receptor (PAFr) is upregulated in small airways and alveoli of smokers and COPD patients. Respirology. 2016;21(3): 504-510. 5. Shukla SD, Mahmood MQ, Weston S, et al. The main rhinovirus respiratory tract adhesion site (ICAM-1) is upregulated in smokers and patients with chronic airflow limitation (CAL). Respir Res. 2017;18(1):6.
Response To the Editor:
We thank Sohal et al for their insightful comments in response to the article entitled “The Role of Infection in Interstitial Lung Diseases—A Review”1 published in this issue of CHEST. Those with chronic lung disease can be susceptible to infection through a variety of mechanisms, including distorted airway/parenchymal architecture and immunosuppressive therapies used to treat underlying diseases; indeed, even the use of inhaled corticosteroids has been implicated in the setting of COPD and asthma.2 The molecular mechanisms of adherence of these pathogens and how these mechanisms interact with the underlying disease processes, as well as the inhaled or systemic therapies used to treat interstitial lung disease (ILD), are an important avenue of research that needs further attention. Our review did not find that infectious triggers, commonly implicated in patients with asthma/COPD, were implicated in ILD exacerbations. Specifically, a study looking at Chlamydia pneumoniae did not find that this was a common trigger in acute exacerbations of ILD.3 Additionally, Wootton et al4 did not find common respiratory pathogens (including rhinovirus) to be a cause for acute exacerbations of idiopathic pulmonary fibrosis; instead, most studies have shown that herpesviruses are more commonly found in the ILD population.4 These studies, of course, were small, and given the inherent heterogeneity of patients with ILD, firm conclusions cannot be drawn at this time.
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Sohal et al point out smoking as yet another contributor putting patients with ILD at risk; this adds yet another layer of complexity, as we do not know the impact of smoking on the progression of idiopathic ILD independent of the natural progression of disease. In healthy individuals, the mucociliary escalator constitutes an important innate pulmonary defense mechanism. Mucociliary dysfunction of the peripheral airways has not been directly shown to cause acute exacerbations of ILD, even though recent studies implicate the mucin gene in the pathogenesis of several ILDs.5 It goes without saying that those with chronic lung disease may be vulnerable to infections through a variety of mechanisms. However, little is known about the cause and natural progression of ILDs, and it may be an oversimplification to connect ILDs (especially the idiopathic forms) to other chronic lung diseases such as asthma/COPD. We agree, however, that further research is necessary to elucidate the underlying pathogenesis of ILDs and the molecular mechanisms that lead to acute exacerbations, including the role of infections. Natalya Azadeh, MD, MPH Andrew H. Limper, MD, FCCP Eva M. Carmona, MD, PhD Jay H. Ryu, MD, FCCP Rochester, MN AFFILIATIONS: From the Division of Pulmonary and Critical Care Medicine, Mayo Clinic. FINANCIAL/NONFINANCIAL DISCLOSURES: See earlier cited article for author conflicts of interest. CORRESPONDENCE TO: Natalya Azadeh, MD, MPH, Division of Pulmonary and Critical Care Medicine, Gonda 18 S, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: azadeh.natalya@ mayo.edu Copyright Ó 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2017.05.022
References 1. Azadeh N, Limper AH, Carmona EM, Ryu JH. The role of infection in interstitial lung diseases: a review. Chest. 2017;152(4):842-852. 2. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009;169(3):219-229. 3. Tomioka H, Sakurai T, Hashimoto K, Iwasaki H. Acute exacerbation of idiopathic pulmonary fibrosis: role of Chlamydophila pneumoniae infection. Respirology. 2007;12(5):700-706. 4. Wootton SC, Kim DS, Kondoh Y, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(12):1698-1702. 5. Peljto AL, Selman M, Kim DS, et al. The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest. 2015;147(2):460-464.
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