A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD
Tom M A Wilkinson, Emmanuel Aris, Simon Bourne, Stuart C Clarke, Mathieu Peeters, Thierry G Pascal, Sonia Schoonbroodt, Andrew C Tuck, Viktoriya Kim, Kristoffer Ostridge, Karl J Staples, Nicholas Williams, Anthony Williams, Stephen Wootton, Jeanne-Marie Devaster, AERIS Study Group, Tom M A Wilkinson, Emmanuel Aris, Simon Bourne, Stuart C Clarke, Mathieu Peeters, Thierry G Pascal, Sonia Schoonbroodt, Andrew C Tuck, Viktoriya Kim, Kristoffer Ostridge, Karl J Staples, Nicholas Williams, Anthony Williams, Stephen Wootton, Jeanne-Marie Devaster, AERIS Study Group
Abstract
Background: The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood. Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these events.
Methods: In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40-85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses. Results are presented for subjects in the full cohort, followed for 1 year. Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses.
Findings: The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50). At AECOPD, the most common bacterial species were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, and the most common virus was rhinovirus. Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when M. catarrhalis was detected regardless of season (5.09 (95% CI 2.76 to 9.41)). When NTHi was detected, the increased risk of exacerbation was greater in high season (October-March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)). Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%). A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031).
Conclusions: AECOPD aetiology varies with season. Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection.
Trial registration number: Results, NCT01360398.
Keywords: Bacterial Infection; COPD Exacerbations; Respiratory Infection; Viral infection.
Conflict of interest statement
Competing interests: TMAW has received reimbursement for travel and meeting attendance from Boehringer Ingelheim and AstraZeneca, outside of the submitted work. SB received grants and assistance in travel to conferences from GSK outside of the submitted work. SCC received a grant from Pfizer outside of the submitted work. KJS received grants from Asthma UK (08/026) and BMA HC Roscoe Award outside of the submitted work, and he has a patent PCT/GB2010/050821 ‘Ex Vivo Modelling of Therapeutic Interventions’ pending. EA, J-MD, SS and TGP are employees of the GSK group of companies. MP was an employee of the GSK group of companies at the time the study was conducted. EA, J-MD, SS and TGP hold shares/restricted shares in the GSK group of companies. KJS, VK, NW, KO, SW and TMAW received an institutional grant from the GSK group of companies to conduct this study. AW and AT declare no conflicts of interest.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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References
- Jenkins CR, Celli B, Anderson JA, et al. . Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J 2012;39:38–45. 10.1183/09031936.00194610
- Rabe KF, Fabbri LM, Vogelmeier C, et al. . Seasonal distribution of COPD exacerbations in the Prevention of Exacerbations with Tiotropium in COPD trial. Chest 2013;143:711–19. 10.1378/chest.12-1277
- Donaldson GC, Wedzicha JA. The causes and consequences of seasonal variation in COPD exacerbations. Int J Chron Obstruct Pulmon Dis 2014;9:1101–10. 10.2147/COPD.S54475
- Garcha DS, Thurston SJ, Patel AR, et al. . Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD. Thorax 2012;67:1075–80. 10.1136/thoraxjnl-2012-201924
- Huang YJ, Sethi S, Murphy T, et al. . Airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease. J Clin Microbiol 2014;52:2813–23. 10.1128/JCM.00035-14
- Wilkinson TM, Hurst JR, Perera WR, et al. . Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD. Chest 2006;129:317–24. 10.1378/chest.129.2.317
- Papi A, Bellettato CM, Braccioni F, et al. . Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006;173:1114–21. 10.1164/rccm.200506-859OC
- Bourne S, Cohet C, Kim V, et al. . Acute Exacerbation and Respiratory InfectionS in COPD (AERIS): protocol for a prospective, observational cohort study. BMJ Open 2014;4:e004546 10.1136/bmjopen-2013-004546
- Vestbo J, Hurd SS, Agusti AG, et al. . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–65. 10.1164/rccm.201204-0596PP
- Hurst JR, Vestbo J, Anzueto A, et al. . Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;363:1128–38. 10.1056/NEJMoa0909883
- Bertens LC, Reitsma JB, Moons KG, et al. . Development and validation of a model to predict the risk of exacerbations in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013;8:493–9. 10.2147/COPD.S49609
- Müllerová H, Shukla A, Hawkins A, et al. . Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study. BMJ Open 2014;4:e006171 10.1136/bmjopen-2014-006171
- Kerkhof M, Freeman D, Jones R, et al. . Predicting frequent COPD exacerbations using primary care data. Int J Chron Obstruct Pulmon Dis 2015;10:2439–50. 10.2147/COPD.S94259
- Bafadhel M, Haldar K, Barker B, et al. . Airway bacteria measured by quantitative polymerase chain reaction and culture in patients with stable COPD: relationship with neutrophilic airway inflammation, exacerbation frequency, and lung function. Int J Chron Obstruct Pulmon Dis 2015;10:1075–83. 10.2147/COPD.S80091
- Barker BL, Haldar K, Patel H, et al. . Association between pathogens detected using quantitative polymerase chain reaction with airway inflammation in COPD at stable state and exacerbations. Chest 2015;147:46–55. 10.1378/chest.14-0764
- Sethi S. Infection as a comorbidity of COPD. Eur Respir J 2010;35:1209–15. 10.1183/09031936.00081409
- Wang H, Gu X, Weng Y, et al. . Quantitative analysis of pathogens in the lower respiratory tract of patients with chronic obstructive pulmonary disease. BMC Pulm Med 2015;15:94 10.1186/s12890-015-0094-z
- Molyneaux PL, Mallia P, Cox MJ, et al. . Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1224–31. 10.1164/rccm.201302-0341OC
- Millares L, Ferrari R, Gallego M, et al. . Bronchial microbiome of severe COPD patients colonised by Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 2014;33:1101–11. 10.1007/s10096-013-2044-0
- Carvalho MGS, Tondella ML, McCaustland K, et al. . Evaluation and improvement of real-time PCR assays targeting lytA, ply, and psaA genes for detection of pneumococcal DNA. J Clin Microbiol 2007;45:2460–6. 10.1128/JCM.02498-06
- Zwaans WA, Mallia P, van Winden ME, et al. . The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease–a systematic review. J Clin Virol 2014;61:181–8. 10.1016/j.jcv.2014.06.025
- George SN, Garcha DS, Mackay AJ, et al. . Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J 2014;44:87–96. 10.1183/09031936.00223113
- Clark TW, Medina MJ, Batham S, et al. . C-reactive protein level and microbial aetiology in patients hospitalised with acute exacerbation of COPD. Eur Respir J 2015;45:76–86. 10.1183/09031936.00092214
- MacDonald M, Korman T, King P, et al. . Exacerbation phenotyping in chronic obstructive pulmonary disease. Respirology 2013;18:1280–1. 10.1111/resp.12197
- Dai MY, Qiao JP, Xu YH, et al. . Respiratory infectious phenotypes in acute exacerbation of COPD: an aid to length of stay and COPD Assessment Test. Int J Chron Obstruct Pulmon Dis 2015;10:2257–63. 10.2147/COPD.S92160
- Murphy TF, Parameswaran GI. Moraxella catarrhalis, a human respiratory tract pathogen. Clin Infect Dis 2009;49:124–31.
- Mallia P, Footitt J, Sotero R, et al. . Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:1117–24. 10.1164/rccm.201205-0806OC
- Ohrui T, Yamaya M, Sekizawa K, et al. . Effects of rhinovirus infection on hydrogen peroxide-induced alterations of barrier function in the cultured human tracheal epithelium. Am J Respir Crit Care Med 1998;158:241–8. 10.1164/ajrccm.158.1.9607117
- Oliver BG, Lim S, Wark P, et al. . Rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages. Thorax 2008;63:519–25. 10.1136/thx.2007.081752
- Segal LN, Rom WN, Weiden MD. Lung microbiome for clinicians. New discoveries about bugs in healthy and diseased lungs. Ann Am Thorac Soc 2014;11:108–16.
- Gulraiz F, Bellinghausen C, Bruggeman CA, et al. . Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelial cells to viral infections. FASEB J 2015;29:849–58.
- Bellinghausen C, Gulraiz F, Heinzmann AC, et al. . Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection. Respir Res 2016;17:68 10.1186/s12931-016-0382-z
- Heinrich A, Haarmann H, Zahradnik S, et al. . Moraxella catarrhalis decreases antiviral innate immune responses by down-regulation of TLR3 via inhibition of p53 in human bronchial epithelial cells. FASEB J 2016;30:2426–34.
- Sethi S, Evans N, Grant BJ, et al. . New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465–71. 10.1056/NEJMoa012561
- Desai H, Eschberger K, Wrona C, et al. . Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014;11:303–9. 10.1513/AnnalsATS.201310-350OC
- Sethi S, Sethi R, Eschberger K, et al. . Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:356–61. 10.1164/rccm.200703-417OC
Source: PubMed