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/.

Figures

Figure 1
Figure 1
Flow chart of patients and sputum sampling in the study.
Figure 2
Figure 2
Percentage of culture-positive or PCR-positive sputum samples at stable state and exacerbation state (full cohort, year 1). (A) Percentage of sputum samples positive for bacteria by culture. (B) Percentage of sputum samples positive for bacteria by PCR*. *Group A streptococcus (Streptococcus pyogenes) was not detected. (C) Percentage of sputum samples positive for virus by PCR. HRV, human rhinovirus; NTHi, non-typeable Haemophilus influenzae.
Figure 3
Figure 3
Percentage of sputum samples that contained more than one bacterial or viral species by culture or PCR at stable state and exacerbation (full cohort, year 1). N, Number of samples identified in each category.
Figure 4
Figure 4
Seasonal distribution of acute exacerbations of COPD (AECOPD) cases with sputum samples: total number and number of cases positive by PCR for non-typeable Haemophilus influenzae (NTHi), M. catarrhalis, human rhinovirus (HRV) or any viral species, and cases negative for bacteria and viruses (full cohort year 1; month of follow-up considered regardless of year).
Figure 5
Figure 5
Effect of presence or new occurrence (detection after negative sputum sample at previous visit) of bacteria (non-typeable Haemophilus influenzae (NTHi) or M. catarrhalis (Mcat)) or human rhinovirus (HRV) on the odds of experiencing acute exacerbations of COPD (AECOPD) rather than being in stable state (full cohort, year 1). Odds ratios (ORs) for AECOPD occurrence were obtained from conditional logistic models. A. ORs for AECOPD occurrence obtained from conditional logistic models containing bacteria culture data, HRV, all viruses other than HRV, and season (high season, October to March; low season, April to September), stratified by subject. The effect of NTHi presence is provided for low and high seasons because the interaction between NTHi and season was statistically significant (p=0.010; more than 100 observations in each combination of factors). The effect of presence of Mcat, HRV, or other viruses did not differ between low and high seasons. The effect of new NTHi, Mcat, HRV, or other virus occurrences did not differ between low and high seasons. B. ORs for AECOPD occurrence obtained from conditional logistic models containing bacteria PCR data, HRV, other viruses, and season, stratified by subject. The effect of NTHi presence is provided in the presence or absence of HRV, and the effect of HRV in the presence or absence of NTHi, because the interaction between NTHi and HRV was statistically significant (p=0.031; more than 50 observations in each combination of factors). The effect of Mcat presence did not differ in the presence or absence of NTHi, HRV, or season. The effect of new Mcat, HRV, or other virus occurrences did not differ between high and low seasons. The effect of new NTHi occurrences was not statistically significant.

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Source: PubMed

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