Background
Acute exacerbations of COPD are associated with impaired quality of life, accelerated lung function decline and place considerable burden on health-care resources [
1‐
3]. They are typically inflammatory events [
4,
5], triggered by bacterial and viral infection [
6], often requiring treatment with antibiotics and oral corticosteroids (OCS) either in an ambulatory setting, or less frequently in hospital [
7]. As a result, they have become a key target for intervention in COPD. With this recognition, the emergence of symptom, pathogen and biomarker-guided strategies now offers scope to phenotype exacerbations, potentially allowing for tailored management approaches [
8].
Pneumonia is more common in patients with COPD [
9], and can be clinically indistinguishable from exacerbations. Numerous factors associated with pneumonia risk have been reported in COPD, including inhaled corticosteroid (ICS) use, comorbidity and nutritional status [
10,
11]. COPD patients requiring hospitalisation for acute respiratory tract illness, often have complicating pneumonic infiltrate evident on chest radiograph (CXR) [
12]. Moreover, these hospitalised episodes are associated with more intense inflammatory responses, differing pathogen profiles and often lead to longer hospital stays and increased rates of readmission [
13‐
15]. This raises important treatment dilemmas, particularly around the use of OCS, risk-stratification for ICS and antibiotic usage. This is particularly relevant in the era of emerging antimicrobial resistance, where clinical strategies to better stratify and target antibiotics effectively are vital.
Validating a diagnosis of pneumonia requires the radiographic identification of pulmonary infiltrate in the context of symptoms of a respiratory tract infection which to date, has largely limited its study to hospitalised events. Given that only a comparatively small proportion of exacerbations require hospitalisation [
16], our understanding of the frequency, nature and impact of pneumonic infiltrates complicating non-hospitalised exacerbations is currently lacking.
In a secondary analysis of the Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) cohort, a prospective, longitudinal study of outpatients with COPD, we used radiological stratification to provide a detailed insight into the aetiology and character of exacerbations complicated by pneumonic change.
Discussion
In this prospective study of outpatients with moderate to very severe COPD, we show that exacerbations with new pneumonic infiltrates were associated with heightened levels of systemic inflammation, greater lung function deterioration and similar microbiological signatures, compared to exacerbations without. Importantly, more than 94% of exacerbations were managed as an outpatient, therefore providing a unique insight into the incidence and significance of pneumonic infiltrate in this clinical setting.
Recent interest has focused on understanding the heterogeneity of exacerbations [
8]. Although the use of CXR has been reported in hospitalised COPD patients [
13,
21,
22], few prospective studies report on its use in such a well-characterised outpatient COPD cohort, and none addressing the microbiological and inflammatory complexities of exacerbations to the extent of the AERIS study. The only other large COPD study collecting radiological data at exacerbation, did not report on inflammatory or microbiological indices [
23]. Although having a similar patient demographic, the differing primary objectives and aims make direct comparisons to our study difficult.
Pneumonic infiltrates were a feature in approximately 20% of exacerbations. Furthermore, half of all infiltrate-associated exacerbations occurred during the winter, and proportionally were a feature in around a third of all exacerbations occurring during that period, therefore contributing considerably to the exacerbation-burden during this time of year. In multivariate analysis seasonality remained an important determinant, with greater odds of having an exacerbation with infiltrate in winter, compared to summer. The seasonal nature of exacerbations and of pneumonia in COPD has previously been described [
6,
11,
24,
25]. Population behaviours, changes in temperature and humidity, as well as cyclical patterns of respiratory pathogens have all been proposed as key determinants [
26]. Understanding whether seasonality could direct exacerbation treatment approaches remains to be seen, but characterising exacerbations using methods such as CXR could guide this approach.
Exacerbations are typically inflammatory events [
5]. In this study, exacerbations with pneumonic infiltrate were associated with greater airway neutrophillic inflammation and showed more intense systemic inflammatory responses than exacerbations without. Additionally, significant decreases in FEV1 at exacerbation onset were seen in those with pneumonic infiltrate. This observed decline, provides a measure of exacerbation severity and may be directly associated with the greater inflammatory responses identified. Neutrophilic inflammation has previously been shown to correlate with greater decreases in lung function during exacerbation [
27,
28], but these studies did not utilise radiological stratification.
The intensity of systemic inflammation at exacerbation has previously been linked to the presence of bacteria [
4], bacterial strain changes [
29] and bacterial-viral co-infection [
28]. In agreement with prior studies [
30,
31], we have previously reported a substantial number of exacerbations associated with viral detection within this cohort [
6]. However, overall the proportion of viral-associated exacerbations with and without pneumonic infiltrate was broadly similar and viral symptoms (cold and/or sore throat) occurred less frequently in exacerbations with pneumonic infiltrate.
Bacteria, particularly HI, have long been regarded as an important cause of exacerbations [
32]. Conversely, studies of hospitalised pneumonia in COPD patients consistently report SP as the most frequently implicated bacteria [
13,
22], similarly for hospitalised pneumonia in patients without COPD [
15]. Like previous studies, our data re-confirms HI as the most frequently detected bacteria at exacerbation, but additionally suggests a potential association between HI and pneumonic infiltrate. By culture, HI was implicated in 52% of exacerbations with infiltrate compared to 38% of those without. However, as HI commonly causes chronic infection in COPD even at stable-state, establishing a causal link between HI detection at exacerbation and risk of pneumonic infiltrate is challenging. In this regard, although new bacterial acquisition did not appear to be associated with pneumonic infiltrate, bacterial strain changes and increasing load of existing pathogens could be key mechanisms, having previously been implicated in exacerbation development and more profound inflammatory responses [
28,
29].
This study adds to the evolving exploration of exacerbation heterogeneity, using radiological stratification in an outpatient COPD population. Current practise varies on whether an acute respiratory illness, complicated by pneumonic infiltrate in COPD patients is included under the diagnosis of exacerbation or considered as pneumonia. There is some evidence to suggest that exacerbations and pneumonia in COPD differ in their aetiology and inflammatory profile and should perhaps be considered distinct, despite being clinically hard to distinguish [
13,
33]. Our findings suggest that the infective aetiology of exacerbations is similar to that of acute events classified as pneumonia in an outpatient clinical setting. The results suggest common mechanisms between pneumonia and exacerbations in patients with COPD and will help to inform exacerbation management.
We recognise that this study has limitations. The use of CXR remains the radiological standard for diagnosing pneumonia, and yet false-positive and false-negative results can occur [
34]. CT scanning, may improve diagnostic accuracy, but is currently more expensive, less readily available and associated with greater radiation dose than plain CXR, making its utilisation currently unfeasible in a study of frequent exacerbators.
The mean exacerbation rate in AERIS reflects the selected cohort of patients with a history of frequent exacerbations. We accept that our findings may not be generalizable to more heterogeneous groups, or those that infrequently exacerbate. Nevertheless, like other studies, the exacerbation rate for the cohort was similar to that in the year prior to enrolment, suggesting a fairly constant phenotype rather than an overestimation of exacerbations [
35,
36].
There are well-established links between ICS use and increased pneumonia risk in COPD [
10,
37]. In our cohort, the majority of patients were already prescribed ICS at enrolment, limiting our ability to assess the impact of ICS use on the risk of developing pneumonic infiltrates. We also acknowledge that differing methodological approaches for determining aetiology, may limit direct comparisons with other studies. However, like a recent report of hospitalised pneumonia, not limited to COPD patients [
38], we utilised sputum for microbiological analysis and similarly identified HI as the most frequently detected bacteria. This contrasts with many other studies of COPD patients hospitalised with pneumonia, where an aetiological diagnosis was predominantly made from blood culture, urinary antigen testing or serological analysis and was typically found to be SP [
13,
21]. However, due to the early identification and treatment of exacerbations, we cannot exclude the possibility that bacteria such as SP may have a role in the later stages of pneumonic exacerbations. Additionally, the use of electronic diary cards and consequently the early capture of exacerbations, may underestimate the frequency of complicating pneumonic infiltrates, as radiological changes in the context of acute lower respiratory tract illness can lag behind clinical symptoms [
39].
Acknowledgements
The authors would like to thank all the study volunteers for their invaluable contribution towards furthering COPD knowledge and each team member for their assistance conducting the study. We acknowledge all members of the AERIS study group. The authors would also like to thank Geraldine Drevon and Regis Azizieh (XPE Pharma & Science, on behalf of GSK Vaccines) for coordination and editorial support. The study was funded by GlaxoSmithKline Biologicals SA.
The AERIS Study Group:
J Alnajar, R Anderson, E Aris, WR Ballou, A Barton, S Bourne, M Caubet, SC Clarke, D Cleary, C Cohet, NA Coombs, K Cox, J-M Devaster, V Devine, N Devos, E Dineen, T Elliot, R Gladstone, S Harden, J Jefferies, V Kim, C Lambert, S Mesia-Vela, P Moris, K Ostridge, TG Pascal, M Peeters, S Schoonbroodt, KJ Staples, A Tuck, L Welsh, V Weynants, TMA Wilkinson, AP Williams, NP Williams, C Woelk, M Wojtas, S Wootton. All members of the AERIS Study Group were involved in the planning, conduct, and/or reporting of the work described in the article.