Exacerbation phenotyping in chronic obstructive pulmonary disease MARTIN MACDONALD, TONY KORMAN, PAUL KING, KAIS HAMZA AND PHILIP BARDIN Monash Lung and Sleep, Monash Medical Centre, Melbourne, Victoria, Australia

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically ‘phenotype’ AECOPD have been proposed, and 52 hospitalized chronic obstructive pulmonary disease exacerbations according to underlying aetiology have now been prospectively phenotyped. Multiple exacerbation phenotypes were identified. A subpopulation coinfected with virus and bacteria had a significantly longer length of hospital stay, and this pilot study indicates that exacerbation phenotyping may be advantageous. Key words: clinical respiratory medicine, chronic obstructive pulmonary disease, emphysema, infection and inflammation, viral infection.

Abbreviation: AECOPD, acute obstructive pulmonary disease.




Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are the cardinal factor associated with mortality, morbidity, impaired quality of life and health-care costs in the disease.1 Current definitions of exacerbation are non-specific,2 implying an inherent assumption that exacerbation events have equivalent aetiologies. However, AECOPD are clearly heterogenous, and we proposed that routine clinical methods may be employed to attribute presumptive clinical aetiology to exacerbations.3 Application of this process would permit identification of differences in population characteristics and clinical outcomes between different exacerbation subpopulations or ‘phenotypes’. This may in turn have therapeutic consequences. Following literature review, the established aetiologies of AECOPD have been précised in the acronym— ABCDEFGX;3 Airway viral infection, Bacterial infection, Coinfection, Depression/Anxiety, Embolism (pulmonary), Failure (cardiac, or failure of lung

Correspondence: Martin Ian MacDonald, Monash Medical Centre—Respiratory and Sleep Medicine, Clayton Rd, Melbourne, Vic. 3163, Australia. Email: [email protected] Received 3 June 2013; invited to revise 17 July 2013; revised 31 July 2013; accepted 3 September 2013 (Associate Editor: Bob Hancox). © 2013 The Authors Respirology © 2013 Asian Pacific Society of Respirology

integrity—pneumothorax), General environment, X (unknown) (Table S1 online). The aim of this pilot study was to investigate the feasibility and putative benefits of our proposed exacerbation phenotyping. Methods employed for phenotype allocation are shown in the online supplement (Table S1 online). Consecutive patients hospitalized with AECOPD (n = 52) provided informed consent and were evaluated prospectively. Those with known alternative respiratory diagnoses or inability to complete questionnaires were excluded. Demographic data included age, gender and smoking status/pack year history, Medical Research Council Dyspnoea score, current medications and vaccination history. Presenting symptoms and symptom duration prior to emergency room presentation were recorded. Each patient underwent nasopharyngeal sampling for respiratory virus multiplex polymerase chain reaction in addition to sputum culture, chest X-ray, serum white blood cell and C-reactive protein. A Hospital Anxiety and Depression Score,4 and any changes in physical, social or therapeutic environment were recorded. Investigation for pulmonary embolism was at the discretion of the treating physician. Patient demographics, exacerbation presentation, clinical severity and outcomes were compared between aetiological subgroups. Groups were compared using univariate analysis of variance. The study population as a whole was elderly with severe disease. Distribution of aetiologies and demographics of phenotypes were shown in the online supplement (Table S2 online). Length of stay was normally distributed after exclusion of four outliers (>2 standard deviation from mean) who had protracted complications not clearly linked to AECOPD. Univariate analysis of variance comparing demographic factors between subpopulations did not identify a statistically significant difference between groups. Mean length of hospital stay was 8 ± 5.9 days for the cohort as a whole. Coinfection resulted in a statistically significant longer length of hospital stay (coinfection 15.7 ± 10.8 vs bacterial 7.0 ± 3.3 (P = 0.001), coinfection vs viral 7.7 ± 4.8 (P < 0.001), coinfection vs non-infectious 4.63 ± 1.2 (P < 0.001); see Fig. 1). Coinfection group included the only Respirology (2013) 18, 1280–1281 doi: 10.1111/resp.12197


Exacerbation phenotyping in COPD

has shown a similar finding,5 but our study has clinical utility as routinely available methods were employed. Other important subpopulations may be identifiable in larger studies. For example, patients in our study with poorly controlled anxiety/depression reported increased symptoms and attended emergency department (ED) earliest but had the least clinically severe exacerbations and shortest length of hospital stay (not significant). This subgroup may benefit from intensive psychosocial interventions rather than routine corticosteroids and antibiotics. Larger studies of AECOPD phenotyping are indicated.


Figure 1 Length-of-stay (LOS) comparison between aetiological phenotype.

fatality and viral/coinfection had highest rates of non-invasive ventilation (NIV) requirement (not significant). This pilot study emphasizes the heterogeneity of AECOPD and demonstrates that refining the term ‘COPD exacerbation’ to reflect underlying exacerbation aetiology may be feasible and clinically relevant. This proposition is supported by our finding that coinfection predicts poorer outcomes. Coinfection identified using more advanced research methods

© 2013 The Authors Respirology © 2013 Asian Pacific Society of Respirology

1 Anzueto A. Impact of exacerbations on COPD. Eur. Respir. Rev. 2010; 19: 113–8. 2 Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest 2000; 117(Suppl. 2): 398S–401S. 3 MacDonald M, Bardin P, Beasley R et al. A hypothesis to phenotype COPD exacerbations by aetiology. Respirology 2011; 16: 264–8. 4 Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 1983; 67: 361–70. 5 Papi A. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am. J. Respir. Crit. Care Med. 2006; 173: 1114–21.

Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 ABCDEFGX classification system for COPD exacerbation aetiology. Table S2 Comparison between aetiological subgroups.

Respirology (2013) 18, 1280–1281

Exacerbation phenotyping in chronic obstructive pulmonary disease.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically 'phe...
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