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Editorial |

Bronchiectasis and COPD Overlap: A Case of Mistaken Identity? FREE TO VIEW

James D. Chalmers, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: J. D. C. reports research grants from Astra Zeneca, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, and Bayer Healthcare unrelated to the present manuscript, as well as personal fees from Astra Zeneca, Boehringer Ingelheim, Napp, Chiesi, Bayer Healthcare, and Pfizer unrelated to the present manuscript.

Scottish Centre for Respiratory Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland

CORRESPONDENCE TO: James D. Chalmers, PhD, Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, Ninewells Ave, University of Dundee, Dundee, DD1 9SY, Scotland


Copyright 2017, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(6):1204-1206. doi:10.1016/j.chest.2016.12.027
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Bronchiectasis (from the Greek “bronkhos,” meaning wind pipe or latterly bronchial tubes, and “ektasis,” meaning stretching out, extension, or dilation) refers to both a radiological appearance usually evaluated by CT imaging and a disease characterized by cough, sputum production, and exacerbations. It is associated with a number of infectious, autoimmune, congenital, and allergic disorders. The disease is associated with neutrophilic inflammation and chronic airway infection.

FOR RELATED ARTICLE SEE PAGE 1255

The finding of radiological bronchiectasis has frequently been reported in patients with COPD, raising the possibility of a COPD phenotype. Fundamental to the radiological diagnosis of bronchiectasis has been the view that at any given level, the diameter of the bronchus should be less than that of the adjacent vessel, and therefore a bronchial/arterial (BA) ratio > 1 indicates radiological bronchiectasis. In this issue of CHEST, Diaz et al have published a key observation that will challenge our view of what bronchiectasis means in COPD. The authors used quantitative CT scanning to objectively measure airway and vascular size and associated features in 21 smokers with a radiological diagnosis of bronchiectasis (including 17 subjects with COPD) and 21 never-smoking control subjects.

Some of the results are unsurprising, particularly that using the BA ratio to objectively diagnose bronchiectasis had a high agreement with radiologist-reported bronchiectasis (90%). Other findings were more striking. Subjects with bronchiectasis had an increased BA ratio, but this was primarily driven by reductions in the vessel diameter. Subjects with “bronchiectasis” did not have major increases in bronchial diameter compared with healthy subjects at the same level but had smaller blood vessels giving the “artificial” appearance of bronchiectasis.

Wall thickness was associated with sputum production, the defining symptom of clinical disease, and inversely related to FEV1, but the BA ratio was not. Oxygen saturations were correlated to bronchial artery diameters, leading the authors to speculate that reduced vessel size may indicate hypoxic vasoconstriction.

The “patients with bronchiectasis” in this study did not have bronchiectasis but a “mistaken identity,” as their bronchi were not ectatic. Does this mean that many patients with COPD bronchiectasis overlap syndrome could be misdiagnosed? This is a small study, and it is important to point out that larger studies will be needed. Nevertheless, the implications for clinical practice are substantial.

Studies to date of the significance of bronchiectasis in COPD have relied on radiologist reporting of bronchiectasis or measurement of the BA ratio, so their interpretation may be refined in view of the findings of Diaz.,

It is widely reported that up to 50% of patients with COPD have bronchiectasis, but the studies supporting this statement suffer from major biases. A meta-analysis recently examined data from six observational studies (881 patients) reporting a mean bronchiectasis prevalence of 54.3%. Patients with COPD and bronchiectasis had more sputum production, more exacerbations, worse lung function, and more bacterial infection. These findings would naturally lead to a conclusion that radiological bronchiectasis should have implications for treatment, such as the use of physiotherapy or long-term antibiotic treatment.

These conclusions may be flawed. The authors appear to have missed or excluded the largest study to report on bronchiectasis to date, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort (N = 2,164), which found an overall prevalence of only 4%, rising to 9% in patients with the most severe COPD. Other limitations of this meta-analysis included pooling data from two studies by the same author from overlapping periods with similar results, suggesting that these cohorts may not have been fully independent, and identification of publication bias for a number of outcomes suggesting statistically that extreme results were being preferentially published from small cohorts.

Larger studies have now been published that strengthen these concerns. Tan et al recently reported data from the Canadian Cohort of Obstructive Lung Disease (CanCOLD) cohort (N = 1,361 participants), including healthy control subjects, at-risk smokers, and patients with COPD, all of whom had CT imaging performed. The results contradict those of the previous meta-analysis. In this cohort, bronchiectasis was reported in 19.9% of normal subjects, confirming that radiological bronchiectasis can be observed in the general population. Corresponding rates were 19.9% for at-risk smokers, 14.1% for patients with mild COPD, and 22.2% for those with moderate COPD. Only patients with severe or very severe COPD had an increased rate of bronchiectasis (35.1%) compared with control subjects. Importantly, bronchiectasis was not associated with chronic sputum production, cough, or exacerbations but was associated with wheeze, dyspnea, and greater symptoms using the COPD Assessment Test score.

This suggests that radiological bronchiectasis is common, but clinically significant bronchiectasis is less frequent. Supporting this, the reportedly high prevalence of bronchiectasis in COPD cohorts is contrasted by the relatively low frequency of COPD reported as an underlying diagnosis in bronchiectasis cohorts, accounting for < 20% of patients on average and 20% in both the US and European bronchiectasis registries., These cohorts are selected based on the clinical syndrome and so would exclude incidental radiological disease.

What do we do in clinical practice with patients with COPD and radiological bronchiectasis? Some patients will have both conditions and should be treated as such, with the clinical history being the key determinant. Patients should have chronic sputum production and positive sputum culture results for pathogenic bacteria with or without frequent exacerbations, also known as clinically significant bronchiectasis.

In patients with radiological bronchiectasis but without clinical features, reduced vascular size may be the cause, particularly if there are no other features, such as frequent exacerbations or bronchial wall thickening on CT scans. Such patients should not be treated according to bronchiectasis guidelines and should not be included in bronchiectasis cohort studies, registries, or clinical trials, but the association should be recognized as potentially being a marker of poorer prognosis.

A third critical possibility that has been largely neglected in the discussion to date is the possibility of nontuberculous mycobacterial (NTM) infection. Andrejak et al reported in a case-control study that COPD increased the risk of NTM infection by 16-fold, with an increase of 29 times in the presence of COPD and inhaled corticosteroid therapy. Char et al studied lung specimens from 142 patients with COPD undergoing lung volume reduction surgery for COPD and found that 10% had evidence of NTM disease (none was clinically suspected of having NTM). Nodular bronchiectasis is one of the most common phenotypes, and NTM infection should be considered in patients with COPD and radiological bronchiectasis. This is particularly important, as increasing numbers of patients with COPD and bronchiectasis are receiving long-term macrolide treatment, with the potential to induce macrolide resistance in NTM if used inappropriately.

Where do we go from here in clinical research? We need to move beyond the simplistic bronchiectasis-COPD clinical “phenotype” concept that appears to be misleading to a more endotypic approach, identifying imaging parameters that can detect bronchial dilatation without relying on a ratio; characterizing the airway inflammatory and microbiota characteristics of COPD, bronchiectasis, and the overlap; and studying predictors of response to targeted treatments such as macrolides, which must be used carefully and responsibly.

Diaz et al have highlighted a key emerging clinical issue that will have wide-reaching implications. Understanding the true clinical significance of the COPD/bronchiectasis overlap is now critical from an antibiotic stewardship and patient outcomes perspective.

References

Aliberti S. .Lonni S. .Dore S. .et al Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J. 2016;47:1113-1122 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis [published ahead of print December 2, 2016].Am J Respir Crit Care Med.
 
Hurst J.R. .Elborn J.S. .De Soyza A. . COPD-bronchiectasis overlap syndrome. Eur Respir J. 2015;45:310-313 [PubMed]journal. [CrossRef] [PubMed]
 
Diaz A.A. .Young T.P. .Maselli D.J. .et al Quantitative CT measures of bronchiectasis in smokers. Chest. 2017;151:1255-1262 [PubMed]journal
 
Ni Y. .Shi G. .Yu Y. .et al Clinical characteristics of patients with chronic obstructive pulmonary disease with co-morbid bronchiectasis: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1465-1475 [PubMed]journal. [PubMed]
 
Agusti A. .Calverley P.M. .Celli B. .et al Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122- [PubMed]journal. [CrossRef] [PubMed]
 
Tan W.C. .Hague C.J. .Leipsic J. .et al Findings on thoracic computed tomography scans and respiratory outcomes in persons with and without chronic obstructive pulmonary disease: a population-based cohort study. PLoS One. 2016;1:e0166745- [PubMed]journal
 
Matsuoka S. .Uchiyama K. .Shima H. .et al Bronchoarterial ratio and bronchial wall thickness on high-resolution CT in asymptomatic subjects: correlation with age and smoking. AJR Am J Roentgenol. 2003;180:513-518 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers J.D. .Aliberti S. .Polverino E. .et al The EMBARC European Bronchiectasis Registry: protocol for an international observational study. ERJ Open Res. 2016;2:- [PubMed]journal
 
Aksamit T.R. .O’Donnell A.E. .Barker A. .et al Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry. Chest. 2017;151:982-992 [PubMed]journal. [CrossRef] [PubMed]
 
Andrejak C. .Nielsen R. .Thomsen V.O. .et al Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013;68:256-262 [PubMed]journal. [CrossRef] [PubMed]
 
Char A. .Hopkinson N.S. .Hansell D.M. .et al Evidence of mycobacterial disease in COPD patients with lung volume reduction surgery: the importance of histological assessment of specimens: a cohort study. BMC Pulm Med. 2014;14:124- [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Aliberti S. .Lonni S. .Dore S. .et al Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J. 2016;47:1113-1122 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis [published ahead of print December 2, 2016].Am J Respir Crit Care Med.
 
Hurst J.R. .Elborn J.S. .De Soyza A. . COPD-bronchiectasis overlap syndrome. Eur Respir J. 2015;45:310-313 [PubMed]journal. [CrossRef] [PubMed]
 
Diaz A.A. .Young T.P. .Maselli D.J. .et al Quantitative CT measures of bronchiectasis in smokers. Chest. 2017;151:1255-1262 [PubMed]journal
 
Ni Y. .Shi G. .Yu Y. .et al Clinical characteristics of patients with chronic obstructive pulmonary disease with co-morbid bronchiectasis: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1465-1475 [PubMed]journal. [PubMed]
 
Agusti A. .Calverley P.M. .Celli B. .et al Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122- [PubMed]journal. [CrossRef] [PubMed]
 
Tan W.C. .Hague C.J. .Leipsic J. .et al Findings on thoracic computed tomography scans and respiratory outcomes in persons with and without chronic obstructive pulmonary disease: a population-based cohort study. PLoS One. 2016;1:e0166745- [PubMed]journal
 
Matsuoka S. .Uchiyama K. .Shima H. .et al Bronchoarterial ratio and bronchial wall thickness on high-resolution CT in asymptomatic subjects: correlation with age and smoking. AJR Am J Roentgenol. 2003;180:513-518 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers J.D. .Aliberti S. .Polverino E. .et al The EMBARC European Bronchiectasis Registry: protocol for an international observational study. ERJ Open Res. 2016;2:- [PubMed]journal
 
Aksamit T.R. .O’Donnell A.E. .Barker A. .et al Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry. Chest. 2017;151:982-992 [PubMed]journal. [CrossRef] [PubMed]
 
Andrejak C. .Nielsen R. .Thomsen V.O. .et al Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013;68:256-262 [PubMed]journal. [CrossRef] [PubMed]
 
Char A. .Hopkinson N.S. .Hansell D.M. .et al Evidence of mycobacterial disease in COPD patients with lung volume reduction surgery: the importance of histological assessment of specimens: a cohort study. BMC Pulm Med. 2014;14:124- [PubMed]journal. [CrossRef] [PubMed]
 
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