COPD exacerbations are a major cause of morbidity and mortality. Recent reports in the medical literature support the long-held clinical notion that COPD subjects vary widely in their susceptibility towards acute exacerbations. The existence and characterization of "frequent exacerbators" and relatively resistant "non-exacerbators" in a recent large observational study has challenged the association of traditional risk factors with acute exacerbations(23
). The findings from our study support the existence of these distinct COPD phenotypes and introduce new plausible risk factors.
The major finding in the recently published ECLIPSE cohort study was the description of stable sub-phenotypes relating to exacerbation susceptibility which appear to be independent
of lung function impairment(23
). Thus, although low FEV1
has been well established as a risk factor for acute exacerbations(13
), its utility may be limited to comparisons between COPD subjects with extremely disparate levels of FEV1
impairment or of different GOLD stages. The disassociation of airflow obstruction with exacerbation frequency is echoed in our cohort in that no significant difference in mean FEV1
% predicted was noted between our frequent and non-exacerbator groups. Likewise, despite inclusion in our multivariate models, FEV1
% predicted was not found to be a significant predictor of frequent exacerbator status. Additional findings which support the concept of these sub-phenotypes as independent phenomena include the lack
of differences in age, gender, or rates of chronic cough or sputum between frequent exacerbators and non-exacerbators. The lack of association with these traditional risk factors may be attributable to the fact our cohort has been enriched with these extreme phenotypes.
Two additional apparent paradoxes regarding the rates of current smoking and medication use in our cohort deserve discussion. First, the trend towards increased
rates of current smoking noted in our nonexacerbator group is not an isolated event – similar observations have been described in other studies(2
). We believe this reflects a "healthy smoker effect" (whereby subjects who are frequently ill are more likely to quit smoking) rather than a biologically protective effect of smoking. A similar statement can be made regarding the significantly higher rates of maintenance medication use among frequent exacerbators. The efficacy of bronchodilators and inhaled and systemic steroids in the treatment and prevention of acute exacerbations has been studied previously(32
). Our results suggest that certain patients with COPD will continue to suffer frequent exacerbations despite
aggressive medical maintenance therapy.
In our cohort, self-reported physician-diagnosed asthma was a significant clinical predictor of frequent exacerbator. The interpretation of this finding can be challenging. First, subjects with asthma and COPD often report a formal diagnosis of both diseases – studies have suggested an overlap rate between 15–34%(37
). Whether this degree of overlap represents a true biological or pathophysiological entity, as outlined by the Dutch hypothesis(44
), or some degree of misclassification remains unresolved. Even in studies that employ rigorous measures such as bronchodilator reversibility testing or methacholine challenge, differentiating between or establishing the co-existence of COPD and asthma remains challenging; subjects with asthma may not demonstrate complete, immediate reversibility(39
) and a significant proportion of COPD subjects will demonstrate some degree of BDR(41
) and a positive response to methacholine challenge(47
). In our cohort, despite the high self-reported rates of physician-diagnosed asthma, the rates of bronchodilator responsiveness and asthma diagnosed before age 18 were low and did not vary by frequent / non-exacerbator status. Furthermore, although significantly more subjects in the frequent exacerbator group reported a diagnosis of asthma, a greater change from baseline FEV1 was observed in the non-exacerbator group (Supplementary Table B
Regardless of whether true biological overlap exists, the significance of physician-diagnosed asthma as a risk factor for exacerbations is plausible. COPD subjects with a history of physician-diagnosed asthma report more respiratory symptoms(48
), worse health status(42
), and are at increased risk of requiring emergency room services or hospitalization(37
). In the United States, COPD subjects with a concurrent diagnosis of asthma have significantly increased respiratory related costs(37
). Thus, the term “physician-diagnosed asthma” may capture an aspect of more symptomatic or severe disease not well quantified by lung function or other traditional risk factors.
Within the subgroup with MMRC dyspnea scores available, several additional clinical predictors of exacerbations were identified, including post-bronchodilator FEF25–75
% predicted and the MMRC score. The modest but significant difference in FEF25–75
% predicted between cases and controls despite a lack of difference in FEV1
% predicted values may reflect worse obstruction at the level of the smallest airways(49
), perhaps beyond some critical threshold, in frequent exacerbators. The significance of the modified MRC dyspnea scale in predicting exacerbations may be due in part to the continued reliance on the subjective report of increased shortness of breath in defining acute exacerbations – whether some subjects perceive or are more likely to report dyspnea and hence be at greater likelihood to meet criteria for an acute exacerbation is debatable. Regardless, the utility of the modified MRC score in predicting frequent exacerbator status beyond FEV1
alone is suggested by this subgroup analysis. The generalizability of the association with the MMRC score is limited by the high rate of missingness for the variable which resulted from strict adherence to a skip pattern in the questionnaire after subjects reported a disability from walking other than heart or lung disease. Post hoc review revealed that the majority of subjects who did not have an MMRC score skipped these questionnaire items due to orthopedic complaints, with a minority of subjects opting out due to vascular or neurological problems. Although there was no difference in the rates of missingness between cases and controls, differential missingness with regards to other variables (such as current smoking) limits this analysis.
We acknowledge several limitations to this study in addition to the ones outlined above. The retrospective and cross sectional nature of the cohort, as well as the reliance upon patient reported exacerbations, predisposes our study to recall bias and resultant misclassification bias with regards to case/control status. The review of medical records for the majority of the subjects to verify reported exacerbations is an advantage of our study design – correlation rates between subject reported exacerbations and the medical record review were high (Rho=0.7, p-value <0.0001). Though the requirement for severe airflow obstruction adds to the uniqueness of our cohort, it also limits the generalizability of our findings. In addition, while we did not directly assess for potentially confounding co-morbid conditions such as heart failure, the non-differential rates of use of cardiac medications such as diuretics, antihypertensive and antiarrhythmic medications argues against differential rates between frequent and non-exacerbators. Lastly, the modest size of our cohort may limit detection of clinical variables with less profound effect sizes (i.e. subject us to false negatives).
Despite these limitations, our study suggests that physician-diagnosed asthma is a significant clinical predictor of frequent exacerbator status in our cohort. Significant differences in FEV1 % predicted, suboptimal medical management, and increased rates of current tobacco use were not the primary causes of frequent exacerbations in our severe COPD subjects. Additional anatomical, environmental, or genetic factors may account for differences in exacerbation frequency phenotypes. Future studies should investigate the role of inflammatory markers and genetic polymorphisms on the risk of frequent exacerbations.