Predictors of Chronic Obstructive Pulmonary Disease Exacerbations

Takeo Ishii; Kozui Kida


Curr Opin Pulm Med. 2014;20(2):138-145. 

In This Article

Abstract and Introduction


Purpose of review A frequent-exacerbation phenotype of chronic obstructive pulmonary disease (COPD) exists that is independent of disease severity. Establishment of methods to predict 'frequent exacerbators' is critical. The purpose of this review is to critically assess the recent literature regarding predicting COPD exacerbations, and to provide recommendations for future research.

Recent findings Although there are many studies in which inflammatory biomarkers have been used in an attempt to predict future exacerbations, it is likely that these biomarkers represent a consequence rather than the cause. Genetic predictors are involved in causal pathways. Thus, genetics should be investigated in order to understand the exacerbation mechanism and to develop new therapeutic approaches. Some single nucleotide-type genetic polymorphisms are associated with exacerbations, and the individuals with genotypes protective against infection are less susceptible to exacerbations. In contrast, we reported that loss of Siglec-14, a lectin likely involved in host defense, was associated with a reduced COPD exacerbation risk.

Summary We should take into consideration that a protein involved in host defense such as Siglec-14, that could also trigger exaggerated response, might also generate unwanted local and systemic inflammation, which could be detrimental to a host and could generate COPD with a frequent-exacerbation phenotype, its progression, and its comorbidities.


The Global Initiative for Chronic Obstructive Lung Disease (GOLD) consensus report proposed a new classification system for chronic obstructive pulmonary disease (COPD) in order to more comprehensively assess disease severity that incorporates symptoms with either dyspnea or health status measures, in addition to a history of COPD exacerbations and airflow limitation.[1] As the new GOLD classification is a better predictor of future exacerbations than the old GOLD classification,[2,3] it could also lead to better treatments for stable COPD with respect to preventing exacerbations. Exacerbations are a leading cause of mortality from and a major cost driver of COPD.[4] Many new drugs, including roflumilast in the United States, are being approved because of their capacity to reduce exacerbations.[5]

Respiratory infections are thought to be common causative agents for COPD exacerbations[6] and were thus investigated. However, little was known about host conditions of COPD patients, until it was reported recently that a frequent-exacerbation phenotype of COPD exists that is independent of disease severity[7] and is stable.[8]

This phenotype is related not only to COPD progression but also to COPD pathogenesis, because this phenotype possibly begins before a patient, particularly a smoker, is diagnosed with COPD. Fletcher and Peto[9] demonstrated the natural course of COPD, the 'Fletcher–Peto curve', and they showed that the expiratory airflow limitation, defined as forced expiratory volume in 1 s, declines with age throughout adulthood, and that smoking, without the effect of mucus hypersecretion, accelerates its decline (Fig. 1a). Subsequently, Burrows[10] indicated that some COPD individuals might have exacerbation and remission periods with each episode leading to a progressive loss of function (Fig. 1b) .[11] Further, before smokers are diagnosed with COPD, severe inflammation secondary to infection in the lungs, due to pulmonary infection during smoking, might also affect the development of emphysema and other airway diseases related to COPD in individuals with a frequent-exacerbation phenotype, especially if this phenotype is mainly determined by genetics.

Figure 1.

Possible 'natural histories' of COPD. (a) A Fletcher–Peto curve, presented in the GOLD guideline. (b) 'Natural histories' that can lead to severe COPD in various manners, as described by Burrows [10]. Some with a frequent-exacerbation phenotype may have repetition of exacerbation and remission leading to progression of COPD, shown as 'B' [11]. COPD, chronic obstructive pulmonary disease. (a) Reproduced with permission from [9]; (b) reproduced with permission from [10] (Copyright Elsevier).

Thus, we now know that a 'frequent-exacerbation' phenotype exists that affects the pathogenesis and progression of COPD, thus necessitating clarification of the factors that could help predict this phenotype.