American Journal of Respiratory and Critical Care Medicine

Over the past decade there has been much research and interest in COPD. As a result, the understanding and management of the disease has improved significantly. Yet, there are many uncertainties and controversies that require further work. This review discusses these controversies and anticipates some of the changes that may occur in the near future in the field of COPD.

Chronic obstructive pulmonary disease (COPD) is a major and rising public health problem because of its high prevalence, important morbidity/mortality, and significant socioeconomic costs (1). Despite these facts, COPD was for many years a somewhat neglected disease; first, it was overshadowed by the social impact of other respiratory diseases, mostly asthma, and second, it was considered a self-inflicted, irreversible, and untreatable disease. The clear success achieved by the respiratory community in treating patients with asthma since the introduction of inhaled corticosteroids (ICS), in combination with scientific evidence showing that this nihilistic approach to COPD was wrong, changed the scenario dramatically and, as a result, there has been much research and interest in COPD. As a result, the current situation with respect to disease understanding and management of COPD is much different and improved, and we sincerely hope that it will become even better. Despite this much more optimistic view, as in any actively evolving field, there are many uncertainties and controversies that require further work. The goal of this article is to review and discuss such controversies and to anticipate some of the changes that may occur in the near future.

Most of our knowledge on the natural history of COPD comes from early seminal studies of population samples (2, 3). These data have resulted in the well-known Fletcher and Peto curve (4, 5), but we tend to forget that the sample size in that study was modest as it contained 792 subjects, male only, and had a selection bias toward wealthy workers. At the same time, their cohort was studied in a time where particulate air pollution was significant, reflected in the high prevalence of cough and phlegm, and the prevalence of smoking was much larger than today. The complete lack of association between lower respiratory tract infections and FEV1 decline has been questioned, both in studies using chronic bronchitis as a surrogate marker as Fletcher and coworkers did (6, 7) and in studies looking at exacerbations and FEV1 decline (810). However, the course of change in FEV1 has not been examined in detail until Kohansal and colleagues examined longitudinal change in FEV1, using data from the Framingham Offspring Cohort (11). The authors found longitudinal changes compatible with those predicted by Fletcher and colleagues but also findings underlining that excess loss of FEV1 is not the whole story behind COPD. Thus, FEV1 undoubtedly does decline over time as depicted by Fletcher and colleagues, but the variation between subjects need more detailed studying, and the issue concerning the “starting point” of the Fletcher curve seems crucial. In the Framingham Offspring Cohort, men reached their maximal lung function at age 23 years whereas women seemed to have achieved their maximal FEV1 before the age of 20 years. This supports the findings of Gold and colleagues of an early peak and decline in FEV1 in smoking adolescent girls (12). The study also questions the existence of a plateau for lung function in men whereas it seemed present—and of considerable duration—in women (11). The existence of a plateau phase has been questioned previously (13) and deserves future attention as time of first decline is obviously important for subsequent course of FEV1. At least as important is the level of maximally attained lung function (14). This is likely to be determined early in life, presumably to some extent prebirth, in line with the Barker hypothesis (15, 16), but a paper from the European Community Respiratory Health Survey strongly suggested that factors in early life have an important impact on adult lung function (17, 18). Other findings emphasizing the importance of early exposures come from the Scottish Renfrew studies, looking at intergenerational trends and the importance of early exposures. The authors found that maternal smoking of 10 cigarettes per day increased risk of COPD in offspring by 1.7 (95% confidence interval, 1.2–2.5) after adjustment for potential confounders. Within families, the effect of maternal smoking of 10 cigarettes per day had the same effect on airflow limitation in the offspring as 10 years of personal smoking by the offspring (19). This is also in line with previous epidemiological findings indicating that most of the impact of socioeconomic status takes place before the age of 20 years (20). Future analyses of other cohorts with information from early childhood are needed. It is likely that the large number of birth cohort studies initiated over the last decades can contribute valuable data on predictors and the importance of maximally attained lung function. It is, however, a major problem that the natural history is usually regarded only as the natural history of FEV1 (5). Change in FEV1 is a poor marker of development and progression of emphysema, and it is generally accepted that the early pathological changes in COPD are not captured by spirometry. We therefore need to use other markers for future studies of the early phases of the natural history of COPD. In addition, they may differ depending on the subtype of COPD at which we are really aiming our focus. Computed tomographic (CT) scanning may be appropriate for emphysema whereas other markers are needed for detection of early airway narrowing. A future challenge will be to link these early changes with what we have already learned from studying FEV1 decline.

Complex diseases such as COPD are most often the result of gene–environment interactions that, through the so-called intermediate phenotypes or endotypes (Figure 1), determine the clinical presentation of the disease (clinical phenotypes) (21, 22). Therefore, a better understanding of these three determinants (genes, environment, and endotypes) and their relationships is key for the understanding of the pathogenesis of the disease.

On the gene side, several genome-wide association studies (GWAS) have now provided results that help us understand better the genetic basis of COPD. These studies have shown, for instance, that the CHRNA3/5, HHIP, and FAM13A (23, 24) as well as the SERPINE2 and XRCC5 loci all appear to be associated with disease susceptibility (25). Yet, a disease rarely is the consequence of an abnormality in a single gene but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems (26). Hence, much more detailed information on the genetics of COPD is required to identify disease modules and pathways as well as the molecular relationships among apparently distinct phenotypes (26, 27).

On the environment side, it is now clear that although tobacco smoking is the main environmental risk factor for COPD, other risk factors must also be operative because many large, population-based, epidemiological studies have now shown that about one-quarter of patients with COPD are never-smokers (28). Indeed, in a review on novel risk factors for COPD in an American Thoracic Society official statement the population-attributable fraction for smoking was less than 80% in most studies reviewed and in some considerably lower (29). The “other” environmental factors are likely to include the inhalation of other pollutants (indoor cooking, work exposure, ambient pollutants) as well as a number of factors discussed previously and related to lung growth and development, both in utero (15, 30) and after birth (including infections, parental smoking exposure, and nutrition among others) (16, 31). In this context, epigenetic changes are likely an important link between the environmental and genetic factors (32).

Last, many different intermediate phenotypes (endotypes) have been proposed in COPD, including alterations in the innate and acquired immune response, tissue repair, accelerated aging and senescence, oxidative stress, enhanced apoptosis, and defective catabasis (Table 1). The latter is a term that describes a key function of macrophages that by engulfing apoptotic cells prevent their secondary necrosis and liberation of intracellular proinflammatory content, as well as promote the secretion by macrophages of prorepair substances such as transforming growth factor-β, hepatocyte growth factor, and vascular endothelial growth factor among others (33). Yet, the precise relationship between them and, most importantly, how to intervene therapeutically is still unclear. Again, the new approach of systems medicine is likely to provide us with this important information (26, 27).

TABLE 1. PROPOSED INTERMEDIATE PHENOTYPES (OR ENDOTYPES) IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Intermediate PhenotypeReference (s)
Elastase–antielastase imbalance7577
Oxidative stress78, 79
Innate immunity abnormalities8082
Acquired immunity abnormalities83, 84
Defective catabasis33
Enhanced apoptosis8587
Accelerated aging8890
Abnormal repair91, 92

References are provided to support each endotype but are not intended to represent a comprehensive list of studies in each category.

Another topic of great interest in the pathogenesis of COPD relates to the episodes of exacerbation (ECOPD) that these patients may present during the course of the disease. Data from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study has shown that there appear to be two groups of patients characterized by either the absence or the frequent presence of ECOPD (34). This is important because the ECOPD are known to influence the progression of the disease and they are a main cause of morbidity/mortality and the biggest source of economic cost in these patients (35). Hence, the comparison in these two well-defined clinical phenotypes of a number of potential mechanisms of ECOPD may shed light on their pathogenesis and, eventually, result in better and more specific treatment alternatives.

The diagnosis of COPD is a clinical diagnosis in that it combines symptoms and/or a relevant exposure to risk factors with the presence of persistent airflow limitation (1) (Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2010 update, available at www.goldcopd.com). Despite this apparently straightforward definition, several questions are currently being debated, often passionately.

Do these GOLD diagnostic criteria preclude the diagnosis of COPD in asymptomatic subjects without apparent exposures, especially in never-smokers? By definition yes, but future research needs to address this, not least by studying clinical features and features of inflammation in persistent airflow limitation in never-smokers without obvious asthma as well as in more detail in subjects with other exposures than cigarette smoke, most importantly exposure to biomass fuel. This is particularly important if we consider that about one-quarter of patients with airflow limitation in epidemiological studies are never-smokers (28).

Should we substitute the currently advocated fixed ratio of FEV1/FVC less than 0.7 with a ratio less than the lower limit of normal (LLN)? We would say “no.” The debate is heated (3638), but the fact is that no one knows whether a clinical diagnosis based on the fixed ratio is different from one based on LLN. We do know that airflow limitation is more frequently found in the elderly and less frequently in younger subjects if the fixed ratio rather than the LLN is applied (39). Nevertheless, COPD is not merely airflow limitation and the virtues of the fixed ratio are simplicity, being established, and being the basis for all trials underlying evidence-based treatment of COPD (1). Besides, the fact that lung function declines physiologically with age does not necessarily mean that we doctors should not care about it. For instance, arterial blood pressure or visual accuracy, to name only two of the functions that normally change with age, are treated when diagnosed and no doctor claims that, because this is a normal condition of aging, nothing need be done. Applying this analogy to the physiological decline in lung function that occurs with age in healthy individuals, it still remains to be seen whether its treatment improves lung function, the capacity of the individual to confront the activities of daily living, their well-being, and, eventually, their prognosis. If that were the case, then the debate about “overdiagnosis” of COPD if the fixed ratio is used will be over.

To what extent is clear differentiation between COPD and asthma important? At present, we split COPD and asthma but accept that within each disease there are specific subgroups that can be defined either by clinical features or specific inflammation characteristics. It is, however, likely that features of inflammatory profile and clinical presentation themselves are more predictive of both prognosis and effect of treatment than diagnostic labeling. In actuality, the current classification of diseases would be significantly changed if the intermediate phenotypes (or endotypes) discussed previously (Table 1 and Figure 1) were considered (22). In fact, patients with COPD without clinical features of asthma but with sputum eosinophilia respond better to both oral and inhaled corticosteroids than patients with no or few eosinophils in sputum (40, 41). However, it is unclear whether using an alternative diagnostic labeling would benefit only a minority segment of patients or whether it would include more diagnosis-typical phenotypes of COPD and asthma; for example, those prone to ECOPD (34). Future studies need to address diagnostic criteria and labeling in a structured, prospective manner. Undoubtedly, use of biomarkers instead of current combinations of clinical history and respiratory physiology will need to be tested prospectively as well (42).

For many years, the assessment of COPD has been based almost exclusively on the severity of airflow limitation (FEV1) (1). The realization that COPD is a complex, multicomponent disease (43, 44) is changing this perspective (45). The BODE (body mass index, FEV1, dyspnea, and exercise capacity) Index was the first attempt to provide a multidimensional index to assess patients with COPD (46). Since its original publication, other composite indices have also been proposed including the ADO (age, dyspnea, FEV1) Index (47) and the DOSE (dyspnea, FEV1, smoking status, and frequency of ECOPD) Index (48). Yet, it should be remembered that these indices have been developed and validated to establish the prognosis of any given patient and, to this end, they are clearly heading in the correct direction to capture the complexity of the disease. By contrast, because all of them lump together a number of markers that describe different domains of the disease into a single parameter, it is entirely plausible that different patients may end up having the same BODE, ADO, or DOSE Index value despite having different contributions from each of the domains that constitute each index, thus falling short to identify, and manage accordingly, the different clinical phenotypes of the disease (21).

To do so, we need to understand the complexity of the disease (42) at, at least, four different levels: genetic, biological, clinical, and environmental (Figure 2). It is envisaged that the combination of high-throughput “omic” techniques and advanced biocomputing methods will allow us to understand the network structure of each of this levels as well as the relationships between the different levels (Figure 2). If so, several different outputs from each level may be of clinical relevance. On the one hand, the genetic level will eventually allow the identification of markers for risk assessment. The biological level may, it is hoped, provide biomarkers for diagnosis, characterization, and also risk assessment of individual patients, as well as potential therapeutic targets for the development of novel therapies. The clinical level is envisaged to provide useful information for more efficient and personalized integrated care strategies. Likewise, it may facilitate the development of a network of guidelines of chronic diseases, nowadays published in almost complete isolation from each other, despite evidence that the strict combination of published guidelines may cause harm (49). Last, a better understanding of the social and environmental level will allow better control of a number of modifiable risk factors.

Another concept that needs to be taken into account for the proper assessment of patients with COPD is that of disease activity (50). Whereas disease activity and disease severity are well-established concepts in other chronic diseases (such as rheumatoid arthritis), in patients with COPD we have traditionally taken measures of disease severity (FEV1) as surrogate markers of disease activity. If we accept that the concept of biological activity of any disease somehow reflects the level of activation of the endotypes discussed previously (Table 1 and Figure 1), then it is entirely conceivable that the activity of a chronic, progressive disease such as COPD may be high during the early stages of its natural history, when by definition airflow limitation will be mild or absent. This clearly dissociates the concepts of activity and severity in COPD. Now the question concerns how to measure disease activity (50). This is a relevant question because the therapeutic goals for an active disease (to reduce biological activity to prevent disease progression) may be radically different from those for a disease that is not active (palliation of symptoms if present).

When considering the burden of COPD and the annual sales of medications to patients with COPD, it is surprising how weak our evidence base was until 10 years ago and how we still lag behind other significant diseases such as hypertension, heart failure, ischemic heart disease, and diabetes when it comes to large randomized controlled trials. It is tempting to think that the respiratory community has been too slow to require strong evidence from the pharmaceutical industry.

However, the situation has changed and, as an example, we now know from meta-analyses of well-conducted trials, mostly from within the last decade, that compared with placebo combination therapy with ICS and long-acting β-agonists reduces overall mortality and the frequency of ECOPD and improves lung function, symptoms, and quality of life (51). Likewise, tiotropium reduces ECOPD frequency and hospital admissions and improves lung function (52). However, we know surprisingly little about combining these treatments, that is, “triple therapy.” After some disappointing findings from an ECOPD study with less than optimal power (53), more recent studies indicate that triple therapy may have clinical benefits (54, 55); nevertheless, larger long-term studies are clearly needed. Also, significant controversy regarding ICS still exists (56, 57). The concept of COPD being a steroid-resistant disease (58) conflicts with the clinical evidence showing an effect of ICS on rate of ECOPD and quality of life (59) as well as FEV1 and symptoms (60, 61). On the other hand, however, it does seem certain that ICS have another adverse effect profile than previously anticipated, with an increased risk of incident pneumonia but no increased risk of mortality from pneumonia (51, 59, 61). The true impact of and mechanism behind the ICS-associated pneumonias deserve further attention.

In the meantime, should dual bronchodilator therapy rather be combined with another antiinflammatory agent such as roflumilast, a novel phosphodiesterase-4 inhibitor? We currently have no clue, but our evidence base for roflumilast is certainly less than that for ICS.

Roflumilast reduces ECOPD in patients with severe and very severe COPD, recurrent exacerbations, and, chronic bronchitis (62, 63). Roflumilast has been found to be efficacious when added to a single long-acting bronchodilator (62), but only with FEV1 as outcome, and no comparisons with ICS exist.

Our greatest current dilemma probably concerns when and how to start medical treatment. In current guidelines (1) emphasis is on delivering maximal treatment to patients with very severe disease as assessed by FEV1. However, we know from large trials that many of the patients with the most severe disease seem to have stable disease with no further progression whereas patients with moderate disease—and potentially even mild disease—have more rapid decline in lung function (64, 65). Although some of this may be due to study inclusion selection bias it underlines the need for a biomarker reflecting ongoing disease progression or disease activity, as mentioned earlier (50). Most likely, a shift in treatment paradigm is needed but lack of studies in patients with mild disease is holding us back. Importantly, the terms “mild” and “early” disease are not necessarily synonymous. Precisely because lung function appears to decline at different speeds in different patients with COPD, it is entirely possible that an older patient has mild airflow limitation (but probably not “early” disease) whereas a middle-aged patient can present with severe airflow, indicating either “early” disease or a different baseline lung function due to suboptimal lung development. These considerations are important if, eventually, randomized clinical trials are to be conducted in “early” versus “mild” disease.

On the other hand, there appears to be a unwritten “dogma” that states that once-daily medication is the best alternative for all patients with COPD. The main argument to support this dogma is that once-daily medication is easier to use and that this improves compliance with treatment, a key aspect in the management of any chronic disease. However, this argument originates from the treatment of chronic asymptomatic diseases, such as arterial hypertension or hypercholesterolemia. Because COPD most often is a symptomatic disease, this concept may not apply automatically to many of those who may actually prefer more frequent relief of their symptoms. In this context, it is worth remembering that the pharmacokinetic profile of available once-daily bronchodilators is characterized by an early peak followed by a progressive decline over the next hour or so, before the next inhalation is taken 24 hours later; their functional effect is still better than before treatment but clearly worse that than achieved at peak. So, if we accept that pharmacological lung deflation is a relevant therapeutic goal, not only because it is at the root of the symptomatic improvement experienced by the patient but, also, because it can contribute to reduce inflammation and, perhaps, enhance repair (66, 67), then we must concede that twice-daily bronchodilator treatment may be a better alternative, at least for some patients (68, 69).

The realization that patients with COPD often suffer from a number of concomitant disorders (44) that increase their demand for health care support, as well as their frailty, has boosted a great deal of interest in integrated care strategies that, using telemedicine tools, allow more efficient management of these patients (7073). Deployment of these (thus far research-based) strategies into real-life settings is not free of difficulties and is a clear challenge for current health care systems, but their potential for transforming these systems and, more importantly, resulting in better and more personalized care of patients with COPD is enormous (74).

In this review article we have tried to summarize some of the many controversies and future perspectives that exist today in the field of COPD. It does not pretend to incorporate all of them in a comprehensively manner, or to be (always) right. Yet, we hope that it may update some readers on the debates, novelties, and prospects that are now occurring in the field of COPD and, beyond this, that it stimulates critical thinking on the issues discussed here.

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Correspondence and requests for reprints should be addressed to Alvar Agustí, M.D., Institut del Tòrax, Hospital Clínic. Villarroel 170, Escala 3, Planta 5, 08036 Barcelona, Spain. E-mail:

Originally Published in Press as DOI: 10.1164/rccm.201103-0405PP on June 16, 2011

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