Person:

Celli, Bartolome

Background: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552). Methods and Findings: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-(\alpha) levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice. Conclusions: Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

The natural history of chronic obstructive pulmonary disease (COPD) is still not well understood. Traditionally believed to be a self-inflicted disease by smoking, now we know that not all smokers develop COPD, that other inhaled pollutants different from cigarette smoke can also cause it, and that abnormal lung development can also lead to COPD in adulthood. Likewise, the inflammatory response that characterizes COPD varies significantly between patients, and not all of them perceive symptoms (mostly breathlessness) similarly. To investigate the variability and determinants of different “individual natural histories” of COPD, we developed a theoretical, multi-stage, computational model of COPD (EASI) that integrates dynamically and represents graphically the relationships between exposure (E) to inhaled particles and gases (smoking), the biological activity (inflammatory response) of the disease (A), the severity (S) of airflow limitation (FEV1) and the impact (I) of the disease (breathlessness) in different clinical scenarios. EASI shows that the relationships between E, A, S and I vary markedly within individuals (through life) and between individuals (at the same age). It also helps to delineate some potentially relevant, but often overlooked concepts, such as disease progression, susceptibility to COPD and issues related to symptom perception. In conclusion, EASI is an initial conceptual model to interpret the longitudinal and cross-sectional relationships between E, A, S and I in different clinical scenarios. Currently, it does not have any direct clinical application, thus it requires experimental validation and further mathematical development. However, it has the potential to open novel research and teaching alternatives.

Understanding the natural history of a disease is as important as knowing its cause(s) for effective disease prevention and treatment. Yet, our current understanding of the natural history of chronic obstructive pulmonary disease (COPD) is incomplete and often controversial. This article discusses the current gaps, and hence opportunities for research, in this field. In particular, it discusses the following six specific questions. 1) Is COPD a “single” disease? 2) Is COPD “only” a lung disease? 3) When does COPD begin or what is “early” COPD? 4) How does COPD “progress”? 5) How do we assess disease “severity”? 6) Can COPD be prevented (beyond smoking cessation) or its course be modified once detected?

Due to well-conducted epidemiological studies and advances in genetics, molecular biology, translational research, the advent of computed tomography of the lungs and bioinformatics, the diagnosis of chronic obstructive pulmonary disease (COPD) as a single entity caused by susceptibility to cigarette smoke is no longer tenable. Furthermore, the once-accepted concept that COPD results from a rapid and progressive loss of lung function over time is not true for a sizeable proportion of adults with the disease. Now we know that some genetic predisposition and/or different environmental interactions (nutritional, infectious, pollution and immunological) may negatively modulate post-natal lung development and lead to poorly reversible airflow limitation later in life, consistent with COPD. We believe it is time to rethink the taxonomy of this disease based on the evidence at hand. To do so, we have followed the principles outlined in the 1980s by J.D. Scadding who proposed that diseases can be defined by four key characteristics: 1) clinical description (syndrome), 2) disorder of structure (morbid anatomy), 3) disorder of function (pathophysiology) and 4) causation (aetiology). Here, we propose a pragmatic approach to the taxonomy of COPD based on different processes that result in a similar syndromic presentation. It can accommodate changes over time, as the pathobiology that may lead to COPD expands. We hope that stakeholders in the field may find it useful to better define the patients now boxed into one single entity, so that specific studies can be designed and conducted for each type of COPDs.