Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Thoracic Society International Conference

San Diego, California / May 15-20, 2009

Chronic obstructive lung disease (COPD) is frequently accompanied by other comorbidities, cardiovascular disease (CVD) in particular. In rethinking the pathogenic process that gives rise to COPD, Dr. Leonardo Fabbri, Department of Respiratory Disease, University of Modena and Reggio Emilia, Italy, noted that smoking, while clearly involved in the initiation of the process that damages the lungs in COPD, likely has a more generalized inflammatory effect, as particles from smoke are found throughout the circulation and in many tissues other than the lungs. Among the various disease states characterized by generalized systemic inflammation is CVD, with almost all COPD patients having at least one comorbidity, “I think it is very important that we recognize COPD as a systemic disease,” Dr. Fabbri remarked. Indeed, when he and colleagues evaluated a group of patients attending a CV clinic for the presence of COPD, they found it in 29% of patients with congestive heart failure, only two of whom were aware of it.

Reframing COPD as a systemic inflammatory process and not simply as a disease of the lungs has several important therapeutic implications. Firstly, as noted by Dr. Bartolome Celli, Tufts University, Boston, Massachusetts, it may help reduce the largely unassailable adverse outcomes that currently afflict COPD patients.

Citing results for the three-year TORCH study (Towards a Revolution in COPD), Dr. Celli noted that the cause of death among COPD participants was respiratory-related in 35% of the cohort overall—28% of them due to COPD directly—but 27% of the deaths were due to CV causes and 21% were due to cancer.

Thus, “extra-pulmonary manifestations” of COPD may well include both CVD and cancer, both of which may share common pathogenic elements with COPD, as Dr. Celli suggested.

Systemic Inflammatory Disease

Rethinking COPD as a systemic inflammatory disease might gain more widespread credibility if there were a marker that was both specific to COPD and which was predictive of outcome. Unfortunately, no such marker has yet been identified. In the lung, inflammation is largely driven by neutrophils, eosinophils, macrophages and monocytes, while activation of lymphocytes is common in both lung and systemic inflammation. C-reactive protein, fibrinogen, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 are more characteristic of a systemic inflammatory state.

An inflammatory marker predictive of COPD would also be most useful if it identified COPD at an early stage of the disease. As noted by Dr. Ravi Kalhan, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, almost all COPD is detected at a relatively advanced stage, when chances of reversing tissue damage are slim. “Right now, we not only have no marker of early disease, we have no definition of early disease,” he told delegates, “and upregulation of systemic inflammation may [give us] a tool to find patients before there is significant lung damage.”

So far, the ongoing prospective CARDIA (Coronary Artery Risk Development in Young Adults) study has demonstrated that the predictable age-related decline in lung function correlates strongly with measurements of both CRP and fibrinogen but only when measured with forced vital capacity (FVC). In contrast, FEV₁ was not related to either CRP or fibrinogen levels based on data from the same prospective cohort study. “We are at a very early stage of measuring systemic inflammation in relation to COPD, but I think we are going to identify a phenotype for inflammation in which susceptible COPD patients are at risk for a broad range of inflammatory-related diseases,” Dr. Kalhan suggested.

Novel Therapies

The identification of inflammatory markers that characterize COPD may also be the first step towards the development of new therapies for its treatment. Currently, most treatments for COPD do not affect systemic inflammatory markers. The long-acting bronchodilator tiotropium improves lung function and quality of life in COPD patients but it does not significantly reduce systemic inflammatory markers such as CRP or TNF-alpha, according to Dr. Klaus Rabe, Department of Respiratory Medicine, Leiden University Medical Centre, The Netherlands. The same is also true of inhaled corticosteroids such as fluticasone, even though the inhaled steroids do dowregulate lung-specific inflammatory cytokines.

The statins, on the other hand, do appear to improve outcome in COPD patients, presumably through their anti-inflammatory systemic effects. In a study by van Gestel et al. (Am J Cardiol 2008;102:192-6), investigators found that statin therapy was associated with a significant 33% improvement in long-term survival in COPD patients. The authors undertook this study on the premise that COPD is an inflammatory disease and the systemic anti-inflammatory effects provided by the statins should improve outcome.

“Classic drugs do not affect systemic inflammation, so if this is important, we need to develop new treatment strategies,” Dr. Rabe reaffirmed. In fact, a number of new therapies are being developed that target inflammatory cell regulation more globally, among them phosphodiesterase-4 (PDE-4) inhibitors.

Of the possible candidates that are being tested as novel therapies for COPD, “the ones that are closest to actually moving from a future therapy to an actual therapy are the PDE-4 inhibitors,” noted Dr. Peter Calverley, School of Clinical Sciences, University Hospital Aintree, Liverpool, UK. Because PDE-4 mediates inflammatory effects not just in the respiratory tract but throughout the body, “a systemically administered drug with systemic effects for a systemic disease makes sense on logic alone,” Dr. Calverley noted.

This logic was supported in a large clinical trial evaluating roflumilast, a once-daily PDE-4 inhibitor and the most potent of the PDE-4 inhibitors tested clinically to date. As reported by Calverley et al. (Am J Respir Crit Care Med 2002;76:154-61), 1513 patients with severe COPD (median FEV₁ 41% predicted) were randomized to roflumilast 500 µg or placebo for 52 weeks. At the end of the 52-week study, the post-bronchodilator FEV₁ had increased by 39 mL in patients treated with roflumilast compared with placebo and patients with very severe COPD experienced fewer exacerbations with roflumilast.

Findings from this study are proof in concept that systemic therapies can improve classical measures of COPD control such as lung function, Dr. Calverley noted, and more data on this agent are expected.

“I believe that systemic inflammation is key to understanding COPD and that measuring inflammation will be absolutely essential to both developing and implementing novel therapies that we need to control the disease process,” confirmed Dr. Steven Rennard, University of Nebraska School of Medicine, Omaha.

Summary

There is expanding evidence that COPD is not just a disease of the lungs but that it is a systemic inflammatory condition that shares pathogenic features with other comorbidities frequently seen with COPD, including CVD. Novel therapies that dampen down systemic inflammation more effectively than inhaled anti-inflammatories are currently being explored in an effort to improve disease control. The hope is that with better control of systemic inflammation, treatment may improve not just lung function but overall prognosis for patients with COPD who remain at high risk for adverse outcomes from respiratory causes and other comorbidities.