DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.
These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.
Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."
COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.
A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.
Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.
"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.
For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).
When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).
And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV1) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).
"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.
Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).
"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."
Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV1 and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."
Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.