Wednesday, January 07, 2009

COPD-Should we consider it one disease ?

Dr. J.J. Reilly authored a thought provoking editorial in the October 9,2008 issue of the NEJM,entitled " COPD and Declining FEV1-Time to Divide and Conquer?"

The editorial was a commentary in part on the publication of the results of the large,multi- center, UPLIFT trial which examined the effects of tiotropium on several outcomes in patients with COPD whose FEV1 values were 70% or less of predicted. Involving some 5993 subjects, the trial authors concluded that there were tiotropium related improvements in lung function and quality of life and fewer exacerbations. However, as has been the case with other trials investigating the effect of pharmacological interventions, there was no reduction in the rate of decline of FEV1., which seems to have become the golden grail of COPD clinical trials.Only smoking cessation and oxygen therapy and -in highly selected patients- lung volume reduction surgery have been shown to conclusively reduce mortality.

Dr. Reilly wonders in we have perhaps over simplified and COPD with a inclusive definition that recognizes only the FEV1. Are there important subtypes and clinical phenotypes lost in the movement to lump all patients with reduction in FEV1 into one category?

Whatever happened to the pink puffers and blue bloaters as described by Fletcher and Peto in the 1970s and taught to students and pulmonary fellows in that era? We thought of non-asthmatic, obstructive chronic lung disease as a spectrum with the prototypical blue bloater at one extreme and the pink puffer at the other with the plurality of patients falling in between having some feature of both.

The PP was thought of as having mainly pan-acinar emphysema with loss of the alveolar-capillary surface area as reflected by a decreased diffusing capacity test and overinflated lungs on x-ray with lung fields bereft of normal arterial lung markings while maintaining nearly normal arterial oxygen levels allegedly at the price of dyspnea.The BB patient typically had a radiograph with "dirty lungs", more sputum production and centrilobular emphysema and was more likely to be hypercapneic and develop right sided heart failure.

Reading the recent large clinical trials you cannot determine if there were subgroups, i.e. maybe those more like the BB patients, who did better.It was always difficult to conceive that any inhaled therapy would improve the PP patients since they had less airway disease and more air space destruction.

The editorial's main point is that thinking about COPD as a singular entity is misleading. There are likely a number of subgroups whose response to therapy may well vary as may their natural history. Perhaps, such groups can be defined on the basis of combinations of clinical,x-ray, physiological and even genetic factors. Post hoc subgroups analysis may be helpful to hypothesis generate. We may be under estimating the value of certain therapies by too much lumping.

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