Mar. 2, 2009 New research shows that individual exacerbations in chronic obstructive lung disease (COPD) themselves increase the likelihood of repeat exacerbations, even after five days of full, asymptomatic recovery—bad news for patients with COPD, where each exacerbation can drive the progression of the disease.
"This concept that exacerbations are not random has important implication for the analysis of clinical trial data and identifies a specific high-risk period for recurrent exacerbation during which preventative interventions might be targeted," wrote lead author, John Hurst, M.D., of the Royal Free and University College Medical School, in London.
The results appeared in the first issue for March of the American Journal of Respiratory and Critical Care Medicine, a publication of the American Thoracic Society.
In patients with COPD, exacerbations are generally defined as an acute worsening of symptoms. Exacerbations in and of themselves are inherently dangerous and can lead to hospitalization and serious complications. But beyond their acute dangers, exacerbations drive lung function decline, and many patients never recover their baseline level of lung function after exacerbations. Prior to this research, however, exacerbations were assumed to be isolated events unrelated to one another despite observational data that suggested a dependency.
To test the validity of this assumption, which not only informs treatment plans for patients with COPD, but also forms the basis of research design and analysis, Dr. Hurst and colleagues analyzed daily symptom diaries that were kept for at least one year by 297 COPD patients, describing nearly 2,000 distinct exacerbation events. Two or more new or worsening symptoms, one of which must be "major" (e.g., dyspnea, more sputum, or a change in color of sputum) constituted an exacerbation, and after five days of symptoms reverting to baseline severity, the exacerbation was considered to be over. A second exacerbation occurring within an eight-week period was considered to be a recurrent exacerbation. The researchers further analyzed seasonality of exacerbations, comparing their winter (November to January) frequency with their summer (June-August) frequency.
In addition to the finding that exacerbations were clustered in time within individuals, the researchers found that they were significantly more common in the winter than the summer. They also noted that "isolated" exacerbations tended on average to be about 25 percent more severe than the first of serial exacerbations.
But most importantly, the researchers identified an eight-week period of time during which monitoring and follow-up is crucial to prevent or minimize further exacerbations in the COPD patient. "Our finding of a high-risk period for recurrent exacerbation may be important in guiding patient follow-up," wrote Dr. Hurst.
"The mechanisms of exacerbation recurrence remain unexplored, and it is unknown whether recurrence is due to persistence of an existing organism or to acquisition of a new one," noted Dr. Hurst. However, there are some clues that may guide future research. "The failure to eradicate bacteria with exacerbation therapy has been associated with an incomplete recovery in inflammatory markers and we have recently reported a relationship between elevated C-reactive protein during the recovery period of an initial exacerbation and shorter time to the next." Furthermore, the paper noted that "symptoms more typical of viral infection are significantly more common during isolated events."
"This knowledge is very important for physicians," wrote Shawn D. Aaron, M.D., of the Ottawa Health Research Institute, in Canada, in an editorial in the same issue of the journal. "Clinicians should now be aware that their patients with COPD who experience an exacerbation may be particularly 'brittle' during a subsequent eight-week period. Close monitoring and follow-up during this time would hopefully lead to earlier therapy for recurrent exacerbations that may improve clinical outcomes."
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