Study looks at 'vicious circle' theory infections in COPD patients

Dec 2 2008

In treating flare-ups in chronic obstructive pulmonary disease (COPD), a major cause of disability and the fourth leading cause of death in the U.S, what was old is important again.

University at Buffalo researchers Sanjay Sethi, M.D., and Timothy F. Murphy, M.D., principal investigators on the longest-running study of infection in COPD patients in the U.S., describe the still somewhat controversial 'vicious circle' theory of chronic infection and inflammation in COPD in the Nov. 27 issue of The New England Journal of Medicine (NEJM). "The infection theory of pathogenesis of COPD, the so-called 'British hypothesis,' was proposed first in the 1950s, but later was discounted completely," said Sethi, lead author and professor in the Division of Pulmonary and Critical Medicine in UB's Department of Medicine, School of Medicine and Biomedical Sciences.

"Now we are setting the record straight, showing that infection indeed is important in the course of COPD.

"The article updates people on this substantial change in the way we think of infection and COPD," said Sethi, "and focuses attention on the problem and encourages more research."

More than 12 million people currently are diagnosed with COPD, according to the National Institutes of Health, and an additional 12 million are thought to be undiagnosed. The economic burden of COPD in the U.S. in 2007 was $42.6 billion in health-care costs and lost productivity.

The discoveries on infection and exacerbation the authors present are based on a Veterans Affairs-funded longitudinal study that has been on-going since 1994 at the Buffalo VA Medical Center, and the work of other researchers. The UB/VA research has yielded several papers and patents to Sethi and Murphy for promising vaccine candidates to prevent bacterial infections in COPD patients.

Sethi and Murphy present the implications of the findings for the practicing physician and advocate the use of a "stratified" approach to antibiotic treatment. The stratified approach distinguishes "uncomplicated COPD," which has a specific set of criteria, from "complicated COPD," which presents a different group of characteristics. Each diagnosis has its recommended choice of antibiotics.

Describing the underlying mechanisms that cause the lung to become more prone to infections in COPD, Sethi noted that current thinking is that smoking or childhood respiratory disease can damage innate lung defense mechanisms.

"Impaired defenses allow bacteria and other microbes to find a niche the lungs," said Sethi. "The body responds to their presence with inflammation, the inflammation damages the airways, which in turn further impairs the lungs' defense mechanisms, setting up the 'vicious circle.'

"Superimposed on this chronic low-grade infection," he continued, "a change in the predominant strain colonizing the airway occurs, which creates COPD flare-ups and initiates an enhanced inflammatory response, which can result in more airway injury and worsened COPD -- creating the 'vicious circle.'

"Fortunately, exciting new therapies for COPD exacerbations, including agents that improve immune responses and specific antimicrobial treatments, are on the horizon," Sethi said.

Co-author Murphy is professor in the Division of Infectious Diseases, UB Department of Medicine.