Key Point:

Some COPD patients appear to have persistent colonization with H influenzae, which could affect the frequency and severity of exacerbations.

BUFFALO—Patients with COPD are often colonized with Haemophilus influenzae, even when their disease is stable. Respiratory infections, often caused by H influenzae, are a common cause of COPD exacerbations. As part of an ongoing prospective study, researchers from the University at Buffalo collected monthly sputum samples from COPD patients over a seven-year period. They have identified a pattern in which H influenzae is isolated from a patient’s sputum at one visit, is absent for two or more months, and then reappears in the patient’s sputum. This led them to conclude that some COPD patients are persistently colonized with H influenzae, and when used alone, sputum cultures underestimate the prevalence of this colonization.¹

Between March 1994 and December 2000, 104 COPD patients visited the study clinic monthly—or more frequently if they had symptoms of an exacerbation. At each visit, sputum and serum samples were obtained, and disease status was evaluated. Quantitative cultures were performed on all sputum samples, H influenzae isolates were typed, and DNA was isolated using polymerase chain reaction. Periods between positive sputum cultures were designated “gaps.”

Of the 104 enrolled patients, 10 had 17 gaps in colonization that lasted six months or longer, in which sputum cultures were negative, only to have the original strain reappear. These 17 gaps were studied extensively to determine whether the patients were continuously colonized despite periods of negative cultures.

None of the cultures that tested negative during the 17 gaps was taken while the patients were receiving antibiotics. H influenzae isolates were subjected to rigorous identification tests. Of the 17 episodes of colonization with intervening gaps, 14 pairs of isolates were identical, and three were closely related.

H influenzae NEVER CLEARED?

One explanation for the gaps in colonization was that they might represent the clearing and reacquisition of the same H influenzae strain. However, the extreme heterogeneity of nontypeable H influenzae made it highly unlikely that patients had reacquired the same strain.¹

Timothy F. Murphy, MD, the study’s lead author, explained that he and his colleagues “found the same strain coming back—except it never really went away.” When patients are treated with antibiotics, it renders the culture negative while the patient is taking the antibiotic. “In many cases,” he said, “the antibiotic does not eradicate the organism from the respiratory tract.” The mechanism of how often antibiotics clear—or fail to clear—different strains is currently being investigated.

“All strains of H influenzae are not the same,” pointed out Dr. Murphy, a Distinguished Professor of Medicine and Microbiology at the University at Buffalo, State University of New York. “Some strains are likely better at persisting than others. In addition, the particular antibiotic used is probably also an important determining factor.”

The fact that the gaps in colonization were preceded and followed by the same strain of H influenzae supports a state of persistent colonization in some COPD patients. The authors noted that when a patient is having COPD symptoms in the absence of a positive sputum culture, the physician probably assumes that the exacerbation has a nonbacterial cause. However, if the patient is colonized with a pathogen at levels undetectable to a sputum culture, a greater proportion of COPD exacerbations may have an underlying bacterial cause.

If this is true, said Dr. Murphy, who is also Chief of the Infectious Diseases Division at Buffalo Veterans Affairs Medical Center, “it would represent a strong rationale to attempt to eradicate colonization, for example, with vaccines, antiadhesive agents, cycling of antibiotics, or other novel approaches.”

EXPLAINING PERSISTENCE

“The mechanism of persistence is of great interest,” observed Dr. Murphy, and has opened the way for two lines of investigation. “One is that H influenzae forms biofilms in the respiratory tract. Biofilms are an altered form of bacterial growth in which bacteria adhere to a surface and are encased within a matrix. Bacteria in biofilms are more difficult for the immune system to eradicate and more resistant to antibiotics,” he said.

A second potential mechanism, according to Dr. Murphy, is that H influenzae enters cells. “The organism is known to be able to survive intracellularly,” he pointed out. “In this way it may ‘hide’ from antibodies and antibiotics, allowing it to persist in the respiratory tract.”

This study points out the importance of assessing the role played by persistent colonization with H influenzae on respiratory tract infections in COPD patients and raises some interesting questions. For example, the authors asked, does colonization with H influenzae influence the likelihood of colonization by another species or strain? In what ways could colonization affect the incidence of viral infections in these patients?

Dr. Murphy added that although the study team also isolated Moraxella catarrhalis and Streptococcus pneumoniae from sputum cultures, persistent colonization seemed to be characteristic only of H influenzae.

—Gale Jurasek

Reference
1. Murphy TF, Brauer AL, Schiffmacher AT, Sethi S. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:266-272.

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