DENVER—Increasingly, microbes appear to be involved in the etiology of some cases of asthma. In addition to previous findings indicating that viral infection may exacerbate acute asthma, emerging evidence now implicates bacterial infection as a cause of chronic asthma. Richard Martin, MD, and colleagues report detecting infection with Mycoplasma pneumoniae or Chlamydia pneumoniae in 31 of 55 asthma patients using a combination of polymerase chain reaction (PCR), serology, and culture.[1] By contrast, PCR revealed mycoplasma infection in only one of 11 normal controls.

“Given that we detected infection in 56% of asthma patients [vs one in 11 control subjects], there may indeed be a link between bacteria in the airways and asthma in some patients,” said Dr. Martin, head of the Pulmonary Division and Vice Chair of the Department of Medicine at National Jewish Medical and Research Center (NJMRC) in Denver. The researchers did not, however, find an association between chronic stable asthma and viral infection.

“We were surprised to find these bacteria in the lower airways of a subset of stable asthmatics,” said coauthor Monica Kraft, MD, Associate Professor in the Department of Medicine and Division of Pulmonary Medicine at NJMRC. “The association raises an interesting ‘chicken versus egg’ issue—did the asthma allow microorganisms to ‘set up shop,’ or do the microorganisms actually cause chronic asthma?” Dr. Kraft told RESPIRATORY REVIEWS. If the latter is true, then antibiotics would be expected to help some patients with asthma.

LONG-TERM ANTIBIOTIC THERAPY?

The authors have garnered support for this idea from both clinical experience and research. “Using an empirical approach, we’ve tried clarithromycin with some of our clinical patients. Anecdotally speaking, we have steroid-dependent asthmatics who improved with clarithromycin,” said Dr. Kraft. “Initially, we tried a six-week course, but we found that respiratory function continued to improve in many patients [if the antibiotic was administered] over three to six months.”

Dr. Martin explained the reason for the lengthy course: “Unfortunately, mycoplasma is difficult to eradicate from the airways. In true pneumonias, even after chest X-rays show that mycoplasma infection is largely cleared from the lungs, some residual infection lingers.”

Dr. Martin and colleagues also back up their clinical experience with experimental evidence. “We’re submitting a manuscript shortly, describing a study demonstrating that asthmatics who are PCR-positive for chlamydia or mycoplasma infection show a 12% to 13% improvement in airway function following clarithromycin treatment,” he reported. Said Dr. Kraft, “Most antibiotics do have some anti-inflammatory quality, so it’s not clear how this works. Hopefully, animal studies will answer this question.”

While the researchers are encouraged by clinical and experimental success with antibiotic therapy in a subset of asthma patients, Dr. Kraft recognizes that long-term antibiotic treatment for asthma may be controversial. In light of concerns regarding general overuse of antibiotics and need to justify long-term administration under managed health care, this approach might be questioned. However, in the absence of a practical means of establishing the diagnosis, she said, “We haven’t found any other way.”

SEROLOGY UNRELIABLE

Despite the experimental evidence for an association between lower airway infection and chronic asthma, testing patients for such infections in the clinical setting is problematic. In the present study, all subjects were seronegative for Mycoplasma pneumoniae, and only three of seven subjects PCR-positive for chlamydia were seropositive. “Seropositivity is not a great marker for mycoplasmalpha- or chlamydialpha-induced asthma. Mycoplasma infection frequently can be shown by PCR to be very active in the airways of seronegative individuals,” explained Dr. Martin. “It seems to be triggering inflammation but may not be potent enough to trigger an immune response,” said Dr. Kraft. On the other hand, she pointed out, “Chlamydia serology tends to give false positives.”

PCR: FUTURE DIAGNOSTIC?

As demonstrated by the present study, PCR remains the only reliable way of demonstrating chronic infection. But PCR requires collecting relevant samples. “The lower airway samples we need for diagnosis require invasive bronchoscopy,” said Dr. Kraft.

Dr. Martin told RESPIRATORY REVIEWS, “We’re trying to work out procedures on cells from induced sputum, which right now is not as sensitive as PCR from samples obtained by bronchoscopy.” For now, PCR testing for lower airway chronic infections may be impractical in the clinical setting.

An interesting finding was that, among the asthma patients tested, users of inhaled corticosteroids were less likely to test positive for the microbes by PCR. Dr. Martin cited evidence for one explanation: “In animal airway studies with another species of Mycoplasma, steroids were equally efficacious with antibiotics in reducing bacterial load and reducing inflammatory processes. We’re developing a mouse model to look at how steroids might work to reduce infection with Mycoplasma pneumoniae.” Dr. Martin is hopeful that animal work will reveal whether corticosteroids have a direct action on the microbes or simply impede infection by blocking inflammation.

Dr. Martin noted another interesting finding: “In patients positive for mycoplasma, especially among those with allergic asthma, there were increased numbers of mast cells in the lungs. It looks like there could be a connection between infection and allergic sensitization.” Yet immunoglobulin E elevation in these individuals was not significant. While this finding is intriguing, the study was not designed to reveal whether infection precedes sensitization or vice versa.

ONE OF MANY TYPES

“In the past few decades, a lot of chronic inflammatory diseases have been shown to have infectious causes—stable asthma may be another,” said Dr. Kraft. “Our work connecting chronic infection with asthma may change how we look at asthma in general. What we’re finding is that asthma is probably not one disease—historically, a lot of phenotypes have been lumped together, but there’s a lot of heterogeneity in phenotype as well as etiology. Separating out the various types of asthma and their causes may be the first step toward finding more effective treatments and preventative strategies.”

—Mimi Zucker, PhD