Tuesday, June 10, 2003

By Anita Srikameswaran, Post-Gazette Staff Writer

About a decade ago, a young woman with severe asthma was referred to a Denver doctor.

She already had undergone myriad tests and was taking several medications, including powerful oral steroids, with little success. The doctor, Richard Martin, of the National Jewish Medical and Research Center, inspected the lung tissue with a special scope and took a biopsy.

When looking at a specimen under powerful magnification, Martin noticed what appeared to be the squiggles of a bacteria called Mycoplasma pneumoniae. Genetic testing of other samples confirmed the presence of the bacteria, which is a common cause of pneumonia in people younger than 40.

The patient did not have pneumonia, but Martin decided to see what would happen if the low-grade infection was treated.

Slowly but surely, her once-disabling asthma symptoms got better. Now working, she no longer requires oral steroids, hospitalizations or even visits the emergency room.

Controlling symptoms   Twenty million Americans had asthma in 2001, according to the National Center for Health Statistics. There were 465,000 hospitalizations and almost 4,500 deaths due to the disease in 2000. More than two-thirds of asthma patients are older than 18, said Dr. Bill Calhoun, director of the Asthma, Allergy and Airway Research Center at the University of Pittsburgh School of Medicine. Many of them developed symptoms as adults. Calhoun is leading the local arm of a multicenter study of people who have severe asthma that cannot be sufficiently controlled with standard therapies. A recent national survey found that two-thirds of patients who had daily symptoms considered their asthma to be well or completely controlled. "I find that really troubling," Calhoun said. "If I had something that bothered me every day, I wouldn't consider that at all well controlled." Guidelines from the National Institutes of Health indicate that appropriately treated patients shouldn't have asthma episodes that require using rescue medications more than twice a week. Getting that symptom-free often requires inhaled steroids, which reduce airway inflammation. Ninety percent of asthma sufferers should be using steroid inhalers, but only a third to a half actually do, Calhoun said. That's partly because the severity of the symptoms can change from week to week and neither patients nor their doctors may recognize when it's getting worse. Dr. David Nash of Children's Hospital prescribes inhaled steroids as a first-line therapy. A nighttime cough, classically between midnight and 4 a.m., is a very specific sign of asthma, he noted. For more information about the Severe Asthma Research Program, call 412-647-0778.   -- Anita Srikameswaran

"She went from being essentially housebound to working, married with kids," Martin said. "Her quality of life tremendously improved."

The doctor began exploring the links between Mycoplasma and asthma. Last year, in a study in the medical journal Chest, Martin and his colleagues found evidence of low-grade airway infection with Mycoplasma or another bacteria called Chlamydia (not the sexually transmitted kind) in 31 out of 55 patients with chronic, stable asthma. Six weeks of antibiotic treatment led to significant lung function improvements for infected patients.

"Unfortunately, we don't have an antibiotic that really kills these organisms," Martin said. "We just have antibiotics that suppress them. So it's really a long-term treatment."

Martin's work "remains controversial," said Dr. Bill Calhoun, director of the Asthma Allergy and Airway Research Center at the University of Pittsburgh Medical Center. "[But] more and more of us now believe he's on to something pretty important."

He noted that scientists at the University of Wisconsin have launched a large study to look more closely at how viruses and bacteria contribute to asthma.

Asthma's toll

According to the U.S. Centers for Disease Control and Prevention, the number of asthma patients doubled between 1982 and 1998. The condition accounts for 14.5 million lost workdays among adults and 14 million lost school days among children, and costs $14 billion annually.

Those figures have inspired researchers to work harder to uncover the causes and workings of asthma, which could be many diseases that produce the same symptoms.

To unravel the complicated interactions between the bacteria, allergy and asthma, Martin turned to mouse experiments.

In asthma, the airways get inflamed, meaning red, warm and swollen. They are also hyperreactive, or "twitchy" as some doctors put it, so irritants such as cold air or perfume can make them narrow, obstructing airflow.

Martin's team noted that asthma patients with Mycoplasma infection had a six-fold higher number of mast cells, which are associated with allergies, in their lung tissue compared with uninfected asthma patients. In some situations, Mycoplasma infection seems to encourage airway inflammation, Martin said.

If a mouse is infected with Mycoplasma bacteria, its airways become hyperreactive and inflamed for about two weeks, and it gets over the illness. The mouse is then sensitized to Mycoplasma allergen. The previous infection seems to block the airway's hyperreactive response upon subsequent exposure to the allergen.

However, Martin explained, if a mouse becomes sensitized to the allergen before being infected with Mycoplasma, the airways are much more reactive than they were with either the allergen or the bacteria alone.

"Now we have a chronic model of 'asthma' in a mouse," he said. "Timing is everything here."

That pathway illustrates the hygiene hypothesis, which says that youngsters who are exposed to many germs are less likely to develop asthma and allergy than children who grow up in very clean environments.

Because of the Mycoplasma work of Martin and others, "I think it's important for people with new-onset asthma to be evaluated for the possibility of an infectious component," said UPMC's Calhoun.

He recently treated five members of a family who developed persistent asthma symptoms within four months of each other, soon after they all took a plane trip. Calhoun performed immunological tests on them that suggested Mycoplasma exposure and treated the family with antibiotics. All of them got substantially better and only the father, who had a history of childhood asthma, still has an occasional attack.

It's not unusual for patients with new-onset asthma to mention having a bad cold or bronchitis shortly before their breathing difficulties began.

"Most physicians and people feel that's just a virus," Martin said. "But many of these upper respiratory infections are really secondary to Mycoplasma pneumoniae infection and not a virus. So a lot of 'viral colds' could be Mycoplasma."

Large epidemiologic studies would have to be done to ascertain what proportion of asthma sufferers carry Mycoplasma or Chlamydia. Martin also is trying to develop a simple diagnostic test that would be less invasive than using the special scope.

The genetic component

Not every one who gets Mycoplasma infection winds up with asthma, of course. Those who do likely already have a genetic predisposition for the condition.

Research into the genetics of the syndrome has been booming in the past five years, Calhoun said. More than 20 susceptibility genes have been identified and there are likely more. But having a gene or two doesn't always translate into actual disease. Scientists are still working on deciphering the interactions between various genes that could lead to breathing problems.

According to Dr. David Nash of Children's Hospital, genetic research will eventually show that all cases of asthma are not the same.

"There are definitely going to be different diseases that follow different courses and maybe, in time, have different therapies directed toward them," he predicted. "Right now if you wheeze, you have asthma and you get pretty much a standard therapy."

Doctors do know that "if both mom and dad have asthma, the chances are about two-thirds to three-quarters that any child will have asthma," Calhoun said. Knowing that could lead parents to make choices, such as quitting smoking, to reduce their child's risk of becoming ill.

Anita Srikameswaran can be reached at anitas@post-gazette.com or 412-263-3858.