What’s going on with NTMs?
There’s a new kind of patient in many pulmonologists’ waiting rooms — and not everyone is pleased. Cases of nontuberculous mycobacteria (NTM) seem to be on the rise, and like it or not, many of these cases are finding their way to the same physicians who treat TB. Like TB, the "atypical" pathogens are acid-fast bacilli; and like TB patients, sufferers from NTM often complain of long-standing fatigue and malaise and a chronic cough. Though the medications used to treat NTMs would sound familiar to anyone who works in a TB clinic, the treatment is long and arduous, with no infrastructure available to help with compliance.
"These patients are very hard to manage, and adherence is terrible," says Charles Daley, MD, associate professor of medicine at the University of California-San Francisco. "Nobody wants them — not the ID docs, not the pulmonologists. They’re all going, Who can I send this patient to?’"
Yet Daley is among a growing handful of TB experts — from the nationally known NTM authorities at National Jewish Hospital in Denver, to a cadre of consultants at the University of Texas Health Center in Tyler — who are using the evident rise in NTMs as an opportunity to carve out a new area of expertise. "I have to admit, as TB goes down in the U.S., some of us are looking for other diseases," he says.
Perception vs. reality
The big question, of course, is whether there really are more NTMs, or whether people are just thinking about them, and therefore finding them more often. Unquestionably, interest in the bugs is higher than it’s ever been. At the first-ever symposium on the subject of NTMs at this spring’s American Thoracic Society conference, the audience was standing room-only. At one point in the proceedings, someone asked how many in the room felt they were seeing an increase in NTMs in their own practices; practically every hand in the room shot up. But since NTMs aren’t infectious like TB, they’re not reportable, so there’s precious little epidemiology to back up that show of hands.
That may be about change. In Florida, one TB expert is trying to set up a statewide reporting system for NTMs. Since diagnosis is a slippery matter, much more complex than with TB, doing so won’t be easy, says Mike Lauzardo, MD, state of Florida deputy TB controller. "Unlike TB, you won’t be able to report on the basis of a single laboratory test," he explains. Instead, all the clinicians in the state who are making the diagnoses will have to buy into the plan.
What Lauzardo really wants is even more ambitious — to get all the Gulf states involved, and to establish a regionwide reporting system. It’s not that he subscribes to the notion (which is now well established, thanks to national TV news coverage) that Florida has more NTMs than other states — or that NTMs are suddenly a bigger problem than, say, TB. "Last year in Florida, it was the summer of the shark," Lauzardo sighs. "This year, it’s the summer of the bug."
Finding better treatment a must
At the same time, Lauzardo believes M. avium is on the rise — "kind of like an epidemic, only in slow motion," is how he describes it. Worse, like other NTM experts, he believes there also is an increase in the so-called rapid-growers of the NTM family — the super-pathogens such as M. abscessus and M. fortuitum, both bugs for which no real cure yet exists. "We need to go from raising our hands at a symposium to actually counting cases," Lauzardo says. "Otherwise, we’re just flapping in the wind."
Because NTMS are so hard to cure, a handful of researchers also is working to build an infrastructure for trials. The first randomized trial of a new therapy for M. avium complex (MAC) disease now is enrolling patients, to see NTM patients are helped by adding to their therapy an aerosolized version of gamma interferon. (Actimmune, which is made by a San Francisco-area biotech shop called InterMune, also will figure in an upcoming trial for multidrug-resistant TB patients, another group in whom it’s given promising results so far.) Daley, who’s running one of the MAC trial sites, would like to make the current trial into something more permanent — a multicenter consortium for NTMs similar to of the TB Trials Consortium at the Division of TB Elimination at the Centers for Disease Control and Prevention in Atlanta.
Lauzardo agrees that there’s much to be learned about NTMs. "I’d say we’re 50 to a 100 years behind TB, in terms of what we know about epidemiology, diagnosis, and treatment," he says.
For example, if there is a rise, what’s behind it? Clearly, the bugs have always been widespread in soil and tap water, experts agree. Lauzardo says he suspects part of the apparent increase may relate to where increasing numbers of people are living — marshy environments where salt and fresh water mix to form a habitat the NTM bugs adore.
Then there’s the showers and hot tub group of theorists. Twenty years ago, hospitals bent on patients safety and environmentalists wanting to save energy all turned down the temperature in their hot-water tanks; the bugs, it is said, are thriving, undeterred by the no-longer-scalding temperatures, in the scum that grows inside faucets. "Some of these hypotheses make good sense, but they’re all still pretty speculative," says Lauzardo.
One thing that’s clear is that the profile of patients with NTMs is changing. In the 1980s, M. avium complex was mostly known as the opportunistic infection that attacked AIDS patients, a phenomenon that all but disappeared with the advent of combination therapies. Traditionally, the other NTM patients were those with some underlying, often chronic disease — emphysema, chronic bronchitis, or in kids, cystic fibrosis, according to Fordham von Reyn, MD, chair of the infectious diseases section at the Dartmouth-Hitchcock Medical Center in Hanover, MA.
Now there seems to be a rise in patients (whom von Reyn calls "primary" MAC sufferers) who are nonsmoking and previously healthy. Often, these are white women around age 50. At the NTM clinic at UT-Tyler, the average age seems to be going down as case numbers rise.
"The average has gone from 65 down to about 50 — we even have one patient who’s 34," says Barbara Brown-Elliot, RN, MS, microbiology supervisor and senior research scientist at the microbiology department at UT-Tyler. "We’re also seeing an increasing number of MAC patients — though whether that’s a function of the disease, or simply because we’re diagnosing more of these cases correctly remains to be seen."
Diagnosis no slam-dunk either
Diagnosis of NTMs is a real headache, experts say. "If you have someone with a big lung cavity and the cultures come back positive for M. avium, that’s a slam-dunk," says Lauzardo. "The real issue lies with more subtle presentations. For example, how aggressively should you treat a middle-aged woman who complains of coughing that’s lasted a year, with subtle X-ray findings?"
Because the bugs are so common in the environment, simply cultivating them once from a patient doesn’t do it, he adds. "Instead, the guidelines say you need to get three cultures at three occasions within a 12-month period. You have to get these multiple cultures along with the right clinical findings and the right X-ray appearance." Not many physicians have much training, either, since NTMs weren’t even on the radar screen when they went to medical school; so it behooves physicians to have a high index of suspicion, says Lauzardo.
With regimens that typically last a year or longer, adherence is another huge problem. "I get a lot of patients referred to me who aren’t doing well, and they often confess that they aren’t taking their meds," says Daley.
Brown-Elliot says her clinic tried using directly observed therapy to boost compliance, but had to abandon the project. "We ran into some political problems," she explains. "The state didn’t like it because it tied up [its] personnel."
When it comes to treatment, there is one bright spot, which is UT-Tyler’s pioneering use of intermittent regimens. Patients tolerate the thrice-weekly meds much better than daily doses, and effectiveness doesn’t seem to suffer, UT-Tyler researchers have found. "Our patients have a hard time tolerating these meds on a daily basis, but they do much better with a little drug holiday," says Brown-Elliot. The regimen the Texans use consists of a macrolide (either azithromycin or clarithromycin); a rifamycin (either rifabutin or ethambutol); and ethambutol. American Thoracic Society guidelines on treatment of NTMs, last published in April 1997, are under revision, with new guidelines expected out soon.
Suggested reading
• Griffith DE, Brown BA, Cegielski P, et al. Early results (at six months) with intermittent clarithromycin-including regimens for lung diseases due to Mycobacterium avium complex. Clin Infect Dis 2000; 30:288-292.
• Griffith DE, Brown BA, Murphy DT, et al. Initial (six-month) results of three-times-weekly azithromycin in treatment regimens for Mycobacterium avium complex lung disease in human immunodeficiency virus-negative patients. J Infect Dis 1998; 121-126.
• Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 2001; 32(11):1,547-1,553.
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