TB's persistent presence

The cycle may have started with an errant cough or sneeze in a grocery store or on a bus. At least that's how local health officials believe the Snohomish County, Wash., boy inhaled the Mycobacterium tuberculosis bacteria.

Once in his lungs, they reproduced slowly until something activated them. At one point, the boy might have been treated with the standard nine-month antibiotics regimen but stopped when he started feeling better. Thus, the tubercle bacillus remained hidden in his system and grew smarter.

This summer, the stealthy invader reactivated, making the boy sick again, the bug this time able to elude the first-line drugs. It also threatened to spread rapidly, leading health workers to scramble to find the boy's circle of contacts -- friends, teachers, family and co-workers, anyone who might have breathed in droplet nuclei of the bacteria when the boy coughed. During the same period, in the same county, a local day care center worker was also diagnosed with active TB. The contact web of the boy and worker grew: 50, 100, 200, 400.

"Our first priority is making sure an active case of TB gets treated and that the patient takes the complete therapy," says Chris Spitters, MD, MPH, TB control officer for the Snohomish County Health District in Everett, Wash. "The next highest priority is contact identification of exposed populations."

So goes the battle to prevent or contain a TB outbreak.

Each year 54 million people are infected with the tubercle bacillus, 6.8 million develop clinical disease and 2.4 million die. And even in the United States, this case is not unusual, Dr. Spitters says. "Certainly we frequently have high school, community college, university or middle school investigations, and the contact list can get quite large," he says. "We have to keep expanding the investigation; if someone in the household is infected, we have to look to their work and leisure environment. ... It can really consume resources."

In the mid-1980s, a decay of the public health infrastructure and underfunding of TB control programs led to a resurgence of the scourge. In response, massive cash infusions beefed up control efforts around the nation. "Since then, the number of cases in the United States has been coming down, but over the last couple of years the decrease is flattening out," says Henry Blumberg, MD, professor of medicine and program director, division of infectious diseases at Emory University School of Medicine in Atlanta. "There is a concern that we may not have learned our previous lesson. Funding for TB control has again been cut, and any progress made is potentially in jeopardy."

Nonetheless, this decline and TB's stigmatized status -- seen as only a disease of the poor -- often keep it off physician radar. "Complacency is not a good idea," says David L. Cohn, MD, professor of medicine at the University of Colorado Health Sciences Center. "We need to get TB to the forefront again. We live in a global village, travel is easier and germs don't respect borders. We must keep it on our radar screens."

Global public health threat

Scientists now believe TB has been a public health concern for thousands of years. Infected tissue samples were recently found in Egyptian mummies. And before the advent of penicillin and other antibiotics, it spread through families and communities.

Even now, it still ranks among the deadliest of infectious diseases. "It is a huge global health problem," Dr. Blumberg says. "And it impacts us [here] because about half of the U.S. cases are among foreign-born persons."

According to the World Health Organization, TB is spreading at the rate of one person per second. It causes more deaths than AIDS and malaria combined. In Africa it is rampant. In Russia a vast majority of cases are multi-drug resistant. In the United States there are areas -- New York, New Jersey, San Francisco and many southern states -- where it spreads, and outbreaks in hospitals, schools and prisons have stunned health officials. "There are pockets in the United States that are as bad as developing countries," says Christine F. Sizemore, PhD, acting chief, Tuberculosis, Leprosy and other Mycobacterial Diseases Section of the National Institute for Allergy and Infectious Diseases. "There is no routine testing, but if the patient comes in coughing, it has already spread."

About one-third of the world's population has the latent form of TB. Most of these people will never get sick. This form is not spread, and treatment requires one antibiotic versus four for active disease. But about 10% of latent cases will activate at some point if not treated. While researchers do not completely understand the triggering mechanism, they do know that those with HIV and other immunocompromised conditions such as diabetes or end-stage renal disease are at greater risk.

Dr. Blumberg suggests that primary care doctors think about latent infection, especially in at-risk groups. "It's important to know your patient population and know who should be targeted for testing," Dr. Blumberg says. "It could probably be incorporated into preventive care."

Those in greatest jeopardy include people recently exposed to active TB or HIV, recent immigrants, immunocompromised patients, those with some cancers and patients taking TNF-alpha blockers. "The epidemiology of TB continues to change, and an ever-increasing number are foreign-born," Dr. Cohn says. "This is a reminder to practitioners who see foreign-born patients to keep TB in mind."

Screening is not a perfect science. Archaic skin tests are only about 75% to 85% effective, and there can be false-positives and false-negatives. QuantiFERON-TB, a new diagnostic blood test, could improve results. According to the Centers for Disease Control and Prevention, compared with skin testing, QFT results are less subject to reader bias and error. "It is Food and Drug Administration-approved and very useful in the diagnosis of latent TB infection," Dr. Cohn says. "It's just starting to happen."

TB is currently treated by means of combination therapy, using cocktails of three to four drugs. For antibacterial activity, isoniazid, rifampin and streptomycin. For inhibiting the development of resistance, isoniazid, rifampin and ethambutol. "We need newer drugs. There has not been a new class of drugs in decades," Dr. Blumberg says. "We need drugs with shorter regimens."

Because treatment adherence is a challenge, Dr. Cohn suggests that physicians enlist local health departments for case management, directly observed therapy (DOT) for high-risk patients and those who often miss appointments for medication refills, and patient incentives such as free transportation for appointments.

Public health initiatives

The Denver Public Health TB Control Program is considered a model in the United States, and several of its physicians lead CDC initiatives.

In the old days, before having effective therapy, Colorado attracted many TB patients, says Dr. Cohn, an associate director at Denver Public Health. "This was because of the perception that high altitude, low oxygen and sunshine would be curative or helpful for TB," he says. "This critical mass of patients, however, did lead to increasing expertise both at Denver Public Health and National Jewish Medical Research Center."

Thirty years ago, Denver Public Health was the first to initiate directly observed therapy for treatment of patients with active TB. DOT is now the standard. "Probably our greatest contribution was to evaluate a 6-month regimen using largely DOT, which was shown to be highly effective," Dr. Cohn says. "This research, along with other similar regimens, led the way to currently recommended regimens for treatment of TB."

Important to the program's success, Dr. Cohn says, is the fact that nurses serve as primary patient contacts. "There is input by physician experts on all of our patients, but the nurses do the lion's share of patient interactions," he says. "This is essential to foster relationships when one is being treated for a chronic disease for many months -- now 6-9 months, 18-24 months in the old days."

Another essential is cooperation. Montana health officials, for instance, joined forces with colleagues in Idaho, Utah and Wyoming to develop regional strategies for education and training, enhanced laboratory services, consultation for clinicians and development of a policy manual for local health departments. Montana's TB infection rate is well below the national average -- about 1.6 of every 100,000 compared to 4.9 nationwide. But there is still a problem, and, therefore, the network is valuable.

"Fifteen Montanans were diagnosed with TB last year, including one who died," says Denise Ingman, manager of the Montana Dept. of Public and Human Services tuberculosis program. "We're especially concerned that one of those cases involved a child, which means the disease was transmitted recently. It wasn't a latent infection that only now flared up."

And the economic costs of tuberculosis control are enormous. According to NIAID, the price tag is an estimated $700 million to $1 billion per year. The average cost per case is about $25,000, and multi-drug resistant cases can be as high as half a million each.

Only about one-quarter of TB patients complete the full 9-month treatment course. When patients start feeling better, they are less likely to continue. And drugs developed in labs in the 1920s are still being used.

"One of the biggest problems treating TB is that treatment takes so long," says Mel Spigelman, MD, director of research and development at the Global TB Alliance in Washington, D.C., a nonprofit public-private partnership working toward the development of new, affordable and accessible medicines. "We need better drugs that get therapy down to two months and deal with drug resistance. Right now we have 10 projects in the pipeline."

This summer, the TB Alliance announced the start of Phase I clinical trials for the lead drug in the pipeline, PA-824. Preclinical studies indicate that it has sterilizing potency and a novel mode of action that could shorten treatment times.

"PA-824's excellent profile means its introduction into a new regimen could help shorten treatment time dramatically and overcome some of the challenges with TB treatment such as multi-drug resistance and the treatment of TB-HIV co-infected patients," Dr. Spigelman says.