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Danger at 30,000 Feet: Time to Re-Invest in TB Control

Reprinted with permission from Association of Public Health Laboratories Lab Matters, Summer 2007.

Printable Version: Danger at 30,000 Feet, Lab Matters, Summer 2007 (PDF)

By Nancy Maddox, writer

When Andrew Speaker boarded a plane from the US to Europe last May, he had no idea he was about to become a media sensation. Speaker, an Atlanta lawyer believed to be infected with extensively drug-resistant tuberculosis (XDR-TB), potentially exposed hundreds of airline passengers to a virulent bacterium. In so doing, he inadvertently focused public attention on a grave and growing problem to a degree that the public health community had been unable to do.

In short, tuberculosis (TB)—commonly considered a disease of the past—is resurging in new, virtually untreatable forms. Ken Castro, director of the CDC Division of Tuberculosis Elimination, said in an interview that XDR-TB, in particular, is “bringing us back to the pre-antibiotic era.”

At the same time, the public health infrastructure set up to monitor and manage cases of tuberculosis in the US has been compromised by years of declining funding.

One effect has been delays in laboratory testing, resulting in unknown prolonged infectiousness of TB patients and increased potential for outbreaks in the United States.

Anthony Tran, manager of APHL’s HIV, STD and TB program, noted that new techniques exist to speed TB diagnosis and the drug susceptibility testing necessary to ensure appropriate treatment. However, he said, the public health laboratories largely responsible for such specialized work are “having trouble just maintaining the status quo, much less bringing in new technologies.”

In addition, many state and local governments have reduced the number of TB controllers who investigate cases of possible TB exposure and assure that patients complete drug regimens.

Without funding to reverse these trends, Speaker’s overseas adventure may be merely a preview of what lies ahead. But such a scenario is entirely avoidable.

FINDING THE FUNDING

Julie Tans-Kersten, advanced microbiologist and TB program coordinator, is one of the laboratorians who handles TB issues at the Wisconsin State Laboratory of Hygiene.

APHL is consulting with congressional leaders and commenting on legislative proposals to boost TB control efforts, including the high-level TB testing performed by the nation’s public health laboratories.

House and Senate versions of two bills are now pending in Congress to increase federal funding for domestic and global TB control. H.R. 1532, introduced by Congressman Gene Green (D-TX), increases domestic federal funding to $528 million (from $137 million) and mentions laboratory diagnostics. However, the bill is expected to undergo significant changes during House Energy and Commerce Committee deliberations.

Its Senate counterpart, S. 1551, was introduced by Senator Sherrod Brown (D-OH). This bill provides $300 million annually and contains several key references to “laboratorians” and to the APHL/CDC National Laboratory Training Network, thanks largely to APHL advocacy.

The global bills, H.R. 1567 and S. 968, were introduced by Congressman Elliot Engel (D-NY) and Senator Barbara Boxer (D-CA). Both provide $330 million in fiscal year 2008 and $450 million thereafter for the Department of State, plus $70 million in fiscal year 2008 and $100 million thereafter for the CDC to assist the World Health Organization (WHO) and the Stop Tuberculosis Partnership, a network of more than 500 organizations and countries working to eradicate TB as a public health problem—a pressing task given that more than a third of the world’s population is infected with the TB bacterium.

If passed into law, this legislation would begin to remedy the effects of decades of government complacency as chronicled in the Institute of Medicine’s 2000 report Ending Neglect: The Elimination of Tuberculosis in the United States.

TB'S HISTORIC IMPACT ON HEALTH

David Warshauer, PhD, deputy director, Communicable Disease Division, at the Wisconsin State Laboratory of Hygiene.

From time immemorial, TB has been a leading cause of premature mortality. The ancient Greeks used the term phthisis—evoking the sound of searing flesh–-to describe the ravages of the disease. The Romans later employed the term consumere, meaning to consume or eat up; an apt description of the lung destruction that accompanies unchecked illness.

Only in the early twentieth century did the developed world experience some relief from the threat of Mycobacterium tuberculosis as sanitation and general living conditions improved. The disease was further curbed with the advent of antibiotics in the 1940s and, in the US, continued a steady decline through 1984.

In that year, said Castro, reductions in TB case rates “came to a screeching halt.” Then, from 1985 to 1992 the US witnessed an unprecedented 20 percent hike in the rate of TB diagnosis.

Authorities credit this resurgence to five factors:

• Elimination of categorical federal funding for TB in 1972 and subsequent reductions in state funding for TB control.



• Onset of the HIV epidemic, leaving thousands of people immunocompromised and extraordinarily susceptible to TB.



• Increased rates of travel and immigration into the US from countries where TB is a common health problem.



• Lax infection control practices, leading to TB outbreaks in prisons and other institutional settings.



• Emergence of multi-drug resistant tuberculosis (MDR-TB) at a time when drug susceptibility testing
  was not routine, resulting in the continued infectiousness of those unknowingly treated with ineffective drugs.

Had the original trend continued and the resurgence been averted, said Castro, “we should have never seen 52,100 cases of excess tuberculosis.”

AN EARLIER CRACKDOWN ON TB
As a result of that experience, in 1992 authorities developed a national action plan to combat MDR-TB and Congress allocated new resources to implement it. An important focus was building national laboratory capacity to speed diagnostic and drug susceptibility testing. For example, the development of new, liquid broth media to culture the extremely slow growing TB bacterium—in place of the solid media previously used—reduced testing turn-around times from a month or more to about two weeks.

Laboratories also placed new emphasis on the molecular fingerprinting of TB strains to track and better understand the mechanisms of disease transmission. And federal dollars rebuilt the research capacity of the National Institutes of Health and other institutions that conduct drug trials and basic scientific research.

As the action plan was carried out, TB case rates resumed their downward march. Last year, 13,767 TB cases—4.6 cases per 100,000 people—were reported in the United States, representing the lowest recorded rate since national reporting began in 1953, and a 3.2 percent decline from the 2005 rate.

But the good news ends there.

COMPLACENCY LED TO NEGLECTED TB PROGRAMS
Lulled by declining TB incidence and distracted by other priorities, the federal government has gradually disinvested in TB control. From 1994 onward the total federal TB program allocation has stood at $136 million to $138 million, with no increases to offset inflation, much less to upgrade or expand laboratory testing or enhance other control activities. Given the flat funding and the CDC funding formula, APHL’s Tran said, “If one laboratory gets more money, another receives less.”

Tight budgets at the state and local levels have exacerbated the problem, leaving some jurisdictions unable to fill federal funding gaps and others to reduce their own contributions to TB control programs.

John Bernardo, a professor at Boston University School of Medicine and the TB medical officer for the Massachusetts Department of Public Health, surveyed members of the National Tuberculosis Controllers Association early this year to gauge the effects of funding shortfalls. His overall assessment is that the TB control infrastructure is “slowly falling apart.”

TB programs, he said, have been forced “to abandon some of the strategies we need to pay attention to reduce the rates further,” such as targeted testing and treatment of latent (i.e., dormant) TB among the homeless, substance users, the disenfranchised and other high-risk populations.

“We’re going to see increasing numbers of cases that are more complicated because of access to care issues and because of drug resistance,” said Bernardo. “As funding for programs becomes more scarce, access to free services gets more limited… People are afraid of showing up if they’re not documented.”

Lack of treatment carries significant risks. An estimated 10-15 million US residents have latent TB infection with the attendant risk of future disease, if untreated. Those with active illness and inappropriate or no medical care will likely suffer severe illness, loss of organ function and eventual death, all the while exposing the community to the bacterium.

“TB is not as infectious as the flu,” said Bernardo, a physician who treats TB patients. “It’s estimated that you need a relatively long exposure to someone who’s actively coughing up organisms before you can see TB on a (sputum) smear. Eight hours on an airplane.” However, he said, there are no hard and fast rules.“I have one case here that we’re looking into now of a gentleman who had Thanksgiving dinner with his family, and out of five people at the table you have two cases. And it was only a three-hour dinner.”

The Massachusetts TB program has been level funded by the CDC since 1993. “That’s a 27 to 30 percent reduction in real spending power,” said Bernardo. Last year, for the first time, the state had to absorb a 5 percent cut, from $1.58 million in 2005 to $1.50 million in 2006.

One consequence of this fiscal insecurity has been an inability to impact overall TB incidence in Massachusetts, which has averaged about 260 new cases per year for the past decade, including a handful of MDR cases. Over time, the state TB program has lost positions for nine field workers—individuals who interface with TB patients on a regular basis to assure compliance with drug regimens and support case management activities.

Other states have suffered similar setbacks. The collective impact of policymakers’ waning commitment to TB control is reflected in nationwide disease data. The average annual percentage decline in the national TB incidence rate slowed from 7.3 percent per year during 1993-2000 to 3.8 percent during 2000 to 2006.

Said Tran, “We’re afraid that curve is going to level out and, bam!, it’s going to be just like 20 years ago and rates will go back up again.” In fact, rates rose in 20 states and the District of Columbia between 2005 and 2006, but these increases were offset by lower rates in other states.

A MORE DANGEROUS TB EMERGES
Even without a national rate increase, health authorities are plenty worried about the emergence of first MDR- and then XDR-TB, potent strains of M. tuberculosis that have evolved antibiotic resistance because of interrupted and/or suboptimal drug regimens.

The number of US residents with MDR-TB—impervious to the two most powerful TB drugs, isoniazid and rifampin—increased 13.3 percent from 2003 to 2004, when there were 129 cases. Worldwide, there are at least 424,000 cases of the MDR strain, and the problem is considered so alarming that the WHO has just released a global response plan.

MDR-TB is treatable, but requires the use of second-line drugs that are more toxic than their first line counterparts. “You need creativity in administering the drugs, because you have to give a lot of drugs,” said Bernardo. “The drugs tend to make people sick, so they don’t want to take them.”

To boost compliance, health agencies routinely use case workers to administer antibiotics directly to patients deemed likely to discontinue therapy. Even then, said Bernardo, “They may take them and vomit them back up. They may hide them in their cheek.”

Once isoniazid and rifampin are no longer viable options, the ability to cure more than 95 percent of patients within six months goes down to 60 to 70 percent, requiring an extensive treatment lasting up to two years.

XDR-TB—resistant to isoniazid, rifampin, a fluoroquinolone and at least one of three injectable second-line drugs—is virtually untreatable, with a mortality rate of 33 percent in the US (compared to less than 5 percent for all US TB cases combined).

The precise extent of XDR-TB is unknown, but is certainly rising. From 2000 to 2004, 2 percent of TB patients whose isolates were tested in a survey of a worldwide laboratory network were determined to have XDR-TB. In the industrialized nations in this survey (including the US), XDR-TB increased from 3 percent of MDR-TB cases in 2000 to 11 percent in 2004.

CDC’s Castro said XDR-TB “has been found in every part of the world it’s been looked for.” It is of grave concern in developing countries and especially in Africa, where a scary XDR-TB outbreak is now underway in South Africa. Forty-eight cases have been documented in the US since 1993.

Because medical research has not been a federal priority, authorities do not expect the next new TB drug to be ready for FDA approval for at least seven years.

These new challenges demand increased and more sophisticated laboratory testing for diagnosis, strain identification and population-based surveillance.

Latent TB infection has long been diagnosed using a skin test that is administered by a trained clinician or health care worker and requires patients to return 48 to 72 hours later for a reading—a huge obstacle for transient and other disadvantaged, high-risk groups. In some TB programs, as many as 40 percent of clients fail to return for a reading.

DIFFICULTIES REMAIN DESPITE NEW TESTS

A new test, QuantiFERON®-TB Gold (QFT-G), overcomes this problem, requiring a single patient visit to draw blood. QFT-G, an immunologic assay that elicits a reaction from immune cells previously exposed to M. tuberculosis, offers other advantages as well. It is less likely to yield a false positive result because of cross-reaction with non-tuberculosis mycobacteria, is not subject to reader bias and is not affected by prior immunization with the bacille Calmette-Guérin vaccine (used outside the US to prevent the most severe form of TB in children).

QFT-G is in limited use throughout the US. Dave Warshauer, deputy director of the Wisconsin State Laboratory of Hygiene’s (WSLH) communicable disease division, said QFT-G is used by a few clinical labs in Wisconsin but not by the WSLH because of logistical considerations; blood specimens must reach the laboratory and be processed within 12 hours.

“For a public health laboratory, it’s very difficult to process a specimen in that time frame,” said Warshauer. “If a specimen is drawn in the morning, we might not get it until 4 p.m., and we don’t have (a second shift of staff) to do it.”

Some labs, he said, perform the first, time-critical part of the test within 12 hours and then freeze the patient’s processed blood plasma so they can batch specimens and carry out the second step on multiple specimens at one time. This batching procedure is cost-effective, but delays results.

Nationwide, QFT-G is in use in fewer than a dozen public health laboratories. In addition to timely specimen processing, other impediments to implementation have been identified by public health laboratories. These include the cost shift from TB program to laboratory, adequate staff to support the testing, difficulties in validating the QFT-G and reimbursement issues.

Work is needed to determine which populations are best served by QFT-G (for example, there are few data on its efficacy in children and the immunocompromised) and to develop systems that allow for timely processing. At the same time, research is needed to evaluate other immunologic assays for latent TB detection, such as the T-SPOT™ test used in Europe and currently awaiting FDA approval in the US.

Prior to the availability of molecular methods, confirmation of active TB took two to three weeks; long enough for scientists to grow the organism in culture (usually from a concentrated sputum specimen), isolate it and identify it using biochemical tests, DNA probes or high-performance liquid chromatography (which produces characteristic patterns of the mycolic acids in the organism’s cell wall).

Nucleic acid amplification tests (NAATs) reduce turn-around-times for positive results to 24 hours; M. tuberculosis complex is identified by detecting its genetic material directly in the primary patient specimen. (All specimens are also routinely cultured to recover mycobacteria isolates.)

Warshauer calls the molecular test “a big breakthrough” that elevates the role of the laboratory by enabling it to deliver real-time results. NAATs, however, necessitate advanced training for scientists and the use of highly sophisticated and costly technology. Only a few dozen reference laboratories and large clinical laboratories now use them, including at least 35 public health laboratories that participate in a CDC-sponsored proficiency testing program. In Wisconsin, a state with 75 confirmed TB cases last year, the test is limited to the WSLH and a large, clinical laboratory in Milwaukee.

DRUG SUSCEPTIBILITY TESTING IS VITAL

A Microbiologist works in a biological safety cabinet in Wisconsin.

A second major area of TB testing is the identification of drug-resistant strains. This information is so important to physicians, and to TB control in general, that 100 percent of the initial TB isolates from Wisconsin patients undergo drug susceptibility testing, mostly at the WSLH or the Milwaukee Public Health Laboratory. If a patient remains culture-positive after three months, laboratorians repeat susceptibility testing on a fresh isolate to determine if drug resistance has developed de novo.

Bernardo said this kind of technology is making the laboratory “more and more key in TB cases, and not just in the beginning when the diagnosis is established, but as the disease is monitored.” He shared one example of a case in which drug susceptibility data had a profound impact on patient care.

“A young woman with TB was getting better on standard treatment,” said Bernardo. “We had a case review on a Thursday afternoon. The nurse managing the case had the lung x-rays and they were improving too. Then I got the susceptibility reports back from the laboratory indicating that this patient has MDR-TB.

The big problem was that she was going to travel the next day on an extended, transcontinental flight. We called the patient and talked her out of going. We readjusted her meds, and she went on her trip a couple weeks later.”

A potential reprise of the Speaker episode was averted. The problem is that such information is seldom quickly forthcoming.

Drug susceptibility testing is typically performed by attempting to grow organisms isolated from a patient specimen in a broth or agar preparation infused with the drug of interest. If the bacteria are able to grow, they are by definition drug-resistant. Even with the newer growth media, however, the process is time-consuming, requiring at least two weeks and sometimes a month or more for drug susceptibility results.

The California State Public Health Laboratory has developed a molecular assay capable of detecting most isoniazid- and rifampin-resistant strains in real-time, but it has not been validated by the CDC. Warshauer said Wisconsin TB controllers “really want” a real-time assay to be available in-state, and he plans to eventually acquire the California protocol. In the absence of CDC validation, however, the WSLH will not be able to implement the assay until it is independently validated in-house—another lengthy and costly process that takes staff away from ongoing diagnostic and drug susceptibility testing.

TRACKING TB'S PATH: GENOTYPING
The third major area of TB testing—genotyping—provides data useful for population-based disease surveillance. The genetic profiles of the organisms infecting patients can reveal whether or not the organisms are clonally related and therefore likely originating from a common source, such as a patient in a hospital or a resident of a nursing home. Sometimes unexpected outbreaks can be discovered this way.

Genetic information is also invaluable to monitor trends over time and to test assumptions and theories about the dynamics of TB transmission. For example, is extended, close contact with an infected individual the sole means of transmission?

Most TB genotyping in the US is performed by the California and Michigan state public health laboratories, under contract to the CDC. Last year, these two labs produced genetic profiles of about 9,000 TB isolates or roughly 80 percent of the culture positive TB cases documented in the US.

The CDC encourages universal genotyping of all culture positive cases and underwrites the cost of the service, although submitting laboratories must pay packaging and shipping costs. Genotyping results are reported back to state or local TB programs and also maintained in a national database run by the CDC.

LABORATORY CENTRAL TO TB CONTROL EFFORTS
Not long after the release of the Institute of Medicine’s seminal TB report in 2000, APHL and the CDC commissioned a task force of health authorities, laboratorians and TB controllers to make recommendations to assure availability of high-quality, cost-effective TB laboratory services. Among its recommendations, the task force advanced a systems approach that places the laboratory in a central coordinating role vis-à-vis clinicians, patients and TB controllers.

Within this model, the public health laboratory plays a leadership role, performing specialized, reference testing and assuring uniform, high-quality mycobacteriology work within a state or local jurisdiction.

“The time has come to take the laboratory out of the basement and put it up front and center as an integral component of TB control programs,” said Castro.

“In the US,” he said, “we have the advantage of having relatively fewer (TB) cases than other parts of the world and the technical capacity to make advances if we invest resources.”

Public health laboratories are eagerly awaiting that investment. Nancy Warren, director of the Pennsylvania Bureau of Laboratories and chair of the erstwhile APHL TB Steering Committee, identified several needs within her own facility.

“If I had more dollars,” she said, “I would be interested certainly in more molecular testing. I might consider the utility of adding on another shift (to speed testing). I would be interested in having laboratorians dedicated to technology transfer… I would purchase equipment helpful to support new technology: a DNA sequencer, another high-performance liquid chromatograph.”

Warren said with current funding, “There’s no way I could afford to do QuantiFERON testing right now.”

Finally she stressed the importance of adequate mycobacteriology training programs for laboratory scientists.

“I don’t know what we would do without the National Laboratory Training Network,” she said. “There’re no other readily accessible training programs. You can put a lecture on anywhere, you can do teleconferences. But mycobacteriology is such a subspecialty. It requires hands-on working with the organisms and there aren’t many places that are equipped to handle the TB bacterium,” (which requires a high-level biosafety containment facility).

Within the past two years, three of Warren’s four dedicated TB scientists have retired, taking with them more than 100 years of collective mycobacteriology experience.

Today, said Warren, the public health community is at a fork in the road.

“I tend to divide mycobacteriology in two camps: inefficient but familiar and the rapid, molecular, innovative way that hinges on dollars, equipment and workforce development. We have a foot in each camp. Historically, public health laboratories have always risen to the challenge of something like TB; it’s part of our core functions. We just need resources to do this.”

On a more philosophical note, Warshauer said, “In public health it’s difficult, because you can’t show what you’ve prevented. People don’t believe you until the funding’s cut… If MDR- or XDR-TB takes hold and there’s no public health infrastructure to control it, we’re going to have a big problem.”

He said, “We had the anthrax event in 2001, and then the government increased funding for bioterrorism. Now we had the Speaker situation. It takes unfortunate events like that to get the public’s attention.”