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TB Notes 1, 2000
My Perspective on TB Control over the Past Two
to Three Decades
by Jeffrey Glassroth, MD
Prof of Medicine, Univ of Wisconsin Medical School
President, American Thoracic Society
In 1975 case rates for tuberculosis (TB) in the United States were
in double digits per 100,000. Increasingly, those patients were
individuals with serious social problems. A major concern at CDC
that year was the screening for TB of newly arriving Vietnamese
refugees; the treatment of active cases was provided, and notification
to local health departments of latently infected individuals was
undertaken. There was also concern about the quality of immigrant
screening done overseas, but the major focus of "imported"
TB was along the border with Mexico. Monitoring of TB drug resistance,
particularly primary resistance (i.e., among persons not previously
treated), was pursued and, reassuringly, indications were found
that these rates were generally stable and low, particularly with
respect to rifampin. A major treatment study was beginning and it
would help to define the role of rifampin in so-called "short-course
chemotherapy," meaning 9 months of daily treatment as opposed
to the standard of 18-24 months that existed at the time. "TB
Today!," an intensive educational program that provided essential
knowledge to TB control staff from around the country, presented
material on TB microbiology and diagnosis that emphasized the (then)
state-of-the-art methods; a description of classical microbiologic
techniques that had changed little in the near-century since Koch
described the tubercle bacillus. Also taught in the course was a
segment on optimizing the use and interpretation of the tuberculin
skin test for identifying TB infection. A study was about to begin
to assess the importance of skin test boosting when sequential tuberculin
tests were applied. Much of what was underlying those efforts with
tuberculin skin testing actually reflected concerns and frustrations
with the use of isoniazid (INH) for treating latent TB infections,
so-called TB prophylaxis. On the one hand prophylaxis was effective
but, on the other hand, it came with a risk of side effects, most
notably hepatitis. The challenge was to identify, via skin testing,
the persons most likely to derive benefit from INH and least likely
to be harmed by it; a classic benefit/risk "equation."
BCG vaccination, though widely used outside the US, was rarely used
here, because of perceived limited effectiveness and problems with
skin test interpretation.
The intervening quarter century has seen remarkable changes with
respect to TB but, in some ways, little has changed. A number of
years ago, then–CDC Director Dr. James Mason urged that CDC's TB
unit not think in terms of TB "control" but of "elimination."
The name of the unit changed to reflect this new, more ambitious
mission. Indeed, in the US, after some years of rising rates, TB
rates are again falling and are a fraction of what they were 25
years ago. However, in many ways the challenges to TB elimination
in the US are greater today than a quarter century ago. Worldwide,
TB prevalence is increasing, and today over 40% of cases reported
in the US are "imported" in the person of immigrants from
high-prevalence countries. The worldwide TB burden is fueled by
HIV infection, an entity unknown in 1975, which facilitates every
aspect of the natural history of TB from transmission to disease.
In recognition of this, and to more efficiently combat these interrelated
public health problems, the TB division at CDC is now administratively
"housed" with the HIV division. Moreover, CDC has dramatically
increased its worldwide collaborations to assist in efforts at containing
Rifampin is now well entrenched as a cornerstone of treatment,
and several related rifamycins have come into use. Short-course
therapy has been further abbreviated to a standard of 6 months'
duration by adding pyrazinamide during the first 2 months of treatment.
Moreover, the proven efficacy of intermittent treatment has facilitated
the widespread use of directly observed or supervised therapy ("DOT")
as a means of improving adherence to treatment and is a major factor
in treatment success. Unfortunately, drug resistance has become
an additional issue contributing to treatment problems. Moreover,
resistance is increasingly a problem with the rifamycins (almost
unheard of 25 years ago), and outbreaks and sporadic cases of multidrug-resistant
TB (MDR TB) represent a major concern for clinicians and public
health officials alike.
Perhaps nowhere has change been more dramatic than in the area
of diagnostics. Although skin testing is fundamentally unchanged,
the microbiologic approach to TB diagnosis has been revolutionized
by the application of molecular biologic techniques. Thus, laboratories
are now capable of obtaining genetic material from small numbers
of tubercle bacilli in specimens, amplifying or multiplying that
material, and then testing the resulting "soup" for specific
segments of DNA or RNA that are unique to TB. Refinements of these
techniques also permit the identification of resistant strains in
some cases and the tracking of outbreaks or mini-epidemics, and
help us better understand the epidemiology of the disease as it
currently exists. Such techniques hold the very real promise of
rapid, highly sensitive, and specific diagnostic tests for TB disease.
Powerful tools indeed!
Image 1: Laboratories are now capable of DNA fingerprinting: amplifying
or multiplying genetic material and testing the material for segments
of DNA or RNA that are unique to TB.
Preventive treatment of latent TB infection still emphasizes the
use of INH. However, because of occasional concerns about resistance
to INH, and also in an effort to reduce the time required to complete
a course of preventive therapy, other regimens — particularly those
using rifampin — have been increasingly used and shown to be effective
(though more costly) alternatives to INH. Although additional studies
have documented the limitations of BCG vaccination, there is increasing
interest, in the US and abroad, that through the technical developments
of recent years, more effective vaccines are feasible. Given the
worldwide problems I have noted, application of a truly effective
vaccine would be a logical strategy for dealing with this disease.
So what has happened in TB in the last 25 years? Lots of change
and technologic development but fundamental challenges remain. Worldwide
the number of cases is rising and treatment is becoming more difficult
in some regions. In the US, numbers have declined but current cases
often require more resources and sophistication to treat than they
did even just a few years ago.