This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCCM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Salfinger, M. Articles by Ashkin, D. Search for Related Content PubMed PubMed Citation Articles by Salfinger, M. Articles by Ashkin, D.

Coming Out of the Darkness

Florida Department of Health
Tallahassee, Florida

David Ashkin, M.D., F.C.C.P.

A.G. Holley Hospital
and
Florida Department of Health
Lantana, Florida

One hundred years ago, on April 7, 1908, Robert Koch arrived in New York City and soon after visited Dr. Hermann Biggs, who began America's first campaign to prevent and control tuberculosis (TB). Koch was particularly impressed with the promptness and completeness of the service he saw rendered by the health department of New York City. "That a physician could leave a throat culture at a drug store in his neighborhood at 5 P.M. and be sure of receiving a report by telephone before 10 o'clock the next morning ..." (1). Sad to note, in many parts of the world, doctors today still rely on smear microscopy to diagnose TB. For these clinicians, without the availability of proper diagnostic tools, they are treating TB "in the dark," which is contributing to the continued spread of the disease as well as the development of drug-resistant strains.

In this issue of the Journal (pp. 787–792), Barnard and colleagues (2) describe a validation study of a commercially available assay detecting, within 24 hours, multidrug-resistant (MDR) TB organisms in sputum specimens. They blindly tested 536 consecutive smear-positive sputum specimens with a line-probe assay for rapid detection for rifampin and isoniazid resistance, using mycobacteria growth indicator tubes and solid Middlebrook agar slants for susceptibility testing as the reference method. There are several take-home messages for readers and policy makers:

1. The investigators' laboratory carries out a major operation serving more than 4 million people with an estimated TB incidence of 932 per 100,000, and an average TB-HIV coinfection rate of 28.2% in 2001–2002. This laboratory processes an impressive 400,000 sputum specimens per year (more than 1,000 per day), resulting in 400,000 smear results, 150,000 broth culture results, and 50,000 drug susceptibility panel results. Alarmingly, 19% of the 536 consecutive smear-positive specimens collected were found to be multidrug resistant! The Foundation for Innovative New Diagnostics (FIND) identified a perfect setting to carry out the validation study and to prove that molecular testing can be accurately performed in a high-TB-prevalence country.
   
2. It may come as a surprise to some readers that a molecular assay (GenoType MTBDRplus in this study) fared better than acid-fast bacilli (AFB) in stained smears examined microscopically and broth culture, which are considered the gold standard tests (96.8 vs. 86.6%). Fifty-five (15.4%) cultures were contaminated and thus no drug susceptibility testing results were available, whereas the molecular assay gave an interpretable result in more than 93% of those samples in 1 to 2 days. A further 15 (2.8%) specimens were culture negative; however, the molecular assay generated interpretable results in 13 (86.7%) specimens. In addition, the line probe served as a quality control when, during the study, seven specimens gave "incorrect" susceptibility results with the gold standard due to faulty isoniazid-containing medium (which would have gone undetected if not for the parallel design of the study).
   
3. The authors also tested a convenience sample of 100 AFB smear–negative sputum specimens of which 25 were culture positive for TB; however, drug susceptibility results were available for only 20 samples. The molecular assay provided results for rifampin in 80% and for isoniazid in 74%. Although the GenoType MTBDRplus was originally designed for drug resistance detection in isolates, it is noteworthy to recognize that even in AFB smear–negative specimens, the sensitivity is approximately 80%.
   
4. Although Barnard and colleagues (2) describe the favorable performance characteristics of the GenoType MTBDRplus, its real benefit will be fully realized when the health care provider/TB control program can swiftly act upon drug resistance results. A recent study from Peru (3) delineated the many steps where delays occur. The total turnaround time from the initial sputum specimen to diagnosis and appropriate treatment was 5 months, almost twice as long as the conventional bacteriologic procedures, including drug susceptibility testing. Many patients with MDR TB and HIV, as seen recently in KwaZulu-Natal (4), die soon after the diagnosis of the disease. It is hoped that with early recognition of MDR TB and prompt initiation of appropriate therapy, these lives may be saved. The Tomsk program can serve as a model (5) for an important paradigm shift, which must take place for successful TB control. Providers and program planners, rather than patients, must assume primary responsibility for ensuring treatment adherence and successful delivery of care.
   
5. The savvy reader will recognize that the researchers used the leftover sediment that is derived after a harsh treatment to eliminate contaminating non–acid-fast organisms. The field of molecular application would benefit from a procedure that would maximize the yield of DNA from sputum samples. Furthermore, the sputum specimen could be easily rendered noninfectious before shipping to a laboratory, thereby reducing shipping cost in the event that the molecular assay is only available in a referral laboratory. In addition, molecular assays do not require expensive installations to meet international biosafety requirements.
   
6. Many may argue that this technology is only needed in areas with high drug resistance. However, it may benefit areas with low drug resistance rates as it may be possible to start fewer drugs on "susceptible" patients, which may reduce costs and potential adverse reactions, as well as detect those "needle-in-a-haystack" drug-resistant cases that occur in low-incidence areas earlier, resulting in the implementation of appropriate therapy sooner.
   

As the World Health Organization calls for more resources to improve the laboratory diagnosis of TB (6), enhanced smear microscopy, broth-based culture media for detection, and susceptibility testing may not be implemented fast enough to cope with increasing drug-resistance prevalence in several parts of the world where TB-HIV coinfection cries for even faster turnaround times. Because of this urgency, the testing for TB warrants a paradigm shift, including widespread utilization of molecular assays.

Twenty-five years ago, John Sbarbaro wrote about the fact that TB provides us with a basis for insight into human institutions, our human organizations, and our human society (7). He described the discovery of streptomycin and isoniazid and continued, "it took until 1961, nine years after the presentation of evidence that we had achieved a significant scientific breakthrough, for the Committee on Therapy of the American Trudeau Society to issue a statement that essentially eliminated bed rest as a therapeutic principle. Now, please understand that I am not ridiculing or criticizing the professionals of the past... [c]learly, we professionals change slowly." With estimates of one person dying of TB every 10 seconds in the world, can we afford to again change so slowly?

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Winslow C-EA. The life of Hermann M. Biggs: physician and statesman of the public health. Philadelphia: Lea & Febiger; 1929.
2. Barnard M, Albert H, Coetzee G, O'Brien R, Bosman ME. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008;177:787–792.[Abstract/Free Full Text]
3. Yagui M, Perales MT, Asencios L, Vergara L, Suarez C, Yale G, Salazar C, Saavedra M, Shin S, Ferrousier O, et al. Timely diagnosis of MDR-TB Ander program conditions: is rapid drug susceptibility testing sufficient? Int J Tuberc Lung Dis 2006;10:838–843.[Medline]
4. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, Zeller K, Andrews J, Friedland G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575–1580.[CrossRef][Medline]
5. Keshavjee S, Gelmanova IY, Pasechnikov AD, Mishustin SP, Andreev YG, Yedilbayev A, Furin JJ, Mukherjee JS, Rich ML, Nardell EA, et al. Treating multidrug-resistant tuberculosis in Tomsk, Russia: developing programs that address the linkage between poverty and disease. Ann N Y Acad Sci [Epub ahead of print] 2007 Oct 22; DOI: 10.1196/annals.1425.009. Most recent version available from: http:dx.doi.org/10.1196/annals.1425.009.[CrossRef][Medline]
6. World Health Organization. The global MDR-TB & XDR-TB response plan: 2007–2008. Geneva: The Organization; 2007. Publication No. WHO/HTM/TB/2007.387.
7. Sbarbaro JA. Tuberculosis: a portal through which to view the future. Am Rev Respir Dis 1982;125:127–132.[Medline]

Related articles in AJRCCM:

Rapid Molecular Screening for Multidrug-Resistant Tuberculosis in a High-Volume Public Health Laboratory in South Africa

Marinus Barnard, Heidi Albert, Gerrit Coetzee, Richard O'Brien, and Marlein E. Bosman
AJRCCM 2008 177: 787-792. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCCM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Salfinger, M. Articles by Ashkin, D. Search for Related Content PubMed PubMed Citation Articles by Salfinger, M. Articles by Ashkin, D.