Notices to Readers Nucleic Acid Amplification Tests for Tuberculosis

Traditional methods for laboratory diagnosis of tuberculosis (TB) may require weeks, and delay can impede treatment and control efforts. Nucleic acid amplification (NAA) tests, such as polymerase chain reaction (PCR) and other methods for amplifying DNA and RNA, may facilitate rapid detection of microorganisms. An NAA test for Mycobacterium tuberculosis complex (Amplified Mycobacterium Tuberculosis Direct Test or MTD {Gen-Probe{Registered}, San Diego, California}) * was recently approved by the Food and Drug Administration (FDA) for use on processed clinical specimens (1), and others are under development. Although NAA tests have been offered by individual laboratories, approval of commercial kits may result in increased use for clinical practice and TB control. This report summarizes potential uses of NAA tests for TB diagnosis and provides interim guidelines for the use of such tests. Current NAA Tests and FDA-Approved Uses

The MTD test uses transcription-mediated amplification to detect M. tuberculosis-complex ribosomal RNA (2). The test is approved for use in conjunction with culture for respiratory specimens that are positive for acid-fast bacilli (AFB) on microscopy and were obtained from untreated patients. Based on the product label (package insert), test sensitivity in clinical trials was 95.5%, and specificity was 100%. The specificity does not indicate the growth of M. tuberculosis from all MTD-positive specimens: trials included MTD-positive, culture-negative specimens from patients with other positive cultures, and there are other reports of test readings "in the low range of positivity" with nontuberculous mycobacteria (2). Users should consult the label for additional information.

When used as approved, a positive MTD test result can provide relatively rapid feedback, indicating a high likelihood of TB. Some public health professionals have considered a negative result to be contributory information for prioritizing contact investigations. False-negative results may be obtained for specimens containing low numbers of M. tuberculosis or substances inhibiting the assay. Regardless of MTD results, mycobacterial culture is required for drug-susceptibility testing and precise species and strain identification. As approved for use on AFB-smear-positive respiratory specimens, MTD tests usually will not change the eligibility of a case for surveillance reporting: patients for whom results are positive generally would meet the surveillance case definition previously published by CDC (3).

Several other NAA tests are under commercial development, including the Roche AmplicorTM test (4), a PCR-based test that amplifies mycobacterial DNA. This test was publicly considered in January 1996 by an FDA advisory panel, which recommended approval for use similar to the MTD. If such tests are approved, principles guiding their use would be similar to those for the MTD test.

Because specimen type and clinical setting affect interpretation of NAA tests, clinicians should provide information about patients and specimens to the laboratory, and laboratory directors should provide information about local test performance and interpretation both when tests are ordered and when results are reported. Clinicians should be educated about use under local conditions (predictive values vary with prevalence of TB and other mycobacterial diseases) and employ results as an adjunct to other clinical and microbiologic information. Off-Label Uses

Although some laboratories use FDA-approved tests for nonapproved indications (off-label uses), available information often is insufficient to guide test interpretations. For example, information is limited regarding test performance for smear-negative specimens, nonrespiratory specimens, or specimens from treated patients: preliminary results suggest NAA tests are less sensitive for smear-negative specimens (4,5), may produce false-positive results (4,5), and often remain positive after cultures become negative during therapy (6,7). Approved NAA tests are different from NAA tests developed by individual laboratories for in-house use (which have not been reviewed by FDA and may perform differently {8,9}) and from the non-NAA AccuProbe{Registered} approved for use on culture isolates. Limitations and Cautions

Used as approved by FDA, NAA tests for TB diagnosis do not replace any previously recommended tests. Material from a clinical specimen should not be reserved for NAA testing if this compromises the ability to perform established tests with better-defined implications (e.g., AFB smear as a guide to infectiousness or culture to confirm diagnosis, determine drug susceptibility, and monitor treatment response). Data are not sufficient to predict interlaboratory variability, the relation of NAA results to infectiousness, or off-label performance. Conclusions

Based on available information, decisions about when and how to use NAA tests for TB diagnosis should be individualized. The tests may enhance diagnostic certainty but should be interpreted in a clinical context and on the basis of local laboratory performance. Implications may differ for public health and individual clinical decisions; the most effective use of these tests to facilitate such decisions is not yet understood, and off-label performance is not well documented.

Reported by: Center for Devices and Radiologic Health; Center for Drug Evaluation and Research, Food and Drug Administration. Advisory Council for the Elimination of Tuberculosis. National Center for HIV, STD, and TB Prevention; National Center for Infectious Diseases; and Public Health Practice Program Office, CDC.

References

1. Nightingale SL. From the Food and Drug Administration: new tuberculosis test approved. JAMA 1996;275:585.

2. Gen-Probe{Registered}. Amplified mycobacterium tuberculosis direct test for in-vitro diagnostic use: 50 test kit {Package insert}. San Diego, California: Gen-Probe{Registered}, July 23, 1996.

3. CDC. Case definitions for public health surveillance. MMWR 1990;39(no. RR-13):41-2.

4. Bennedsen J, Ostergaard Thomsen V, Pfyffer GE, et al. Utility of PCR in diagnosing pulmonary tuberculosis. J Clin Microbiol 1996;34:1407-11.

5. Bradley SP, Reed SL, Catanzaro A. Clinical efficacy of the amplified Mycobacterium tuberculosis direct test for the diagnosis of pulmonary tuberculosis. Am J Respir Crit Care Med 1996;153:1606-10.

6. Hellyer TJ, Fletcher TW, Bates JH, et al. Strand displacement amplification and the polymerase chain reaction for monitoring response to treatment in patients with pulmonary tuberculosis. J Infect Dis 1996;173:934-41.

7. Moore DF, Curry JI, Knott CA, Jonas V. Amplification of rRNA for assessment of treatment response of pulmonary tuberculosis patients during antimicrobial therapy. J Clin Microbiol 1996;34:1745-9.

8. Noordhoek GT, Kolk AH, Bjune G, et al. Sensitivity and specificity of PCR for detection of Mycobacterium tuberculosis: a blind comparison study among seven laboratories. J Clin Microbiol 1994;32:277-84.

9. CDC. Diagnosis of tuberculosis by nucleic acid amplification methods applied to clinical specimens. MMWR 1993;42:35.

* Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

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