Report of an Expert Consultation on the Uses of Nucleic Acid Amplification Tests for the Diagnosis of Tuberculosis

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General Considerations

1. Optimum patient care and public health must be cornerstones of the recommendations.
2. Many TB suspects are seen initially by less experienced clinicians who may delay specific treatment until laboratory results confirm the diagnosis. On the assumption that, generally, knowledge and skills for TB diagnosis will remain stable or deteriorate, the laboratory will play an increasingly critical role in reducing delays in the initiation of TB treatment.
3. NAA testing has significant potential added value for clinicians and TB control officials.
   1. Earlier diagnosis leads to earlier initiation of treatment, a reduced period of infectiousness, and improved patient outcomes.
   2. Earlier notification of TB cases to public health authorities should permit public health interventions sooner and may engage a TB expert sooner in the care of the TB patient.
   3. Earlier detection of M. tuberculosis bacteria in sputum specimens can facilitate earlier infection control (respiratory isolation) decisions.
   4. Earlier differentiation of AFB-smear positive specimens containing M. tuberculosis from those containing other mycobacteria can eliminate unnecessary contact investigations.
   5. Prompt confirmation of tuberculosis may help avoid inappropriate empirical use of fluoroquinolones as monotherapy of pneumonias, a practice which is suspected to lead to development of tuberculosis resistant to fluoroquinolones.
4. NAA tests have limitations, and caution must be taken when interpreting NAA test results.
   1. The FDA-approved NAA tests for TB have slightly less sensitivity than culture-isolation methods, and the 15% to 20% of U.S. TB cases that are reported with negative culture results may also have negative NAA test results. Thus, a negative NAA test result does not exclude the diagnosis of TB.
   2. Sputum specimens (up to 20% in some studies) may contain inhibitors that prevent or reduce amplification to cause false-negative NAA test results, although inhibitors rarely cause false-negative NAA test results in smear-positive specimens (<3% of samples).
   3. Several sporadic or systematic errors can cause false-positive NAA test results.
5. Costs and funding issues
   1. Only FDA-approve d or laboratory-validated analyte specific reagent (ASR) tests are eligible for Medicare or Medicaid reimbursement.
   2. The FDA-approved tests are
      1. a substantial added cost to the laboratory;
      2. additional tests that augment but do not replace any current laboratory test;
      3. labor intensive, technically demanding, and not suitable for automation; and
      4. susceptible to end-product contamination and amplification inhibition.
   3. NAA tests can provide substantial savings
      1. for the patient (earlier diagnosis, improved outcomes, reduced health-care costs)
      2. for the health care provider (definitive diagnosis earlier, focused diagnostic testing, optimum patient care);
      3. for the hospital (less potential for nosocomial transmission, briefer period of respiratory isolation if TB is excluded); and
      4. for the public health program (interrupt transmission earlier, abbreviated period for transmission, focused contact investigations).
6. Turnaround time (TAT) must be as brief as possible to maximize benefits of NAA testing. The key TAT is the interval from specimen collection to time that the laboratory report is communicated to the health care provider.
7. Good communication between laboratorians, health care providers, and public health officials is critical to optimizing the benefits of NAA testing. Standard language or statements to include in laboratory reports of NAA test results are needed.
8. Education of laboratorians, clinicians, health care providers, TB controllers, and policy makers on the appropriate use and interpretation of NAA tests for the diagnosis of TB will be essential.
9. For general medical care and public health systems, a single, simple algorithm for NAA testing is preferred. Some special circumstances, such as infection control and inpatient medical care, may require separate algorithms.
10. There are only two FDA-approved tests which may be impractical for use by laboratories with a small volume of testing.
11. Analyte Specific Reagent (ASR) tests for detecting M. tuberculosis bacteria (e.g., real-time PCR assays) with excellent sensitivity, specificity, speed, and ease-of-use have been recently independently developed, validated, and implemented in a variety of laboratories.
    1. Home-brew tests themselves are not regulated by the FDA, but the components (ASRs) that compose them may be regulated if purchased from a manufacturer. ASRs used in home-brew tests for TB are classified as Class III medical devices by the FDA (21 CFR 864.4020) and must be cleared or approved by FDA before they can be marketed in the United States (21 CFR 864.4020)
    2. Laboratories developing and performing home-brew tests as a diagnostic service are required to meet CLIA high-complexity certification requirements, to comply with CLIA quality control requirements, and to establish the performance of the in-house test following CLIA regulations.
    3. The ordering of home-brew tests that are developed using ASRs is limited under section 520(e) of the Federal Food, Drug and Cosmetic Act to physicians and other persons authorized by applicable State law to order such tests.
    4. The laboratory that develops and performs a home-brew test using an ASR is required to inform the ordering person of the test result by appending to the test report the statement: “This test was developed and its performance characteristics determined by (Laboratory Name).” It has not been cleared or approved by the U.S. Food and Drug Administration. ” (21 CFR 809.30(e))
12. Cost efficiency, rapid turnaround time, and expertise could be enhanced by establishing high-volume regional laboratories offering molecular tests.
13. Sufficient information is available for making recommendations for respiratory specimens.
14. Further research is needed before specific recommendations can be made on the use of NAA testing in the diagnosis of TB in children who cannot produce sputum and in the diagnosis of extrapulmonary TB, although there is much anecdotal evidence of the utility of such testing in individual cases.