On September 30, 1999, the Food and Drug Administration approved
a reformulated Amplified Mycobacterium Tuberculosis Direct Test* (MTD)
(Gen-Probe®, San Diego, California) for detection of
Mycobacterium tuberculosis in acid-fast
bacilli (AFB) smear-positive and smear-negative respiratory specimens from
patients suspected of having tuberculosis (TB). MTD and one other nucleic acid
amplification (NAA) test, the
Amplicor® Mycobacterium Tuberculosis Test (Amplicor)
(Roche® Diagnostic Systems, Inc., Branchburg, New Jersey), previously had been approved
for the direct detection of M. tuberculosis in respiratory specimens that have
positive AFB smears. This notice updates the original summary published in 1996
(1) and provides suggestions for using and interpreting NAA test results for
managing patients suspected of having TB.
The appropriate number of specimens to test with NAA will vary depending on
the clinical situation, the prevalence of TB, the prevalence of nontuberculous
mycobacteria (NTM), and laboratory proficiency
(2,3). Based on available information, the
following algorithm is a reasonable approach to NAA testing of respiratory specimens
from patients with signs or symptoms of active pulmonary TB for whom a
presumed diagnosis has not been established.
Algorithm
Collect sputum specimens on 3 different days for AFB smear
and mycobacterial culture.
Perform NAA test on the first sputum specimen collected, the first
smear-positive sputum specimen, and additional sputum specimens as indicated below.
If the first sputum specimen is smear-positive and NAA-positive, the
patient can be presumed to have TB without additional NAA testing. However,
unless concern exists about the presence of NTM, the NAA test adds little to
the diagnostic work-up.
If the first sputum is smear-positive and NAA-negative, a test for
inhibitors should be done. The inhibitor test can be done as an option with Amplicor.
To test for inhibitors of MTD, spike an aliquot of the lysated sputum sample
with lysed M. tuberculosis (approximately 10 organisms per reaction, or
an equivalent amount of M. tuberculosis rRNA) and repeat the test starting
with amplification.
If inhibitors are not detected, additional specimens (not to exceed a total
of three) should be tested. The patient can be presumed to have
NTM if a second sputum specimen is smear-positive, NAA-negative, and has
no inhibitors detected.
If inhibitors are detected, the NAA test is of no diagnostic help.
Additional specimens (not to exceed a total of three) can be tested with NAA.
If sputum is smear-negative and MTD-positive†, additional specimens (not
to exceed three) should be tested with MTD. The patient can be
presumed to have TB if a subsequent specimen is MTD-positive.
If sputum is smear-negative and
MTD-negative†, an additional specimen
should be tested with MTD. The patient can be presumed not to be infectious if
all smear and MTD results are negative. The clinician must rely on
clinical judgement in decisions regarding the need for antituberculous therapy
and further diagnostic work-up because negative NAA results do not exclude
the possibility of active pulmonary TB.
If the indicated repeat NAA testing fails to verify initial NAA test results,
the clinician must rely on clinical judgement in decisions regarding the need
for antituberculous therapy, further diagnostic work-up, and isolation.
Ultimately, the patient's response to therapy and culture results are used
to confirm or refute a diagnosis of TB.
Cautions
NAA tests can enhance diagnostic certainty, but they do not replace AFB smear
or mycobacterial culture, and they do not replace clinical judgement. Clinicians
should interpret these tests based on the clinical situation, and laboratories should
perform NAA testing only at the request of the physician and only on selected
specimens. Laboratorians should not reserve material from clinical specimens for NAA testing
if this compromises the ability to perform the other established tests that have
better-defined diagnostic utility and implications. Specificity of NAA tests varies
between laboratories as a result of unrecognized procedural differences and differences
in cross-contamination rates (4). Multiple specimens from the same patient should
not be tested together to reduce risks of methodologic errors. Laboratory directors
should provide to clinicians information on the performance of NAA tests in the local
setting, including sensitivity and specificity compared with culture for both smear-positive
and smear-negative respiratory specimens. Substantial discrepancies can
indicate problems with either culture or NAA technique. The number of NAA tests
repeated because of failure of negative and positive controls also should be reported.
Clinicians should understand the impact that changes in sensitivity, specificity, prevalence of
TB, and prevalence of other mycobacterial diseases can have on the predictive value of
the NAA test. Information is limited regarding NAA test performance for
nonrespiratory specimens, or specimens from treated patients. NAA tests often remain positive
after cultures become negative during therapy and can remain positive even
after completion of therapy.
References
CDC. Nucleic acid amplification tests for tuberculosis. MMWR 1996;45:950--1.
Cohen RA, Muzaffar S, Schwartz D, et al. Diagnosis of pulmonary tuberculosis using
PCR assays on sputum collected within 24 hours of hospital admission. Am J Respir Crit
Care Med 1998;157:156--61.
Jonas V, Acedo M, Clarridge JE, et al. A multi-center evaluation of MTD and culture
compared to patient diagnosis [Abstract]. In: Abstracts of the 98th General Meeting of the
American Society for Microbiology, 1998:358 (no. L-31).
Ridderhoff J, Williams L, Legois S, Bussen M, Metchock L, Kubista R. Assessment
of laboratory performance with nucleic acid amplification (NAA) tests for
Mycobacterium tuberculosis (M.tb) [Abstract]. In: Abstracts of the 98th General Meeting of the
American Society for Microbiology, 1998:360(no. L-43).
* Use of trade names and commercial sources is for identification only and does not
constitute endorsement by CDC or the U.S. Department of Health and Human Services.
† Amplicor is not approved for use with smear-negative samples.
.
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