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Laurie Barclay, MD

is a freelance reviewer and writer for Medscape.

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Laurie Barclay, MD
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January 20, 2009 — The US Centers for Disease Control and Prevention (CDC) have issued updated guidelines for the use
of nucleic acid amplification (NAA) tests in the diagnosis of tuberculosis (TB). The new recommendations are published in the
January 16 issue of the Morbidity & Mortality Weekly Report. Guidelines regarding NAA tests to diagnose TB were first
published in 1996 and updated in 2000.

"Since then, NAA testing has become a routine procedure in many settings because NAA tests can reliably detect
Mycobacterium tuberculosis bacteria in specimens 1 or more weeks earlier than culture," write D. Alland, MD, from New
Jersey Medical School, Newark, and colleagues from the Division of Tuberculosis Elimination, National Center for HIV/AIDS,
Viral Hepatitis, STD, and TB Prevention, CDC. "Earlier laboratory confirmation of TB can lead to earlier treatment initiation,
improved patient outcomes, increased opportunities to interrupt transmission, and more effective public health interventions."

In June 2008, CDC and the Association of Public Health Laboratories convened a panel of clinicians, laboratory scientists, and
TB control officials to evaluate the existing guidelines and to update recommendations for the use of NAA tests for laboratory
confirmation of TB.

On the basis of that panel's report and consultations with the Advisory Council for the Elimination of TB, CDC issued a new
recommendation: NAA testing should be done on at least 1 respiratory specimen from each patient who has signs and
symptoms of pulmonary TB and for whom a diagnosis of TB is being considered but has not yet been established when the
test result would change case management or TB control activities, such as contact investigations.

That new recommendation led to a revised algorithm for testing and interpretation, as follows:

As previously recommended, respiratory specimens such as sputum should be routinely collected; processed by
liquefying, decontamination, and concentration; and tested with acid-fast bacilli (AFB) smear microscopy and culture.
Specimen collection and microbiologic testing should not be delayed pending NAA test results.
Each patient to be tested by NAA should have at least 1, and preferably the first, diagnostic specimen processed,
suspended in enough buffer solution to ensure adequate sample volume for all planned tests (eg, microscopy, culture,
and NAA), and tested using an NAA test for TB. The manufacturer's instructions or a validated standard operating
procedure should be followed for NAA testing.
NAA test results should be interpreted in conjunction with the AFB smear results.
If the results of both the NAA and the AFB smear are positive, the patient should be presumed to have TB and should
start anti-TB treatment pending culture results. In AFB smear–positive cases, the positive predictive value of US Food
and Drug Administration (FDA)–approved NAA tests for TB is more than 95%.
If the NAA result is positive and the AFB smear result is negative, the clinician should use his or her judgment to decide
whether to start anti-TB treatment while awaiting culture results and whether additional diagnostic testing is needed. An
additional specimen using NAA to confirm the NAA result may be helpful. If 2 or more specimens are NAA-positive, a
patient can be presumed to have TB, pending culture results.

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If the NAA result is negative and the AFB smear result is positive, a test for inhibitors should be performed and an
additional specimen should be tested with NAA, because 3% to 7% of sputum specimens may contain inhibitors that
prevent or decrease amplification, causing false-negative NAA results.
The NAA test is of no diagnostic value for specimens in which inhibitors are detected. While awaiting results of
culture and additional diagnostic testing, clinicians should use their judgment to determine whether to start
anti-TB treatment.
If inhibitors are not detected, clinicians should use their judgment to decide whether anti-TB treatment should be
started pending culture results and to decide whether to perform additional diagnostic testing. If a second
specimen is smear positive and NAA negative and has no inhibitors detected, the patient can be presumed to
have an infection with nontuberculous mycobacteria.
If the results of both the NAA and the AFB smear are negative, clinicians should use their judgment to decide whether
to start anti-TB treatment pending results of culture and additional diagnostic tests. In patients suspected to have TB
despite a negative AFB smear, currently available NAA tests are insufficiently sensitive to exclude the diagnosis of TB,
as they detect only 50% to 80% of pulmonary TB cases in which AFB smear is negative and culture is positive.

Cautions noted by the panel in following the above algorithm are as follows:

Culture remains the gold standard for laboratory confirmation of TB and is needed for bacterial drug-susceptibility
testing and genotyping.
The interval from specimen collection to informing the treating clinician of the laboratory report should be as brief as
possible (=48 hours).
Currently available NAA tests should not be ordered routinely when the clinical suspicion of TB is low.
Clinicians should interpret all laboratory results in the context of the complete clinical situation.
Although the costs of adding NAA testing to the routine testing of respiratory specimens from patients suspected to
have TB might be considerable, NAA testing has the potential to provide overall cost savings to the treatment center
and TB control program.
For NAA testing of AFB smear–negative specimens, laboratories must use an FDA-approved test or a test produced
and validated in accordance with applicable FDA and Clinical Laboratory Improvement Amendments regulations.
NAA testing may be impractical in laboratories with a low test volume, both for procedural and economic reasons.
Referral of samples for NAA testing to high-volume laboratories should be considered.
For nonrespiratory specimens or specimens from patients receiving treatment, evidence is limited concerning NAA test
performance.

"These guidelines do not address the use of molecular tests for detecting drug resistance, which is an urgent public health
and diagnostic need," the panel concludes. "No molecular drug-susceptibility tests (DSTs) have been approved by FDA for
use in the United States, although well-characterized molecular DSTs are commercially available in Europe and elsewhere.
Nonetheless, a proposed revision of the Diagnostic Standards and Classification of Tuberculosis in Adults and Children is
likely to support the use of molecular DSTs for AFB smear-positive sputum sediments from TB patients who are suspected to
have drug-resistant disease or who are from a region or population with a high prevalence of drug resistance."

Morb Mortal Wkly Rep. 2009;58:7–10.

Medscape Medical News © 2009

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