naats and clinical prediction rules for tb in acute care 1219
during the mid-1990s to the mid-2000s.35–42 One study was conducted in a network of facilities across the United States.40 Almost all studies included a CPR by initially conducting a derivation cohort37,40,41 or case-control study36,38 and selecting a threshold value for the CPR that prioritized sensitivity over specificity for detection of patients without pulmonary TB.36–42 In 2 studies, criteria were identified only through a cohort35 or case-control42 study. Nearly all studies subsequently used either a prospective39,40 or retrospective37,41 study design to validate the CPRs. None of the studies validated the CPRs in indepen- dent populations or settings.35–42 CPRs consisted of 4–13 criteria and included TB risk factors,
clinical symptoms or signs, or laboratory and radiographic findings.35–42 The sensitivity of the CPRs for detection of
patients with culture-positive pulmonary TB was 81%– 100%,35–42 and only 1 CPR had a sensitivity less than 90%.42 Specificity of the CPRs for identification of patients without TB was 14%–63%,35–42 and the CPR with the lowest specifi- city36 was evaluated in a cohort of patients admitted to an acute care facility with a diagnosis of pneumonia. All CPRs had a negative predictive value of at least 92% for ruling out pulmonary TB, while the positive predictive value for detection of pulmonary TB was 3%–26%.35–42 Differences in the patient populations included in the studies as well as the criteria included in CPRs may, in part, explain the varying estimates of diagnostic performance.
Limitations of Clinical Prediction Rules
Several factors may limit the generalizability of published CPRs. Because most studies were conducted during the 1990s35–40 when TB was more common among US-born than foreign-born persons, the risk factors used to identify patients with pulmonary TB may not be applicable to the majority of current TB patient populations. Also, because most studies were conducted in academic healthcare facilities in urban areas with high TB burden, it is unclear how these CPRs would per- form in areas with low TB burden and in nonacademic facilities. Finally, to our knowledge, no studies have documented the cost- effectiveness of implementing these CPRs. Nevertheless, a recently published CPR41 incorporates risk
factors that reflect the current epidemiology of TB patients, such as foreign birth and immunosuppressing conditions such as diabetes and end-stage renal disease (Figure 1). This CPR could be part of an infection prevention strategy that also employs an NAAT.
naats for diagnosis of pulmonary tb
NAATs use deoxyribonucleic acid amplification–based methods to amplify target nucleic acid regions that are unique to M. tuberculosis complex bacteria, and they can be used directly on clinical specimens such as sputumsamples. There are 2 types of NAATs: laboratory-developed tests, which vary widely in their design and methods, and standardized commercial kits.45
At present, 2 commercial NAATs have received market authorization from the FDA. Both commercial tests are authorized for use on AFB smear-positive and smear-negative respiratory specimens from patients with suspected pulmonary TB. The enhanced Amplified Mycobacterium Tuberculosis Direct Test (E-MTD, Hologic Gen-Probe, San Diego, CA) combines isothermal transcription-mediated amplification of a portion of the 16S rRNA for M. tuberculosis complex with a hybridization probe specific to the bacteria.46 The Xpert MTB/ RIF assay (Cepheid, Sunnyvale, CA) is an automated cartridge- based test that uses a hemi-nested real-time polymerase chain reaction assay to amplify an 81-base-pair core region of the rpoB gene for M. tuberculosis complex.12 The Xpert assay also utilizes 5 molecular beacon probes to detect mutations in the core region of the rpoB gene that are associated with rifampin resistance.12 Because the Xpert assay detects silent and missense mutations in the rpoB gene,12 results from an additional NAAT test, such as a pyrosequencing assay,47 that determines theDNA sequence of the rpoB gene are needed to confirmthe presence of mutations associated with rifampin resistance.48 In addition, phenotypic drug susceptibility testing of cultured isolates is required to confirm rifampin resistance. Despite the fact that NAATs have been available in clinical
practice for almost 2 decades, several factors have limited use of these tests in the United States: (1) cost and availability of the tests; (2) delayed time interval between specimen collection and communication of the laboratory report to the treating healthcare provider; and (3) laboratory policies that restrict these tests for the use on AFB smear-positive respiratory specimens.49 The most recent CDC guidelines regarding use of NAATs for diagnosis of TB recommend that testing become a standard practice in the United States to aid in the initial evaluation of patients with suspected pulmonary TB.49 To maximize the benefits of NAATs, these tests should be interpreted in con- junction with AFB smear results for respiratory specimens and should be performed in all patients in whom a diagnosis of pulmonary TB is being considered and in whom the results would influence clinical and public health decision making.49
Diagnostic Accuracy of NAATs for Pulmonary TB
Several meta-analyses have been published on the performance of laboratory-developed tests50,51 and commercial kits52 com- pared to cultures for diagnosis of pulmonary TB. For both laboratory-developed and commercial NAATs, pooled sensi- tivity and specificity estimates varied by AFB sputum smear status.50–52 Compared to patients with negative AFB sputum smears, patients with positive smears had higher pooled sensitivity estimates (laboratory-developedNAAT: 96%vs 72%; commercial NAAT: 96% vs 66%) and lower pooled specificity estimates (laboratory-developed NAAT: 81% vs 91%; com- mercialNAAT: 85%vs 98%).50–52 These studies did not include data on the Xpert assay because this assay was only recently developed and authorized for use in the United States. To date, few meta-analyses on the diagnostic accuracy of the Xpert assay
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