An assessment of nucleic acid amplification testing for active mycobacterial infection


Linked evidence of effectiveness of NAAT in the diagnosis of MTB



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Linked evidence of effectiveness of NAAT in the diagnosis of MTB

Is it accurate?


Summary—What is the diagnostic accuracy of NAAT (with or without AFB microscopy) versus culture compared with AFB versus culture in the detection of MTB?

Diagnostic accuracy meta-analyses were conducted for multiple comparisons and the results are summarised below.

Culture as the reference standard



Even though culture is considered to be the ‘gold standard’ diagnostic test for TB, it is an imperfect reference standard because not all patients who receive a clinical diagnosis of TB based on other findings such as histopathology, clinical symptoms and responsiveness to anti-TB drugs will be culture-positive.

The pooled sensitivity and specificity of culture and NAAT using clinical diagnosis as a reference standard showed that:

  • 24% of patients clinically diagnosed with TB had a false-negative culture result compared with 14% having a false-negative NAAT.

  • Thus, a large proportion of NAAT ‘false-positive’ patients (i.e. NAAT-positive, culture-negative) would be clinically diagnosed as having TB.

Therefore, NAAT is likely to be more effective at confirming the presence of an MTB infection than the meta-analysis using culture as the reference standard would suggest.

AFB microscopy plus NAAT compared with culture

The pooled sensitivity and specificity for AFB microscopy plus NAAT compared with culture was 94% (95%CI 91, 98) and 88% (95%CI 82, 92), respectively, and did not differ significantly to those for sputum and non-sputum specimens when analysed separately:

  • 6% of patients will have a false-negative result and 12% of patients will have false-positive results.

The summary LR+ and LR– values for the ability of AFB plus NAAT to correctly diagnose the presence or absence of TB in patients when compared with culture suggest that:

  • In sputum specimens AFB plus NAAT correctly identified most patients as either culture-positive or culture-negative.

  • In non-sputum specimens AFB plus NAAT correctly identified most patients who were culture-negative and showed strong diagnostic evidence for confirmation of culture-positive TB.

NAAT versus culture

Compared with culture the pooled sensitivity and specificity of NAAT for all specimens were 89% (95%CI 85, 92) and 94% (95%CI 91, 96), respectively, and did not differ significantly when sputum and non-sputum specimens were analysed separately:

  • Overall, 11% of patients had false-negative results and 6% false-positive results.

The SROC curve showed some threshold effect, suggesting that in-house NAAT was less specific than commercial NAAT when compared with culture, especially in countries with a high incidence of TB and when testing non-sputum specimens.

The summary LR+ and LR– values for the ability of NAAT to correctly diagnose the presence or absence of TB in patients when compared with culture suggest that:

  • Both in-house NAATs and the commercial Xpert NAAT had diagnostic value in confirming or excluding culture-positive disease.

  • Overall, patients with a positive NAAT result were likely to have culture-positive TB, whereas patients with a negative NAAT result were unlikely to be falsely negative.

In the context of interpreting NAAT results in conjunction with AFB findings:

  • When specimens are AFB-positive, NAAT could confidently exclude the likelihood of culture-positive TB, but a positive NAAT result did not eliminate the possibility of being culture-negative. The explanation for this result is that culture is an imperfect reference standard. Culture in AFB-positive specimens likely resulted in misclassification of many of the 22% false-positive results seen for NAAT.

  • In AFB-negative specimens a positive NAAT result was likely to correctly confirm the presence of MTB. However, interpretation of a negative NAAT result is dependent on the type of specimen tested:

    • In patients with AFB-negative sputum a negative NAAT indicated that the patient may not be culture-positive but it could not be ruled out.

    • In patients with AFB-negative non-sputum specimens a negative NAAT result provided no additional useful information. This is likely due to the paucibacillary nature of AFB-negative specimens.

There was no difference in the diagnostic accuracy of NAAT compared with culture between HIV-positive and HIV-negative patients.

NAAT was both highly sensitive (93%; 95%CI 85, 97) and highly specific (98%; 95%CI 96, 99) compared with culture-based DST in identifying rifampicin-resistant MTB.

Comparison of NAAT, AFB microscopy and AFB plus NAAT using culture as the reference standard

AFB plus NAAT had the highest false-positive rate, at 12%, with NAAT at 6% and AFB at 2%:

  • A false-positive result means a patient will receive treatment for a short time (until clinical unresponsiveness is noted or culture results are available) for a disease they do not have.

AFB microscopy had the highest false-negative rate, at 38%; NAAT and AFB plus NAAT were much lower at 11% and 6%m, respectively:

  • The consequences of a false-negative result are much more severe, as the patient may remain untreated for a longer time period and could potentially spread the disease to more individuals.

Studies were included to assess the accuracy of NAAT according to criteria outlined in Box 3.

Box 3 PICO criteria for identification of studies relevant to an assessment of the accuracy of NAAT



Population

Patients with clinical signs and symptoms of active TB who have a specimen suitable for AFB microscopy and culture, and who have had < 3 days of anti-TB treatment

Intervention

NAAT with or without AFB microscopy for the detection of MTB-complex DNA and genetic mutations associated with anti-TB drug resistance

Comparator

AFB microscopy

Reference standard

Culture ± DST

Outcomesa


  • Sensitivity

  • Specificity

  • Positive/negative predictive value

  • Level of agreement (concordance of data)

  • Diagnostic yield

Publication type

All study designs listed in the ‘Diagnostic accuracy’ column of Table 13

Search period

2005 – June 2014

Language

Non-English language articles were excluded unless they provided a higher level of evidence than the English language articles identified

a Due to the large volume of studies, included studies were limited to those that provided 2x2 data suitable for meta-analysis of sensitivity, specificity and likelihood ratios

Pre-specified subgroups for analysis included patients with a high pre-test probability of active TB (e.g. those from a country with high rates of TB) versus those with a low pre-test probability of TB. Although studies conducted in countries with a high incidence of TB were a good surrogate for patients with a high pre-test probability of having TB, there was no good surrogate for patients with a low pre-test probability of having TB. Many of the patients in those studies conducted in countries with a low incidence of TB were most likely recent immigrants from high-incidence countries. Those studies that used extrapulmonary specimens were a more appropriate surrogate for patients with a low pre-test probability of having TB, as the incidence of TB was lower in these patients.

A total of 79 studies provided data to assess the diagnostic accuracy of NAAT and AFB microscopy compared with culture in mixed pulmonary and/or extrapulmonary specimens from patients suspected of having an MTB infection. Culture methods included standard diagnostic laboratory procedures such as L-J or Ogawa solid media and/or liquid BACTEC media. Of these 79 studies, 20 (10 using an in-house NAAT and 10 using the commercial Xpert NAAT) provided data using mixed pulmonary and extrapulmonary specimens, 34 (21 in-house NAAT and 13 Xpert) using sputum specimens and 40 (29 in-house NAAT and 11 Xpert) using non-sputum specimens. Eight studies only provided data for the accuracy of NAAT compared with culture in patients with AFB-negative specimens. Eleven studies (1 in-house NAAT 10 Xpert) assessed the diagnostic accuracy of NAAT compared with culture to identify patients with drug-resistant MTB infections; 3 of the included studies only provided data for this outcome. The study profiles, patient characteristics and quality appraisal of these studies are listed in Table 96 (Appendix F) and the extracted 2x2 data are presented in Appendix C (Table 71 to Table 90). An overall summary of the body of evidence is presented in Table 19.

Table 19 Body of evidence matrix for studies reporting on the accuracy of AFB and NAAT compared with culture in diagnosing MTB infections



Component

A

Excellent

B

Good

C

Satisfactory

D

Poor

Evidence-base a

One or more level I studies with a low risk of bias or several level II studies with a low risk of bias










Consistency




Most studies consistent and inconsistency may be explained







Clinical impact




Substantial







Generalisability




Population(s) studied in the body of evidence are similar to target population







Applicability




Applicable to Australian healthcare context with few caveats







a Level of evidence determined from the NHMRC evidence hierarchy (see Table 13).

Source: Adapted from NHMRC (2009)



The proportion of patients diagnosed with culture-positive MTB varied greatly among studies. In the 68 studies that compared the diagnostic accuracy of AFB microscopy and NAAT with culture in patients suspected of having TB, the proportion of patients from whom MTB could be cultured ranged from 1% to 81%, with a mean of 30%. The mean proportion of patients with culture-positive MTB infections was greater in countries with a high incidence of TB (> 100 cases per 100,000 people; 33%) than in those with intermediate (100–10 cases per 100,000 people; 29%) or low incidence (< 10 cases per 100,000 people; 24%) rates. As expected, the mean proportion of culture-positive specimens was greater in patients with AFB-positive specimens (80%, range 27–100%) than in AFB-negative specimens (19%, range 1–72%). The proportion of culture-positive specimens identified for all subgroups are listed in Table 93 (Appendix D).

Comparison of NAAT and culture, using clinical diagnosis as a reference standard


In order to compare the sensitivity and specificity of culture and NAAT, using clinical diagnosis as a reference standard, meta-analysis was conducted using data from 10 of the included studies that provided data using a clinical reference standard. The basis for a positive clinical diagnosis differed between studies but included some or all of the following: clinical findings, AFB microscopy, histology/cytology, chest radiographic findings, site-specific CT scan / MRI results, culture results and response to anti-TB drug therapy. The pooled sensitivity for culture versus clinical diagnosis was 76% (95%CI 54, 90) compared with 86% (95%CI 77, 92) for NAAT versus clinical diagnosis (Figure 11). This indicated that 24% of patients clinically diagnosed with TB will have a false-negative culture result compared with 14% having a false-negative NAAT (1 – sensitivity). This finding was consistent with the proportion of culture-positive cases reported in the Tuberculosis notifications in Australia, 2010 Annual Report10; 78% of all MTB cases were confirmed by culture.

Forest plot showing the pooled sensitivity and specificity values <a href=for culture compared with NAAT, using a clinical reference standard, and for NAAT compared with culture in the same subset of studies" align="bottom" width="602" height="141" border="0">

Figure 11 Forest plot showing the pooled sensitivity and specificity values for culture compared with NAAT, using a clinical reference standard, and for NAAT compared with culture in the same subset of studies



CRS = clinical reference standard; K = the number of studies; NAAT = nucleic acid amplification testing


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