Systematic review and meta-analysis of antigen detection tests for the diagnosis of tuberculosis

Abstract

Tests that detect Mycobacterium tuberculosis antigens in clinical specimens could provide rapid direct evidence of active disease. We performed a systematic review to assess the diagnostic accuracy of antigen detection tests for active tuberculosis (TB) according to standard methods and summarized test performance using bivariate random effects meta-analysis. Overall, study quality was a concern. For pulmonary TB (47 studies, 5,036 participants), sensitivity estimates ranged from 2% to 100% and specificity from 33% to 100%. Lipoarabinomannan (LAM) was the antigen most frequently targeted (23 studies, 49%). The pooled sensitivity of urine LAM was higher in HIV-infected than HIV-uninfected individuals (47%; 95% confidence interval [CI], 26 to 68% versus 14%; 95% CI, 4 to 38%); pooled specificity estimates were similar: 96%; 95% CI, 81 to 100% and 97%; 95% CI, 86 to 100%, respectively. For extrapulmonary TB (21 studies, 1,616 participants), sensitivity estimates ranged from 0% to 100% and specificity estimates from 62% to 100%. Five studies targeting LAM, ESAT-6, Ag85 complex, and the 65-kDa antigen in cerebrospinal fluid, when pooled, yielded the highest sensitivity (87%; 95% CI, 61 to 98%), but low specificity (84%; 95% CI, 60 to 95%). Because of the limited number of studies targeting any specific antigen other than LAM, we could not draw firm conclusions about the overall clinical usefulness of these tests. Further studies are warranted to determine the value of LAM detection for TB meningitis in high-HIV-prevalence settings. Considering that antigen detection tests could be translated into rapid point-of-care tests, research to improve their performance is urgently needed.

Fig. 1.

Antigen-capture ELISA. (Far left) Antigen-specific monoclonal or polyclonal antibodies are coated onto the surface of plastic wells. (Second from left) The specimen containing the antigen to be measured is added. The antigen released is then “captured” by the antigen-specific antibodies. (Third from left) The captured antigen(s) are detected by secondary antibodies using the same antibody or an antibody directed toward an epitope that is different from the epitope recognized by the capture antibody. These secondary antibodies can be directly labeled with moieties, like biotin, or enzymes, like horseradish peroxidase. When biotin is used, visualization requires the addition of streptavidin conjugated to enzyme (horseradish peroxidase or alkaline phosphatase). (Far right) The appropriate substrate is added. The result is visualized by the color generated and measured with an ELISA plate reader. (Reprinted from reference with permission of the publisher.)

Fig. 2.

Flow of studies in the review of antigen detection tests for the diagnosis of pulmonary and extrapulmonary TB. *, two of the papers in the extrapulmonary TB group are also included in the pulmonary TB group.

Fig. 3.

Forest plots of sensitivity and specificity for antigen detection tests for pulmonary TB, all studies. For letters preceding author names: A, serum; B, sputum; C, urine. (Lowercase letters following year of study indicate distinct studies.) TP, true positive; FP, false positive; FN, false negative; TN, true negative. The 95% confidence intervals (CI) are included between the brackets. The figure shows the sensitivity and specificity estimates for individual studies (squares) and 95% CIs (black horizontal lines).

Fig. 4.

Forest plots of sensitivity and specificity for urine LAM for pulmonary TB. Studies of HIV-infected patients are identified with “*.” TP, true positive; FP, false positive; FN, false negative; TN, true negative. 95% confidence intervals (CI) are included between the brackets. The figure shows the sensitivity and specificity estimates for individual studies (squares) and 95% CIs (black horizontal lines).

Fig. 5.

Forest plots of sensitivity and specificity for antigen detection tests for the diagnosis of extrapulmonary TB, all studies. For letters preceding author names: A, biopsy specimen; B, cerebrospinal fluid; C, lymph node aspirate; D, pleural fluid; E, serum; F, urine. TP, true positive; FP, false positive; FN, false negative; TN, true negative. The 95% confidence intervals (CI) are included between the brackets. The figure shows the sensitivity and specificity estimates for individual studies (squares) and 95% CIs (black horizontal lines).

Fig. 6.

Summary HROC plot of sensitivity and specificity for antigen detection tests of cerebrospinal fluid for the diagnosis of tuberculous meningitis. The width of the circles is proportional to the number of patients in each study. The square is the summary value for sensitivity and specificity.