Andrew Ramsay

Performance of Purified Antigens for Serodiagnosis of Pulmonary Tuberculosis: a Meta-Analysis

ABSTRACT Serological antibody detection tests for tuberculosis may offer the potential to improve diagnosis. Recent meta-analyses have shown that commercially available tests have variable accuracies and a limited clinical role. We reviewed the immunodiagnostic potential of antigens evaluated in research laboratories (in-house) for the serodiagnosis of pulmonary tuberculosis and conducted a meta-analysis to evaluate the performance of comparable antigens. Selection criteria included the participation of at least 25 pulmonary tuberculosis patients and the use of purified antigens. Studies evaluating 38 kDa, MPT51, malate synthase, culture filtrate protein 10, TbF6, antigen 85B, α-crystallin, 2,3-diacyltrehalose, 2,3,6-triacyltrehalose, 2,3,6,6′-tetraacyltrehalose 2′-sulfate, cord factor, and TbF6 plus DPEP (multiple antigen) were included in the meta-analysis. The results demonstrated that (i) in sputum smear-positive patients, sensitivities significantly ≥50% were provided for recombinant malate synthase (73%; 95% confidence interval [CI], 58 to 85) and TbF6 plus DPEP (75%; 95% CI, 50 to 91); (ii) protein antigens achieved high specificities; (iii) among the lipid antigens, cord factor had the best overall performance (sensitivity, 69% [95% CI, 28 to 94]; specificity, 91% [95% CI, 78 to 97]); (iv) compared with the sensitivities achieved with single antigens (median sensitivity, 53%; range, 2% to 100%), multiple antigens yielded higher sensitivities (median sensitivity, 76%; range, 16% to 96%); (v) in human immunodeficiency virus (HIV)-infected patients who are sputum smear positive, antibodies to several single and multiple antigens were detected; and (vi) data on seroreactivity to antigens in sputum smear-negative or pediatric patients were insufficient. Potential candidate antigens for an antibody detection test for pulmonary tuberculosis in HIV-infected and -uninfected patients have been identified, although no antigen achieves sufficient sensitivity to replace sputum smear microscopy. Combinations of select antigens provide higher sensitivities than single antigens. The use of a case-control design with healthy controls for the majority of studies was a limitation of the review. Efforts are needed to improve the methodological quality of tuberculosis diagnostic studies.

A systematic review of commercial serological antibody detection tests for the diagnosis of extrapulmonary tuberculosis

Conventional diagnostic tests for tuberculosis have several limitations and are often unhelpful in establishing the diagnosis of extrapulmonary tuberculosis. Although commercial serological antibody based tests are available, their usefulness in the diagnosis of extrapulmonary tuberculosis is unknown. A systematic review was conducted to assess the accuracy of commercial serological antibody detection tests for the diagnosis of extrapulmonary tuberculosis. In a comprehensive search, 21 studies that reported data on sensitivity and specificity for extrapulmonary tuberculosis were identified. These studies evaluated seven different commercial tests, with Anda-TB IgG accounting for 48% of the studies. The results showed that (1) all commercial tests provided highly variable estimates of sensitivity (range 0.00–1.00) and specificity (range 0.59–1.00) for all extrapulmonary sites combined; (2) the Anda-TB IgG kit showed highly variable sensitivity (range 0.26–1.00) and specificity (range 0.59–1.00) for all extrapulmonary sites combined; (3) for all tests combined, sensitivity estimates for both lymph node tuberculosis (range 0.23–1.00) and pleural tuberculosis (range 0.26–0.59) were poor and inconsistent; and (4) there were no data to determine the accuracy of the tests in children or in patients with HIV infection, the two groups for which the test would be most useful. At present, commercial antibody detection tests for extrapulmonary tuberculosis have no role in clinical care or case detection.

Rural poverty and delayed presentation to tuberculosis services in Ethiopia

To measure time to initial presentation and assess factors influencing the decision to seek medical attention, we interviewed 243 patients undergoing sputum examination for the diagnosis of tuberculosis (TB) at a rural health centre near Awassa, Ethiopia. A structured questionnaire was used. Median (mean + SD) patient delay was 4.3 (9.8 + 12.4) weeks. Delays over 4 weeks were significantly associated with rural residence, transport time over 2 h, overnight travel, transport cost exceeding US

New and improved tuberculosis diagnostics: evidence, policy, practice, and impact

1.40, having sold personal assets prior to the visit, and use of traditional medicine. The majority of patients cited economic or logistical barriers to health care when asked directly about causes of delay. Case‐finding strategies for TB must be sensitive to patient delay and health systems must become more accessible in rural areas.

Optimizing sputum smear microscopy for the diagnosis of pulmonary tuberculosis

Purpose of review The aim is to summarize the evidence base for tuberculosis (TB) diagnostics, review recent policies on TB diagnostics, and discuss issues such as how evidence is translated into policy, limitations of the existing evidence base, and challenges involved in translating policies into impact. Recent findings Case detection continues to be a major obstacle to global TB control. Fortunately, due to an unprecedented level of interest, funding, and activity, the new diagnostics pipeline for TB has rapidly expanded. There have been several new policies and guidelines on TB diagnostics. However, there are major gaps in the existing pipeline (e.g. lack of a point-of-care test) and the evidence base is predominantly made up of research studies of test accuracy. Summary With the availability of new diagnostics and supporting policies, the next major step is translation of policy into practice. The impact of new tests will depend largely on the extent of their introduction and acceptance into the global public sector. This will itself depend in part on policy decisions by international technical agencies and national TB programs. With the engagement of all key stakeholders, we will need to translate evidence-based policies into epidemiological and public health impact.

Duration and associated factors of patient delay during tuberculosis screening in rural Cameroon

Karen R Steingart, Andrew Ramsay and Madhukar Pai Author for correspondence Deptartment of Epidemiology, Biostatistics & Occupational Health, McGill University, Respiratory Epidemiology & Clinical Research Unit, Montréal Chest Institute, 1020 Pine Avenue West, Montréal H3A 1A2, Canada Tel.: +1 514 398 5422 Fax: +1 514 398 4503 madhukar.pai@mcgill.ca Expert Rev. Anti Infect. Ther. 5(3), 327–331 (2007)

Bleach Sedimentation: An Opportunity to Optimize Smear Microscopy for Tuberculosis Diagnosis in Settings of High Prevalence of HIV

Objectives  (i) To determine patient delay – the time from the onset of symptoms to presentation at a health facility – and its causes in patients undergoing sputum smear examination in Cameroon; and (ii) to compare the results with those of a previous study in Ethiopia.

Same-day smears in the diagnosis of tuberculosis

BACKGROUND The purpose of the study was to evaluate the performance and feasibility of tuberculosis diagnosis by sputum microscopy after bleach sedimentation, compared with by conventional direct smear microscopy, in a setting of high prevalence of HIV. METHODS In a community-based study in Kenya (a population in which 50% of individuals with tuberculosis are infected with HIV), individuals with suspected pulmonary tuberculosis submitted 3 sputum specimens during 2 consecutive days, which were examined by blind evaluation. Ziehl-Neelsen-stained smears were made of fresh specimens and of specimens that were processed with 3.5% household bleach followed by overnight sedimentation. Two different cutoffs for acid-fast bacilli (AFB) per 100 high-power fields (HPF) were used to define a positive smear: >10 AFB/100 HPF and 1 AFB/100 HPF. Four smear-positive case definitions, based on 1 or 2 positive smears with the 1 AFB or 10 AFB cutoff, were used. RESULTS Of 1879 specimens from 644 patients, 363 (19.3%) and 460 (24.5%) were positive by bleach sedimentation microscopy, compared with 301 (16.0%) and 374 (19.9%) by direct smear microscopy, with use of the 10 AFB/100 HPF (P < .001) and 1 AFB/100 HPF (P < .001) cutoffs, respectively. Regardless of the case definition used, bleach sedimentation microscopy detected significantly more positive cases than did direct smear microscopy: 26.7% (172 of 644) versus 21.7% (140 of 644), respectively, with the case definition of 1 positive smear and the 1 AFB/100 HPF cutoff (P < .001), and 21.4% (138 of 644) versus 18.6% (120 of 644), respectively, with the case definition of 1 positive smear and the 10 AFB/100 HPF cutoff (P < .001). Inter- and intrareader reproducibility were favorable, with kappa coefficients of 0.83 and 0.91, respectively. Bleach sedimentation was relatively inexpensive and was not time consuming. CONCLUSIONS Bleach sedimentation microscopy is an effective, simple method to improve the yield of smear microscopy in a setting of high prevalence of HIV. Further evaluation of this method, under operational conditions, is urgently needed to determine its potential as a tool for tuberculosis control.

Commercial serological tests for the diagnosis of tuberculosis: do they work?

Objective  To assess the feasibility of completing the diagnosis of tuberculosis (TB) in 1 day by collecting only on‐the‐spot specimens.

Translating tuberculosis research into global policies: the example of an international collaboration on diagnostics.

Karen R Steingart, Andrew Ramsay & Madhukar Pai† †Author for correspondence McGill University, Dept. of Epidemiology, Biostatistics & Occupational Health, Montreal, Canada and, Respiratory Epidemiology & Clinical Research Unit, Montreal Chest Institute 1020 Pine Avenue West, Montreal, Canada Tel.: +1 514 398 5422; Fax: +1 514 398 4503; madhukar.pai@mcgill.ca ‘Both pulmonary and extrapulmonary TB present diagnostic challenges.’