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      Contact investigation for tuberculosis: a systematic review and meta-analysis


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          Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.

          We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.

          After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I 2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I 2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I 2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I 2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I 2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I 2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I 2=99.5%). There was substantial heterogeneity among published studies.

          Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.

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          The binomial distribution of meta-analysis was preferred to model within-study variability.

          When studies report proportions such as sensitivity or specificity, it is customary to meta-analyze them using the DerSimonian and Laird random effects model. This method approximates the within-study variability of the proportion by a normal distribution, which may lead to bias for several reasons. Alternatively an exact likelihood approach based on the binomial within-study distribution can be used. This method can easily be performed in standard statistical packages. We investigate the performance of the standard method and the alternative approach. We compare the two approaches through a simulation study, in terms of bias, mean-squared error, and coverage probabilities. We varied the size of the overall sensitivity or specificity, the between-studies variance, the within-study sample sizes, and the number of studies. The methods are illustrated using a published meta-analysis data set. The exact likelihood approach performs always better than the approximate approach and gives unbiased estimates. The coverage probability, in particular for the profile likelihood, is also reasonably acceptable. In contrast, the approximate approach gives huge bias with very poor coverage probability in many cases. The exact likelihood approach is the method of preference and should be used whenever feasible.
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            Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight.

            In April 1994, a passenger with infectious multi-drug resistant tuberculosis traveled on commercial-airline flights from Honolulu to Chicago and from Chicago to Baltimore and returned one month later. We sought to determine whether she had infected any of her contacts on this extensive trip. Passengers and crew were identified from airline records and were notified of their exposure, asked to complete a questionnaire, and screened by tuberculin skin tests. Of the 925 people on the airplanes, 802 (86.7 percent) responded. All 11 contacts with positive tuberculin skin tests who were on the April flights and 2 of 3 contacts with positive tests who were on the Baltimore-to-Chicago flight in May had other risk factors for tuberculosis. More contacts on the final, 8.75-hour flight from Chicago to Honolulu had positive skin tests than those on the other three flights (6 percent, as compared with 2.3, 3.8, and 2.8 percent). Of 15 contacts with positive tests on the May flight from Chicago to Honolulu, 6 (4 with skin-test conversion) had no other risk factors; all 6 had sat in the same section of the plane as the index patient (P=0.001). Passengers seated within two rows of the index patient were more likely to have positive tuberculin skin tests than those in the rest of the section (4 of 13, or 30.8 percent, vs. 2 of 55, or 3.6 percent; rate ratio, 8.5; 95 percent confidence interval, 1.7 to 41.3; P=0.01). The transmission of Mycobacterium tuberculosis that we describe aboard a commercial aircraft involved a highly infectious passenger, a long flight, and close proximity of contacts to the index patient.
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              Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis.

              Numerous studies have been published on the new Mycobacterium tuberculosis (MTB)-specific IFN-gamma release assays. However, their prognostic value for progression from latent tuberculosis infection (LTBI) to active TB has yet to be established. To compare the QuantiFERON-TB Gold In-Tube assay (QFT) with the tuberculin skin test (TST) in recently exposed close contacts of active TB cases with respect to their development of TB disease within 2 years. Close contacts (n = 601) of MTB-positive source cases underwent both TST and QFT testing and were subsequently observed for 103 (+/-13.5) weeks. Risk factors for MTB infection were evaluated by multivariate analysis. For the TST, 40.4% (243/601) of contacts were positive at a 5-mm cutoff, whereas only 66 (11%) were QFT positive. QFT positivity, but not TST, was associated with exposure time (P < 0.0001). Six contacts progressed to TB disease within the 2-year follow-up. All were QFT positive and had declined preventive treatment, equating to a progression rate of 14.6% (6/41) among those who were QFT positive. The progression rate for untreated TST-positive subjects was significantly lower (P < 0.003), at 2.3% (5 of 219), and one subject who progressed was TST negative. Results suggest that QFT is a more accurate indicator of the presence of LTBI than the TST and provides at least the same sensitivity for detecting those who will progress to active TB. The high rate of progression to active TB of those who are QFT positive (14.6%), which is far greater than the 2.3% found for those who are TST positive, has health and economic implications for enhanced TB control, particularly if this higher progression rate is seen in studies of other at-risk populations.

                Author and article information

                Eur Respir J
                Eur. Respir. J
                The European Respiratory Journal
                European Respiratory Society (442 Glossop Road, Sheffield, S10 2PX, UK )
                January 2013
                30 August 2012
                : 41
                : 1
                : 140-156
                [* ]Woolcock Institute of Medical Research, University of Sydney
                [# ]Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney
                []Discipline of Medicine, Sydney Medical School, University of Sydney
                [+ ]Dept of Respiratory Medicine, Liverpool Hospital , Sydney, Australia
                Author notes
                G.J. Fox, Woolcock Institute of Medical Research, University of Sydney, 431 Glebe Point Road, Glebe, Sydney 2037, Australia. E-mail: greg.fox@ 123456sydney.edu.au
                Copyright © ERS 2013

                ERJ Open articles are open access and distributed under the terms of the ( Creative Commons Attribution Licence 3.0>)

                : 03 May 2012
                : 10 August 2012
                Original Article

                Respiratory medicine
                contact tracing,early diagnosis,human,mycobacterium tuberculosis,systematic review,tuberculosis


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