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      Pathogenesis of tuberculosis: the 1930 Lübeck disaster revisited

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          Abstract

          During the 1930 Lübeck Mycobacterium bovis bacille Calmette–Guérin (BCG) disaster, 251 neonates received three oral BCG doses accidentally contaminated by virulent Mycobacterium tuberculosis; 67 (26.7%) infants died of tuberculosis. BCG reversion to pathogenicity did not occur. Detailed post mortem examinations clarified contested aspects of tuberculosis pathogenesis. Gastrointestinal infection was seldom “silent” and did not cause typical primary pulmonary lesions. In 15 infants, primary pulmonary foci were found but these resulted from vaccine ingestion and aspiration and were not caused by gastrointestinal infection spreading to the lungs without trace of its journey, as claimed by prominent researchers such as Calmette and von Behring. Further, among 60 infants in whom post mortem evaluation was completed, a “silent” gastrointestinal infection without an intestinal primary focus was found in only one. Lymphohaematogenous-disseminated tuberculosis caused death in 24/67 (35.8%) infants and tuberculous meningitis in a further 17/67 (25.4%). Gastrointestinal tuberculosis complications caused death in 26/67 (38.8%) infants. Half of the tuberculosis-attributed deaths had occurred by 3 months, 93% by 6 months and 100% by 12 months; remarkably no further deaths or tuberculosis recurrences occurred within 5 years post-vaccination/infection. These findings provide graphic confirmation that the early introduction of chemoprophylaxis in recently M. tuberculosis-infected young children is critical and urgent.

          Abstract

          The Lübeck disaster emphasises that tuberculosis disease in nearly all infants develops soon after primary infection. Failure to institute chemoprophylaxis as soon as possible post-infection exposes infants to a considerable risk of serious disease or death. https://bit.ly/3yjk7kC

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          Revisiting the timetable of tuberculosis

          Tuberculosis has a much shorter incubation period than is widely thought, say Marcel A Behr and colleagues, and this has implications for prioritising research and public health strategies
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            The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis

            Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood. We conducted an individual participant data meta-analysis of cohort studies in which children (<19 years of age) with close tuberculosis exposure were investigated for tuberculosis and followed for incident disease. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models, and estimated adjusted hazard ratios (AHR) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. We pooled participant-level data from 46 cohort studies in 34 countries. We included 137,647 exposed children followed for 429,538 child-years, during which 1,299 prevalent and 999 incident cases were diagnosed. The two-year risk of developing tuberculosis among infected children not receiving preventive therapy was 19.0% from 0 to 5 years of age. The effectiveness of preventive therapy was 63% (AHR, 0.37, 95% confidence intervals [CI], 0.30–0.47) among all exposed children, and 85% (AHR, 0.15, 95% CI, 0.11–0.20) among those with a positive test of infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit. The risk of developing tuberculosis among exposed infants and young children is very high. The majority of cases occurred within weeks of contact investigation initiation and may not be preventable through prophylaxis. This suggests that alternative strategies for prevention, such as earlier initiation of preventive therapy through earlier diagnosis of adult cases or community-wide screening approaches, are needed.
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              100 years of Mycobacterium bovis bacille Calmette-Guérin

              Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.
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                Author and article information

                Journal
                Eur Respir Rev
                Eur Respir Rev
                ERR
                errev
                European Respiratory Review
                European Respiratory Society
                0905-9180
                1600-0617
                30 June 2022
                29 June 2022
                : 31
                : 164
                : 220046
                Affiliations
                [1 ]Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg, Western Cape Province, South Africa
                [2 ]Max Planck Institute for Infection Biology, Berlin, Germany
                [3 ]Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
                [4 ]Hagler Institute for Advanced Study, Texas A&M University, College Station, TX, USA
                [5 ]Dept of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
                [6 ]Global TB Program, Dept of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
                [7 ]Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
                [8 ]German Center for Infection Research (DZIF)
                [9 ]Respiratory Medicine and International Health, University of Lübeck, Lübeck, Germany
                Author notes
                Corresponding author: Peter Donald ( prd@ 123456sun.ac.za )
                Author information
                https://orcid.org/0000-0001-9090-7869
                https://orcid.org/0000-0002-8091-3509
                Article
                ERR-0046-2022
                10.1183/16000617.0046-2022
                9488810
                35768133
                7009bbe2-5b06-4440-b85a-af01b2af9a7f
                Copyright ©The authors 2022

                This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org

                History
                : 03 March 2022
                : 02 May 2022
                Funding
                Funded by: Deutsches Zentrum für Infektionsforschung, doi 10.13039/100009139;
                Award ID: 02.709
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