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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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              Tuberculous meningitis and miliary tuberculosis: the Rich focus revisited.

              Tuberculous meningitis (TBM) develops most often when a caseating meningeal or sub-cortical focus, the Rich focus, discharges its contents into the subarachnoid space. It is recognized that TBM is frequently accompanied by miliary tuberculosis, but the relationship between the development of the Rich focus and miliary tuberculosis remains controversial. The original descriptions of Arnold Rich and Howard McCordock are reviewed together with the work of other pathologists and the observations of the natural history of tuberculosis by astute clinicians such as Arvid Wallgren and Edith Lincoln. Rich and McCordock dissociated miliary tuberculosis from a role in the pathogenesis of TBM, and this view continues to appear in reviews and textbooks dealing with TBM. We suggest, particularly in childhood, that miliary tuberculosis is indeed directly involved in the pathogenesis of TBM in as much as that the overwhelming bacillaemia that accompanies miliary tuberculosis serves to increase the likelihood that a meningeal or sub-cortical Rich focus will be established, which may in its turn caseate and give rise to TBM.
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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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