Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health

Incidence of tuberculosis among children living in contact with smear-positive tuberculosis: Advantages and limits of the Quantiferon TB gold in tube test

Objective/background: Children living in contact with smear-positive pulmonary tuberculosis (TB) patients are highly exposed to TB infection. Our objective was to estimate the incidence of TB in children living in contact with a Smear Positive (M+) pulmonary tuberculosis (PTM+) index case during 2 years following exposure. Methods: This was a descriptive, cohort, prospective, multicenter study of children aged from 6 months to 15 years in contact with a PTM+ case. The recruitment of children has been based on the diagnosed PTM+ index case and taken in charge by the Services of Control of Tuberculosis and Respiratory Diseases located in Algiers during 2014. Seven centers were selected. All children were tested using the Quantiferon TB gold in tube (QTR) test and the tuberculin skin test (TST). For TST, an induration diameter ≥10 mm was considered positive. Results: We included 456 children living in contact with a PTM+ patient. The results for TST and QFT were available for 319 children. The mean age of the children was 6.7 years (standard deviation = 3.9). The sex ratio (Male/Female) was 1.26, and 15.8% (50) did not have a Bacilli of Calmette & Guerin (BCG) vaccination scar. Among the children, 46.1% (147) and 43.4% (138) were positive for QFT and TST, respectively, and 6.1% (19) have received isoniazid preventive therapy. Fifty-one children progressed to TB and received antitubercular treatment. We analyzed and compared our results between children who progressed to TB and those who did not progress to TB. Finally, we discuss our methodology and results in relation to the literature

Etude des facteurs de risque du cancer du sein en Algérie

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Anesthésie locale en chirurgie buccale chez les sujets cardiaques

En chirurgie buccale, l’utilisation d’un vasoconstricteur pour l’anesthésie locale chez les patients souffrant d’une maladie cardiovasculaire est controversée. Objectif – Identifier les évènements cardiovasculaires indésirables survenant au décours d’extractions dentaires réalisées sous anesthésie locale (mépivacaine avec noradrénaline) chez des patients atteints de diverses maladies cardiovasculaires. Matériel et méthodes – Etude prospective monocentrique, effectuée entre avril 2002 et mars 2005, chez des sujets cardiaques soumis à un traitement anticoagulant au long cours. Résultats – Quatre cent trente sept séances d’extractions dentaires ont été réalisées chez 268 patients. La moyenne d’âge était de 49,63 ± 1,57 ans et le sex ratio M/F de 1,4. Les pathologies les plus fréquemment rencontrées étaient les suivantes : prothèses valvulaires (42,5 %), valvulopathies rhumatismales (28,3 %), maladies coronariennes (13,1 %). Aucun évènement cardiovasculaire grave n’est survenu. Sept malaises (2,6 %) rapidement régressifs ont été observés. L’existence d’une coronaropathie p : 0,60, de troubles du rythme cardiaques p : 1,00, d’une hypertension artérielle p : 1,00 (toutes ces pathologies étant stabilisées par un traitement médical), la présence de troubles de la conduction ne nécessitant pas l’implantation d’un pace maker p : 0,43, d’une insuffisance cardiaque p : 0,67, d’une importante cardiomégalie radiologique p : 1,00, d’une altération de la fonction ventriculaire gauche p : 0,25, d’une hypertension artérielle pulmonaire p : 1,00 et la prise de β-bloquants p : 1,00 n’ont pas favorisé la survenue de ces malaises. Conclusion – Aucun évènement cardiovasculaire grave n’a été observé dans cette étude. Le rapport bénéfices/risques est en faveur de l’utilisation d’un vasoconstricteur pour l’anesthésie locale en chirurgie buccale chez les sujets cardiaques

Avulsions dentaires chez les patients cardiaques traités par anticoagulants : résultats d'un essai thérapeutique acénocoumarol versus héparine calcique

Background - En chirurgie buccale, la prise en charge des cardiaques sous anticoagulants est controversée. Objectif - Comparer l'incidence des complications hémorragiques des avulsions dentaires sous acénocoumarol avec un International Normalized Ratio la veille de l'acte entre 2.00 - 4.50, versus le relais par l'héparine calcique, en utilisant dans tous les cas des mesures locales d'hémostase. Matériel et méthodes - Essai thérapeutique randomisé, contrôlé, en aveugle, monocentrique, réalisé entre avril 2002 et mars 2005. Les patients ont été hospitalisés en cardiologie au moins 48 heures avant les extractions dentaires. L'analyse a porté sur 135 patients dans le groupe acénocoumarol, 133 dans le groupe héparine. Critère de jugement - Incidence des saignements post-opératoires nécessitant l'application de mesures d'hémostase locale, et de l'hématome buccal. Résultats - Dans chacun des groupes acénocoumarol et héparine calcique, le nombre des séances d'extractions était respectivement de 229 et 208, le nombre de dents extraites / malade / séance étant respectivement de 1.96 ± 0.23 et 1.92 ± 0.22 (p = 0.80). Le jour de l'acte, l'International Normalized Ratio était de 3.40 ± 0.16 dans le groupe acénocoumarol, le rapport temps de Céphaline Activé malade / temps de Céphaline Activé témoin de 1.45 ± 0.10 dans le groupe héparine. L'incidence du saignement a été plus élevée après le relais par l'héparine : 15.8 % contre 6.7 %, p = 0.02, avec un risque relatif de 2.40. Le saignement est survenu entre J0 - J6. Tous les cas d'hémorragie ont été traités uniquement par les mesures locales d'hémostase. Conclusion - Les résultats de ce premier essai thérapeutique comparant la poursuite de l'acénocoumarol au relais par l'héparine calcique en chirurgie dentaire ont des conséquences cliniques et économiques très importantes. Ils montrent que le rapport bénéfice-risque est plutôt en faveur de la poursuite de l'acénocoumarol et la réalisation des avulsions dentaires avec un International Normalized Ratio pré-opératoire ≤ 4.50. (Med Buccale Chir Buccale 2009 ; 15 : 63-74)

Facteurs de risque hémorragique chez les patients sous antivitamine K en chirurgie buccale

Background – En chirurgie dentaire, la prise en charge des patients cardiaques sous antivitamines K constitue un problème de pratique courante. Objectif – Chez les patients traités par acénocoumarol, identifier les facteurs qui augmentent l’incidence du saignement après extractions dentaires. Matériel et méthodes – Étude de cohorte, en aveugle, dans laquelle les extractions dentaires ont été réalisées chez des patients cardiaques traités par acénocoumarol, avec un INR la veille de l’intervention (INR1) compris entre 2,00 et 4,50, en appliquant dans tous les cas des mesures locales d’hémostase : oxycellulose  +  suture  +  gouttière hémostatique. Une évaluation préopératoire de l’INR (INR2) a été effectuée systématiquement. Le score traumatique correspond au nombre de racines extraites par séance. Les résultats sont exprimés avec un intervalle de confiance à 95 %. Résultats – Deux cent vingt neuf séances d’extractions ont été réalisées chez 135 malades, âgés de 50,32 ± 2,12 ans, avec un sex ratio H/F de 1,25, le nombre d’extractions par patient et par séance est de 1,96 ± 0,23 dents et le degré du traumatisme chirurgical par séance de 2,89 ± 0,24. L’INR1 et l’INR2 étaient respectivement de 3,30 ± 0,11 et de 3,40 ± 0,16. Un saignement a compliqué 9 séances d’extractions (6,7 %), et il est survenu après la 48ème heure dans 4 cas (44,4 %). Chez les patients qui ont saigné, l’INR2 moyen était de 3,33 ± 0,70 et de 3,40 ± 0,16 chez les patients qui n’ont pas saigné, p = 0,86. Le score traumatique était de 4,89 ± 3,11 en cas de saignement contre 2,80 ± 0,22, p = 0,02. Conclusion – Chez les patients cardiaques traités par acénocoumarol, c’est le degré du traumatisme chirurgical qui constitue le facteur hémorragique et non pas la valeur de l’INR préopératoire. D’où l’intérêt de la surveillance postopératoire, à la fois chirurgicale et biologique (contrôle de la valeur de l’INR), qui doit être particulièrement rigoureuse notamment en cas d’extractions multiples

Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included mycobacterium tuberculosis, TB, tuberculosis, and contact. We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health

The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis

Background: 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. Methods: In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022). Findings: In total, study groups from 46 cohort studies in 34 countries—29 (63%) prospective studies and 17 (37%) retrospective—agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4–37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30–0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05–0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit. Interpretation: The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches. Funding: National Institutes of Health