High fructose-containing drinking water-induced steatohepatitis in rats is prevented by the nicotinamide-mediated modulation of redox homeostasis and NADPH-producing enzymes.

An imbalance in the redox state, increased levels of lipid precursors and overactivation of de novo lipogenesis determine the development of fibrosis during nonalcoholic steatohepatitis (NASH). We evaluated the modulation of NADPH-producing enzymes associated with the antifibrotic, antioxidant and antilipemic effects of nicotinamide (NAM) in a model of NASH induced by excess fructose consumption. Male rats were provided drinking water containing 40% fructose for 16 weeks. During the last 12 weeks of fructose administration, water containing NAM was provided to some of the rats for 5 h/day. The biochemical profiles and the ghrelin, leptin, lipoperoxidation and TNF-α levels in serum and the glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and NADP+-dependent isocitric dehydrogenase (IDP) levels, the reduced/oxidized glutathione (GSH/GSSG) and reduced/oxidized nicotinamide adenine dinucleotide (phosphate) (NAD(P)H/NAD(P)+) ratios, and the levels of various lipogenic and fibrotic markers in the liver were evaluated. The results showed that hepatic fibrosis induced by fructose consumption was associated with weight gain, hunger-satiety system dysregulation, hyperinsulinemia, dyslipidemia, lipoperoxidation and inflammation. Moreover, increased levels of hepatic G6PD and ME activity and expression, the NAD(P)H/NAD(P)+ ratios, and GSSG concentration and increased expression of lipogenic and fibrotic markers were detected, and these alterations were attenuated by NAM administration. Specifically, NAM diminished the activity and expression of G6PD and ME, and this effect was associated with a decrease in the NADPH/NADP+ ratios, increased GSH levels and decreased lipoperoxidation and inflammation, ameliorating fibrosis and NASH development. NAM reduces liver steatosis and fibrosis by regulating redox homeostasis through a G6PD- and ME-dependent mechanism.

meso-Acetoxymethyl BODIPY dyes for photodynamic therapy: improved photostability of singlet oxygen photosensitizers.

We report two BODIPY based photosensitizers (Br2BOAc and I2BOAc) featuring an acetoxymethyl substituent at the meso-position. These photosensitizers show improved photostability against singlet oxygen, when compared to a BODIPY photosensitizer lacking the acetoxymethyl group. Both compounds were evaluated for photodynamic therapy against HeLa cells and photodynamic inactivation against E. coli bacteria. We show that the compounds readily embed in the lipid membranes of HeLa cervical cancer cells and efficiently induced light-dependent apoptosis at nanomolar concentration. Also, both compounds showed a substantial degree of photoinactivation of E. coli bacteria when used at low micromolar concentrations.

In vitro activity of N-benzenesulfonylbenzotriazole on Trypanosoma cruzi epimastigote and trypomastigote forms.

Chagas disease is still an important health problem in Central and South America. However, the only drugs currently available for specific treatment of this disease may induce toxic side effects in the host. The aim of this work was to determine the activity of N-benzenesulfonylbenzotriazole (BSBZT) against the protozoan parasite Trypanosoma cruzi. The effects of BSBZT and benzotriazole (BZT) were compared to those of benznidazole (BZL) on epimastigote and trypomastigote forms. BSBZT was found to have an in vitro growth inhibitory dose-dependent activity against epimastigotes, with flow cytometry analysis confirming that the treated parasites presented size reduction. BSBZT showed an IC(50) of 21.56 µg/mL (81.07 µM) against epimastigotes at 72 h of incubation, whereas BZT did not affect the growth of this parasite form. Furthermore, the toxic effect of BSBZT, was stronger and appeared earlier (at 24h) in trypomastigotes than in epimastigotes, with the LC(50) of this compound being 28.40 µg/mL (106.79 µM) against trypomastigotes. The concentrations of BSBZT used in this study presented low hemolytic activity and cytotoxicity. Consequently, at concentrations near IC(50) and LC(50) (25µg/mL), BSBZT caused only 2.4% hemolysis and 15% of RAW 264.7 cell cytotoxicity. These results reveal the potential of BSBZT as a prototype in drug design for developing new anti-T. cruzi compounds.

A structured community engagement strategy to support uptake of TB active case-finding.

BACKGROUND: In Lima, Peru, a mobile TB screening program ("TB Móvil") was implemented in high TB prevalence districts to increase TB screening. Community engagement activities to promote TB Móvil were simultaneously conducted. OBJECTIVE: To describe a structured, theory-driven community engagement strategy to support the uptake of TB Móvil. METHODS: We adapted Popular Opinion Leader (POL), an evidence-based social networking intervention previously used in Peru to promote HIV testing, for TB Móvil. Community health workers, women who run soup kitchens, and motorcycle taxi drivers served as "popular opinion leaders" who disseminated information about TB Móvil in everyday conversations, aided by a multi-media campaign. Performance indicators of POL included the number/characteristics of persons screened; number of multimedia elements; and proportion of persons with abnormal radiographs hearing about TB Móvil before attending. RESULTS: Between February 2019 and January 2020, 63,899 people attended the TB Móvil program at 210 sites; 60.1% were female. The multimedia campaign included 36 videos, 16 audio vignettes, flyers, posters, community murals and "jingles." Among attendees receiving an abnormal chest X-ray suggestive of TB, 48% (6,935/14,563) reported hearing about TB Móvil before attending. CONCLUSIONS: POL promotes the uptake of TB Móvil and should be considered as a strategy for increasing TB screening uptake.

CONTEXTE: À Lima, Pérou, un programme mobile de dépistage de la TB (« TB Móvil ¼) a été mis en place dans les quartiers à forte prévalence de TB afin d'accroître le dépistage de la maladie. Des activités de mobilisation communautaire visant à promouvoir TB Móvil ont été menées en parallèle. L'objectif de ce rapport est de décrire une stratégie structurée de mobilisation communautaire, fondée sur des principes théoriques, afin de soutenir le recours au programme TB Móvil. MÉTHODES: Nous avons adapté à TB Móvil l'intervention factuelle de réseautage social appelée « Popular Opinion Leader (POL; leader d'opinion) ¼, précédemment utilisée au Pérou pour promouvoir le dépistage du VIH. Les agents de santé communautaires, les femmes responsables de la soupe populaire et les chauffeurs de mototaxis étaient des leaders d'opinion. Ils communiquaient des informations sur TB Móvil lors de leurs conversations quotidiennes, qui étaient étayées par une campagne multimédia. Les indicateurs de performance des POL comprenaient le nombre/les caractéristiques des personnes dépistées, le nombre d'éléments multimédias et le pourcentage de personnes avec cliché radiographique anormal qui avaient entendu parler de TB Móvil avant de se faire dépister. RÉSULTATS: Entre février 2019 et janvier 2020, 63 899 personnes ont pris part au programme TB Móvil dans 210 sites ; 60,1% étaient des femmes. La campagne multimédia reposait sur 36 vidéos, 16 vignettes audio, des prospectus, des posters, des peintures murales dans la communauté et des « jingles ¼. Parmi les personnes dont la radiographie pulmonaire était anormale et évocatrice de TB, 48% (6 935/14 563) ont rapporté avoir entendu parler de TB Móvil avant de venir consulter. CONCLUSIONS: L'intervention POL, qui semblait renforcer le recours au programme TB Móvil, peut donc servir d'une stratégie de promotion du dépistage de la TB.

A rapid review of treatment literacy materials for tuberculosis patients.

OBJECTIVE: To assess available treatment literacy materials for patients undergoing treatment for tuberculosis (TB). DESIGN: We conducted a rapid review by searching the US Centers for Disease Control's Find TB Resources website and the websites of health departments and TB-focused organizations. We included English-language documents intended to educate TB patients about anti-tuberculosis treatment. We evaluated the format, readability, and content of documents, and audience. We defined 12 essential content elements based on those previously identified as facilitating human immunodeficiency virus treatment literacy. RESULTS: Of the 205 documents obtained, 45 were included in our review. The median reading grade level was 7 (IQR 5-8). The median number of essential content elements present was 6 (IQR 4-8), with the most comprehensive document containing 11 of the 12 elements. Only two documents were written for children with TB or their care givers, and two for patients with drug-resistant TB. Many documents contained paternalistic and non-patient-centered language. CONCLUSION: We found few examples of comprehensive, patient-centered documents. Work is needed to achieve consensus as to the essential elements of TB treatment literacy and to create additional materials for children, patients with drug-resistant TB, and those with lower literacy levels.

A systematic review of national policies for the management of persons exposed to tuberculosis.

OBJECTIVE: To describe mandates and policy gaps in tuberculosis (TB) contact investigation and management. DESIGN: We conducted a systematic review of national TB policy documents obtained using a systematic internet search and by contacting national TB programs. We included policies published in English, Spanish, and French, and abstracted data using a standardized form. RESULTS: We reviewed policy documents for 68 of 216 (31%) countries and territories. All countries recommended performing contact investigations, but 40% did not specify how contacts enter the health system for evaluation or who was responsible for this process. All countries recommended preventive therapy for contacts, but in 14 (21%) countries only young children were eligible. While four preventive therapy regimens exist, 48 (71%) countries recommended only isoniazid monotherapy. In addition, 28 (41%) countries lacked guidance on whether to give preventive therapy to contacts exposed to drug-resistant TB. Policies in 28 (41%) countries lacked recommendations for managing contacts with the human immunodeficiency virus (HIV) after new TB exposure. CONCLUSION: Policies recommending contact investigation and preventive therapy for contacts are widespread, but policy gaps exist in the areas of ensuring accountability and the management of vulnerable populations such as people living with HIV and those exposed to drug-resistant TB.

Barriers to the treatment of childhood tuberculous infection and tuberculosis disease: a qualitative study.

SETTING: In 2012, Peru's National TB Program (NTP) reported approximately 2400 incident cases of tuberculosis (TB) disease in children aged <15 years. Peru's TB burden is concentrated in the Lima metropolitan area, particularly in poor districts such as El Agustino and La Victoria, where this study was conducted. OBJECTIVE: To identify barriers to the treatment of childhood tuberculous infection and TB disease in Lima from the perspective of front-line providers and patients' families. DESIGN: We conducted 10 semi-structured focus groups with 53 purposefully sampled primary care providers, community health workers, and parents/guardians of pediatric TB patients. We also completed nine in-depth interviews with National TB Program administrators and pulmonologists specializing in TB. Two authors performed inductive thematic analysis and identified emerging themes. RESULTS: Four main treatment barriers emerged from the data: 1) dosing errors, 2) time- and labor-intensive preparation and administration of medications, 3) provider concern that isoniazid preventive therapy (IPT) generates isoniazid resistance, and 4) poor adherence to IPT. CONCLUSION: Our findings highlight the urgent need for child-friendly formulations, provider and parent/guardian education about IPT, and strategies to promote adherence to IPT, including support and supervision by health workers and/or regimens with fewer doses.

Prevalence of pyrazinamide resistance and Wayne assay performance analysis in a tuberculosis cohort in Lima, Peru.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) regimens often contain pyrazinamide (PZA) even if susceptibility to the drug has not been confirmed. This gap is due to the limited availability and reliability of PZA susceptibility testing. OBJECTIVES: To estimate the prevalence of PZA resistance using the Wayne assay among TB patients in Lima, Peru, to describe characteristics associated with PZA resistance and to compare the performance of Wayne with that of BACTEC™ MGIT™ 960. METHODS: PZA susceptibility using the Wayne assay was tested in patients diagnosed with culture-positive pulmonary TB from September 2009 to August 2012. Factors associated with PZA resistance were evaluated. We compared the performance of the Wayne assay to that of MGIT 960 in a convenience sample. RESULTS: The prevalence of PZA resistance was 6.6% (95%CI 5.8-7.5) among 3277 patients, and 47.7% (95%CI 42.7-52.6) among a subset of 405 MDR-TB patients. In multivariable analysis, MDR-TB (OR 86.0, 95%CI 54.0-136.9) and Latin American-Mediterranean lineage (OR 3.40, 95%CI 2.33-4.96) were associated with PZA resistance. The Wayne assay was in agreement with MGIT 960 in 83.9% of samples (κ 0.66, 95%CI 0.56-0.76). CONCLUSION: PZA resistance was detected using the Wayne assay in nearly half of MDR-TB patients in Lima. This test can inform the selection and composition of regimens, especially those dependent on additional resistance.

Representative drug susceptibility patterns for guiding design of retreatment regimens for MDR-TB.

BACKGROUND: There is no gold standard on how national tuberculosis programs should design retreatment regimens. Often drug susceptibility testing (DST) is not available for all patients, and representative DST patterns in patient populations are used to guide therapy. OBJECTIVES: To examine DST patterns in different patient populations based on previous treatment and to estimate the number of effective anti-tuberculosis agents in several retreatment regimens. METHODS: We reviewed DST results from patients treated with individualized regimens in Peru between January 1998 and July 2004. We stratified patients into four groups based on previous treatment exposure from Group 1 who had failed only one regimen to Group 4 who had failed three regimens. We compared resistance frequencies across the four groups. In Groups 1 and 3, the number of likely effective agents under six possible retreatment regimen scenarios was estimated. RESULTS: Resistance to second-line drugs was significantly higher in groups with more previous courses of treatment. A few retreatment regimens could be identified that would allow at least 80% of patients to receive at least four likely effective drugs. CONCLUSION: Because it is associated with resistance frequencies, previous treatment exposure can serve to guide the design of non-individualized MDR-TB regimens.

Two methods for setting child-focused tuberculosis care targets.

OBJECTIVE: To allocate resources for household contact investigations, tuberculosis (TB) programs need estimates of the numbers of child contacts requiring care. DESIGN: We developed two methods to estimate annual numbers of child contacts aged 0-14 years requiring evaluation and treatment. Method 1 combines local data using simple formulas. Using publicly available data, Method 2 uses a linear regression model based on Demographic and Health Survey and World Bank data to estimate the number of children per household, then combines these results with case notifications and risk estimates of disease and infection. RESULTS: Applying Method 1 to data from Malawi indicated that every year ~21 000 child contacts require evaluation and ~1900 should be diagnosed with TB. Applying Method 2 to all countries suggested that, globally, 2.41 million (95% uncertainty interval [UI] 2.36-2.46) children aged <5 years, and 5.07 million (95%UI 4.81-5.34) children aged 5-14 years live in households of adult patients with known TB. Of these, 239 014 (95%UI 118 649-478581) and 419 816 (95%UI 140600-1 268805), respectively, will have TB. An additional 848 453 (95%UI 705838-1 017551) and 2660 885 (95%UI 2080517-3 413 189), respectively, will be infected. CONCLUSION: It is feasible to use available data to set programmatic evaluation and treatment targets to improve care for child contacts of patients with TB.

Objectif : Pour allouer des ressources aux recherches de contacts domiciliaires, les programmes de lutte contre la tuberculose (TB) ont besoin d'estimations du nombre d'enfants contacts nécessitant une prise en charge.Schéma : Nous avons élaboré deux méthodes afin d'estimer les nombres annuels d'enfants contacts âgés de 0­14 ans requérant une évaluation et un traitement. La Méthode 1 combine des données locales utilisant des formules simples. En utilisant les données disponibles publiquement, la Méthode 2 se sert d'un modèle de régression linéaire basé sur les données de l'Enquête Démographie et Santé et celles de la Banque Mondiale afin d'estimer le nombre d'enfants dans chaque famille, puis de combiner ces résultats avec ceux de la déclaration des cas et des estimations de risque de maladie et d'infection.Résultats : En appliquant la Méthode 1 aux données du Malawi, nous avons abouti à ce que ~21 000 enfants contacts par an requéraient une évaluation et ~1900 devraient avoir un diagnostic de TB. Appliquer la Méthode 2 à tous les pays a suggéré que, dans le monde, 2,41 millions d'enfants âgés de <5 ans (intervalle d'incertitude [II] à 95% 2,36­2,46 millions) et 5,07 millions (II95% 4,81­5,34 millions) d'enfants âgés de 5­14 ans vivent dans des foyers comprenant un patient adulte atteint de TB chaque année. Parmi eux, 239 014 (II95% 118 649­478 581) et 419 816 (II95% 140 600­1 268 805), respectivement, auront la TB et 848 453 autres enfants (II95% 705838­1017 551) et 2660 885 (II95% 2080 517­3413 189) seront infectés.Conclusion : Il est possible d'utiliser les données disponibles pour établir des objectifs d'évaluation programmatique et de traitement afin d'améliorer la prise en charge des enfants contacts de patients tuberculeux.

Objetivo: Para designar los recursos necesarios para la evaluación de contactos de pacientes con tuberculosis (TB), los programas necesitan estimados de cuántos contactos niños requieren atención.Diseño: Desarrollamos dos métodos de estimar cuántos contactos que tienen 0­14 años requieren evaluación y tratamiento cada año. Método 1 usa información local y fórmulas sencillos. Usando información pública, Método 2 usa un modelo de regresión lineal basado en datos de las Encuestas Demográficas y de Salud y del Banco Mundial para estimar el número de niños en cada domicilio, y luego combina estos resultados con números reportados de casos de TB y con estimados del riesgo de enfermedad e infección con TB.Resultados: Aplicando el Método 1 a datos de Malawi indica que cada año, ~21 000 contactos niños deben ser evaluados y ~1900 deben ser diagnosticados con TB. Aplicando el Método 2 a datos de todos los países del mundo indica que cada año, al nivel mundial, hay 2,41 millón (intervalo de incertidumbre [II] de 95% 2,36­2,46 millón) de niños de edad <5 años, y 5,07 millón (II95% 4,81­5,34 millón) de niños que tienen 5­14 años, quienes viven en domicilios de adultos que se sabe son pacientes con TB. De estos niños, 239 014 (II95% 118649­478 581) y 419816 (II95% 140600­1 268 805), respectivamente, estarán enfermos con TB. Además, 848 453 (II95% 705838­1 017551) y 2 660 885 (II95% 2080 517­3 413189) estarán infectados con TB pero no enfermos.Conclusión: Es factible usar datos disponibles para generar metas programáticas para la evaluación y el tratamiento, con el fin de mejorar la atención a los contactos niños de pacientes con TB.

Presumptive treatment of multidrug-resistant tuberculosis in household contacts.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing global health threat that often requires presumptive treatment in the absence of drug susceptibility testing (DST) results. OBJECTIVE: To compare two approaches to the treatment of MDR-TB contacts with no DST results who develop TB disease. DESIGN: We conducted a retrospective cohort study of adults treated for TB disease who were contacts of patients living with MDR-TB. Subjects had been treated according to one of two presumptive treatment strategies: 1) regimens containing exclusively first-line drugs, and 2) regimens that included both first- and second-line drugs that were adjusted if and when DST results became available. The primary endpoint was a composite of death and treatment failure. RESULTS: Household contacts of MDR-TB patients who developed TB disease and were treated with first-line regimens were significantly more likely to experience unfavorable end-of-treatment outcomes than those treated with presumptive MDR-TB regimens (RR 2.88, 95%CI 1.24-6.68). CONCLUSION: Household contacts of MDR-TB patients who develop TB disease but have no DST results should receive regimens containing second-line drugs selected based on the infecting strain of the index patient. Regimens containing only first-line anti-tuberculosis drugs significantly increase the risk of unfavorable outcomes.

rpoB gene mutations in clinical isolates of multidrug-resistant Mycobacterium tuberculosis in northern Lima, Peru.

In many developing countries and outside hospital settings, the characteristics of endemic Mycobacterium tuberculosis strains resistant to multiple drugs remain unknown. In a community-based referral and therapy program in northern Lima, Peru, beginning in 1996, patients found to be failures on standard regimens were referred for drug-susceptibility testing of their isolates, and those found to be infected with M. tuberculosis isolates resistant to at least rifampin were treated with individualized regimens based on their infecting strains. Isolates from 42 of these patients were subjected to DNA sequencing of the rpoB gene region responsible for rifampin resistance. We determined the frequency of types of mutations in the rpoB gene among these Peruvian isolates.

Retreatment management strategies when first-line tuberculosis therapy fails.

SETTING: Public ambulatory centers in northern Lima, Peru. OBJECTIVE: To compare two retreatment strategies in Category I failures. DESIGN: Retrospective cohort study of Category I failures enrolled between February 1997 and October 2001. Strategy A was a nationwide approach, applying a Category II regimen; if that regimen failed, a standardized regimen including second-line drugs was used. Strategy B was a pilot protocol designed to diagnose and treat multidrug-resistant tuberculosis (MDR-TB); this strategy included drug susceptibility testing (DST) and eliminated the Category II regimen. RESULTS: Of 125 patients that Category I failed to cure, 73 entered Strategy A and 52 entered Strategy B. Almost 90% of those with DST results had MDR-TB. Strategy B was three times more likely than Strategy A to cure patients (79% vs. 38%, RR = 2.9, 95% CI 1.7-5.1) and five times more likely to cure patients than the Category II regimen alone (79% vs. 15%, RR 5.2, 95% CI 3.0-9.2). Strategy B also significantly reduced delays to MDR-TB diagnosis and to the initiation of MDR-TB therapy. CONCLUSIONS: Under program conditions, a retreatment strategy based on DST and eliminating the Category II regimen can improve clinical outcomes among Category I treatment failures found to have active, infectious MDR-TB.

Acquisition of drug resistance in multidrug-resistant Mycobacterium tuberculosis during directly observed empiric retreatment with standardized regimens.

The risk of acquiring additional drug resistance in strains of multidrug-resistant tuberculosis (MDR-TB) during failure of empiric standardized retreatment regimens is poorly defined. We sought to estimate this risk by comparing drug susceptibility profiles and RFLP patterns of paired MDR-TB isolates collected from 27 patients before and after retreatment failure. Among 23 patients with paired isolates with concordant RFLP patterns, 19 (83%) had become resistant to at least one additional drug after failed retreatment. In this limited group of MDR-TB patients, acquisition of resistance was common during failure of empiric drug regimens. Further study is needed to confirm these findings.

Drug resistance profiles of Mycobacterium tuberculosis isolates: five years' experience and insight into treatment strategies for MDR-TB in Lima, Peru.

SETTING: Lima, Peru. OBJECTIVE: To describe drug resistance profiles of TB isolates from patients at risk for multidrug-resistant tuberculosis (MDR-TB), and to consider the implications of these findings for treatment. DESIGN: Descriptive study of drug susceptibility testing (DST) results for TB isolates from 1680 patients referred for suspicion of MDR-TB between 1996 and 2001. RESULTS: Of 1680 isolates tested, 1144 (68%) were resistant to at least one anti-tuberculosis drug and 926 (55%) were MDR-TB strains. Of 926 MDR isolates, 50 (5%) were resistant to INH and RMP alone, while 367 (40%) were resistant to at least five first-line drugs. We identified 146 unique drug resistance profiles, the most common of which accounted for 11% of drug-resistant isolates. The annual prevalence of isolates with resistance to at least five first-line drugs rose significantly during the study period, from 29% to 37% (P = 0.00086). CONCLUSIONS: This is a group of patients with TB disease among whom the prevalence of a broad spectrum of often highly drug-resistant strains appears to be increasing over time. A single standardized retreatment regimen may be inadequate to cure most patients. Capacity for drug sensitivity testing is essential for development of multiple standardized retreatment or individualized treatment regimens and epidemiological surveillance for planning.

Map the gap: missing children with drug-resistant tuberculosis.

BACKGROUND: The lack of published information about children with multidrug-resistant tuberculosis (MDR-TB) is an obstacle to efforts to advocate for better diagnostics and treatment. OBJECTIVE: To describe the lack of recognition in the published literature of MDR-TB and extensively drug-resistant TB (XDR-TB) in children. DESIGN: We conducted a systematic search of the literature published in countries that reported any MDR- or XDR-TB case by 2012 to identify MDR- or XDR-TB cases in adults and in children. RESULTS: Of 184 countries and territories that reported any case of MDR-TB during 2005-2012, we identified adult MDR-TB cases in the published literature in 143 (78%) countries and pediatric MDR-TB cases in 78 (42%) countries. Of the 92 countries that reported any case of XDR-TB, we identified adult XDR-TB cases in the published literature in 55 (60%) countries and pediatric XDR-TB cases for 9 (10%) countries. CONCLUSION: The absence of publications documenting child MDR- and XDR-TB cases in settings where MDR- and XDR-TB in adults have been reported indicates both exclusion of childhood disease from the public discourse on drug-resistant TB and likely underdetection of sick children. Our results highlight a large-scale lack of awareness about children with MDR- and XDR-TB.

Cadre : La pénurie d'informations publiées sur la tuberculose multirésistante (TB-MDR) de l'enfant entrave les efforts visant à en améliorer le diagnostic et le traitement.Objectif : Décrire le manque de reconnaissance de la TB-MDR et de la TB ultra-résistante (TB-XDR) de l'enfant dans la littérature publiée.Schéma : Nous avons réalisé une recherche systématique de la littérature publiée dans les pays qui ont déclaré au moins un cas de TB-MDR ou -XDR avant 2012 afin d'identifier des cas de TB-MDR ou -XDR chez des adultes et des enfants.Résultats : Sur les 184 pays et territoires qui ont déclaré des cas de TB-MDR entre 2005 et 2012, nous avons identifié des cas de TB-MDR de l'adulte dans la littérature dans 143 (78%) pays et des cas de TB-MDR pédiatrique dans 78 (42%) pays. Sur les pays qui ont déclaré des cas de TB-XDR, nous avons identifié des cas adultes dans la littérature dans 55 (60%) pays et des cas pédiatriques dans 9 (10%) pays.Conclusion : L'absence de publications documentant les cas de TB-MDR et -XDR chez l'enfant dans des régions où la TB-MDR et la TB-XDR ont été déclarées chez les adultes témoigne à la fois d'une exclusion de la maladie de l'enfant du discours public sur la TB pharmacorésistante et probablement d'une sous-détection des enfants malades. Nos résultats mettent en évidence un manque de connaissance à grande échelle de la TB-MDR et de la TB-XDR de l'enfant.

Marco de referencia: La falta de información publicada sobre los niños con tuberculosis multidrogo-resistente (TB-MDR) es un obstáculo a los esfuerzos para abogar por mejores diagnósticos y tratamientos.Objetivos: Describir la falta de reconocimiento en la literatura publicada de la TB-MDR y la TB extremadamente resistente (TB-XDR) en los niños.Métodos: Para los países que hasta 2012 habían informado de algún caso de TB-MDR o TB-XDR, realizamos una búsqueda sistemática de la literatura publicada para identificar casos de TB-MDR o TB-XDR en adultos y en niños.Resultados: De los 184 países y territorios que informaron algún caso de TB-MDR durante 2005­2012, encontramos reportes de casos de TB-MDR en adultos en la literatura publicada para 143 (78%) países, y reportes de casos de TB-MDR pediátricos para 78 (42%) países. De los 92 países que informaron algún caso de TB-XDR, encontramos reportes de casos de TB-XDR en adultos en la literatura publicada para 55 (60%) países y reportes de casos de TB-XDR pediátricos para 9 (10%) países.Conclusión: La ausencia de publicaciones que documentan casos de TB-MDR y TB-XDR pediátricos en lugares donde casos de TB-MDR y TB-XDR en adultos han sido reportados indica tanto la exclusión de enfermedad infantil del discurso público sobre la TB drogo-resistente y la probable sub-detección de niños enfermos. Nuestros resultados recalcan la falta de reconocimiento a gran escala de los niños con TB-MDR y TB-XDR.

Setting priorities for a research agenda to combat drug-resistant tuberculosis in children.

SETTING: Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. OBJECTIVE: To systematically identify and rank research priorities in childhood drug-resistant TB. DESIGN: Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. RESULTS: A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. CONCLUSION: This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children.

Contexte : De nombreuses lacunes en matière de connaissances entravent la prévention et le traitement de la tuberculose (TB) pharmacorésistante. L'identification des priorités de recherche est vitale pour informer et développer des stratégies afin de répondre à ce problème négligé.Objectif : Tenter d'identifier systématiquement et de classer par ordre les priorités en matière de recherche sur la TB pharmacorésistante de l'enfant.Schéma: Ayant adapté la méthode de Child Health and Nutrition Research Initiative (CHNRI) (Initiative de recherche en santé et en nutrition de l'enfant), nous avons compilé 53 questions de recherche dans quatre domaines, puis les avons classées en trois types de recherche différents. Nous avons invité des experts en TB pharmacorésistante de l'enfant à classer ces questions grâce à une enquête en ligne.Résultats : Un total de 81 personnes ont participé à l'enquête. La question de recherche qui a été classée première était l'identification des meilleures associations d'outils de diagnostic existants pour permettre un diagnostic précoce. Les questions considérées comme prioritaires en matière de traitement étaient centrées sur des interventions visant à améliorer les résultats du traitement, à réduire les effets secondaires des médicaments et à déterminer la durée idéale du traitement. La prévalence de la TB pharmacorésistante était la priorité dans le domaine de l'épidémiologie. Les questions relatives au développement ont été considérées comme hautement prioritaires et se sont focalisées sur des interventions d'amélioration du diagnostic, du traitement et des modalités de délivrance du traitement.Conclusion : Cette enquête est la première qui vise à identifier et à hiérarchiser les priorités de recherche relatives à la TB pharmacorésistante de l'enfant. Son résultat constitue une ressource pour guider la recherche afin d'améliorer la prévention et le traitement de la TB pharmacorésistante de l'enfant.

Marco de referencia: Numerosas lagunas de conocimiento obstaculizan la prevención y el tratamiento de la tuberculosis drogorresistente (TB-DR) en niños. Es esencial identificar cuales son las áreas prioritarias de investigación para informar y desarrollar estrategias para hacer frente a este problema descuidado.Objetivo: Identificar sistemáticamente las prioridades de investigación en la TB-DR en niños, y construir una clasificación jerárquica de ellas.Diseño: Se adaptó la metodología de la Iniciativa de Investigación en Salud y Nutrición Infantil (CHNRI). Recopilamos 53 preguntas de investigación en cuatro áreas de investigación y luego las clasificamos entre tres tipos de investigación. Invitamos a expertos en TB-DR en niños a que asignen puntajes a cada una de estas preguntas usando una encuesta en línea.Resultados: Un total de 81 individuos participaron en la encuesta. La pregunta de investigación con el puntaje más alto fue de identificar la mejor combinación de existentes herramientas de diagnosis para llegar a un diagnóstico precoz. Preguntas con altos puntajes relacionadas al tratamiento se centraron en entender las razones y las intervenciones para mejorar los resultados del tratamiento, los efectos adversos de los fármacos y la duración óptima del tratamiento. La prevalencia de la TB-DR fue la pregunta con el más alto puntaje en el área de epidemiología. Las preguntas de tipo desarrollo con puntajes más altos se centraron en las intervenciones para el diagnóstico óptimo, el tratamiento óptimo y las modalidades óptimas de prestación del tratamiento.Conclusión: Este ha sido el primer esfuerzo de identificar y clasificar jerárquicamente las prioridades de investigación en la TB-DR en niños. El resultado es un recurso para orientar la investigación para mejorar la prevención y el tratamiento de la TB-DR en niños.

Counting children with tuberculosis: why numbers matter.

In the last 5 years, childhood tuberculosis (TB) has received increasing attention from international organisations, national TB programmes and academics. For the first time, a number of different groups are developing techniques to estimate the burden of childhood TB. We review the challenges in diagnosing TB in children and the reasons why cases in children can go unreported. We discuss the importance of an accurate understanding of burden for identifying problems in programme delivery, targeting interventions, monitoring trends, setting targets, allocating resources appropriately and providing strong advocacy. We briefly review the estimates produced by new analytical methods, and outline the reasons for recent improvements in our understanding and potential future directions. We conclude that while innovation, collaboration and better data have improved our understanding of the childhood TB burden, it remains substantially incomplete.