Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Serum biomarkers in patients with unilateral or bilateral active pulmonary tuberculosis: Immunological networks and promising diagnostic applications.

The present observational study was designed to characterize the integrative profile of serum soluble mediators to describe the immunological networks associated with clinical findings and identify putative biomarkers for diagnosis and prognosis of active tuberculosis. The study population comprises 163 volunteers, including 84 patients with active pulmonary tuberculosis/(TB), and 79 controls/(C). Soluble mediators were measured by multiplexed assay. Data analysis demonstrated that the levels of CCL3, CCL5, CXCL10, IL-1ß, IL-6, IFN-γ, IL-1Ra, IL-4, IL-10, PDGF, VEGF, G-CSF, IL-7 were increased in TB as compared to C. Patients with bilateral pulmonary involvement/(TB-BI) exhibited higher levels of CXCL8, IL-6 and TNF with distinct biomarker signatures (CCL11, CCL2, TNF and IL-10) as compared to patients with unilateral infiltrates/(TB-UNI). Analysis of biomarker networks based in correlation power graph demonstrated small number of strong connections in TB and TB-BI. The search for biomarkers with relevant implications to understand the pathogenetic mechanisms and useful as complementary diagnosis tool of active TB pointed out the excellent performance of single analysis of IL-6 or CXCL10 and the stepwise combination of IL-6 â†’ CXCL10 (Accuracy = 84 %; 80 % and 88 %, respectively). Together, our finding demonstrated that immunological networks of serum soluble biomarkers in TB patients differ according to the unilateral or bilateral pulmonary involvement and may have relevant implications to understand the pathogenetic mechanisms involved in the clinical outcome of Mtb infection.

Brazilian Thoracic Association recommendations for the management of post-tuberculosis lung disease / Recomendações da Sociedade Brasileira de Pneumologia e Tisiologia para o manejo da doença pulmonar pós-tuberculose

ABSTRACT Historically, all efforts against tuberculosis were focused on rapid diagnosis and effective treatment to break the chain of transmission of Mycobacterium tuberculosis. However, in the last few years, more and more evidence has been found on the dramatic consequences of the condition defined as post-tuberculosis lung disease (PTLD). Approximately one third of patients surviving pulmonary tuberculosis face considerable ongoing morbidities, including respiratory impairment, psychosocial challenges, and reduced health-related quality of life after treatment completion. Given the important global and local burden of tuberculosis, as well as the estimated burden of PTLD, the development of a consensus document by a Brazilian scientific society-Sociedade Brasileira de Pneumologia e Tisiologia (SBPT)-was considered urgent for the prevention and management of this condition in order to allocate resources to and within tuberculosis services appropriately and serve as a guide for health care professionals. A team of eleven pulmonologists and one methodologist was created by the SBPT to review the current evidence on PTLD and develop recommendations adapted to the Brazilian context. The expert panel selected the topics on the basis of current evidence and international guidelines. During the first phase, three panel members drafted the recommendations, which were divided into three sections: definition and prevalence of PTLD, assessment of PTLD, and management of PTLD. In the second phase, all panel members reviewed, discussed, and revised the recommendations until a consensus was reached. The document was formally approved by the SBPT in a special session organized during the 2023 SBPT Annual Conference.

RESUMO Historicamente, todos os esforços contra a tuberculose concentraram-se no diagnóstico rápido e no tratamento efetivo para quebrar a cadeia de transmissão do Mycobacterium tuberculosis. No entanto, nos últimos anos, têm sido encontradas mais e mais evidências sobre as dramáticas consequências da condição definida como doença pulmonar pós-tuberculose (DPPT). Aproximadamente um terço dos pacientes que sobrevivem à tuberculose pulmonar enfrenta morbidades consideráveis e persistentes, incluindo comprometimento respiratório, desafios psicossociais e redução da qualidade de vida relacionada à saúde após o término do tratamento. Diante da importante carga global e local da tuberculose, bem como da carga estimada da DPPT, considerou-se urgente o desenvolvimento de um documento de consenso por uma sociedade científica brasileira - a Sociedade Brasileira de Pneumologia e Tisiologia (SBPT) - para a prevenção e manejo dessa condição, a fim de alocar recursos de forma adequada para e nos serviços de tuberculose e servir de guia para os profissionais de saúde. Uma equipe de onze pneumologistas e um metodologista foi criada pela SBPT para revisar as evidências atuais sobre a DPPT e desenvolver recomendações adaptadas ao contexto brasileiro. O painel de especialistas selecionou os temas com base nas evidências atuais e diretrizes internacionais. Durante a primeira fase, três membros do painel redigiram as recomendações, que foram divididas em três seções: definição e prevalência de DPPT, avaliação da DPPT e manejo da DPPT. Na segunda fase, todos os membros do painel analisaram, discutiram e revisaram as recomendações até chegar a um consenso. O documento foi aprovado formalmente pela SBPT em sessão especial organizada durante o Congresso Anual da SBPT de 2023.

A campanha de vacinação contra o SARS-CoV-2 no Brasil e a invisibilidade das evidências científicas / The SARS-CoV-2 vaccination campaign in Brazil and the invisibility of science evidences

Resumo O presente texto trata de refletir sobre a campanha de vacinação contra COVID-19 no Brasil à luz da consideração das evidências científicas no processo de tomada de decisão. O Brasil possui um dos maiores e mais completos programas de vacinação do mundo, o Programa Nacional de Imunizações (PNI). Infelizmente, no contexto atual, com as interferências políticas do governo federal, o PNI perdeu seu protagonismo na condução da campanha de vacinação contra a COVID-19. Apesar de ser uma campanha de vacinação com muito potencial e uma das mais aceitas pela população entre os países no mundo, apresentou muitos problemas e deixou diversas lacunas no cenário brasileiro. Nesse sentido, é fundamental que as evidências científicas de qualidade produzidas nesse período possam guiar uma remodelagem constante da estratégia de vacinação. Quatro pontos merecem ser destacados: 1) o intervalo entre as doses; 2) a intercambialidade entre vacinas; 3) a vacinação em adolescentes; e 4) a necessidade de melhores evidências para definir a estratégia de vacinação em certos grupos e faixas etárias.

Abstract This paper reflects on the vaccination campaign against COVID-19 in Brazil in light of the consideration of scientific evidence in the decision-making process. Brazil has one of the largest and most complete vaccination programs in the world, the National Immunization Program (Programa Nacional de Imunizações or PNI). Unfortunately, in the current context, with the political interference of the federal government, the PNI lost its role in conducting the vaccination campaign against COVID-19. Despite being a vaccination campaign with a lot of potential and one of the most accepted by the population among countries in the world, it presented many problems and left several gaps in the Brazilian scenario. In this sense, it is essential that the quality scientific evidence produced during this period can guide a constant remodeling of the vaccination strategy. Four points deserve to be highlighted: 1) the interval between doses; 2) the interchangeability between vaccines; 3) vaccination in children and adolescentes; and 4) the need for better evidence to define the vaccination strategy in certain groups and age groups.

Barriers faced by patients in the diagnosis of multidrug-resistant tuberculosis in Brazil

ABSTRACT OBJECTIVE To understand patients' narratives about the barriers they faced in the diagnosis and treatment of multidrug-resistant tuberculosis, and their consequences in Rio de Janeiro State, Brazil. METHODS This is a qualitative cross-sectional study with non-probabilistic sampling. A theoretical saturation criterion was considered for composing the number of interviewees. Semi-structured interviews were conducted from August to December 2019 with 31 patients undergoing treatment for multidrug-resistant tuberculosis at an outpatient referral center in Rio de Janeiro. Data were transcribed and processed with the aid of the NVIVO software. Interviews were evaluated by content analysis, and their themes, cross-referenced with participants' characterization data. RESULTS Our main findings were: a) participants show a high proportion of primary drug resistance, b) patients experience delays in the diagnosis and effective treatment of multidrug-resistant tuberculosis ; c) healthcare providers fail to value or seek the diagnosis of drug-resistant tuberculosis, thus beginning the inadequate treatment for drug-susceptible tuberculosis, d) primary health units show low report rates of active case-finding and contact monitoring, and e) patients show poor knowledge about the disease. CONCLUSIONS We need to improve referral systems, and access to the diagnosis and effective treatment of multidrug-resistant tuberculosis; conduct an active investigation of contacts; intensify the training of healthcare providers, in collaboration with medical and nursing schools, in both public and private systems; and promote campaigns to educate the population on tuberculosis signs and symptoms.

Clinical Impact of the Line Probe Assay and Xpert® MTB/RIF Assay in the Presumptive Diagnosis of Drug-Resistant Tuberculosis in Brazil: A Pragmatic Clinical Trial

ABSTRACT Background: Rapid molecular methods such as the line probe assay (LPA) and Xpert® MTB/RIF assay (Xpert) have been recommended by the World Health Organization for drug-resistant tuberculosis (DR-TB) diagnosis. We conducted an interventional trial in DR-TB reference centers in Brazil to evaluate the impact of the use of LPA and Xpert. Methods: Patients with DR-TB were eligible if their drug susceptibility testing results were available to the treating physician at the time of consultation. The standard reference MGITTM 960 was compared with Xpert (arm 1) and LPA (arm 2). Effectiveness was considered as the start of the appropriate TB regimen that matched drug susceptibility testing (DST) and the proportions of culture conversion and favorable treatment outcomes after 6 months. Results: A higher rate of empirical treatment was observed with MGIT alone than with the Xpert assay (97.0% vs. 45.0%) and LPA (98.2% vs. 67.5%). Patients started appropriate TB treatment more quickly than those in the MGIT group (median 15.0 vs. 40.5 days; p<0.01) in arm 1. Compared to the MGIT group, culture conversion after 6 months was higher for Xpert in arm 1 (90.9% vs. 79.3%, p=0.39) and LPA in arm 2 (80.0% vs. 83.0%, p=0.81). Conclusions: In the Xpert arm, there was a significant reduction in days to the start of appropriate anti-TB treatment and a trend towards greater culture conversion in the sixth month.

Tuberculosis and COVID-19, the new cursed duet: what differs between Brazil and Europe? / Tuberculose e COVID-19, o novo dueto maldito: quais as diferenças entre Brasil e Europa?

ABSTRACT On April 1st, 2020, COVID-19 surpassed tuberculosis regarding the number of deaths per day worldwide. The combination of tuberculosis and COVID-19 has great potential for morbidity and mortality. In addition, the COVID-19 pandemic has had a significant impact on the diagnosis and treatment of tuberculosis. In this review article, we address concurrent tuberculosis and COVID-19, with particular regard to the differences between Brazil and Europe. In addition, we discuss priorities in clinical care, public health, and research.

RESUMO Em 1º de abril de 2020, a COVID-19 ultrapassou a tuberculose em número de óbitos por dia no mundo. A associação da tuberculose com a COVID-19 apresenta grande potencial de morbidade e mortalidade. Além disso, a pandemia de COVID-19 tem tido um impacto significativo no diagnóstico e tratamento da tuberculose. Neste artigo de revisão, abordamos tuberculose e COVID-19 concomitantes, com particular atenção às diferenças entre Brasil e Europa. Além disso, discutimos as prioridades em atendimento clínico, saúde pública e pesquisa.

Diagnosis of tuberculosis: a consensus statement from the Brazilian Thoracic Association / Consenso sobre o diagnóstico da tuberculose da Sociedade Brasileira de Pneumologia e Tisiologia

ABSTRACT Early, accurate diagnosis of tuberculosis is one of the major pillars of the control of the disease. The purpose of this consensus statement is to provide health professionals with the most current, useful evidence for the diagnosis of tuberculosis in Brazil. To that end, the Tuberculosis Committee of the Brazilian Thoracic Association brought together 14 members of the Association with recognized expertise in tuberculosis in Brazil to compose the statement. A nonsystematic review of the following topics was carried out: clinical diagnosis, bacteriological diagnosis, radiological diagnosis, histopathological diagnosis, diagnosis of tuberculosis in children, and diagnosis of latent tuberculosis infection.

RESUMO O diagnóstico precoce e adequado da tuberculose é um dos pilares mais importantes no controle da doença. A proposta deste consenso brasileiro é apresentar aos profissionais da área de saúde um documento com as evidências mais atuais e úteis para o diagnóstico da tuberculose. Para tanto, a Comissão de Tuberculose da Sociedade Brasileira de Pneumologia e Tisiologia reuniu 14 membros da Sociedade com reconhecida experiência em tuberculose no Brasil. Foi realizada uma revisão não sistemática dos seguintes tópicos: diagnóstico clínico, diagnóstico bacteriológico, diagnóstico radiológico, diagnóstico histopatológico, diagnóstico da tuberculose na criança e diagnóstico da tuberculose latente.

Predictors of mortality in multidrug-resistant tuberculosis patients from Brazilian reference centers, 2005 to 2012

ABSTRACT Objectives To determine the main predictors of death in multidrug-resistant (MDRTB) patients from Brazil. Design Retrospective cohort study, a survival analysis of patients treated between 2005 and 2012. Results Of 3802 individuals included in study, 64.7% were men, mean age was 39 (1-93) years, and 70.3% had bilateral pulmonary disease. Prevalence of human immunodeficiency virus (HIV) was 8.3%. There were 479 (12.6%) deaths. Median survival time was 1452 days (4 years). Factors associated with increased risk of death were age greater than or equal to 60 years (hazard rate [HR] = 1.6, confidence interval [CI] = 1.15-2.2), HIV co-infection (HR = 1.46; CI = 1.05-1.96), XDR resistance pattern (HR = 1.74, CI = 1.05-2.9), beginning of treatment after failure (HR = 1.72, CI = 1.27-2.32), drug abuse (HR = 1.64, CI = 1.22-2.2), resistance to ethambutol (HR = 1.30, CI = 1.06-1.6) or streptomycin (HR = 1.24, CI = 1.01-1.51). Mainly protective factors were presence of only pulmonary disease (HR = 0.57, CI = 0.35-0.92), moxifloxacin use (HR = 0.44, CI = 0.25-0.80), and levofloxacin use (HR = 0.75; CI = 0.60-0.94). Conclusion A more comprehensive approach is needed to manage MDRTB, addressing early diagnostic, improving adhesion, and comorbidities, mainly HIV infection and drug abuse. The latest generation quinolones have an important effect in improving survival in MDRTB.

Clinical aspects in patients with pulmonary infection caused by mycobacteria of the Mycobacterium abscessus complex, in the Brazilian Amazon / Aspectos clínicos em pacientes com infecção pulmonar por micobactérias do complexo Mycobacterium abscessus na Amazônia brasileira

ABSTRACT Objective: To describe the clinical manifestations of patients with pulmonary infection caused by mycobacteria of the Mycobacterium abscessus complex (MABSC), and to compare these manifestations with those of patients infected with other nontuberculous mycobacteria (NTM). Methods: This was a retrospective cohort study involving 43 patients divided into two groups: the MABSC group, consisting of patients with pulmonary infection caused by MABSC (n = 17); and the NTM group, consisting of patients with pulmonary infection caused by NTM other than MABSC (n = 26). Patients were previously treated with a regimen of rifampin, isoniazid, pyrazinamide, and ethambutol before the diagnosis of NTM was confirmed by two culture-positive sputum samples. The nucleotide sequences of the hsp65, 16S rRNA, and/or rpoB genes were analyzed to identify the mycobacteria. Data were collected on demographic, clinical, and radiological characteristics, as well as on treatment responses and outcomes. Results: Loss of appetite was the only clinical manifestation that was significantly more common in the MABSC group than in the NTM group (p = 0.0306). The chance of having to use a second treatment regimen was almost 12 times higher in the MABSC group than in the NTM group. Treatment success was significantly higher in the NTM group than in the MABSC group (83.2% vs. 17.6%; p < 0.0001). The chance of recurrence was approximately 37 times higher in the MABSC group than in the NTM group. Conclusions: In the study sample, treatment response of pulmonary disease caused by MABSC was less favorable than that of pulmonary disease caused by other NTM.

RESUMO Objetivo: Descrever as manifestações clínicas de pacientes com infecção pulmonar por micobactérias do complexo Mycobacterium abscessus (CMA) e compará-las com as daqueles infectados com outras micobactérias não tuberculosas (MNT). Métodos: Estudo de coorte retrospectivo envolvendo 43 pacientes divididos em dois grupos: grupo CMA, com pacientes com infecção pulmonar por CMA (n = 17); e grupo MNT, com pacientes com infecção pulmonar por MNT que não CMA (n = 26). Os pacientes foram previamente tratados com o esquema rifampicina, isoniazida, pirazinamida e etambutol antes de o diagnóstico de MNT ser confirmado com culturas positivas em duas amostras de escarro diferentes. As sequências nucleotídicas dos genes hsp65, RNAr 16S e/ou rpoB foram analisadas para a identificação das micobactérias. Foram coletadas características demográficas, clínicas e radiológicas, assim como respostas terapêuticas e desfechos. Resultados: A única manifestação clínica significativamente mais frequente no grupo CMA que no grupo MNT foi hiporexia (p = 0,0306). A chance de haver a necessidade de utilização de um segundo esquema terapêutico foi quase 12 vezes maior no grupo CMA que no grupo MNT. O sucesso terapêutico foi significativamente maior no grupo MNT que no grupo CMA (83,2% vs. 17,6%; p < 0,0001). A chance de recidiva no grupo CMA foi aproximadamente 37 vezes maior que no grupo MNT. Conclusões: Na amostra estudada, a resposta terapêutica da doença pulmonar causada por CMA evoluiu de forma menos favorável do que naquela causada pelas demais MNT.

New and repurposed drugs to treat multidrug- and extensively drug-resistant tuberculosis / Novos fármacos e fármacos repropostos para o tratamento da tuberculose multirresistente e extensivamente resistente

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.

RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a "praga branca", e resultados promissores estão sendo relatados.

Risk factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil.

OBJECTIVE: To analyze the prevalence and factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil. METHODS: This is a cross-sectional study of cases of tuberculosis tested for first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) in Espírito Santo between 2002 and 2012. We have used laboratory data and registration of cases of tuberculosis - from the Sistema Nacional de Agravos de Notificação and Sistema para Tratamentos Especiais de Tuberculose. Individuals have been classified as resistant and non-resistant and compared in relation to the sociodemographic, clinical, and epidemiological variables. Some variables have been included in a logistic regression model to establish the factors associated with resistance. RESULTS: In the study period, 1,669 individuals underwent anti-tuberculosis drug susceptibility testing. Of these individuals, 10.6% showed resistance to any anti-tuberculosis drug. The rate of multidrug resistance observed, that is, to rifampicin and isoniazid, has been 5%. After multiple analysis, we have identified as independent factors associated with resistant tuberculosis: history of previous treatment of tuberculosis [recurrence (OR = 7.72; 95%CI 4.24-14.05) and re-entry after abandonment (OR = 3.91; 95%CI 1.81-8.43)], smoking (OR = 3.93; 95%CI 1.98-7.79), and positive culture for Mycobacterium tuberculosis at the time of notification of the case (OR = 3.22; 95%CI 1.15-8.99). CONCLUSIONS: The partnership between tuberculosis control programs and health teams working in the network of Primary Health Care needs to be strengthened. This would allow the identification and monitoring of individuals with a history of previous treatment of tuberculosis and smoking. Moreover, the expansion of the offer of the culture of tuberculosis and anti-tuberculosis drug susceptibility testing would provide greater diagnostic capacity for the resistant types in Espírito Santo. OBJETIVO: Analisar a prevalência e fatores associados à tuberculose resistente no Espírito Santo. MÉTODOS: Estudo transversal dos casos de tuberculose testados para fármacos de primeira linha (isoniazida, rifampicina, pirazinamida, etambutol e estreptomicina) no Espírito Santo entre 2002 e 2012. Foram utilizados dados laboratoriais e de registro de casos de tuberculose - Sistema Nacional de Agravos de Notificação e Sistema para Tratamentos Especiais de Tuberculose. Os indivíduos foram classificados em resistentes e não resistentes, e comparados para variáveis sociodemográficas, clínicas e epidemiológicas. Algumas variáveis foram inclusas em um modelo de regressão logística para estabelecimento de fatores associados à resistência. RESULTADOS: No período do estudo, 1.669 indivíduos tiveram o teste de sensibilidade aos fármacos antituberculose realizado. Destes, 10,6% apresentaram resistência a qualquer droga antituberculose. A taxa de multirresistência observada, isto é, à rifampicina e isoniazida, foi de 5%. Após a análise múltipla, foram identificados como fatores associados independentes para tuberculose resistente: história de tratamento prévio para tuberculose [Recidiva (OR = 7,72; IC95% 4,24-14,05) e reingresso após abandono (OR = 3,91; IC95% 1,81-8,43)], tabagismo (OR = 3,93; IC95% 1,98-7,79) e cultura positiva para Mycobacterium tuberculosis no momento da notificação do caso (OR = 3,22; IC95% 1,15-8,99). CONCLUSÕES: É necessário o fortalecimento da parceria entre os programas de controle de tuberculose e as equipes de saúde que atuam na rede de Atenção Primária à Saúde. Isso possibilitaria identificar e acompanhar indivíduos com história de tratamento prévio para tuberculose e tabagismo. Além disso, a ampliação da oferta de cultura e Teste de Sensibilidade a fármacos antituberculose proporcionaria maior capacidade diagnóstica para as formas resistentes no Espírito Santo.

Risk factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil / Fatores associados à tuberculose resistente no Espírito Santo, Brasil

ABSTRACT OBJECTIVE To analyze the prevalence and factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil. METHODS This is a cross-sectional study of cases of tuberculosis tested for first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) in Espírito Santo between 2002 and 2012. We have used laboratory data and registration of cases of tuberculosis – from the Sistema Nacional de Agravos de Notificação and Sistema para Tratamentos Especiais de Tuberculose. Individuals have been classified as resistant and non-resistant and compared in relation to the sociodemographic, clinical, and epidemiological variables. Some variables have been included in a logistic regression model to establish the factors associated with resistance. RESULTS In the study period, 1,669 individuals underwent anti-tuberculosis drug susceptibility testing. Of these individuals, 10.6% showed resistance to any anti-tuberculosis drug. The rate of multidrug resistance observed, that is, to rifampicin and isoniazid, has been 5%. After multiple analysis, we have identified as independent factors associated with resistant tuberculosis: history of previous treatment of tuberculosis [recurrence (OR = 7.72; 95%CI 4.24–14.05) and re-entry after abandonment (OR = 3.91; 95%CI 1.81–8.43)], smoking (OR = 3.93; 95%CI 1.98–7.79), and positive culture for Mycobacterium tuberculosis at the time of notification of the case (OR = 3.22; 95%CI 1.15–8.99). CONCLUSIONS The partnership between tuberculosis control programs and health teams working in the network of Primary Health Care needs to be strengthened. This would allow the identification and monitoring of individuals with a history of previous treatment of tuberculosis and smoking. Moreover, the expansion of the offer of the culture of tuberculosis and anti-tuberculosis drug susceptibility testing would provide greater diagnostic capacity for the resistant types in Espírito Santo.

RESUMO OBJETIVO Analisar a prevalência e fatores associados à tuberculose resistente no Espírito Santo. MÉTODOS Estudo transversal dos casos de tuberculose testados para fármacos de primeira linha (isoniazida, rifampicina, pirazinamida, etambutol e estreptomicina) no Espírito Santo entre 2002 e 2012. Foram utilizados dados laboratoriais e de registro de casos de tuberculose – Sistema Nacional de Agravos de Notificação e Sistema para Tratamentos Especiais de Tuberculose. Os indivíduos foram classificados em resistentes e não resistentes, e comparados para variáveis sociodemográficas, clínicas e epidemiológicas. Algumas variáveis foram inclusas em um modelo de regressão logística para estabelecimento de fatores associados à resistência. RESULTADOS No período do estudo, 1.669 indivíduos tiveram o teste de sensibilidade aos fármacos antituberculose realizado. Destes, 10,6% apresentaram resistência a qualquer droga antituberculose. A taxa de multirresistência observada, isto é, à rifampicina e isoniazida, foi de 5%. Após a análise múltipla, foram identificados como fatores associados independentes para tuberculose resistente: história de tratamento prévio para tuberculose [Recidiva (OR = 7,72; IC95% 4,24–14,05) e reingresso após abandono (OR = 3,91; IC95% 1,81–8,43)], tabagismo (OR = 3,93; IC95% 1,98–7,79) e cultura positiva para Mycobacterium tuberculosis no momento da notificação do caso (OR = 3,22; IC95% 1,15–8,99). CONCLUSÕES É necessário o fortalecimento da parceria entre os programas de controle de tuberculose e as equipes de saúde que atuam na rede de Atenção Primária à Saúde. Isso possibilitaria identificar e acompanhar indivíduos com história de tratamento prévio para tuberculose e tabagismo. Além disso, a ampliação da oferta de cultura e Teste de Sensibilidade a fármacos antituberculose proporcionaria maior capacidade diagnóstica para as formas resistentes no Espírito Santo.

Is there a rationale for pulmonary rehabilitation following successful chemotherapy for tuberculosis? / Existe razão para reabilitação pulmonar após o tratamento quimioterápico bem-sucedido para tuberculose?

ABSTRACT The role of tuberculosis as a public health care priority and the availability of diagnostic tools to evaluate functional status (spirometry, plethysmography, and DLCO determination), arterial blood gases, capacity to perform exercise, lesions (chest X-ray and CT), and quality of life justify the effort to consider what needs to be done when patients have completed their treatment. To our knowledge, no review has ever evaluated this topic in a comprehensive manner. Our objective was to review the available evidence on this topic and draw conclusions regarding the future role of the "post-tuberculosis treatment" phase, which will potentially affect several million cases every year. We carried out a non-systematic literature review based on a PubMed search using specific keywords (various combinations of the terms "tuberculosis", "rehabilitation", "multidrug-resistant tuberculosis", "pulmonary disease", "obstructive lung disease", and "lung volume measurements"). The reference lists of the most important studies were retrieved in order to improve the sensitivity of the search. Manuscripts written in English, Spanish, and Russian were selected. The main areas of interest were tuberculosis sequelae following tuberculosis diagnosis and treatment; "destroyed lung"; functional evaluation of sequelae; pulmonary rehabilitation interventions (physiotherapy, long-term oxygen therapy, and ventilation); and multidrug-resistant tuberculosis.The evidence found suggests that tuberculosis is definitively responsible for functional sequelae, primarily causing an obstructive pattern on spirometry (but also restrictive and mixed patterns), and that there is a rationale for pulmonary rehabilitation. We also provide a list of variables that should be discussed in future studies on pulmonary rehabilitation in patients with post-tuberculosis sequelae.

RESUMO O papel da tuberculose como uma prioridade de saúde pública e a disponibilidade de ferramentas diagnósticas para avaliar o estado funcional (espirometria, pletismografia e DLCO), a gasometria arterial, a capacidade de realizar exercícios, as lesões (radiografia de tórax e TC) e a qualidade de vida justificam o esforço de se considerar o que deve ser feito quando os pacientes completam seu tratamento. Até onde sabemos, nenhuma revisão avaliou esse tópico de forma abrangente. Nosso objetivo foi revisar as evidências disponíveis e obter algumas conclusões sobre o futuro papel da fase de "tratamento pós-tuberculose", que irá potencialmente impactar milhões de casos todos os anos. Realizou-se uma revisão não sistemática da literatura tendo como base uma pesquisa no PubMed usando palavras-chave específicas (várias combinações dos termos "tuberculose", "reabilitação", "tuberculose multirresistente", "doença pulmonar", "doença pulmonar obstrutiva", e "medidas de volume pulmonar"). As listas de referências dos artigos principais foram recuperadas para melhorar a sensibilidade da busca. Foram selecionados manuscritos escritos em inglês, espanhol e russo. As principais áreas de interesse foram sequelas de tuberculose após diagnóstico e tratamento; "pulmão destruído"; avaliação funcional das sequelas; intervenções de reabilitação pulmonar (fisioterapia, oxigenoterapia de longo prazo e ventilação); e tuberculose multirresistente. As evidências encontradas sugerem que a tuberculose é definitivamente responsável por sequelas funcionais, principalmente causando um padrão obstrutivo na espirometria (mas também padrões restritivos e mistos) e que há razão para a reabilitação pulmonar. Fornecemos também uma lista de variáveis a serem discutidas em futuros estudos sobre reabilitação pulmonar em pacientes com sequelas pós-tuberculose.

Preditores dos desfechos do tratamento da tuberculose / Predictors of tuberculosis treatment outcomes

OBJETIVO: Analisar os desfechos do tratamento da tuberculose e seus preditores. MÉTODOS: Estudo longitudinal de coorte de pacientes com tuberculose tratados entre 2004 e 2006 no Instituto de Pesquisa Evandro Chagas, na cidade do Rio de Janeiro. As razões de risco ajustadas (RRa) dos preditores foram estimadas. RESULTADOS: Foram incluídos 311 pacientes. As taxas de cura, de abandono, de mortalidade e de falha terapêutica foram, respectivamente, 72 por cento, 19 por cento, 6 por cento e 2 por cento. A troca de regime terapêutico por eventos adversos foi necessária em 8 por cento. O alcoolismo (RRa, 0,30), uso do regime estreptomicina+etambutol+ofloxacina (SEO; RRa, 0,32), infecção por HIV sem tratamento antirretroviral (TARV; RRa, 0,36) e o uso do regime rifampicina+isoniazida+pirazinamida+etambutol (RRa, 0,58) reduziram a probabilidade de cura. A faixa etária mais jovem (RRa, 3,84) e o alcoolismo (RRa, 1,76) aumentaram a probabilidade do abandono. Não foi possível determinar as RRa para os demais desfechos devido a suas baixas prevalências. Entretanto, medidas do risco relativo (RR) identificaram os seguintes potenciais preditores do óbito: uso de esquema SEO (RR, 11,43), infecção pelo HIV sem TARV (RR, 9,64), forma clínica disseminada (RR, 9,09), ausência de confirmação bacteriológica (RR, 4,00), diabetes mellitus (RR, 3,94) e comportamento homo/bissexual (RR, 2,97). A baixa renda (RR, 11,70) foi potencial preditor para falha terapêutica, ao passo que infecção pelo HIV com uso de TARV (RR, 2,46) e forma clínica disseminada (RR, 3,57) foram potenciais preditores para troca do esquema por evento adverso. CONCLUSÕES: O esquema SEO deve ser utilizado transitoriamente quando possível. Os dados confirmam a importância de TARV e sugerem a necessidade de seu início precoce.

OBJECTIVE: To analyze tuberculosis treatment outcomes and their predictors. METHODS: This was a retrospective longitudinal cohort study involving tuberculosis patients treated between 2004 and 2006 at the Instituto de Pesquisa Evandro Chagas, in the city of Rio de Janeiro. We estimated adjusted risk ratios (ARRs) for the predictors of treatment outcomes. RESULTS: Among 311 patients evaluated, the rates of cure, treatment abandonment, treatment failure, and mortality were 72 percent, 19 percent, 2 percent, and 6 percent, respectively. Changes in the treatment regimen due to adverse events occurred in 8 percent. The factors found to reduce the probability of cure were alcoholism (ARR, 0.30), use of the streptomycin+ethambutol+ofloxacin (SEO) regimen (ARR, 0.32), HIV infection without the use of antiretroviral therapy (ART; ARR, 0.36), and use of the rifampin+isoniazid+pyrazinamide+ethambutol regimen (ARR, 0.58). Being younger and being alcoholic both increased the probability of abandonment (ARR, 3.84 and 1.76, respectively). It was impossible to determine the ARR for the remaining outcomes due to their low prevalence. However, using the relative risk (RR), we identified the following potential predictors of mortality: use of the SEO regimen (RR, 11.43); HIV infection without ART (RR, 9.64); disseminated tuberculosis (RR, 9.09); lack of bacteriological confirmation (RR, 4.00); diabetes mellitus (RR, 3.94); and homosexual/bisexual behavior (RR, 2.97). Low income was a potential predictor of treatment failure (RR, 11.70), whereas disseminated tuberculosis and HIV infection with ART were potential predictors of changes in the regimen due to adverse events (RR, 3.57 and 2.46, respectively). CONCLUSIONS: The SEO regimen should not be used for extended periods. The data confirm the importance of ART and suggest the need to use it early.