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© 2016 Conde et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.B

Background: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR-TB) evaluated under field conditions in high burden countries.Methods: Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes.Results: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7-111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0-41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%-34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07).Conclusions: This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized. [ABSTRACT FROM AUTHOR]

BACKGROUND The bacille Calmette–Guérin (BCG) vaccine has immunomodulatory “off-target” effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], −0.7 to 5.5; P=0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, −1.2 to 3.5; P=0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.) [ABSTRACT FROM AUTHOR]

Objectives: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19., Design: Phase III double-blind randomised controlled trial., Setting: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic., Participants: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG., Intervention: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989)., Main Outcome Measures: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion)., Results: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group., Conclusions: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19., Trial Registration: ClinicalTrials.gov NCT04327206., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC), Melbourne Children’s Clinician-Scientist Fellowship Grant (KPP). Outside of the submitted work, JCr has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir-Paxlovid (Pfizer). KG is a member of the Royal Children’s Hospital (RCH) Human Research Ethics Committee (the primary ethics committee providing approval for the BRACE trial) and Director of Research Operations at RCH; she abstained from all discussion, voting, approval and review related to the BRACE trial. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Various novel platform technologies have been used for the development of COVID-19 vaccines. In this nested cohort study among healthcare workers in Australia and Brazil who received three different COVID-19-specific vaccines, we (a) evaluated the incidence of adverse events following immunization (AEFI); (b) compared AEFI by vaccine type, dose and country; (c) identified factors influencing the incidence of AEFI; and (d) assessed the association between reactogenicity and vaccine anti-spike IgG antibody responses. Of 1302 participants who received homologous 2-dose regimens of ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac), 1219 (94%) completed vaccine reaction questionnaires. Following the first vaccine dose, the incidence of any systemic reaction was higher in ChAdOx1-S recipients (374/806, 46%) compared with BNT162b2 (55/151, 36%; p  = 0.02) or CoronaVac (26/262, 10%; p  < 0.001) recipients. After the second vaccine dose, the incidence of any systemic reaction was higher in BNT162b2 recipients (66/151, 44%) compared with ChAdOx1-S (164/806, 20%; p  < 0.001) or CoronaVac (23/262, 9%; p  < 0.001) recipients. AEFI risk was higher in younger participants, females, participants in Australia, and varied by vaccine type and dose. Prior COVID-19 did not impact the risk of AEFI. Participants in Australia compared with Brazil reported a higher incidence of any local reaction (170/231, 74% vs 222/726, 31%, p  < 0.001) and any systemic reaction (171/231, 74% vs 328/726, 45%, p  < 0.001), regardless of vaccine type. Following a primary course of ChAdOx1-S or CoronaVac vaccination, participants who did not report AEFI seroconverted at a similar rate to those who reported local or systemic reactions. In conclusion, we found that the incidence of AEFI was influenced by participant age and COVID-19 vaccine type, and differed between participants in Australia and Brazil.

Species belonging to the Mycobacterium kansasii complex (MKC) are frequently isolated from humans and the environment and can cause serious diseases. The most common MKC infections are caused by the species M. kansasii ( sensu stricto ), leading to tuberculosis-like disease. However, a broad spectrum of virulence, antimicrobial resistance and pathogenicity of these non-tuberculous mycobacteria (NTM) are observed across the MKC. Many genomic aspects of the MKC that relate to these broad phenotypes are not well elucidated. Here, we performed genomic analyses from a collection of 665 MKC strains, isolated from environmental, animal and human sources. We inferred the MKC pangenome, mobilome, resistome, virulome and defence systems and show that the MKC species harbours unique and shared genomic signatures. High frequency of presence of prophages and different types of defence systems were observed. We found that the M. kansasii species splits into four lineages, of which three are lowly represented and mainly in Brazil, while one lineage is dominant and globally spread. Moreover, we show that four sub-lineages of this most distributed M. kansasii lineage emerged during the twentieth century. Further analysis of the M. kansasii genomes revealed almost 300 regions of difference contributing to genomic diversity, as well as fixed mutations that may explain the M. kansasii 's increased virulence and drug resistance.

An accelerated local injection site reaction following Bacille Calmette-Guérin (BCG) vaccination has been associated with underlying active tuberculosis (TB) in high TB-prevalence settings. The clinical significance of this accelerated BCG reaction in individuals without TB symptoms, particularly in low TB-prevalence countries, is unclear. Using safety surveillance data and baseline interferon-gamma release assays (IGRA) within an international randomised trial of BCG vaccination in healthcare workers (the BRACE trial), we aimed to determine the incidence, and investigate for clinical implications, of an accelerated BCG reaction in asymptomatic adults in low and high TB-prevalence settings. An accelerated BCG reaction occurred in 755/1984 (38 %) of BCG-vaccinees. Although more frequently painful, tender, erythematous and/or swollen within the first fourteen days of vaccination, compared with non-accelerated reactions, the majority of injection site reactions were mild and did not meet criteria for an adverse event. Prior mycobacterial exposure, through prior BCG vaccination (OR 2.46, 95%CI 1.93-3.13, p < 0.001) or latent TB infection (OR 4.17, 95%CI 1.16-14.93, p = 0.03), and female sex (OR 1.27, 95%CI 1.03-1.57, p = 0.02), were key determinants for the occurrence of an accelerated BCG reaction. The development of an accelerated local reaction to BCG vaccination in an individual without prior history of BCG vaccination, should prompt consideration of further investigations for potential underlying TB infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: The effectiveness of BCG vaccine for adult pulmonary tuberculosis remains uncertain. In this study, we aimed to evaluate the effect of vaccination with BCG-Denmark to prevent initial and sustained interferon-γ release assay conversion in Brazilian health-care workers., Methods: This substudy is a nested randomised controlled trial embedded within the BRACE trial (NCT04327206). Specifically, this substudy enrolled Brazilian health-care workers (aged ≥18 years) from three sites in Brazil (Manaus, Campo Grande, and Rio de Janeiro) irrespective of previously receiving BCG vaccination. Participants were excluded if they had contraindications to BCG vaccination, more than 1 month of treatment with specific tuberculosis treatment drugs, previous adverse reactions to BCG, recent BCG vaccination, or non-compliance with assigned interventions. Those eligible were randomly assigned (1:1) to either the BCG group (0·1 mL intradermal injection of BCG-Denmark [Danish strain 1331; AJ Vaccines, Copenhagen]) or the placebo group (intradermal injection of 0·9% saline) using a web-based randomisation process in variable-length blocks (2, 4, or 6), and were stratified based on the study site, age (<40, ≥40 to <60, ≥60 years), and comorbidity presence (diabetes, chronic respiratory disease, cardiac condition, hypertension). Sealed syringes were used to prevent inadvertent disclosure of group assignments. The QuantiFERON-TB Gold (QFT) Plus test (Qiagen; Hilden, Germany) was used for baseline and 12-month tuberculosis infection assessments. The primary efficacy outcome was QFT Plus conversion (≥0·35 IU/mL) by 12 months following vaccination in participants who had a negative baseline result (<0·35 IU/mL)., Findings: Between Oct 7, 2020, and April 12, 2021, 1985 (77·3%) of 2568 participants were eligible for QFT Plus assessment at 12 months and were included in this substudy; 996 (50·2%) of 1985 were in the BCG group and 989 (49·8%) were in the placebo group. Overall, 1475 (74·3%) of 1985 participants were women and 510 (25·7%) were men, and the median age was 39 years (IQR 32-47). During the first 12 months, QFT Plus conversion occurred in 66 (3·3%) of 1985 participants, with no significant differences by study site (p=0·897). Specifically, 34 (3·4%) of 996 participants had initial QFT conversion in the BCG group compared with 32 (3·2%) of 989 in the placebo group (risk ratio 1·09 [95% CI 0·67-1·77]; p=0·791)., Interpretation: BCG-Denmark vaccination did not reduce initial QFT Plus conversion risk in Brazilian health-care workers. This finding underscores the need to better understand tuberculosis prevention in populations at high risk., 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 United Health Group Foundation, Epworth Healthcare, and individual donors., Translation: For the Portuguese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/and declare: the trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), Investigator Grant (NC); Melbourne Children's Clinician-Scientist Fellowship Grant (KPP); Institutional support for research grants, presentations, meeting attendance and participation on Scientific Advisory Boards related to pertussis, RSV, pneumococcal, meningococcal and COVID-19 diseases from GlaxoSmithKline, Merck Sharpe & Dohme, Pfizer, Clover Biopharmaceuticals and Resvinet Foundation (PCR); grant support from Sanofi, MSD & CEPI for COVID-19 vaccine/drug research (JC). PCR has participated on Astra Zeneca COVID-19 Scientific Advisory Board and has a bacteriotherapy patent pending. JC participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda), Nirmatrelvir/Ritonavir-Paxlovid (Pfizer) and recently presented to Foro Latinoamericano para Asesores Médicos en Vacunas (Pfizer). NW has participated in the Covalia COVID-19 DNA vaccine trial in an advisory/data safety monitoring board capacity. KG is a member of the Royal Children's Hospital (RCH) Human Research Ethics Committee (the primary ethics committee providing approval for the BRACE trial) and Director of Research Operations at RCH; she abstained from all discussion, voting, approval and review related to the BRACE trial., (© 2024 The Author(s).)

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 10 5 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., Competing Interests: We declare no competing interests., (© 2023 Published by Elsevier Ltd.)

Introduction and Objectives: Post-tuberculosis lung disease (PTLD), as other chronic respiratory disorders, may have infectious complications; some of them can be prevented with vaccinations. So far, no document has discussed the potential role of vaccination in PTLD. Therefore, the objective of this review was to describe vaccination recommendations to prevent infections potentially capable of complicating PTLD., Materials and Methods: A non-systematic review of the literature was conducted. The following keywords were used: tuberculosis, vaccination, vaccines and PTLD. PubMed/MEDLINE and Embase were used as the search engine, focusing on English-language literature only., Results: We identified 9 vaccines potentially useful in PTLD. Influenza, pneumococcal and anti-COVID-19 vaccinations should be recommended. Patients with PTLD can also benefit from vaccination against shingles. Vaccination against pertussis is mainly relevant during childhood. Diphtheria, tetanus and measles vaccination are recommended for general population and should be considered in patients with PTLD not previously vaccinated. Tdap (Tetanus, diphtheria, and pertussis) booster should be repeated in every adult every ten years. Vaccination against BCG retains its importance during early childhood in countries where TB is endemic., Conclusions: Vaccination deserves to be considered among the strategies to prevent and/or mitigate PTLD complications. Further evidence is necessary to better understand which vaccines have the greatest impact and cost-benefit., Competing Interests: Conflicts of interest None., (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Definitions and measures of asthma control used in clinical trials and practice often vary, as highlighted in the manuscript, "Is asthma control more than just an absence of symptoms? An expert consensus statement". Furthermore, the authors discussed differences between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma. Given these disparities, there is a need for consensus regarding what constitutes well-controlled asthma and, especially, how best it can be measured and recorded. In the current work, we describe our data and provide more detail on the methodology from a two-stage Delphi survey and a structured literature review, which were designed to reach a consensus definition of asthma control and alleviate misalignments between patients and HCPs. Survey data were collected using a two-stage Delphi technique; a method used to collate expert opinions over a series of sequential questionnaires to reach a consensus. The collated Delphi survey data were compared with results from a comprehensive, structured literature review of 216 publications, to assess if there was a correlation between existing guidance and measures of asthma control used in clinical trials and standard clinical practice. In order to collate and interpret findings from the Delphi survey, responses from 82 panelists (73 HCPs and 9 authors) were qualitatively analyzed, quantitatively categorized, and presented as percentages or counts in Excel databases, which are detailed in the current work. Searches conducted using PubMed and Cochrane identified 664 manuscripts, and Embase was used to identify 89 congress abstracts. After applying a stringent screening method using predefined key words, the structured literature review consisted of 185 peer-reviewed manuscripts and 31 congress abstracts, and assessed existing guidance and measures of asthma control used in clinical trials. In this publication, we provide further insight into the predefined keywords, search strings, and strategy applied to identify manuscripts and congress abstracts for inclusion/exclusion, and detail methods for data extraction. Together, the data from the Delphi survey and structured literature review aimed to provide greater insights into challenges and approaches in achieving asthma control in clinical practice, with the potential for results to be used to guide a universally accepted definition and measure of asthma control that can be used and understood by patients, HCPs, and researchers. Qualitative and quantitative methodology and analysis from the Delphi survey and literature review search strategy can potentially be used to identify disparities and explore expert opinion and relevant literature in other therapeutic areas to guide a consensus where disparities exist., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. Spanevello reports consulting fees from GSK; payment or honoraria from AstraZeneca, Chiesi, and GSK; and participation on a data safety monitoring board or advisory board for GSK. L. Pérez de Llano reports grants or contracts from AstraZeneca, Esteve, FAES Pharma, and Teva, consulting fees from AstraZeneca, GEBRO, Gilead, GSK, MSD, Novartis, and Sanofi; payment or honoraria from AstraZeneca, Chiesi, Esteve, GSK, LEO Pharma, MSD, Novartis, and Sanofi; support for attending meetings and/or travel from AstraZeneca, Chiesi, FAES Pharma, GSK, and Novartis; and participation on a data safety monitoring board or advisory board for AstraZeneca. C. Domingo Ribas has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GSK, Menarini, Novartis, Pfizer, and Stallergenes, and declares no specific conflicts of interest to report regarding this paper. J.D. Blakey reports grants or contracts from AstraZeneca, GSK, and Novartis; consulting fees from Boehringer Ingelheim, Chiesi, and GSK; payment or honoraria from AstraZeneca, Chiesi, and GSK; support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, and GSK; receipt of medical writing support from GSK and Teva; payment to their institution for advisory work from Asthma Australia; and unpaid advisory work from Asthma WA. H. Inoue declares research grants from Boehringer Ingelheim, payment or honoraria for lectures and advisory committees from AstraZeneca, Boehringer Ingelheim, GSK, Kyorin, Novartis, and Sanofi. G.W. Canonica declares no conflict of interest for the current paper, and reports having received research grants as well as being lecturer or having received advisory board fees from A.Menarini, Allergy Therapeutics, Anallergo, AstraZeneca, Chiesi, FAES Pharma, Firma, Genentech, GSK, Guidotti-Malesci, Hal Allergy, Innovacaremd, Novartis, OmPharma, RedMaple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, ThermoFisher, Uriach Pharma, and Valeas. D. Yang, and M. Dalcolmo declare that they have no disclosures of interest. G. Garcia declares participation in advisory boards for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi; participation in sponsored activities for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Sanofi, and Phoenix; principal investigator for AstraZeneca, Boehringer Ingelheim, Chiesi, Covance, GSK, Iqvia, Novartis, Parexel, PPD, Sanofi, and Zambon. S. Mokashi, A. Kurne, and A. Butta were GSK employees at the time of study conduct and hold shares in GSK., (© 2023 Published by Elsevier Inc.)

Multiple factors, including vaccine platform and prior vaccinations, influence vaccine responses. We compared antibody responses to CoronaVac (Sinovac) and ChAdOx1-S (AstraZeneca-Oxford) vaccination in 874 healthcare workers in Brazil. As participants were randomised to BCG vaccination or placebo in the preceding 0-6 months as part of the BCG vaccination to reduce the impact of COVID-19 in healthcare workers (BRACE) trial, we also investigated the influence of recent BCG vaccination on antibody responses to these COVID-19 vaccines. Twenty-eight days after the second dose of each vaccine, ChAdOx1-S induced a stronger anti-spike IgG response than CoronaVac vaccination. Recent BCG vaccination did not impact IgG antibody responses to ChAdOx1-S or CoronaVac., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Messina, Sperotto, Puga, da Silva, de Oliveira, Moore, Pittet, Jamieson, Dalcolmo, dos Santos, Jardim, Lacerda, Curtis and Croda.)

Background: BCG vaccination, originally used to prevent tuberculosis, is known to "train" the immune system to improve defence against viral respiratory infections. We investigated whether a previous BCG vaccination is associated with less severe clinical progression of COVID-19 METHODS: A case-control study comparing the proportion with a BCG vaccine scar (indicating previous vaccination) in cases and controls presenting with COVID-19 to health units in Brazil. Cases were subjects with severe COVID-19 (O2 saturation < 90%, severe respiratory effort, severe pneumonia, severe acute respiratory syndrome, sepsis, and septic shock). Controls had COVID-19 not meeting the definition of "severe" above. Unconditional regression was used to estimate vaccine protection against clinical progression to severe disease, with strict control for age, comorbidity, sex, educational level, race/colour, and municipality. Internal matching and conditional regression were used for sensitivity analysis., Results: BCG was associated with high protection against COVID-19 clinical progression, over 87% (95% CI 74-93%) in subjects aged 60 or less and 35% (95% CI - 44-71%) in older subjects., Conclusions: This protection may be relevant for public health in settings where COVID-19 vaccine coverage is still low and may have implications for research to identify vaccine candidates for COVID-19 that are broadly protective against mortality from future variants. Further research into the immunomodulatory effects of BCG may inform COVID-19 therapeutic research., (© 2023. The Author(s).)

Purpose: Definitions and measures of asthma control used in clinical trials and in clinical practice vary considerably. There is also misalignment between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma control. This study aimed to progress towards a consensus definition of asthma control, and evaluate disparities between HCP and patient perspectives., Basic Procedures: A two-stage Delphi questionnaire involving asthma specialists sought to identify areas of consensus on aspects of asthma control in clinical practice. Results were compared with those of a structured literature review to assess if existing guidance and measures of asthma control used in studies correlated with practice. Eighty-two panelists took part in the Delphi questionnaire. The structured literature review included 185 manuscripts and 31 abstracts., Main Findings: Panelists agreed that there was no standard definition of asthma control, confirmed by a total of 19 different composite consensus/guideline definitions and/or validated measures of control being identified across the Delphi study and literature review. Panelists agreed on the positive associations of well-controlled asthma with patient outcomes, but not on the components or thresholds of a working definition of control., Principal Conclusions: A universally accepted definition and measure of asthma control that is utilized and understood by patients, HCPs, and researchers is required., (Copyright © 2022. Published by Elsevier Ltd.)

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.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs. METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants. RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified. CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

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.

Introduction: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19., Methods and Analysis: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections., Ethics and Dissemination: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system., Trial Registration: ClinicalTrials.gov NCT04327206., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new ( i.e. bedaquiline, delamanid) and repurposed ( i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care., Competing Interests: Conflict of interest: S. Borisov has nothing to disclose. Conflict of interest: E. Danila has nothing to disclose. Conflict of interest: A. Maryandyshev has nothing to disclose. Conflict of interest: M. Dalcolmo has nothing to disclose. Conflict of interest: S. Miliauskas has nothing to disclose. Conflict of interest: L. Kuksa reports personal fees for trial participation from Otsuka and Tibotec, personal fees for lectures from Johnson and Johnson Services Inc., outside the submitted work. Conflict of interest: S. Manga has nothing to disclose. Conflict of interest: A. Skrahina has nothing to disclose. Conflict of interest: S. Diktanas reports personal fees for trial participation from Otsuka, grants for meeting attendance from Janssen (Sirturo), outside the submitted work. Conflict of interest: L.R. Codecasa has nothing to disclose. Conflict of interest: A. Aleksa has nothing to disclose. Conflict of interest: J. Bruchfeld has nothing to disclose. Conflict of interest: A. Koleva has nothing to disclose. Conflict of interest: A. Piubello has nothing to disclose. Conflict of interest: Z.F. Udwadia has nothing to disclose. Conflict of interest: O.W. Akkerman has nothing to disclose. Conflict of interest: E. Belilovski has nothing to disclose. Conflict of interest: E. Bernal has nothing to disclose. Conflict of interest: M.J. Boeree has nothing to disclose. Conflict of interest: J. Cadiñanos Loidi has nothing to disclose. Conflict of interest: Q. Cai has nothing to disclose. Conflict of interest: J.J. Cebrian Gallardo has nothing to disclose. Conflict of interest: M. Dara has nothing to disclose. Conflict of interest: E. Davidavičienė has nothing to disclose. Conflict of interest: L. Davies Forsman has nothing to disclose. Conflict of interest: J. De Los Rios has nothing to disclose. Conflict of interest: J. Denholm has nothing to disclose. Conflict of interest: J. Drakšienė has nothing to disclose. Conflict of interest: R. Duarte has nothing to disclose. Conflict of interest: S.E. Elamin has nothing to disclose. Conflict of interest: N. Escobar Salinas has nothing to disclose. Conflict of interest: M. Ferrarese has nothing to disclose. Conflict of interest: A. Filippov has nothing to disclose. Conflict of interest: A. Garcia has nothing to disclose. Conflict of interest: J.M. García-García has nothing to disclose. Conflict of interest: I. Gaudiesiute has nothing to disclose. Conflict of interest: B. Gavazova has nothing to disclose. Conflict of interest: R. Gayoso has nothing to disclose. Conflict of interest: R. Gomez Rosso has nothing to disclose. Conflict of interest: V. Gruslys has nothing to disclose. Conflict of interest: G. Gualano has nothing to disclose. Conflict of interest: W. Hoefsloot has nothing to disclose. Conflict of interest: J. Jonsson has nothing to disclose. Conflict of interest: E. Khimova has nothing to disclose. Conflict of interest: H. Kunst has nothing to disclose. Conflict of interest: R. Laniado-Laborín has nothing to disclose. Conflict of interest: Y. Li has nothing to disclose. Conflict of interest: C. Magis-Escurra has nothing to disclose. Conflict of interest: V. Manfrin has nothing to disclose. Conflict of interest: V. Marchese has nothing to disclose. Conflict of interest: E. Martínez Robles has nothing to disclose. Conflict of interest: A. Matteelli has nothing to disclose. Conflict of interest: J. Mazza-Stalder has nothing to disclose. Conflict of interest: C. Moschos has nothing to disclose. Conflict of interest: M. Muñoz-Torrico has nothing to disclose. Conflict of interest: H. Mustafa Hamdan has nothing to disclose. Conflict of interest: B. Nakčerienė has nothing to disclose. Conflict of interest: L. Nicod has nothing to disclose. Conflict of interest: M. Nieto Marcos has nothing to disclose. Conflict of interest: D.J. Palmero has nothing to disclose. Conflict of interest: F. Palmieri has nothing to disclose. Conflict of interest: A. Papavasileiou has nothing to disclose. Conflict of interest: M-C. Payen has nothing to disclose. Conflict of interest: A. Pontarelli has nothing to disclose. Conflict of interest: S. Quirós has nothing to disclose. Conflict of interest: A. Rendon has nothing to disclose. Conflict of interest: L. Saderi has nothing to disclose. Conflict of interest: A. Šmite has nothing to disclose. Conflict of interest: I. Solovic has nothing to disclose. Conflict of interest: M.B. Souleymane has nothing to disclose. Conflict of interest: M. Tadolini has nothing to disclose. Conflict of interest: M. van den Boom has nothing to disclose. Conflict of interest: M. Vescovo has nothing to disclose. Conflict of interest: P. Viggiani has nothing to disclose. Conflict of interest: A. Yedilbayev has nothing to disclose. Conflict of interest: R. Zablockis has nothing to disclose. Conflict of interest: D. Zhurkin has nothing to disclose. Conflict of interest: M. Zignol has nothing to disclose. Conflict of interest: D. Visca has nothing to disclose. Conflict of interest: A. Spanevello has nothing to disclose. Conflict of interest: J.A. Caminero has nothing to disclose. Conflict of interest: J-W. Alffenaar has nothing to disclose. Conflict of interest: S. Tiberi has nothing to disclose. Conflict of interest: R. Centis has nothing to disclose. Conflict of interest: L. D'Ambrosio has nothing to disclose. Conflict of interest: E. Pontali has nothing to disclose. Conflict of interest: G. Sotgiu has nothing to disclose. Conflict of interest: G.B. Migliori has nothing to disclose., (Copyright ©ERS 2019.)

The Special Tuberculosis Treatment Information System (SITE-TB) arose mainly from the need to routinely monitor all persons with drug-resistant tuberculosis (DR-TB) in Brazil, as well as to qualify tuberculosis' drug control. Developed by the Professor Hélio Fraga Reference Center and the Management Sciences for Health/Brazil Project, this online system was implemented in 2013 in all Brazilian states. In addition to DR-TB, the system registers people with drug-sensitive tuberculosis with special regimen indications, and those with nontuberculous mycobacterial infections identified by differential diagnosis of tuberculosis. All confirmed tuberculosis cases should be notified on the Notifiable Diseases Information System (SINAN). In situations where treatment with special regimens is necessary, the case is closed on SINAN and notified on SITE-TB. Professionals from tuberculosis reference centers report and monitor these cases on the system, as well as manage tuberculosis' drugs.

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019., (Copyright © 2019. Published by Elsevier Ltd.)

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., (Copyright © 2018 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.)

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.