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Abstract Background India accounts for one-fifth of the global incident cases of tuberculosis(TB). The country presently has the world's largest directly observed treatment, short course (DOTS) programme, that has shown impressive results and covers almost 100% of the billion-plus Indian population. Despite such a successful programme, the majority of Indian patients with tuberculosis prefer private healthcare, although repeated audits of this sector have shown the quality to be poor. We aimed to ascertain the level of awareness and knowledge of private patients with tuberculosis attending our clinic at a tertiary private healthcare institute with regards to the DOTS programme, understanding the reasons behind their preference for private healthcare, and evaluating their perceptions and reasons for accepting or failing to accept directly observed therapy as a treatment option. Methods A structured interview schedule was administered to private patients with tuberculosis at the P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India between January 2006 to November 2007. Results Only 30 of 200 patients (15%) were aware of the DOTS programme. After being explained what directly observed therapy was, 136 patients (68%) found this form of treatment unacceptable.183 patients (91.5%) preferred buying the drugs themselves to visiting a DOTS centre. 90 patients (45%) were not prepared to be observed while swallowing their TB drugs, finding it an intrusion of privacy. Conclusions Our study reveals a poor knowledge and awareness of the DOTS programme among the cohort of TB patients that we interviewed. The control of TB in India will undoubtedly benefit from more patients being attracted to and treated by the existing DOTS programmes. However, directly observed treatment, in its present form, is considered too rigid and intrusive and is unlikely to be accepted by a majority of patients seeking private healthcare. Novel strategies and more flexible options will have to be devised to ensure higher cure rates without compromising patient choice.

Background: Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances., Objectives: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials., Sources: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials)., Content: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research., Implications: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB., Competing Interests: Transparency declaration IM, MB, DC, KD, GG, CRH, YK, CLa, CLi, HMM, GT, ZU, RvC, GEV, RJW, and LG have nothing to declare. HRS reports honoraria in 2018 for speaking at and attending an event organized by the Latvian Society Against Tuberculosis, which was sponsored by Otsuka and Johnson and Johnson; NIP has received grant funding paid to institution from Janssen, drug donation for trials from Pfizer and Sanofi, and speaker fees from Janssen., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level., (© 2024. Springer Nature Limited.)

Millions of workers are exposed to substances known to cause occupational interstitial lung diseases (ILDs), particularly in developing countries. However, the burden of the disease is likely to be underestimated due to under-recognition, under-reporting or both. The diagnosis of occupational ILD requires a high level of suspicion and a thorough occupational history, as occupational and non-occupational ILDs may be clinically, functionally and radiologically indistinguishable, leading to delayed diagnosis and inappropriate management. A potential occupational aetiology should always be considered in the differential diagnosis of ILD, as removal from the workplace exposure, with or without treatment, is a key therapeutic intervention and may lead to significant improvement. In this article, we provide an overview of the 'traditional' inorganic dust-related ILDs but also address idiopathic pulmonary fibrosis and the immunologically mediated chronic beryllium disease, sarcoidosis and hypersensitivity pneumonitis, with emphasis on the importance of surveillance and prevention for reducing the burden of these conditions. To this end, health-care professionals should be specifically trained about the importance of occupational exposures as a potential cause of ILD., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management., Competing Interests: Conflict of interest: S.K. Rajan reports grants to their institution, consulting fees and lecture fees from Cipla and Boehringer Ingelheim; speaker fees from the Indian Chest Society; and support from Cipla to attend a European Respiratory Society meeting, all in the 36 months prior to manuscript submission. V. Cottin reports an unrestricted grant to their institution from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Roche, Galapagos, Galecto, Shionogi, Fibrogen, RedX Pharma and PureTech; payment or honoraria and support for attending meetings from Boehringer Ingelheim and Roche; and participation on a data safety monitoring board or advisory board for Roche/Promedior, Celgene/Bristol Myers Squibb and Galapagos, all in the 36 months prior to manuscript submission. R. Dhar reports external expert contracts from Cipla and Boehringer Ingelheim; speaker fees from the Indian Chest Society, Cipla and Boehringer Ingelheim; and support for attendance at a European Respiratory Society meeting from Cipla. S. Danoff reports grant funding from Bristol Myers Squibb (Myositis ILD Trial), Boehringer Ingelheim (INBUILD and INBUILD-ON Trials) and Roche/Genentech (TRAIL Trial); royalties from UpToDate; advisory board fees from Boehringer Ingelheim and Lupin Pharma; payment for presentations from the France Foundation; funding for travel to present lectures from Boehringer Ingelheim; and participation on data safety monitoring boards for Galecto and Galapagos, all in the 36 months prior to manuscript submission; as well as a role as senior medical adviser and interim CMO for the Pulmonary Fibrosis Foundation and membership of the board of directors of the American Thoracic Society. K.R. Flaherty reports research grants paid to their institution by Boehringer Ingelheim; and consulting fees paid to them by Boehringer Ingelheim, Roche/Genentech, Blade Therapeutics, Shionogi, DevPro, AstraZeneca, Pure Health, Fibrogen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean and PureTech, all in the 36 months prior to manuscript submission. K.K. Brown reports lung fibrosis research grants from the National Heart, Lung, and Blood Institute; being an external science advisor to AbbVie, CSL Behring, Dispersol, Huitai Biomedicine, Lilly, RedX Pharma, Theravance and Translate Bio; being a DMC chair for Biogen; scientific advisory board membership for Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, DevPro Biopharma, Galapagos NV, Galecto, Open Source Imaging Consortium, Pliant, Sanofi and Third Pole; DMC membership for Humanetics; and a scientific collaboration with Sekisui Medical Co., all in the 36 months prior to manuscript submission; as well as leadership or fiduciary roles for the Fleischner Society and Open Source Imaging Consortium. A. Mohan declares no competing interests. E. Renzoni declares a research contract payment and advisory board meeting payment to their institution by Boehringer Ingelheim; lecture fees paid to their institution by Boehringer Ingelheim, Roche and Chiesi; and registration and travel expenses for the American Thoracic Society conference, paid by Boehringer Ingelheim, all in the 36 months prior to manuscript submission. M. Mohan reports no competing interests. Z. Udwadia reports no competing interests. P. Shenoy reports no competing interests. D. Currow reports intellectual property payments and royalties from Mayne Pharma International Pty Ltd, a manufacturer of sustained-release morphine; and consulting fees from Helsinn Pharmaceuticals, in the 36 months prior to manuscript submission; as well as leadership or fiduciary roles for the Dust Diseases Board of New South Wales and the Board of the Cancer Institute NSW. A. Devraj reports consulting fees from Boehringer Ingelheim, Roche, Galecto, Galapagos, Brainomix and Vicore, all in the 36 months prior to manuscript submission. B. Jankharia reports payment or honoraria to their institution from Cipla India, Lupin India, Boehringer Ingelheim and German Remedies India, all in the 36 months prior to manuscript submission; as well as being a past president of the Indian Musculoskeletal Society and the Indian Radiology and Imaging Association. R. Kulshrestha reports no competing interests. S. Jones reports grants to their institution from Boehringer Ingelheim and Trevi for being Chair of Action for Pulmonary Fibrosis (APF) and President of the European Pulmonary Fibrosis Federation (EU-IPFF) (both these organisations implement projects in partnership with industry; the author is not involved in these projects and does not gain personally); reports payment or honoraria from Boehringer Ingelheim, Vicore and Roche (paid to their institution); and participation on a data safety monitoring board or advisory board as Galecto DSMB for an anti-fibrotic therapy, in the 36 months prior to manuscript submission. C. Ravaglia reports no competing interests. S. Quadrelli reports speaker fees from Boehringer Ingelheim in the 36 months prior to manuscript submission. R. Iyer reports no competing interests. S. Dhooria reports no competing interests. M. Kolb reports research funding for pre-clinical work from Boehringer Ingelheim and Pieris; research funding for a clinical project from Roche; consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, AbbVie, Belerophon, Algernon, CSL Behring, United Therapeutics and AstraZeneca; payment or honoraria from Novartis, Boehringer Ingelheim and Roche; payment for court testimony from Roche; participation on a data safety monitoring board or advisory board for Covance and United Therapeutics; and an allowance paid to their institution from the European Respiratory Society relating to their duties as European Respiratory Journal Chief Editor, all in the 36 months prior to manuscript submission. A.U. Wells reports payments or honoraria from Boehringer Ingelheim and Roche; and participation on a data safety monitoring board or advisory board for Boehringer Ingelheim, Roche and Veracyte, all in the 36 months prior to manuscript submission., (Copyright ©The authors 2023.)

Background: The impact of low body mass index (BMI) at initiation of rifampicin-resistant tuberculosis (RR-TB) treatment on outcomes is uncertain. We evaluated the association between BMI at RR-TB treatment initiation and end-of-treatment outcomes., Methods: We performed an individual participant data meta-analysis of adults aged ≥18 years with RR-TB whose BMI was documented at treatment initiation. We compared odds of any unfavorable treatment outcome, mortality, or failure/recurrence between patients who were underweight (BMI <18.5 kg/m2) and not underweight. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using logistic regression, with matching on demographic, clinical, and treatment-related factors. We evaluated effect modification by human immunodeficiency virus (HIV) status and other variables using likelihood ratio tests. We also estimated cumulative incidence of mortality during treatment stratified by HIV., Results: Overall, 5148 patients were included; 1702 (33%) were underweight at treatment initiation. The median (interquartile range) age was 37 years (29 to 47), and 455 (9%) had HIV. Compared with nonunderweight patients, the aOR among underweight patients was 1.7 (95% CI, 1.4-1.9) for any unfavorable outcome, 3.1 (2.4-3.9) for death, and 1.6 (1.2-2.0) for failure/recurrence. Significant effect modification was found for World Health Organization region of treatment. Among HIV-negative patients, 24-month mortality was 14.8% (95% CI, 12.7%-17.3%) for underweight and 5.6% (4.5%-7.0%) for not underweight patients. Among patients with HIV, corresponding values were 33.0% (25.6%-42.6%) and 20.9% (14.1%-27.6%)., Conclusions: Low BMI at treatment initiation for RR-TB is associated with increased odds of unfavorable treatment outcome, particularly mortality., Competing Interests: Potential conflicts of interest. D. F. is a staff member of the World Health Organization (WHO). I. M. R. reports consulting fees from WHO, DR-TB, for the regional Green Light Committee (rGLC) mission in Pakistan, Yemen, Syria, Jordan, and Lebanon; WHO, drug-resistant tuberculosis(DR-TB) guideline writing for Eastern Mediterranean Regional Office; and WHO, situational analysis of the 10 DR-TB high burden countries after the United Nations High Level Meeting, all paid to self; payment or honoraria for international DR-TB trainings at The Union (on line), International tuberculosis (TB) infection training at The Union (on line), and DR-TB training for Middle East Response countries at international organization for migration, all paid to self; payment for expert testimony from Teladoc Health International (clinical cases, second medical opinion in complex infectious diseases management), paid to self; and participation on Novel triple-dose tuberculosis retreatment regimens (TriDoRe; NCT04260477) and received no payment. S. K. reports support for the present study from the Eli Lilly Foundation (grant to Brigham & Women’s Hospital to support multidrug-resistant tuberculosis (MDR-TB) program supports in Russia; The donor had no involvement in data collection, manuscript preparation, or interpretation.) and Advance Access & Delivery (nongovernmental organization) as a board member. D. M. reports support for the present manuscript through funding provided in 2018–2019 by WHO, ATS/ERS/CDC/IDSA, for establishment of the individual participant data dataset, no funding for this analysis, paid to their institution; participation in scientific advisory committee for 2 trials of MDRTB in South Africa (no honoraria); and served as chair of the Canadian Thoracic Society–TB Committee (unpaid). A. T. reports a grant from Brazilian Ministry of Science, Technology and Innovation, as a direct grant to self outside of the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The present study was initiated to understand the proportion of predominant variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in postvaccination infections during the Delta dominated second wave of coronavirus disease 2019 (COVID-19) in the Mumbai Metropolitan Region (MMR) in India and to understand any mutations selected in the postvaccination infections or showing association with any patient demographics. Samples were collected (n = 166) from severe/moderate/mild COVID-19 patients who were either vaccinated (COVISHIELD/COVAXIN-partial/fully vaccinated) or unvaccinated, from a city hospital and from home isolation patients in MMR. A total of 150 viral genomes were sequenced by Oxford Nanopore sequencing and the data of 136 viral genomes were analyzed for clade/lineage and for identifying mutations. The sequences belonged to three clades (21A, 21I, and 21J) and their lineage was identified as either Delta (B.1.617.2) or Delta+ (B.1.617.2 + K417N) or sub-lineages of Delta variant (AY.120/AY.38/AY.99). A total of 620 mutations were identified of which 10 mutations showed an increase in trend with time (May-October 2021). Associations of six mutations (two in spike, three in orf1a, and one in nucleocapsid) were shown with milder forms of the disease and one mutation (in orf1a) with partial vaccination status. The results indicate a trend toward reduction in disease severity as the wave progressed., (© 2022 Wiley Periodicals LLC.)

Background: The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear., Methods: Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care., Results: The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics., Conclusions: Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

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.

The global tuberculosis burden remains substantial, with more than 10 million people newly ill per year. Nevertheless, tuberculosis incidence has slowly declined over the past decade, and mortality has decreased by almost a third in tandem. This positive trend was abruptly reversed by the COVID-19 pandemic, which in many parts of the world has resulted in a substantial reduction in tuberculosis testing and case notifications, with an associated increase in mortality, taking global tuberculosis control back by roughly 10 years. Here, we consider points of intersection between the tuberculosis and COVID-19 pandemics, identifying wide-ranging approaches that could be taken to reverse the devastating effects of COVID-19 on tuberculosis control. We review the impact of COVID-19 at the population level on tuberculosis case detection, morbidity and mortality, and the patient-level impact, including susceptibility to disease, clinical presentation, diagnosis, management, and prognosis. We propose strategies to reverse or mitigate the deleterious effects of COVID-19 and restore tuberculosis services. Finally, we highlight research priorities and major challenges and controversies that need to be addressed to restore and advance the global response to tuberculosis., Competing Interests: Declaration of interests NM reports grants from Pfizer and Roche to his institution, outside the submitted work. CC reports research funding from Sanofi Pasteur, awarded to her institution; she is a member of the scientific advisory committee for the BCHW: Burden of COVID-19 Among Health Care Workers project. The other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: None

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis. The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally. This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year. All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines. Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10-80% in the remaining 5 countries). The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3-7) in the overall cohort and 6 (4-8) among patients with a final outcome). For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13-23) (in days 553 (385-678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30-90) days for the whole cohort and 60 (30-100) for patients with a final outcome and, respectively, of 55 (30-90) and 60 (30-90) days for culture conversion. Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up., (Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis -Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella , fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age., 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 © 2021 Taur, Gowri, Pandrowala, Iyengar, Chougule, Golwala, Chandak, Agarwal, Keni, Dighe, Bodhanwala, Prabhu, George, Fouzia, Edison, Arunachalam, Madkaikar, Dalvi, Yadav, Bargir, Kambli, Rawat, Das, Joshi, Pilania, Jindal, Bhat, Bhattad, Unni, Radhakrishnan, Raj, Uppuluri, Patel, Lashkari, Aggarwal, Kalra, Udwadia, Bafna, Kanade, Puel, Bustamante, Casanova and Desai.)

Background: Multidrug-resistant tuberculosis (MDR-TB) is an increasing problem worldwide, and 24% occurs in India. Linezolid is associated with improved MDR-TB treatment outcomes but causes significant side-effects and drug susceptibility testing (DST) is rarely available. This study assessed whether clinical factors could predict linezolid resistance., Methods: An observational cohort of adults and adolescents with MDR-TB at a tertiary care hospital in Mumbai, India was analyzed for clinical, laboratory, and radiographic findings associated with linezolid resistance., Results: In total, 343 MDR-TB patients had linezolid DST performed, and 23 (6.7%) had linezolid-resistant MDR-TB. Univariable analysis associated linezolid resistance with underweight (odds ratio (OR)-1.07, 95% confidence interval (CI):1.01-1.12); number of previous providers (OR:1.03, 95% CI:1.00-1.05); previous treatment with linezolid (OR:1.12, 95% CI:1.06-1.05), bedaquiline (OR:1.55, 95% CI:1.22-1.98), or clofazimine (OR:1.08 95% CI:1.03-1.16); cavitary disease (OR:1.10, 95% CI:1.04-1.16) and percent lung involvement (OR:1.02, 95% CI:1.01-1.03) on radiograph. DST associated linezolid resistance with resistance to fluoroquinolones (OR:1.08, 95% CI:1.01-1.14), injectables (OR:1.09, 95% CI:1.03-1.15), ethionamide (OR:1.09, 95% CI:1.03-1.15), and PAS (OR:1.13, 95% CI:1.06-1.21). In multivariate analysis, only prior linezolid and percent lung involvement were associated with linezolid resistance., Conclusion: To maximize treatment benefits while minimizing toxicity, DST remains an important tool to identify linezolid resistance., 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., (© 2020 The Authors.)

Tuberculosis is one of the top ten causes of death and the leading cause from a single infectious agent. Drug-resistant Tuberculosis continues to be a public health crisis. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people with drug-resistant Tuberculosis. Patients with pulmonary Tuberculosis can spread the disease by coughing, sneezing, or simply talking. For that reason, it is important to diagnosis Tuberculosis in order to start treatment as soon as possible. In the present manuscript we present the case of a 25-year-old Indian HIV-negative female, no comorbidity, with a history of drug susceptible tuberculosis diagnosed in 2015 which advanced in extensively drug-resistant tuberculosis after two years of treatment. This case report highlights the risk of mismanagement of patient affected by Tuberculosis and the consequences related which could harm the patient's health., (Copyright © 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Interstitial lung disease (ILD) is a complex and heterogeneous group of acute and chronic lung diseases of several known and unknown causes. While clinical practice guidelines (CPG) for idiopathic pulmonary fibrosis (IPF) have been recently updated, CPG for ILD other than IPF are needed., Methods: A working group of multidisciplinary clinicians familiar with clinical management of ILD (pulmonologists, radiologist, pathologist, and rheumatologist) and three epidemiologists selected by the leaderships of Indian Chest Society and National College of Chest Physicians, India, posed questions to address the clinically relevant situation. A systematic search was performed on PubMed, Embase, and Cochrane databases. A modified GRADE approach was used to grade the evidence. The working group discussed the evidence and reached a consensus of opinions for each question following face-to-face discussions., Results: Statements have been made for each specific question and the grade of evidence has been provided after performing a systematic review of literature. For most of the questions addressed, the available evidence was insufficient and of low to very low quality. The consensus of the opinions of the working group has been presented as statements for the questions and not as an evidence-based CPG for the management of ILD., Conclusion: This document provides the guidelines made by consensus of opinions among experts following discussion of systematic review of evidence pertaining to the specific questions for management of ILD other than IPF. It is hoped that this document will help the clinician understand the accumulated evidence and help better management of idiopathic and nonidiopathic interstitial pneumonias., Competing Interests: None

Clofazimine (CFZ), an old hydrophobic riminophenazine, has a wide range of antimycobacterial activity ranging from leprosy to nontuberculous mycobacterial diseases. CFZ has several advantages such as a favorable pharmacokinetic profile, dose-dependent side effects as well as low price. In this narrative review, we have assessed the clinical development of CFZ, starting from the potential in vitro mechanism of actions, to the spectrum of side effects and potential drug-drug interactions, highlighting its current place in therapy and future possible use in leprosy, nontuberculous mycobacterial diseases and drug-resistant tuberculosis.

Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015., Methods: A retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15., Results: A total of 134 patients were selected. Median (IQR) age at admission was 33 (26-41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively)., Conclusions: Tailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

Drug-resistant forms of tuberculosis (DR-TB) are a significant cause of global morbidity and mortality and the treatment of DR-TB is characterized by long and toxic regimens that result in low rates of cure. There are few formal studies documenting the quality of DR-TB treatment services provided globally, but the limited data that do exist show there is a quality crisis in the field. This paper reviews current issues impacting quality of care in DR-TB, including within the areas of patient-centeredness, safety, effectiveness and equity. Specific issues affecting DR-TB quality of care include: 1) the use of regimens with limited efficacy, significant toxicity, and high pill burden; 2) standardized treatment without drug susceptibility testing; 3) non-quality assured medications and drug stock outs; 4) lack of access to newer and repurposed drugs; 5) high rates of adverse events coupled with minimal monitoring and management; 6) care provided by multiple providers in the private sector; 7) depression, anxiety, and stress; and 8) stigma and discrimination. The paper discusses potential ways to improve quality in each of these areas and concludes that many of these issues arise from the traditional "public health approach" to TB and will only transformed when a human-rights based approach is put into practice., (© 2019 The Authors. Published by Elsevier Ltd.)

The emergence of antimicrobial resistance against Mycobacterium tuberculosis, the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug-resistant tuberculosis (MDR-TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR-TB achieved a successful outcome. For many years, patients with drug-resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR-TB through drug-specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor-made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high-burden/resource-limited settings. More recently, MDR-TB treatment outcomes have dramatically improved with the use of bedaquiline-based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure-rates, and may substantially decrease the duration of MDR-TB treatment necessary to achieve relapse-free cure., (© 2018 Asian Pacific Society of Respirology.)

Background: Tuberculosis (TB) remains the most common cause of infectious disease deaths worldwide. What is perhaps less appreciated is that the caseload of tuberculosis patients in South Asia is staggering.South Asia has almost 40% of the global TB burden with 4,028,165 cases in 2015. This region also has a disproportionate share of TB deaths (681,975 deaths, 38% of the global burden). Worldwide just 12.5% of TB cases are in HIV positive individuals, but much research and investment has focused on HIV-associated TB. Only 3.5% of patients with tuberculosis in South Asia have HIV co-infection. Not surprisingly with such a huge burden of disease, this region has an estimated 184,336 multi drug resistant (MDR) cases among notified TB cases which accounts for a third of global MDR burden. Crucially, at least 70% of the estimated MDR cases remain untreated in this region and MDR treatment success ranged from only 46% for India to 88% for Sri Lanka in the 2012 cohort that received treatment. This region represents many of the drivers of the modern TB epidemic: rapid urbanization and high density populations with dramatically rising incidence of diabetes, a burgeoning and largely unregulated private sector with escalating drug resistance and high air pollution both outdoor and household., Conclusion: From bacterial biochemistry to policy implementation, we suggest ways in which South Asia can seize the opportunity lead global TB elimination by demonstrating feasibility in some of the world's most densely populated cities and remotest reaches of the Himalayas. Clearly political will is essential, but we cannot defeat TB without understanding how to eliminate it in South Asia., Competing Interests: NANAThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Progressive fibrotic interstitial lung diseases (ILDs) are characterised by major reductions in quality of life and survival and have similarities to certain malignancies. However, palliative care expertise is conspicuously inaccessible to many patients with ILD. Unmet patient and caregiver needs include effective pharmacological and psychosocial interventions to improve quality of life throughout the disease course, sensitive advanced care planning, and timely patient-centred end-of-life care. The incorrect perception that palliative care is synonymous with end-of-life care, with no role earlier in the course of ILD, has created a culture of neglect. Interventions that aim to improve life expectancy are often prioritised without rigorous assessment of the individual's health and psychosocial needs, thereby inadvertently reducing quality of life. As in malignant disorders, radical interventions to slow disease progression and palliative measures to improve quality of life should both be prioritised. Efficient patient-centred models of palliative care must be validated, taking into account religious and cultural differences, as well as variability of resources. Effective implementation of palliative care for ILD will require multidisciplinary participation from clinicians, specialist nurses, psychologists, social workers, and, in some countries, non-governmental faith and community-based organisations with access to palliative care expertise., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective/background: The in vitro drug-susceptibility testing of Mycobacterium tuberculosis reports isolates as resistant or susceptible on the basis of single critical concentrations. It is evident that drug resistance in M. tuberculosis is quite heterogeneous, and involves low level, moderate level, and high level of drug-resistant phenotypes. Thus, the aim of our study was to correlate rrs (X52917) and eis (AF144099) promoter mutations, found in M. tuberculosis isolates, with corresponding minimum inhibitory concentrations of amikacin, kanamycin, and capreomycin., Methods: Ninety M. tuberculosis clinical isolates were analyzed in this study. The minimum inhibitory concentrations were determined by MGIT 960 for 59 isolates with resistance-associated mutations in the rrs and eis promoter gene regions, and 31 isolates with wild-type sequences, as determined by the GenoType MTBDRsl (version 1) assay., Results: The rrs A1401G mutation was identified in 48 isolates resistant to the second-line injectables. The eis promoter mutations C-14T (n=3), G-10C (n=3), G-10A (n=3), and C-12T (n=2) were found within 11 isolates with various resistance profiles to the second-line injectables. Thirty-one isolates had wild-type sequences for the rrs and eis promoter gene regions of interest, one of which was amikacin, kanamycin, and capreomycin resistant. The isolates with the rrs A1401G mutation had amikacin, kanamycin, and capreomycin minimum inhibitory concentrations of >40mg/L, >20mg/L, and 5-15mg/L, respectively. The isolates with eis promoter mutations had amikacin, kanamycin, and capreomycin minimum inhibitory concentrations of 0.25-1.0mg/L, 0.625-10mg/L, and 0.625-2.5mg/L, respectively., Conclusion: This study provides a preliminary basis for the prediction of phenotypic-resistance levels to the second-line injectables based upon the presence of genetic mutations associated with amikacin, kanamycin, and capreomycin resistance. The results suggest that isolates with eis promoter mutations have consistently lower resistance levels to amikacin, kanamycin, and capreomycin than isolates with the rrs A1401G mutation., (Copyright © 2015. Published by Elsevier Ltd.)

This study correlates MICs of rifampicin (RIF) and isoniazid (INH) with GenoType MTBDRplus assay results for drug-resistant Mycobacterium tuberculosis (MTB) clinical isolates. MICs of RIF and INH were established for 84 and 90 isolates, respectively, testing 7 concentrations of each drug. Genotypic resistance to each drug was determined by GenoType MTBDRplus assay with 50 representative mutations confirmed by pyrosequencing, with mutations in the rpoB gene associated with RIF resistance and mutations in the katG and/or inhA genes associated with INH resistance. Based upon the correlation of MICs with specific genetic profiles, relative resistance levels were established for each isolate. Results indicate that MTB phenotypic resistance, currently based upon the testing of isolate susceptibility to a single drug concentration, may be more accurately profiled via quantitative MICs, and therefore, the correlation of molecular diagnostic results with specific MICs may allow for more optimal treatment of infections., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To correlate gyrA mutations found on the Genotype MTBDRsl assay in Mycobacterium tuberculosis (MTB) isolates with Minimum Inhibitory Concentrations (MICs) to the fluoroquinolones compounds ofloxacin (OFX) and moxifloxacin (MXF)., Methods: MICs for OFX and MXF were ascertained for 93 archived clinical MTB isolates that showed gyrA mutations at Ala90Val, Ser91Pro, Asp94Ala, Asn/Tyr, Gly and His. Thirty fluoroquinolones susceptible isolates as determined by presence of all wild-type gyrA bands on the Genotype MTBDRsl assay were also included., Results: gyrA mutations at Ala90Val (n = 25), Ser91Pro (n = 6), Asp94Ala (n = 4), Asp94Asn/Tyr (n = 13), Asp94Gly (n = 42) and Asp94His (n = 3) were observed. Isolates with mutations at Ala90Val or Ser91Pro had MIC90 of 4.0 μg/ml and 1.0 μg/ml for OFX and MXF, respectively, and isolates with mutations at Asp 94Ala, Asn/Tyr, Gly and His had MIC90 of 8.0 μg/ml, and 2.5 μg/ml for OFX and MXF, respectively., Conclusions: MTB MICs were found to be consistently lower for MXF than for OFX among isolates with the same gyrA mutation (e.g. Ala90Val). The majority of MTB isolates containing mutations at Asp94Ala, Asn/Tyr, Gly and His in gyrA were associated with a moderate level of resistance to MXF (MIC = 2.5 μg/ml), although 3 isolates with the mutations Asp94Asn/Tyr/Gly were associated with a high level of resistance to both fluoroquinolones (MXF MICs = 5.0-8.0 μg/ml, OFX MICs = ≥10.0 μg/ml)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis--ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis--and increased funding to strengthen global control efforts, research, and advocacy--even more pressing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Significant adverse events (AE) have been reported in patients receiving medications for multidrug- and extensively-drug-resistant tuberculosis (MDR-TB & XDR-TB). However, there is little prospective data on AE in MDR- or XDR-TB/HIV co-infected patients on antituberculosis and antiretroviral therapy (ART) in programmatic settings., Methods: Médecins Sans Frontières (MSF) is supporting a community-based treatment program for drug-resistant tuberculosis in HIV-infected patients in a slum setting in Mumbai, India since 2007. Patients are being treated for both diseases and the management of AE is done on an outpatient basis whenever possible. Prospective data were analysed to determine the occurrence and nature of AE., Results: Between May 2007 and September 2011, 67 HIV/MDR-TB co-infected patients were being treated with anti-TB treatment and ART; 43.3% were female, median age was 35.5 years (Interquartile Range: 30.5-42) and the median duration of anti-TB treatment was 10 months (range 0.5-30). Overall, AE were common in this cohort: 71%, 63% and 40% of patients experienced one or more mild, moderate or severe AE, respectively. However, they were rarely life-threatening or debilitating. AE occurring most frequently included gastrointestinal symptoms (45% of patients), peripheral neuropathy (38%), hypothyroidism (32%), psychiatric symptoms (29%) and hypokalaemia (23%). Eleven patients were hospitalized for AE and one or more suspect drugs had to be permanently discontinued in 27 (40%). No AE led to indefinite suspension of an entire MDR-TB or ART regimen., Conclusions: AE occurred frequently in this Mumbai HIV/MDR-TB cohort but not more frequently than in non-HIV patients on similar anti-TB treatment. Most AE can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe AE in the management of co-infected patients are justified, however, they should not cause delays in the urgently needed rapid scale-up of antiretroviral therapy and second-line anti-TB treatment.

Background: Although pulmonary abnormalities have been recognized in patients with inflammatory bowel diseases (IBD), their prevalence and clinical significance are not known., Aim: To study the prevalence and clinical significance of pulmonary abnormalities in patients with IBD., Methods: Ninety-five non-consecutive patients with IBD (12 Crohn's disease, 83 ulcerative colitis; mean age 41.9 [SD 13] years; 47 women) were prospectively studied from January 2007 to March 2010. Pulmonary function tests (PFT) and high-resolution CT (HRCT) chest were performed in them. PFT were compared to those in 270 healthy (control) subjects matched for age, sex and smoking status., Results: Twenty-seven (28.5%) patients and 11 (4%) control subjects had abnormal PFT (p < 0.0001). Small airway obstruction was seen in 18 patients, restrictive defect in six and mixed defect in three. Twenty-one (22%) patients had abnormal HRCT findings - bronchiectasis and nodules (nine patients each, including one with nodules who later developed active tuberculosis after infliximab therapy), parenchymal bands (8), mediastinal lymphadenopathy (five, including two with tuberculosis on histology and culture), emphysema (5), brochiolitis (2), pleural effusion or thickening (2), pericardial effusion (2), patchy consolidation (1), ground-glass opacities (1) and lung metastasis (1). Three patients had symptoms (one asthma, two cough)., Conclusion: PFT and HRCT chest showed abnormality in about one-quarter of patients with IBD. A majority of patients with these abnormalities were asymptomatic.