Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.

BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes. METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone. RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities. CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.

Identifying patients with multidrug-resistant tuberculosis who may benefit from shorter durations of treatment.

OBJECTIVE: Studying treatment duration for rifampicin-resistant and multidrug-resistant tuberculosis (MDR/RR-TB) using observational data is methodologically challenging. We aim to present a hypothesis generating approach to identify factors associated with shorter duration of treatment. STUDY DESIGN AND SETTING: We conducted an individual patient data meta-analysis among MDR/RR-TB patients restricted to only those with successful treatment outcomes. Using multivariable linear regression, we estimated associations and their 95% confidence intervals (CI) between the outcome of individual deviation in treatment duration (in months) from the mean duration of their treatment site and patient characteristics, drug resistance, and treatments used. RESULTS: Overall, 6702 patients with successful treatment outcomes from 84 treatment sites were included. We found that factors commonly associated with poor treatment outcomes were also associated with longer treatment durations, relative to the site mean duration. Use of bedaquiline was associated with a 0.51 (95% CI: 0.15, 0.87) month decrease in duration of treatment, which was consistent across subgroups, while MDR/RR-TB with fluoroquinolone resistance was associated with 0.78 (95% CI: 0.36, 1.21) months increase. CONCLUSION: We describe a method to assess associations between clinical factors and treatment duration in observational studies of MDR/RR-TB patients, that may help identify patients who can benefit from shorter treatment.

Chronic pulmonary aspergillosis in a tertiary tuberculosis institute: A common entity missed commonly.

The disease chronic pulmonary aspergillosis (CPA), which has 3 million cases globally, has a substantial impact on global health. The morbidity and mortality it cause are also rather severe. Patients with modest immune suppression or those with underlying structural and chronic lung illnesses are more likely to develop this condition. CPA pose a diagnostic and management challenge to clinicians. The condition causes patients to have persistent respiratory difficulties, which lowers their quality of life, and the therapy is lengthy and offers few choices. Particularly in a nation like India, where tuberculosis (TB) is prevalent and patients exhibit identical signs and symptoms, a strong index of suspicion is required. Treated pulmonary TB patients, presenting with symptoms or chest x-ray abnormalities, especially those with presence of cavity are also more prone to develop CPA. The constellation of symptoms together with presence of microbiological criteria and suggestive radiology can help to reach at the diagnosis. The field of mycology has made major developments, but there is still much to understand about this illness and to establish timely diagnoses and make the best use of the existing treatment choices. The burden of CPA in patients with treated TB is highlighted in this article along with the most recent research and clinical guidelines.

Basic spirometry and advanced pulmonary function tests - NATCON 2022.

At the 77th National Conference on Tuberculosis and Chest Diseases, which took place on February 27, 2023, a pre-conference workshop on Basic Spirometry and Advanced Pulmonary Function Tests was held under the auspices of NATCON-2022. With the assistance of highly experienced faculty who are national and international level experts in their fields, the workshop covered all important aspects of basic spirometry and advanced Pulmonary Function Tests.

Prevention of relapse in drug sensitive pulmonary tuberculosis patients with and without vitamin D3 supplementation: A double blinded randomized control clinical trial.

BACKGROUND: The immunomodulatory effects of vitamin D are widely recognized and a few studies have been conducted to determine its utility in the treatment of tuberculosis, with mixed results. This study was conducted to see if vitamin D supplementation in patients with active pulmonary tuberculosis (PTB) in the Indian population contributed to sputum smear and culture conversion as well as the prevention of relapse. METHODS: This randomized double-blind placebo-controlled trial was conducted in three sites in India. HIV negative participants aged 15-60 years with sputum smear positive PTB were recruited according to the Revised National Tuberculosis Control Program guidelines and were randomly assigned (1:1) to receive standard anti-tubercular treatment (ATT) with either supplemental dose of oral vitamin D3 (60,000 IU/sachet weekly for first two months, fortnightly for next four months followed by monthly for the next 18 months) or placebo with same schedule. The primary outcome was relapse of PTB and secondary outcomes were time to conversion of sputum smear and sputum culture. RESULTS: A total of 846 participants were enrolled between February 1, 2017 to February 27, 2021, and randomly assigned to receive either 60,000 IU vitamin D3 (n = 424) or placebo (n = 422) along with standard ATT. Among the 697 who were cured of PTB, relapse occurred in 14 participants from the vitamin D group and 19 participants from the placebo group (hazard risk ratio 0.68, 95%CI 0.34 to 1.37, log rank p value 0.29). Similarly, no statistically significant difference was seen in time to sputum smear and sputum culture conversion between both groups. Five patients died each in vitamin D and placebo groups, but none of the deaths were attributable to the study intervention. Serum levels of vitamin D were significantly raised in the vitamin D group as compared to the placebo group, with other blood parameters not showing any significant difference between groups. CONCLUSIONS: The study reveals that vitamin D supplementation does not seem to have any beneficial effect in the treatment of PTB in terms to the prevention of relapse and time to sputum smear and culture conversion. TRIAL REGISTRATION: CTRI/2021/02/030977 (ICMR, Clinical trial registry-India).

Clinical spectrum of TB in elderly in a TB & respiratory institution.

Tuberculosis has maximum burden among young population in developing countries like India. However, children and elderly form a special group where TB may have atypical presentation. This presents with epidemiological, diagnostic and treatment challenges in these groups which may need special attention in the national programmes for TB. Due to atypical presentation, elderly population is vulnerable to frequent misdiagnosis and disease may already be in advanced stage when correct diagnosis is made. Not only this, adjustment of drug dosages and high chances of adverse drug reaction make the management of TB more complicated in elderly. Mortality due to TB is also higher in this group as compared to young patients of TB. This view point briefly highlights the epidemiological, clinical and disease outcome aspects of TB disease in elderly patients.

Indian Guidelines on Nebulization Therapy.

Inhalational therapy, today, happens to be the mainstay of treatment in obstructive airway diseases (OADs), such as asthma, chronic obstructive pulmonary disease (COPD), and is also in the present, used in a variety of other pulmonary and even non-pulmonary disorders. Hand-held inhalation devices may often be difficult to use, particularly for children, elderly, debilitated or distressed patients. Nebulization therapy emerges as a good option in these cases besides being useful in the home care, emergency room and critical care settings. With so many advancements taking place in nebulizer technology; availability of a plethora of drug formulations for its use, and the widening scope of this therapy; medical practitioners, respiratory therapists, and other health care personnel face the challenge of choosing appropriate inhalation devices and drug formulations, besides their rational application and use in different clinical situations. Adequate maintenance of nebulizer equipment including their disinfection and storage are the other relevant issues requiring guidance. Injudicious and improper use of nebulizers and their poor maintenance can sometimes lead to serious health hazards, nosocomial infections, transmission of infection, and other adverse outcomes. Thus, it is imperative to have a proper national guideline on nebulization practices to bridge the knowledge gaps amongst various health care personnel involved in this practice. It will also serve as an educational and scientific resource for healthcare professionals, as well as promote future research by identifying neglected and ignored areas in this field. Such comprehensive guidelines on this subject have not been available in the country and the only available proper international guidelines were released in 1997 which have not been updated for a noticeably long period of over two decades, though many changes and advancements have taken place in this technology in the recent past. Much of nebulization practices in the present may not be evidence-based and even some of these, the way they are currently used, may be ineffective or even harmful. Recognizing the knowledge deficit and paucity of guidelines on the usage of nebulizers in various settings such as inpatient, out-patient, emergency room, critical care, and domiciliary use in India in a wide variety of indications to standardize nebulization practices and to address many other related issues; National College of Chest Physicians (India), commissioned a National task force consisting of eminent experts in the field of Pulmonary Medicine from different backgrounds and different parts of the country to review the available evidence from the medical literature on the scientific principles and clinical practices of nebulization therapy and to formulate evidence-based guidelines on it. The guideline is based on all possible literature that could be explored with the best available evidence and incorporating expert opinions. To support the guideline with high-quality evidence, a systematic search of the electronic databases was performed to identify the relevant studies, position papers, consensus reports, and recommendations published. Rating of the level of the quality of evidence and the strength of recommendation was done using the GRADE system. Six topics were identified, each given to one group of experts comprising of advisors, chairpersons, convenor and members, and such six groups (A-F) were formed and the consensus recommendations of each group was included as a section in the guidelines (Sections I to VI). The topics included were: A. Introduction, basic principles and technical aspects of nebulization, types of equipment, their choice, use, and maintenance B. Nebulization therapy in obstructive airway diseases C. Nebulization therapy in the intensive care unit D. Use of various drugs (other than bronchodilators and inhaled corticosteroids) by nebulized route and miscellaneous uses of nebulization therapy E. Domiciliary/Home/Maintenance nebulization therapy; public & health care workers education, and F. Nebulization therapy in COVID-19 pandemic and in patients of other contagious viral respiratory infections (included later considering the crisis created due to COVID-19 pandemic). Various issues in different sections have been discussed in the form of questions, followed by point-wise evidence statements based on the existing knowledge, and recommendations have been formulated.

Factors affecting the treatment outcome of injection based shorter MDR-TB regimen at a referral centre in India.

Rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) is a significant burden on global tuberculosis (TB) prevention and eradication efforts. MDR-TB can be treated, but it is expensive, takes a long time (typically two years) and contains potentially toxic drugs. Under certain conditions, the WHO recommends standard regimens lasting 9 to 11 months rather than individual regimens lasting at least 18-20 months. The current study sought to identify factors associated with treatment outcomes in RR/MDR-TB patients receiving an injection-based regimen for 9-11 months. This ambispective (prospective and retrospective) observational study was conducted at a tertiary tuberculosis institute in New Delhi, India. Between February 2021 and March 2022, patients with RR/MDR-pulmonary TB who received an injection-based shorter regimen were enrolled. Factors related to treatment outcomes were investigated and compared in patients who had a successful outcome versus those who did not. A total of 55 patients were enrolled, with 50.91% being successful (cured/treatment completed) and 49.09% failing (including failure, lost to follow up, death, and regimen change). The following factors were significantly associated with the unsuccessful outcome, according to univariate analysis: BMI (<18.5 kg/m2), anaemia, previous anti-TB treatment, bilateral chest X-ray involvement, and far advanced disease on chest X-ray. BMI (<18.5 kg/m2), anaemia, and far advanced disease on chest X-ray were all significantly associated with mortality. Anaemia was associated with an unsuccessful outcome (p=0.049) and mortality (p=0.048) in the multiple logistic regression analysis. Early treatment initiation, improved nutrition and anaemia, and regular monitoring can all improve RR/MDR-TB patients' outcomes and prognoses.

Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol.

INTRODUCTION: Drug-resistant tuberculosis (DR-TB) is a global public health problem. Patients suffer for months if undiagnosed or treated inadequately, transmitting DR-TB in the community before succumbing to the disease. Early diagnosis, prompt treatment initiation and completion play a significant role in treatment success. However, extended regimens with injectable result in poor treatment adherence and outcomes. Our objective is to evaluate the effectiveness, safety and tolerability of various doses and duration of linezolid (LZD) in combination with bedaquiline (BDQ) and pretomanid (Pa) after 26 weeks of treatment in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary TB. METHODS AND ANALYSIS: A multicentric, randomised pragmatic clinical trial in India will enrol participants in one of the three arms-control arm (arm 1): BDQ, Pa and LZD 600 mg daily for 26 weeks or intervention arms (arm 2): BDQ, Pa and LZD 600 mg for 9 weeks followed by 300 mg for 17 weeks or arm 3: BDQ, Pa and LZD 600 mg for 13 weeks followed by 300 mg for 13 weeks. The primary endpoint is the proportion of patients with favourable outcomes as sustained cure and treatment completion. The secondary endpoint is unfavourable outcomes, including deaths, treatment failure, toxicity/adverse events and lost to follow-up till 48 weeks post-treatment. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of participating institutes and the National Institute for Research in TB. The trial results will help establish evidence towards a safe and effective dose of LZD that can be used in a fully, all-oral short course regimen for highly DR-TB patients. The results of this study will be shared with the National TB Elimination Programme of the country and the WHO guidelines development group through publications and dissemination meetings. TRIAL REGISTRATION NUMBER: NCT05040126.

A new role of extracorporeal membrane oxygenation in the management of tuberculosis with acute respiratory distress syndrome: A case report and review of literature.

Pulmonary tuberculosis (PTB) can lead to acute respiratory distress syndrome (ARDS), which can be at times fatal. Venovenous extracorporeal membrane oxygenation (VV-ECMO) ensures adequate oxygenation and carbon dioxide removal, avoiding ventilator-induced lung injury. We present a case where a young woman with refractory respiratory failure caused by PTB, unresponsive to conventional mechanical ventilation, but was successfully managed with prolonged VV-ECMO support. The patient diagnosed with PTB was started on antitubercular treatment but went into respiratory failure and ARDS. The patient was put on mechanical ventilation, on which she was not improving. The patient was then put on ECMO. On the 9th day, lung compliance and gas exchange were good enough to resume conventional mechanical ventilation. ECMO was weaned and removed. This is one of few cases of survival of the patient with PTB with ARDS utilizing ECMO.

Treatment interruption patterns and adverse events among patients on bedaquiline containing regimen under programmatic conditions in India.

BACKGROUND: The study aimed to analyze frequency and severity of adverse events (AEs) and other reasons for interruption of treatment and loss to follow up (LTFU) during first six months of treatment among tuberculosis patients on bedaquiline containing regimens. METHODS: This pilot exploratory observational study included 275 patients enrolled consecutively over two years who received bedaquiline containing regimen under programmatic conditions in India. RESULTS: Among 275 patients with median age of 25 years, 86 (31.3%) patients had at least one interruption with 122 total episodes of interruption. Among these 70 were temporary, 35 were permanent interruptions and 17 were LTFU. The AEs due to drugs were the commonest reason for interruption observed in 81.4% of temporary interruption group and 97.1% of permanent interruption group. Among a total 192 adverse event episodes, (49.5%) were minor (grade 1-2) and (50.5%) were serious (grade 3-5). Personal factors were the commonest reason for interruption observed in LTFU (94.1%) group. The most common temporarily interrupted drug was bedaquiline in 8.7% and permanently stopped drug was linezolid in 5% of patients. CONCLUSIONS: Our study observed that drug related AEs are important risk factors associated with treatment interruptions in bedaquiline containing regimens. Bedaquiline is the most common temporarily interrupted drug due to AEs.

Pre-conference workshop on drug resistant TB - NATCON 2020.

Pre-conference workshop on Drug Resistant Tuberculosis was conducted under the banner of NATCON-2020 on 18th December 2020. The workshop covered various aspects of diagnosis including newer rapid genotypic methods, and gene sequencing. The workshop deliberated on the latest recommendations of the global and national guidelines about the management of DR-TB patients. Case scenarios focusing on the management of MDR TB and XDR TB patients were presented and the principles of making the regimen for DR-TB patients were discussed. Various aspects of shorter MDR TB regimen including bedaquiline containing shorter regimen and all oral longer regimen for DR-TB patients were also presented to the participants. The participants were also informed regarding what is in store in the near future at global and national level regarding the management of DR-TB patients. The participants included students, teaching faculty and the practicing physicians. The workshop informed the delegates on the latest recommendations of the global and national guidelines about the management of DR-TB. The detailed deliberations were very useful for the participants in their day-to-day clinical practice. The main highlights of the workshop have been mentioned below.

Screening for Tuberculosis in Migrants: A Survey by the Global Tuberculosis Network.

Tuberculosis (TB) does not respect borders, and migration confounds global TB control and elimination. Systematic screening of immigrants from TB high burden settings and-to a lesser degree TB infection (TBI)-is recommended in most countries with a low incidence of TB. The aim of the study was to evaluate the views of a diverse group of international health professionals on TB management among migrants. Participants expressed their level of agreement using a six-point Likert scale with different statements in an online survey available in English, French, Mandarin, Spanish, Portuguese and Russian. The survey consisted of eight sections, covering TB and TBI screening and treatment in migrants. A total of 1055 respondents from 80 countries and territories participated between November 2019 and April 2020. The largest professional groups were pulmonologists (16.8%), other clinicians (30.4%), and nurses (11.8%). Participants generally supported infection control and TB surveillance established practices (administrative interventions, personal protection, etc.), while they disagreed on how to diagnose and manage both TB and TBI, particularly on which TBI regimens to use and when patients should be hospitalised. The results of this first knowledge, attitude and practice study on TB screening and treatment in migrants will inform public health policy and educational resources.

Tobacco use, tuberculosis and Covid-19: A lethal triad.

Smoking, TB and Covid-19 are high prevalence entities with public health consequences. All three of them have a possible complex interaction at cellular level. Smoking behavior makes it difficult to maintain infection control measures. Smoking is known to increase TB infection and also adversely affect treatment outcomes in TB. There is also upcoming evidence which suggests that smoking and TB increase the risk of severe Covid-19 symptoms. Simple infection control measures like, social distancing, cough etiquette, isolation, hand hygiene, quarantine, use of masks etc. play a pivotal role in prevention of these diseases. There is need of strengthening of the public health policies and incorporation of the Covid-19 safety awareness measures into the various national programmes.

Dr PK Sen TAI gold medal oration.

The current write-up is for Dr P.K.Sen TAI Gold Medal Oration Award for 2020 conferred to Dr Rupak Singla and delivered on 19 th December 2020. The title chosen for the oration was "Introduction and scale up of new anti-TB drugs in India: role of NITRD.Ë® However, in the oration the role this institute has played for overall scale up of Drug-resistant TB services in India under National Tuberculosis Elimination Programme (NTEP) at different times from the beginning of national TB programme has also been presented. National Institute of TB and Respiratory Diseases has travelled with our country from beginning of DR-TB care. It demonstrated for the first time use of a Standardized Treatment Regimen with second line drugs for MDR-TB in field conditions. NITRD assisted NTEP for the concept of DST guided treatment. This institute guided NTEP for the management of MDR-TB failure patients with Pre-XDR and XDR-TB. Also, NITRD assisted India for the introduction of newer DR-TB drugs and scale up of newer drugs across the country. The strength of NITRD include clinical expertise, laboratory support and training division. NITRD commitment is strong and will continue to support NTEP for all endeavors in future also.

Adverse drug reactions & drug interactions in MDR-TB patients.

Multiple drugs taken for long duration in tuberculosis (TB) treatment, especially drug resistant TB (DR-TB), may produce adverse drug reactions (ADRs). Although any anti-TB drug can cause ADRs, but these are more common with drugs used for treatment of DR-TB. However, most of ADRs with these drugs are mild or moderate and can be managed if adequate supervision and monitoring is done. However, few ADRs can be severe or potentially life-threatening and may require removal of the offending drug(s). TB patients having comorbidities and on treatment for them may experience drug interaction with anti TB drugs and may require dose modification or change of drug. For a good TB treatment outcome patient's compliance should be ensured, and adverse events and drug interactions should be appropriately addressed by the clinicians. This article outlines the majority of the possible ADRs to anti-TB drugs used for management of DR-TB and their common drug interactions with practical recommendations to identify the possible drug(s) responsible and the most adequate management in each situation.

An overview of pulmonary infections due to rapidly growing mycobacteria in South Asia and impressions from a subtropical region.

Background: Rapidly growing mycobacteria (RGM) comprise nearly half of the validated species of nontuberculous mycobacteria (NTM) and have been reported to have a higher incidence in Asia as compared to Europe and America. There is limited information on RGM infections from South Asia. Hence, the present study aimed to ascertain the incidence of pulmonary infections due to RGM in Delhi and to review the status of available information on the prevalence of RGM in South Asia, a region endemic for tuberculosis. Methods: We analyzed 933 mycobacterial isolates obtained from pulmonary samples in Delhi and performed species identification by polymerase chain reaction (PCR)-restriction analysis (restriction fragment length polymorphism) and line probe assay. Drug susceptibility testing (DST) was performed by broth microdilution method. We also reviewed reports available on pulmonary infections in South Asia, attributed to RGM. Results: Of the 933 mycobacterial isolates studied, NTM were identified in 152 (16.3%). Of these, 65/152 (42.8%) were RGM comprising Mycobacterium fortuitum (34/65; 52.3%), Mycobacterium abscessus (25/65; 38.5%), Mycobacterium chelonae (3/65; 4.61%), Mycobacterium mucogenicum (2/65; 3.1%), and Mycobacterium smegmatis (1/65; 1.5%). On applying the American Thoracic Society/Infectious Diseases Society of America guidelines, 11/25 (44%) M. abscessus, 3/3 (100%) M. chelonae, and both isolates of M. mucogenicum were found to be clinically relevant. DST revealed that maximum susceptibility of the RGM was seen to linezolid, clarithromycin, and amikacin. Conclusions: Of the RGM isolated in the present study, 16/65 (24.6%) were found to be clinically relevant. Hence, it is important to recognize these organisms as potential pathogens to identify patients with RGM disease to initiate appropriate therapy.