Genomic revolution: Transforming tuberculosis diagnosis and treatment with the use of Whole Genome Sequencing - A consensus statement.

Tuberculosis (TB) is a preventable, treatable, and curable disease. However, in 2020, 9∙9 million people were estimated to have developed tuberculosis, and 1.5 million people were estimated to have died from it. Whereas in India, 2.6 million were diagnosed with TB and 436,000 succumbed to TB in 2019. India (26%) is the major contributor to the global drop in TB cases. The COVID-19 pandemic has substantially reduced access to services for the diagnosis and treatment of TB, resulting in an increase in deaths and a reversal in global progress. [1] Presently, TB incidence is falling at a rate of 2% per year, obstructed mainly by the rearing pandemic of drug-resistant tuberculosis (DRTB). Particularly concerning is multi-drug resistant TB (MDRTB), defined as resistance towards isoniazid (INH) and rifampicin (RIF). [2] The World Health Organization (WHO) targeted to reduce worldwide TB incidence by 90% until 2035. (1) Early initiation of effective treatment based on susceptibility patterns of the Mycobacterium tuberculosis complex (MTBC) is considered key to successful TB control in countries with high DRTB incidence. Worldwide MDRTB treatment outcomes are poor, with cure rates less than 60% (2) due to the lack of comprehensive Drug Susceptibility Testing (DST) in most high MDRTB burden countries. This is leading to the inadequate anti-TB activity of the provided regimens (3-5), unlike regimens advised for DST assure optimal results. (6) In addition to resistances to the established regimens, the resistance to the newer DRTB drugs is increasing. On World TB Day 2022, Academy of Advanced Medical Education, Thyrocare Technologies Limited and HyastackAnalytics - IITB along with expert pulmonologist and renowned physicians from India convened for an advisory board meeting in Delhi on 20th March 2022 to discuss the role of Whole Genome Sequencing (WGS) in the diagnosis and management of TB. Objectives and specific topics relating to WGS in MDRTB were discussed, each expert shared their views, which led to a group discussion with a commitment to putting the patient first, and increasing their collective efforts, the organizations recognized that it is possible to make this goal a reality. The organizations involved in the discussion have declared their commitment to engaging in collaborative efforts to tackle DRTB detection efficiently. They advocate for strengthening access to WGS TB services, controlling and preventing TB, improving surveillance and drug resistance management, and investing in research and development. This Round Table serves as a framework to build on and ensure that the goal of ending TB is achievable with WGS services wherever needed. Post discussion, a uniform consensus was said to be arrived if more than 80% board members agreed to the statement. The present paper is the outcome of aspects presented and discussed in the advisory board meeting.

Ending TB in South-East Asia: flagship priority and response transformation.

Over the decades, the global tuberculosis (TB) response has evolved from sanatoria-based treatment to DOTS (Directly Observed Therapy Shortcourse) strategy and the more recent End TB Strategy. The WHO South-East Asia Region, which accounted for 45% of new TB patients and 50% of deaths globally in 2021, is pivotal to the global fight against TB. "Accelerate Efforts to End TB" by 2030 was adopted as a South-East Asia Regional Flagship Priority (RFP) in 2017. This article illustrates intensified and transformed approaches to address the disease burden following the adoption of RFP and new challenges that emerged during the COVID-19 pandemic. TB case notifications improved by 25% and treatment success rates improved by 6% between 2016 and 2019 due to interventions ranging from galvanising political commitments to empowering and engaging communities. Cumulative TB programme budget allocations in 2022 reached US$ 1.4 billion, about two and a half times the budget in 2016. An ambitious Regional Strategic Plan towards ending TB, 2021-2025, identifies priority interventions that will need investments of up to US$ 3 billion a year to fully implement them. Moving forward, countries in the Region need to leverage RFP and take up intensified, people-centred, holistic interventions for prevention, diagnosis, treatment and care of TB with commensurate investments and cross-ministerial and multi-sectoral coordination.

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).

Treatment Strategy for Rifampin-Susceptible Tuberculosis.

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

Air pollution and its effects on emergency room visits in tertiary respiratory care centers in Delhi, India.

Environmental pollution has harmful effects on human health, particularly the respiratory system. We aimed to study the impact of daily ambient air pollution on daily emergency room visits for acute respiratory symptoms. This study was conducted in two tertiary respiratory care centres in Delhi, India. Daily counts of emergency room visits were collected. All patients attending the emergency room were screened for acute onset (less than 2 weeks) of respiratory symptoms and were recruited if they were staying in Delhi continuously for at least 4 weeks and having onset (≤2 weeks) of respiratory symptoms. Daily average air pollution data for the study period was obtained from four continuous ambient air quality monitoring stations. A total of 61,285 patients were screened and 11,424 were enrolled from June 2017 to February 2019. Cough and difficulty in breathing were most common respiratory symptoms. Poor air quality was observed during the months of October to December. Emergency room visits with acute respiratory symptoms significantly increased per standard deviation increase in PM10 from lag days 2-7. Increase in wheezing was primarily seen with increase in NO2. Pollutant levels have effect on acute respiratory symptoms and thus influence emergency room visits. *************************************************************** *Appendix Authors list Kamal Singhal,1 Kana Ram Jat,2 Karan Madan,3 Mohan P. George,4 Kalaivani Mani,5 Randeep Guleria,3 Ravindra Mohan Pandey,5 Rupinder Singh Dhaliwal,6 Rakesh Lodha,2 Varinder Singh1 1Department of Paediatrics, Lady Hardinge Medical College and associated Kalawati Saran Children's Hospital, New Delhi, India 2Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India 3Department of Pulmonary Medicine, Critical Care and Sleep Disorders, All India Institute of Medical Sciences, New Delhi, India 4Department of Environment, Delhi Pollution Control Committee, Kashmere Gate, New Delhi, India 5Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India 6Department of Non-communicable Diseases, Indian Council of Medical Research, New Delhi, India.

Building communities of practice through case-based e-learning to prevent and manage TB among people living with HIV-India.

BACKGROUND: Co-management of HIV-TB coinfection remains a challenge globally. Addressing TB among people living with HIV (PLHIV) is a key priority for the Government of India (GoI). In 2016, GoI implemented single-window services to prevent and manage TB in PLHIV. To strengthen HIV-TB service delivery, case-based e-learning was introduced to health care providers at Antiretroviral Therapy centres (ARTc). METHODS: We implemented a hub and spoke model to deliver biweekly, virtual, case-based e-learning at select ARTc (n = 115), from four states of India-Delhi, Uttar Pradesh, Andhra Pradesh and Tamil Nadu. We evaluated feasibility and acceptability of case-based e-learning and its impact on professional satisfaction, self-efficacy, knowledge retention using baseline and completion surveys, session feedback, pre-and post-session assessments. We reviewed routine programmatic data and patient outcomes to assess practices among participating ARTc. RESULTS: Between May 2018 and September 2020, 59 sessions were conducted with mean participation of 55 spokes and 152 participants. For 95% and 88% of sessions ≥ 80% of respondents agreed that topics were clear and relevant to practice, and duration of session was appropriate, respectively. Session participants significantly improved in perceived knowledge, skills and competencies (+ 8.6%; p = 0.025), and technical knowledge (+ 18.3%; p = 0.04) from baseline. Participating ARTc increased TB screening (+ 4.2%, p < 0.0001), TB diagnosis (+ 2.7%, p < 0.0001), ART initiation (+ 4.3%, p < 0.0001) and TB preventive treatment completion (+ 5.2%, p < 0.0001). CONCLUSION: Case-based e-learning is an acceptable and effective modus of capacity building and developing communities of practice to strengthen integrated care. E-learning could address demand for accessible and sustainable continuing professional education to manage complex diseases, and thereby enhance health equity. We recommend expansion of this initiative across the country for management of co-morbidities as well as other communicable and non-communicable diseases to augment the existing capacity building interventions by provide continued learning and routine mentorship through communities of practice.

Direct Molecular Detection of Drug-Resistant Tuberculosis from Transported Bio-Safe Dried Sputum on Filter-Paper.

In 2019, amongst half a million new rifampicin-resistant tuberculosis (TB) cases, 78% were multi drug-resistant TB (MDR-TB). Access to rapid and Universal-Drug susceptibility testing (DST) to patients in remote areas is a major challenge to combat drug-resistant TB. To overcome this challenge, we had recently reported the development of 'TB Concentration & Transport kit' for bio-safe ambient temperature transport of dried sputum on filter-paper (Trans-Filter). The present study was conducted to evaluate the utility of DNA extracted from sputum on Trans-Filter in a Multiplex PCR-based sequencing assay (Mol-DSTseq) for diagnosing drug-resistant TB. The developed Mol-DSTseq assays were standardized on Mycobacterium tuberculosis clinical isolates (n = 98) and further validated on DNA extracted from sputum on Trans-Filter (n = 100). Using phenotypic DST as gold standard, the Mol-DSTseq assay showed 100% (95% Confidence Interval [CI] 79.4-100%) and 73.3% (95% CI 54.1-87.7%) sensitivity for detecting rifampicin and isoniazid resistance with a specificity of 85.1% (95% CI 66.2-95.8%) and 100% (95% CI:82.3-100%), respectively. For fluoroquinolones and aminoglycosides, the Mol-DSTseq assay showed a sensitivity of 78.5% (95% CI 49.2-95.3%) and 66.6% (95% CI 9.4-99.1%) with a specificity of 88.2% (95% CI 72.5-96.7%) and 100% (95% CI 93.1-100%), respectively. The Mol-DSTseq assays exhibited a high concordance of ~ 83-96% (κ value: 0.65-0.81) with phenotypic DST for all drugs. In conclusion, the 'TB Concentration and Transport kit' was compatible with Mol-DSTseq assays and has the potential to provide 'Universal-DST' to patients residing in distant areas in high burden countries, like India for early initiation of anti-tubercular treatment.

Geographic information system-based mapping of air pollution & emergency room visits of patients for acute respiratory symptoms in Delhi, India (March 2018-February 2019).

Background & objectives: Studies assessing the spatial and temporal association of ambient air pollution with emergency room visits of patients having acute respiratory symptoms in Delhi are lacking. Therefore, the present study explored the relationship between spatio-temporal variation of particulate matter (PM)2.5 concentrations and air quality index (AQI) with emergency room (ER) visits of patients having acute respiratory symptoms in Delhi using the geographic information system (GIS) approach. Methods: The daily number of ER visits of patients having acute respiratory symptoms (less than or equal to two weeks) was recorded from the ER of four hospitals of Delhi from March 2018 to February 2019. Daily outdoor PM2.5 concentrations and air quality index (AQI) were obtained from the Delhi Pollution Control Committee. Spatial distribution of patients with acute respiratory symptoms visiting ER, PM2.5 concentrations and AQI were mapped for three seasons of Delhi using ArcGIS software. Results: Of the 70,594 patients screened from ER, 18,063 eligible patients were enrolled in the study. Winter days had poor AQI compared to moderate and satisfactory AQI during summer and monsoon days, respectively. None of the days reported good AQI (<50). During winters, an increase in acute respiratory ER visits of patients was associated with higher PM2.5 concentrations in the highly polluted northwest region of Delhi. In contrast, a lower number of acute respiratory ER visits of patients were seen from the 'moderately polluted' south-west region of Delhi with relatively lower PM2.5 concentrations. Interpretation & conclusions: Acute respiratory ER visits of patients were related to regional PM2.5 concentrations and AQI that differed during the three seasons of Delhi. The present study provides support for identifying the hotspots and implementation of focused, intensive decentralized strategies to control ambient air pollution in worst-affected areas, in addition to the general city-wise strategies.

Correlation of inhA mutations and ethionamide susceptibility: Experience from national reference center for tuberculosis.

BACKGROUND: Detection of ethionamide (ETH) resistance is crucial as it is part of antitubercular regime. It is crucial to examine the role of inhA gene mutations as a surrogate marker for the detection of ETH resistance, in the Indian context. The present retrospective study was designed with this objective. SUBJECTS AND METHODS: The study was conducted in National Reference Laboratory within the tertiary care institute from January 1, 2018, to June 30, 2019, over 18 months duration. A total of 6612 sputum samples from presumptive multidrug-resistant tuberculosis (TB) patients were received from four districts of Delhi, outdoor and inpatients. Line probe assay (LPA) was performed for smear-positive or culture-positive samples for Mycobacterium tuberculosis. All isolates found to be INH resistant by LPA were cultured and phenotypic susceptibility to ETH was conducted for selected isolates as per the guidelines. RESULTS: A total of 246 isolates were analyzed, for which phenotypic susceptibility to ETH and mutations in inhA were available. ETH resistance was detected among 87/108 (80.5%) isolates with inhA mutation. Sensitivity and specificity of inhA mutation for detection of ETH resistance were 80.5% and 83.8%, respectively. No inhA mutation was detected in 29/116 (25%) ETH-resistant isolates in our study, whereas ETH was found to be phenotypically susceptible in spite of the presence of inhA mutation among 21/130 (16.1%) isolates. CONCLUSIONS: Mutations in inhA gene in LPA predict ETH resistance with fairly good sensitivity and specificity. However, it is imperative to perform phenotypic detection of ETH resistance at proper concentration, in addition to detecting inhA mutation.

Compatibility of a novel filter paper-based bio-safe sputum transport kit with line probe assay for diagnosing drug-resistant tuberculosis: a single-site evaluation study.

BACKGROUND: Near-patient access to appropriate tests is a major obstacle for the efficient diagnosis of tuberculosis (TB) and associated drug resistance. METHODS: We recently developed the "TB Concentration & Transport" kit for bio-safe, ambient-temperature transportation of dried sputum on Trans-Filter, and the "TB DNA Extraction" kit for DNA extraction from Trans-Filter for determining drug resistance by DNA sequencing. In the present study, we evaluated the compatibility of Kit-extracted DNA with Hain's line probe assays (LPAs), which are endorsed by National TB programmes for the detection of drug resistance in sputum collected from presumptive multidrug-resistant TB patients (n=207). RESULTS: Trans-Filter-extracted DNA was seamlessly integrated with the LPA protocol (Kit-LPA). The sensitivity of Kit-LPA for determining drug resistance was 83.3% for rifampicin (95% CI 52-98%), 77.7% for isoniazid (95% CI 52-94%), 85.7% for fluoroquinolones (95% CI 42-100%) and 66.6% for aminoglycosides (95% CI 9-99%), with a specificity range of 93.7% (95% CI 87-97) to 99.1% (95% CI 95-100) using phenotypic drug susceptibility testing (DST) as a reference standard. A high degree of concordance was noted between results obtained from Kit-LPA and LPA (99% to 100% (κ value: 0.83-1.0)). CONCLUSIONS: This study demonstrates successful integration of our developed kits with LPA. The adoption of these kits across Designated Microscopy Centres in India can potentially overcome the existing challenge of transporting infectious sputum at controlled temperature to centralised testing laboratories and can provide rapid near-patient cost-effective "Universal DST" services to TB subjects residing in remote areas.

The Role of Cartridge-Based Nucleic Acid Amplification Test (CBNAAT), Line Probe Assay (LPA), Liquid Culture, Acid-Fast Bacilli (AFB) Smear and Histopathology in the Diagnosis of Osteoarticular Tuberculosis.

BACKGROUND: There is a paucity of data on the role of molecular methods in the diagnosis of osteoarticular tuberculosis. The present study was conducted to define the role of molecular (CBNAAT, LPA), phenotypic (AFB smear and culture) and histopathological evaluation in the diagnosis of osteoarticular TB. METHODS: Seventy-seven consecutive cases of osteoarticular tuberculosis were grouped into presumptive TB cases (group A) and presumptive drug-resistant cases (group B). Tissue samples obtained were submitted for CBNAAT, LPA, AFB smear, liquid culture and histological examinations. The diagnostic accuracy of each test was reported against histologically diagnosed cases and in all tests in tandem. RESULTS: Group A and group B had 65 and 12 cases, respectively. The diagnostic accuracy for tuberculosis was 84.62% by CBNAAT, 70.77% by LPA, 86.15% by molecular tests (combined), 47.69% by AFB smear, 50.77% by liquid culture and 87.69% by histology in group A, and 91.67% for CBNAAT, 83.33% for LPA, 91.67% for molecular tests (combined), 25% for AFB smear, 16.67% for liquid culture and 83.33% for histology in group B. The drug resistance detection rate was 4.62% on CBNAAT, 3.08% on LPA, 6.15% on molecular tests (combined) and 1.54% on DST in group A, while it was 33.33% on CBNAAT, 58.33% on LPA, 58.33% on molecular tests (combined) and 16.67% on DST among group B cases. Similar sensitivity rates for the various tests were obtained among both the groups on comparison with histology (taken as denominator). The addition of molecular methods increased the overall diagnostic accuracy (all tests in tandem) from 93.8 to 100% in group A and from 83.3 to 100% in group B cases. CONCLUSION: No single tests could diagnose tuberculosis in all cases; hence, samples should be evaluated by molecular tests (CBNAAT and LPA), AFB smear, culture and histological examinations simultaneously. The molecular tests have better demonstration of drug resistance from mycobacterial culture. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43465-020-00326-w.

Effects of ambient air pollution on emergency room visits of children for acute respiratory symptoms in Delhi, India.

The present study explored the association between daily ambient air pollution and daily emergency room (ER) visits due to acute respiratory symptoms in children of Delhi. The daily counts of ER visits (ERV) of children (≤15 years) having acute respiratory symptoms were obtained from two hospitals of Delhi for 21 months. Simultaneously, data on daily concentrations of particulate matter (PM10 and PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and ozone (O3) and weather variables were provided by the Delhi Pollution Control Committee. K-means clustering with time-series approach and multi-pollutant generalized additive models with Poisson link function was used to estimate the 0-6-day lagged change in daily ER visits with the change in multiple pollutants levels. Out of 1,32,029 children screened, 19,120 eligible children having acute respiratory symptoms for ≤2 weeks and residing in Delhi for the past 4 weeks were enrolled. There was a 29% and 21% increase in ERVs among children on high and moderate level pollution cluster days, respectively, compared to low pollution cluster days on the same day and previous 1-6 days of exposure to air pollutants. There was percentage increase (95% CI) 1.50% (0.76, 2.25) in ERVs for acute respiratory symptoms for 10 µg/m3 increase of NO2 on previous day 1, 46.78% (21.01, 78.05) for 10 µg/m3 of CO on previous day 3, and 13.15% (9.95, 16.45) for 10 µg/m3 of SO2 on same day of exposure. An increase in the daily ER visits of children for acute respiratory symptoms was observed after increase in daily ambient air pollution levels in Delhi.

A living WHO guideline on drugs to prevent covid-19.

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

To study the impact of active case finding (ACF) among the TB patients detected in South Delhi.

BACKGROUND: TB is one of the top 10 causes of death worldwide. The WHO adopted the End TB Strategy with ambitious goal of ending the global TB epidemic by 2030. The targets for this were 95% reduction in number of TB deaths, 90% reduction in TB incidence rate between 2015 and 2035 and to ensure that no family is burdened with catastrophic expenditure due to TB. Enhanced case detection is one of the components of End TB strategy adopted by WHO and within this Active Case Finding has an important place. However, its role in the Indian context needs to be assessed. AIMS AND OBJECTIVES: To study the impact of Active Case Finding (ACF) in National Tuberculosis Elimination Program (NTEP) implementing area of National Institute of TB and Respiratory Diseases New Delhi in terms of case detection and treatment outcome. MATERIALS AND METHODS: The TB patients detected during ACF through house to house survey in vulnerable population were identified, evaluated and followed up. Data from ACF records and TB treatment cards were filled in a pretested proforma and compared with passive case detection in the previous month from same area. RESULTS: In December 2017 a total 8600 vulnerable population (living in slums, camps and night shelters) were screened over two weeks of whom 85 were found to have symptoms suggestive of TB of whom 19 were PTB that gives a case detection rate of 220 per lakh population. PTB case detection rate by passive case finding (PCF) in November 2017 from the same area of our study was found to be 63 per lakh population. This difference between the detection rate in ACF and passive case findings was statistically significant with Z proportion test and p value <0.00001. Treatment success rate was 75% and lost to follow up rate was 25% patients among the PTB patients detected in ACF. In passive case detection from the same area in November 2017 treatment success rate was 81.8% and lost to follow up rate (LTFU) was 18% in PTB patients. Even though LTFU rate was slightly higher but was not statistically significant. CONCLUSION: ACF is an effective way to find additional cases of TB. ACF is more labour intensive than PCF but if judiciously used under national programme to target specific vulnerable population of society it can produce additional number of TB cases which otherwise would have gone undiagnosed. However, treatment outcome for these patients is below the target and hence to get the maximum impact of ACF there is a need to enhance the adherence to treatment through different methodologies. Poor treatment adherence will lead to increase transmission risk in communities and greater chance of developing drug resistance. Further studies with larger representative population should be undertaken in order to get more conclusive.

A living WHO guideline on drugs to prevent COVID-19

Clinical question What is the role of drugs in preventing covid-19? Why does this matter?There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline.

Evaluation of 'TBDetect' sputum microscopy kit for improved detection of Mycobacterium tuberculosis: a multi-centric validation study.

OBJECTIVES: The present study aimed to evaluate the performance of the 'TBDetect' kit-based bio-safe fluorescent microscopy filter (BioFM-Filter) microscopy in comparison with direct smear microscopy and culture for the detection of pulmonary tuberculosis (TB) in a multi-centric setting in India. METHODS: The TBDetect kit enables sputum concentration through filtration using the BioFM-Filter for improved and bio-safe smear microscopy. We evaluated the performance of the TBDetect kit in a six-site multi-centric validation study on sputum collected from 2086 presumptive TB patients. RESULTS: The combined positivity of TBDetect microscopy performed on these sputum samples was 20% (n = 417/2086) vs 16.1% of light-emitting diode fluorescence microscopy (LED-FM, n = 337/2086) and 16% of Ziehl Neelsen (ZN) smear microscopy (n = 333/2086). The increment in positivity of TBDetect over both LED-FM and ZN smears was significant (p < 0.001). The overall sensitivity of TBDetect for six sites was ~55% (202/367, 95% confidence interval (CI): 50, 60%) vs 52% (191/367, 95% CI: 47, 57%) for LED-FM (p 0.14) and 50.9% (187/367, 95% CI: 46, 56%) for ZN smear (p < 0.05), using Mycobacterium Growth Indicator Tube culture (MGIT, n = 1949, culture positive, n = 367) as the reference standard. A bio-safety evaluation at six sites confirmed efficient sputum disinfection by TBDetect; 99.95% samples (1873/1874) were sterile after 42 days of incubation. Scientists and technicians at the study sites indicated the ease of use and convenience of TBDetect microscopy during feedback. CONCLUSIONS: TBDetect added value to the smear microscopy test due to its improved performance, convenience and user safety. These findings indicate that equipment-free TBDetect technology has the potential to improve TB diagnosis in basic laboratory settings by leveraging on the existing nationwide network of designated microscopy centres and primary healthcare centres.

Multicentric validation of indigenous molecular test Truenat™ MTB for detection of Mycobacterium tuberculosis in sputum samples from presumptive pulmonary tuberculosis patients in comparison with reference standards.

BACKGROUND & OBJECTIVES: : Early case detection is essential to interrupt transmission and to prevent further spread of tuberculosis (TB) in high endemic settings. Nucleic acid amplification tests (NAATs) with visual read-outs are ideal as point-of-care tests. Truenat™ MTB is an indigenous chip-based NAAT for detection of Mycobacterium tuberculosis, which involves extraction of DNA and real-time polymerase chain reaction (PCR) using portable, automated, battery-operated instruments. The current multicentric study was aimed to evaluate Truenat for detection of MTB in sputum samples obtained from patients with presumptive pulmonary TB with reference to culture as gold standard and Xpert as a comparator. METHODS: : The study was conducted at four sites, namely ICMR-National Institute for Research in Tuberculosis, Chennai; All India Institute of Medical Sciences, New Delhi; ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra; and National Institute of TB and Respiratory Diseases, New Delhi. Patients suspected to have TB were screened for eligibility. Two sputum samples were collected from each patient. Tests included smear, Xpert and Truenat directly from the sputum sample and culture by Lowenstein-Jensen (L-J) medium and MGIT960 from decontaminated pellets. Sample used for Truenat assay was coded. Resolution of Truenat false positives was done using an in-house PCR with TRC4 primers. RESULTS: : The study enrolled 2419 presumptive TB patients after screening 2465 patients, and 3541 sputum samples were collected from the enrolled patients. Results of 2623 samples were available for analysis. Truenat showed a positivity rate of 48.5 per cent as compared to 37.0 per cent by Xpert. The sensitivities of Truenat and Xpert were was 88.3 and 79.7 per cent, respectively in comparison with culture. INTERPRETATION & CONCLUSIONS: : Truenat MTB identified more positives among culture-confirmed samples than Xpert and had higher sensitivity. In addition, other advantageous operational features of Truenat MTB were identified which would be useful in field settings.

A living WHO guideline on drugs for COVID-19

What is the role of drug interventions in the treatment of patients with covid-19? The latest version of this WHO living guidance focuses on remdesivir, following the 15 October 2020 preprint publication of results from the WHO SOLIDARITY trial. It contains a weak or conditional recommendation against the use of remdesivir in hospitalised patients with covid-19 The first version on this living guidance focused on corticosteroids. The strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, and a weak or conditional recommendation against systemic corticosteroids in patients with non-severe covid-19 are unchanged.

Demographic profile, clinical and microbiological predictors of mortality amongst admitted pediatric TB patients in a tertiary referral tuberculosis hospital.

BACKGROUND: Pediatric tuberculosis (TB) constitutes 8% of the total caseload of TB. Children are particularly vulnerable to dissemination of disease and mortality. AIM: To determine mortality rate, elucidate type of TB, causes and predictors of mortality, if any, in admitted pediatric TB patients. METHODS: Present retrospective study was conducted in a tertiary referral center over last 6½ year on children who died out of total TB admissions. RESULTS: Out of total 1380 pediatric (<15 years of age) TB admissions, 74 children died, a mortality rate of 5.36%. Mean age was 11.4 years with highest mortality 47 (63.51%) in patients from 11 to 14 years age group. Significant majority 58 (78.38%) patients were females (p < 0.011). Range of hospital stay was 0-113 days with 7 (9.5%), 9 (12.16%) and 27 (36.48%) children dying on day of admission, next day and 3rd-7th day respectively, therefore a total of 43 (58.11%) died within first week of admission. Most 60 (81.08%) patients belonged to poor socio-economic status. History of contact was present in 12 (16.22%) cases while none had diabetes. 31 (41.89%) patients had sepsis and severe anemia (Hb ≤ 6 g %) was present in 6 (8.11%) patients at admission, out of which 4 died on the same day of admission, even before blood could be arranged. Most patients 68 (91.89%) had pulmonary TB with 25 children having concomitant extrapulmonary involvement, while 4 (5.41%) had meningeal TB and 2 (2.70%) had disseminated TB with HIV. Microbiological confirmation was achieved in 51 (68.92%) (48 PTB and 3 EPTB) cases while 23 (31.08%) were clinically diagnosed. Bilateral extensive fibro-cavitary disease with infiltrations was the commonest. Drug resistance was confirmed in 21 (28.38%) with 2, 5, 8, 5 and 1 patient diagnosed with mono H, RR, MDR, pre-XDR and XDR respectively but results of 9 patients were received posthumously. Treatment given was category 1, category 2 and regimens for drug resistant TB in 24 (32.43%), 29 (39.19%) and 21 (28.37%) cases respectively based on prior history of ATT and drug sensitivity. Adverse drug reactions were noted in 12 (16.21%) cases. Noted immediate causes of mortality were cardio-respiratory failure, sudden pneumothorax, massive hemoptysis, sepsis, extensive pulmonary disease and aspiration pneumonia. The pointers towards mortality include female gender, severe malnutrition, anemia, extensive disseminated disease and drug resistant TB. Ignorance, dependency of children on parents, poor adherence and late referrals into the system lead to delayed diagnosis and initiation of proper regimen based treatment. CONCLUSION: Early referrals of non-responders and failures to centers equipped with programmatic management facilities are essential for proper, timely management of pediatric TB to reduce mortality.

Nikshay Poshan Yojana (NPY) for tuberculosis patients: Early implementation challenges in Delhi, India.

BACKGROUND: Nutrition support is one of the essential factors for envisioning Tuberculosis (TB) elimination in India by 2025. In this regard, Government of India introduced Nikshay Poshan Yojana (NPY) through Direct Benefit Transfer (DBT) as monthly financial assistance towards nutrition for TB patients in April, 2018. Assessment of early implementation challenges of the scheme is essential. OBJECTIVE: (a) To determine the number (proportion) of TB patients who received the benefits (b) to explore the challenges encountered by the health care providers in delivering the NPY through DBT (c) to explore the ways the incentives were utilised by the patients. MATERIAL AND METHODS: It was a cross-sectional study conducted among patients registered for TB treatment at Ladosarai and Mehrauli DOTS centre between July-September, 2018.Health providers engaged in implementation of NPY at the study sites were also interviewed. The data were collected through structured questionnaires, double entered and analyzed in Epi Data. RESULTS: Out of 119 patients registered, we interviewed 57 (47.9%) patients. Of which, 30 (52.6%) had received NPY for 2 months in the fourth and fifth month of treatment. The health providers reported increased workload, lack of training and complex reporting formats as main hurdles in implementation of the scheme. While, the patients cited non-availability of bank accounts and unlinked bank account with Aadhar card as difficulties to receive NPY through DBT. CONCLUSION: Nearly half of the interviewed TB patients received nutritional incentives of NPY through DBT for 2 months. Non-availability of bank accounts and unlinked bank accounts were some challenges faced by both health providers and patient. It is recommended to address these implementation on time in order to reap the benefit of scheme in improving nutritional status of TB patients. Further studies are needed to determine the effect of nutrition support on TB patients.