Nutritional supplementation to prevent tuberculosis incidence in household contacts of patients with pulmonary tuberculosis in India (RATIONS): a field-based, open-label, cluster-randomised, controlled trial.

BACKGROUND: In India, tuberculosis and undernutrition are syndemics with a high burden of tuberculosis coexisting with a high burden of undernutrition in patients and in the population. The aim of this study was to determine the effect of nutritional supplementation on tuberculosis incidence in household contacts of adults with microbiologically confirmed pulmonary tuberculosis. METHODS: In this field-based, open-label, cluster-randomised controlled trial, we enrolled household contacts of 2800 patients with microbiologically confirmed pulmonary tuberculosis across 28 tuberculosis units of the National Tuberculosis Elimination Programme in four districts of Jharkhand, India. The tuberculosis units were randomly allocated 1:1 by block randomisation to the control group or the intervention group, by a statistician using computer-generated random numbers. Although microbiologically confirmed pulmonary tuberculosis patients in both groups received food rations (1200 kcal, 52 grams of protein per day with micronutrients) for 6 months, only household contacts in the intervention group received monthly food rations and micronutrients (750 kcal, 23 grams of protein per day with micronutrients). After screening all household contacts for co-prevalent tuberculosis at baseline, all participants were followed up actively until July 31, 2022, for the primary outcome of incident tuberculosis (all forms). The ascertainment of the outcome was by independent medical staff in health services. We used Cox proportional hazards model and Poisson regression via the generalised estimating equation approach to estimate unadjusted hazard ratios, adjusted hazard ratios (aHRs), and incidence rate ratios (IRRs). This study is registered with CTRI-India, CTRI/2019/08/020490. FINDINGS: Between Aug 16, 2019, and Jan 31, 2021, there were 10 345 household contacts, of whom 5328 (94·8%) of 5621 household contacts in the intervention group and 4283 (90·7%) of 4724 household contacts in the control group completed the primary outcome assessment. Almost two-thirds of the population belonged to Indigenous communities (eg, Santhals, Ho, Munda, Oraon, and Bhumij) and 34% (3543 of 10 345) had undernutrition. We detected 31 (0·3%) of 10 345 household contact patients with co-prevalent tuberculosis disease in both groups at baseline and 218 (2·1%) people were diagnosed with incident tuberculosis (all forms) over 21 869 person-years of follow-up, with 122 of 218 incident cases in the control group (2·6% [122 of 4712 contacts at risk], 95% CI 2·2-3·1; incidence rate 1·27 per 100 person-years) and 96 incident cases in the intervention group (1·7% [96 of 5602], 1·4-2·1; 0·78 per 100 person-years), of whom 152 (69·7%) of 218 were patients with microbiologically confirmed pulmonary tuberculosis. Tuberculosis incidence (all forms) in the intervention group had an adjusted IRR of 0·61 (95% CI 0·43-0·85; aHR 0·59 [0·42-0·83]), with an even greater decline in incidence of microbiologically confirmed pulmonary tuberculosis (0·52 [0·35-0·79]; 0·51 [0·34-0·78]). This translates into a relative reduction of tuberculosis incidence of 39% (all forms) to 48% (microbiologically confirmed pulmonary tuberculosis) in the intervention group. An estimated 30 households (111 household contacts) would need to be provided nutritional supplementation to prevent one incident tuberculosis. INTERPRETATION: To our knowledge, this is the first randomised trial looking at the effect of nutritional support on tuberculosis incidence in household contacts, whereby the nutritional intervention was associated with substantial (39-48%) reduction in tuberculosis incidence in the household during 2 years of follow-up. This biosocial intervention can accelerate reduction in tuberculosis incidence in countries or communities with a tuberculosis and undernutrition syndemic. FUNDING: Indian Council of Medical Research-India TB Research Consortium.

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).

The RATIONS (Reducing Activation of Tuberculosis by Improvement of Nutritional Status) study: a cluster randomised trial of nutritional support (food rations) to reduce TB incidence in household contacts of patients with microbiologically confirmed pulmonary tuberculosis in communities with a high prevalence of undernutrition, Jharkhand, India.

INTRODUCTION: India has the largest burden of cases and deaths related to tuberculosis (TB). Undernutrition is the leading risk factor accounting for TB incidence, while severe undernutrition is a common risk factor for mortality in patients with TB in India. The impact of nutritional supplementation on TB incidence is unknown, while few underpowered studies have assessed its impact on TB mortality. We designed an open-label, field-based cluster randomised trial to assess the impact of nutritional supplementation (with food rations) on TB incidence in a group at higher risk of TB infection and disease, viz household contacts (HHC) of patients with microbiologically confirmed pulmonary TB (PTB) in Jharkhand, a state with a high prevalence of undernutrition. METHODS AND ANALYSIS: We shall enrol 2800 adult patients with PTB of the national TB programme, across 28 treatment units in 4 districts, and their approximately 11 200 eligible contacts. The sample size has 80% power to detect the primary outcome of 50% reduction in incidence of active TB in HHC over 2 years of follow-up. Patients and HHC in both the arms will undergo nutritional assessment and counselling. Patients will receive monthly food rations (supplying 1200 kcal and 52 g proteins/day) and multivitamins along with antitubercular treatment. The HHC in the intervention arm will receive food rations (supplying 750 kcal and 23 g proteins/day) and multivitamins while HHC in control arm will be on usual diet. The secondary outcomes in HHC will include effects on nutritional status, non-TB infections. Secondary outcomes in patients are effects on TB mortality, adherence, adverse effects, nutritional and performance status. Substudies will examine micronutrient status and effects on dietary intake, body composition, muscle strength and immune function. ETHICS AND DISSEMINATION: The institutional ethics committee of ICMR-NIRT, Chennai, approved the study (289/NIRT-IEC/2018). The results will be disseminated in publications and presentations. TRIAL REGISTRATION NUMBER: Clinical Trial Registry of India: CTRI/2019/08/020490.

Understanding the gaps in elimination of tuberculosis in India.

Tuberculosis (TB) is a highly infectious disease, and it has the highest global burden on India with 21% prevalence rate and 27% of patients who do not receive pertinent medical treatment. Although India spends 23 billion dollars annually towards medical expenses for TB, India still ranks among the top 2 countries with the highest incidence and prevalence rates with more than 300,000 deaths excluding the patients with HIV and TB calling for prompt consideration. India faces a great challenge socially and economically. They lack a uniform health care system, making it burdensome to use effective surveillance techniques for prevention of TB. Currently, India is working on resolving the issue meticulously through the web-based application program 'Nikshay' with other strategies like Revised National Tuberculosis Control Program (RNTCP) and World Health Organization's The End TB Strategy. India's cardinal goal is to make advanced diagnostic tools made available and public-private healthcare sector collaboration. India needs to focus more on primary prevention by effective policy formation and campaign which promote proper sanitation and vaccine administration while educating the layman.

White paper on challenges and opportunities for TB elimination with focus on COVID & Post-COVID era developed through scientific roundtable resolutions at NATCON 2020.

A group of TB experts with vast clinical and epidemiological experience were drawn from a pool of doctors, epidemiologists and scientists participating in NATCON 2020 Conference in a closed-door session to discuss, highlight, and prioritize key resolutions that are most pertinent at present to eliminate TB from India and other developing countries in the Covid and post-COVID era. These Scientific experts were non-industry persons who met on 17th December, 2020 and used the prevailing scientific literature along with 2019 Joint Monitoring Mission document as a starting point of the discussion on this specific topic to build an agreement upon the resolutions. After the meeting on the virtual platform, all the attending doctors gave a set of recommendations on rebuilding TB Elimination programme in the Covid and Post-Covid era. Focused scientific roundtable discussion on rebuilding TB Elimination Post-Covid. Develop actionable recommendations for the scientific community and the government leadership to consider in moving forward. To prioritize the recommendations in the categories of Build-Prevent-Detect-Treat.

New National Tuberculosis Elimination Program(NTEP) logo: Observation and comments.

The new National Tuberculosis Elimination Program (NTEP) launched with its new logo in early 2020. Logo have been launched is circular with yellow and red colour. Name of program is in circular and with caption "TB Harega Desh Jeetega". There is red colour joyful person surrounded by National Flag with image of lung in the logo. Present letter highlights observation and comments on the new NTEP logo.

Chasing END TB 2025: Arithmetic needed for logistics!

India adopted changes in NTEP (Erstwhile RNTCP, Revised National TB Program, renamed as National TB Elimination Program) in the recent years with an aim to End TB by 2025 way ahead of the global target of ending TB by 2030. It is taking a long time for the changes to trickle down to the grass root level to change the behavior of the ground level force to understand and adopt to the changes that are being ordered and several other changes that are being pushed to the field in tandem. This has made field workers to be on their toes to understand and implement all the changes. The logistics like referral forms, GeneXpert/CBNAAT cartridges, slides etc., required for the program need to be calculated and used as per the changes. Shortages in the procurement or indenting will result in hampering the smooth functioning of the program. Accordingly, we calculated the logistics required for the patients estimated to occur in an area depending on the previous year's patient load. The breakup of the patients was adopted from the available references given. Also, the 2019 data of the load of different type of patients in India and the world were also taken. Total logistics were calculated for two hundred patients. Based on the calculations, a generic formula was derived. When the total number of patients in the previous year/quarter/or any period is N, then below is the formula which can estimate the required logistics for the next similar period.

Risk of infection associated with Janus Kinase (JAK) inhibitors and biological therapies in inflammatory intestinal disease and rheumatoid arthritis. Prevention strategies. / Riesgo de infección asociado a los inhibidores de las quinasas Janus (JAK) y las terapias biológicas en enfermedad inflamatoria intestinal y artritis reumatoide. Estrategias de prevención.

Patients with certain immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), have an increased risk of severe infectious diseases than the general population, which are mainly associated with the immunosuppressive treatments that they receive. These treatments act on the immune system through different mechanisms, causing different degrees of immunosuppression and a variable risk depending on whether the pathogen is a virus, bacteria or fungus. This article reviews the most relevant literature on the subject, which was selected and discussed by a panel of experts. The aim of this article is to review the risk of infections in patients with IBD and RA, and the potential preventive measures.

Efficacy of vitamin D3 supplementation for the prevention of pulmonary tuberculosis and mortality in HIV: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Observational data suggest that low vitamin D status is associated with an increased incidence of pulmonary tuberculosis and mortality among people living with HIV. The primary aims of this study were to assess the effect of vitamin D3 supplementation on the risk of mortality and incidence of pulmonary tuberculosis among adults initiating antiretroviral therapy (ART). METHODS: This was a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation among adults living with HIV who initiated ART and had serum 25-hydroxyvitamin D concentrations of less than 30 ng/mL at four large HIV care and treatment centres in Dar es Salaam, Tanzania. Patients were excluded if they were younger than 18 years, pregnant at the time of randomisation, or were enrolled in any other clinical trial. Patients were randomly assigned 1:1 to receive either weekly oral 50 000 IU vitamin D3 supplements (cholecalciferol) for the first month of ART followed by daily 2000 IU vitamin D3 supplements or a matching weekly and daily placebo regimen. The randomisation list was computer-generated by a non-study statistician with sequence blocks of ten that were stratified by study clinic. Complete allocation concealment was ensured and patients, field team, and investigators were masked to group assignment. The trial follow-up duration was 1 year and the primary efficacy outcomes were death and incident pulmonary tuberculosis. An intention-to-treat analysis was followed for all-cause mortality; participants diagnosed with or receiving treatment for pulmonary tuberculosis at randomisation, or suspected to have tuberculosis at randomisation and who later had that diagnosis confirmed, were excluded from analyses of pulmonary tuberculosis incidence. Safety was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01798680, and is completed. FINDINGS: Between Feb 24, 2014, and Feb 24, 2017, 6250 adults initiating ART had serum 25-hydroxyvitamin D screening, 4000 of whom were enrolled in the trial and followed up for 1 year (follow-up of all participants was completed on March 7, 2018). 2001 patients were randomly assigned to the vitamin D3 supplementation group, and 1999 to the placebo group. 415 deaths were recorded: 211 in the vitamin D3 group and 204 in the placebo group. Among all randomly assigned participants, there was no overall effect of vitamin D3 supplementation on the risk of mortality (hazard ratio [HR] 1·04, 95% CI 0·85-1·25; p=0·73). There was also no difference in the overall incidence of pulmonary tuberculosis between the vitamin D3 (50 events in 1812 patients analysed) and placebo groups (64 events in 1827 patients; HR 0·78, 0·54-1·13; p=0·19). The vitamin D3 regimen did not increase the risk of hypercalcaemia (three events in the vitamin D3 group and two events in the placebo group; relative risk 1·25, 95% CI 0·43-3·66; Fisher's exact p=1·00). 101 hospital admissions were reported in the vitamin D3 group and 94 in the placebo group (incidence rate ratio 1·06, 95% CI 0·80-1·41; p=0·66). INTERPRETATION: Additional research is needed before vitamin D3 supplementation should be considered for implementation in HIV care and treatment programmes for the prevention of pulmonary tuberculosis or mortality. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Why are people dying due to tuberculosis? A study from Alappuzha District, Kerala, India.

BACKGROUND: Tuberculosis (TB)is a major killer disease worldwide. It is the ninth leading cause of death worldwide and the leading cause from a single infectious agent. In India also, TB kills about 480,000 persons every year and more than 1400 every day. Vision of the National TB Control Programme is TB-Free India with zero deaths, disease and poverty due to TB. Specific targets set in the End TB strategy include a 90% reduction in TB deaths and an 80% reduction in TB incidence by 2030, compared with 2015. Understanding about real cause of death is important to plan strategies to further prevent TB deaths. In the above circumstances we conducted a study, the objective of which was to find out the cause of deaths among patients registered in RNTCP unit of Alappuzha district of Kerala, India. METHODS: In RNTCP a patient who died during the course of treatment regardless of cause is declared as 'Died' due to TB. During the year 2015, 1618 cases were registered in RNTCP of Alappuzha district of which 90 patients died, showing a case fatality rate of 5.56%. Verbal autopsy can be considered as an essential public health tool for studying reasonable estimate of the cause of death at a community level even though not an accurate method at individual level. As part of the study, we visited the 4 RNTCP units of the district and collected the address of the TB patients who died in the area. With the help of the field staff we visited their houses and filled the death audit form of RNTCP along with the additional details. Verbal autopsy was conducted using WHO verbal autopsy format 2012 with immediate house hold contacts. RESULTS: Out of 90 deaths which occurred, three addresses could not be traced and another 15 patient relatives could not be contacted as they migrated out or were not available at their homes on two visits. Among them, mean age was found to be 62.6 years (SD+12.9). Males were 67 (77%) and rest 20 (23%)were females. Cause of death was analysed after Verbal autopsy for 72 deaths. Among 72 deaths, it was found that 29 (40.3%) had nothing other than TB, where as cause of death for 13 (18.1%) patients was myocardial infarction, 11 (15.3%) had cancer, 2 (2.8%) stroke and 17 (23.7%) other causes which include bronchiectasis, COPD, chicken pox, hepatitis, renal failure, and suicide. Only in 35 cases nothing other than TB could be suggested as a cause of death. Thus in 52 out of 87 (60%) cases, the causes of death were diseases other than TB. CONCLUSION: Among the TB deaths in Alappuzha district, 60% of deaths were due to diseases other than TB. Along with early diagnosis of all TB cases, screening for co-morbidity, appropriate management of co-morbidity and periodic clinical review of TB patients should also be part of the major strategies to prevent TB related deaths.

Fifth year of a public-private partnership to improve the case detection of tuberculosis in India: A role model for future action?

BACKGROUND: There is limited access to radiology facilities in most parts of India leading to significant under diagnosis and underreporting of smear negative clinically diagnosed tuberculosis (CDTB). Public Private Partnership (PPP) has a lot to contribute towards addressing this gap through providing access to chest x-ray (CXR) in far-off locations. METHOD: Mobile vans equipped with digital CXR equipment and support staff were provided by a Corporate Hospital working closely with government, with scheduled visits to government peripheral health institutes. Patients received upfront CXR and sputum microscopy along with GeneXpert in accordance with the revised TB diagnostic algorithm prescribed by the national program, Following a successful pilot in 2014 in district Rewari, "TB free Haryana" was launched in November 2015 with a phased roll out in 16 districts by 2018. RESULTS: The pilot initiative in 2014 confirmed practical and clinical feasibility and revealed a high rate (30% of people screened) of CDTB i.e. symptomatic cases with radiologic abnormalities compatible with Pulmonary TB. In the first year (2016), 5 districts were covered and a total of 3340 CXRs were carried out. There was an increase in the case notification rates of new CDTB (smear negative) in 2016 compared to 2015 (p = 0.036); yielding an additional 180 cases and an 11.67% increase in case detection. Scale up to a total of 13 and 16 districts took place successfully in 2017 and 2018 respectively; with 6268 CXRs and 8021 CXRs done in the respective years. CONCLUSION: PPP can involve Corporate Hospitals to improve the existing diagnostic infrastructure and provides access to CXR in a not-for-profit sustainable collaboration, with scale-up to the state level; and potential to replicate this initiative in other states.

Minipigs as a neonatal animal model for tuberculosis vaccine efficacy testing.

Many vaccines against childhood diseases are administered early after birth, but vaccine development studies frequently test efficacy in adult rather than in neonatal animal models. In countries with endemic tuberculosis (TB), Bacillus Calmette-Guerin (BCG) is administered as part of the neonatal vaccine regimen because it prevents against the disseminated form of TB in children, although it has variable efficacy against pulmonary TB. Several promising new vaccines against TB are currently being tested in adult animal models. Here we evaluated neonatal piglets as an animal model to test vaccine efficacy. For this purpose, minipigs were vaccinated or not with BCG 48 h after birth and their immune response followed longitudinally until adolescence. We characterized the memory and activation phenotype of T cells, cytokine profile, and monocyte activation in response to BCG stimulation from 4 weeks of age into adolescence- age of 24 weeks. Immunological responses in vaccinated and non-vaccinated animals were further monitored upon infection with a low dose exposure to Mycobacterium tuberculosis strain HN878 via the aerosol route. Comparing the immunological response elicited by BCG vaccination in minipigs vs similar studies in infants, suggest that minipigs have the potential to serve as an effective neonatal animal model for vaccine development.

Tackling drug-resistant tuberculosis: we need a critical synergy of product and process innovations.

The End TB Strategy diagnostic pillar calls for access to high-sensitivity diagnostic testing and universal rapid drug susceptibility testing (DST). The recommended diagnostic technologies available in low and middle-income, high-burden countries for multidrug-resistant tuberculosis (MDR-TB) are essentially limited to Xpert® MTB/RIF and MTB/RIF Ultra assays, culture DST and the line-probe assays. The primary reasons for slow scale-up are insufficient political will, and therefore, insufficient funding for qualified human resources, and safe laboratory and health system infrastructure. Innovative approaches to enable the private health sector to provide high-quality diagnosis are also needed. The Essential Diagnostics List provides impetus and a standard benchmark for the rational implementation of MDR-TB diagnostics, but the epidemic will ultimately only be favorably impacted by complete end-to-end solutions to patients that address the complete cascade of care, including patient-centered diagnosis and treatment of TB and MDR-TB, management of comorbidities and social protection. By scaling up access to the currently available diagnostics, we lay the groundwork for future innovations for rapid accurate diagnosis of MDR-TB, which in turn will bring us closer to meeting the targets in the End TB Strategy.

Multidrug-resistant tuberculosis in South Korea: a retrospective analysis of national registry data in 2011-2015.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) poses a threat to public health as a result of high treatment costs and unsatisfactory outcomes.OBJECTIVE: To elucidate trend, demographic and clinical characteristics and treatment outcomes of patients with MDR-TB between 2011 and 2015 in South Korea.METHOD: Data of patients with MDR-TB diagnosed between 1 January 2011 and 31 December 2015 were retrieved from the nationwide Internet-based TB notification system and analysed retrospectively.RESULTS: During the study period, 5192 MDR-TB patients were notified. We identified an increasing number of MDR-TB patients among foreign populations (from 1.3% to 7.7%), decreasing resistance rates to other anti-TB drugs (e.g., resistance to pyrazinamide, from 40.9% to 28.2%), a decreasing interval from treatment initiation to negative conversion of sputum culture (from 165.7 to 103.7 days) and shortening of treatment duration (719.7 to 613.2 days). However, treatment success rates did not change, and had an average of 65.7%.CONCLUSION: Despite decreasing resistance rates to other drugs and faster treatment responses, treatment outcomes did not improve during the study period. Strict management of MDR-TB patients on treatment should be adopted to improve treatment outcomes.

Second nationwide anti-tuberculosis drug resistance survey in Namibia.

SETTING: Namibia ranks among the 30 high TB burden countries worldwide. Here, we report results of the second nationwide anti-TB drug resistance survey.OBJECTIVE: To assess the prevalence and trends of multidrug-resistant TB (MDR-TB) in Namibia.METHODS: From 2014 to 2015, patients with presumptive TB in all regions of Namibia had sputum subjected to mycobacterial culture and phenotypic drug susceptibility testing (DST) for rifampicin, isoniazid, ethambutol and streptomycin if positive on smear microscopy and/or Xpert MTB/RIF.RESULTS: Of the 4124 eligible for culture, 3279 (79.5%) had Mycobacterium tuberculosis isolated. 3126 (95%) had a first-line DST completed (2392 new patients, 699 previously treated patients, 35 with unknown treatment history). MDR-TB was detected in 4.5% (95%CI 3.7-5.4) of new patients, and 7.9% (95%CI 6.0-10.1) of individuals treated previously. MDR-TB was significantly associated with previous treatment (OR 1.8, 95%CI 1.3-2.5) but not with HIV infection, sex, age or other demographic factors. Prior treatment failure demonstrated the strongest association with MDR-TB (OR 17.6, 95%CI 5.3-58.7).CONCLUSION: The prevalence of MDR-TB among new TB patients in Namibia is high and, compared with the first drug resistance survey, has decreased significantly among those treated previously. Namibia should implement routine screening of drug resistance among all TB patients.

Immunization With Mycobacterium tuberculosis Antigens Encapsulated in Phosphatidylserine Liposomes Improves Protection Afforded by BCG.

Liposomes have been long considered as a vaccine delivery system but this technology remains to be fully utilized. Here, we describe a novel liposome-based subunit vaccine formulation for tuberculosis (TB) based on phosphatidylserine encapsulating two prominent TB antigens, Ag85B, and ESAT-6. We show that the resulting liposomes (Lipo-AE) are stable upon storage and can be readily taken up by antigen presenting cells and that their antigenic cargo is delivered and processed within endosomal cell compartments. The Lipo-AE vaccine formulation combined with the PolyIC adjuvant induced a mixed Th1/Th17-Th2 immune response to Ag85B but only a weak response to ESAT-6. An immunization regimen based on systemic delivery followed by mucosal boost with Lipo-AE resulted in the accumulation of resident memory T cells in the lungs. Most importantly though, when Lipo-AE vaccine candidate was administered to BCG-immunized mice subsequently challenged with low dose aerosol Mycobacterium tuberculosis, we observed a significant reduction of the bacterial load in the lungs and spleen compared to BCG alone. We therefore conclude that the immunization with mycobacterial antigens delivered by phosphatidylserine based liposomes in combination with Poly:IC adjuvant may represent a novel BCG boosting vaccination strategy.

Strategy to sensitize private practitioners on RNTCP through medico-social workers in urban field practice area of a Medical College in Bengaluru, Karnataka.

BACKGROUND: India accounts for 25% of global TB burden and majority of TB patients seek care from private practitioners. It becomes imperative to involve private practitioners with newer strategies to strengthen the Revised National Tuberculosis Control Program (RNTCP). A study was conducted to assess the knowledge, attitude and practices among private practitioners with regards to tuberculosis case detection and referral and to demonstrate the feasibility of utilizing existing medico-social worker of a medical college in sensitizing the private practitioners. METHODS: An intervention study was conducted during 2017. In an urban field practice area of a medical college, 34 allopathic private practitioners (PP) from six slums formed the study population. The RNTCP trained Medico social workers (MSW) of medical college provided repeated sensitization to private practitioners on case referrals. The data of KAP among private practitioners was collected. The output of repeated sensitization was measured by comparing the number of cases referred by Private Practitioners to DMC during the pre and post intervention period. RESULTS: Only 1 in 2 practitioners were aware about the duration of cough in presumptive TB cases. Nearly 44% of them were not aware about the first investigation of choice under RNTCP; 53% of the doctors did not know about the total number of sputum samples to be collected. After the sensitization of PPs by MSWs the number of presumptive pulmonary cases was increased by more than two folds. CONCLUSION: The strategy of utilizing the services of medico-social workers employed in a medical college to sensitize the private practitioners is feasible and has demonstrated the increase in number of presumptive TB case referrals to DMCs.

Parenteral Vaccination With a Tuberculosis Subunit Vaccine in Presence of Retinoic Acid Provides Early but Transient Protection to M. Tuberculosis Infection.

Most microbes invading through mucosal surfaces cause disease and therefore strategies to induce mucosal immune responses are strongly needed. Vitamin A metabolites, such as retinoic acid (RA), play crucial roles in programming T and B cells to home to mucosal compartments, therefore we evaluated the capacity of RA to elicit mucosal immune responses against tuberculosis (TB) after parenteral vaccination. We found that mice immunized through subcutaneous injections with the TB subunit vaccine (CAF01+H56) in presence of RA show enhanced mucosal H56-specific IgA responses and enhanced Ag-specific CD4+ T lymphocytes homing to the lung as compared with control mice. Immunization with CAF01+H56 in presence of RA resulted in lower bacterial loads in the lungs of mice 14 days after challenge with virulent Mycobacterium tuberculosis (Mtb) as compared to mice immunized in the absence of RA or vaccinated with BCG. Higher amounts of IFNγ and IL-17 pro-inflammatory cytokines were found in lung homogenates of mice immunized with CAF01+H56 and RA 24 h after Mtb infection. However, 6 weeks after infection the protection was comparable in vaccinated mice with or without RA even though treatment with RA during immunization is able to better contain the inflammatory response by the host. Furthermore, at later stage of the infection a higher percentage of Mtb specific CD4+PD1+ T lymphocytes were found in the lungs of mice immunized with CAF01+H56 and RA. These data show that an enhanced mucosal immune response is generated during parenteral vaccination in presence of RA. Furthermore, RA treatment contained the bacterial growth at an early stage of the infection and limited the inflammatory response in the lung at later time points.

People- and patient-centred care for tuberculosis: models of care for tuberculosis.

SETTING: The first pillar in the World Health Organisation's (WHO's) End TB strategy is 'Integrated, patient-centred tuberculosis (TB) care and prevention'. However, what are patient- and people-centred care, and why are they important for TB care and prevention? OBJECTIVE AND RATIONALE: To define the concept of patient-centred care, the rationale for it, and its evolution into people-centred care; and to explore evidence on whether people-centred approaches work for TB and present key areas where continuous efforts are needed to support their implementation. RESULTS: Based on the reasoning and the evidence presented, we propose four areas where further action is needed to ensure that people-centred TB care and prevention can achieve their potential: 1) reaching consensus on definitions and terminology; 2) strengthening research; 3) using and evaluating new technology; and 4) nurturing country leadership and advocacy. CONCLUSION: Integrated, people-centred TB care and prevention should be a guiding light for all those involved in the quest to eliminate TB. However, much still needs to be done to bridge the gaps between the potential and actual performance of national programmes.

Involving private practitioners in the Indian tuberculosis programme: a randomised trial.

OBJECTIVES: To assess a multicomponent intervention to improve private practitioners (PPs) involvement in referral of presumptive pulmonary TB (PTB) cases to the Revised National TB Control Programme (RNTCP) for sputum examination. METHODS: Randomised controlled trial. We randomly allocated all 189 eligible PPs in Tumkur city, South India, to intervention or control arm. The intervention, implemented between December 2014 and January 2016, included two sets of activities, one targeted at health system strengthening (building RNTCP staff capacity to collaborate with PPs, provision of feedback on referrals through SMS) and one targeted at intervention PPs (training in RNTCP, provision of referral pads and education materials and monthly visits to PPs by RNTCP staff). Crude and adjusted referral and PTB case-finding rate ratios were calculated with negative binomial regression. RESULTS: PPs referred 836 individuals (548 from intervention and 169 from control arm PPs) of whom 176 were diagnosed with bacteriologically confirmed PTB. The proportion (95% confidence interval) of referring PPs [0.59 (0.49, 0.68) vs. 0.42 (0.32, 0.52) in the intervention and control arm, respectively], mean referral rate per PP-year [(5.7 (3.8, 8.7) vs. 1.8 (1.2, 2.8)] and smear-positive PTB case-finding rate per PP-year [(1.5 (0.9, 2.2) vs. 0.6 (0.3, 0.9)] were significantly higher in the intervention than the control arm. Stratifying by qualification, a statistically significant difference in the above indicators remained only among GPs and internists. Overall, surgeons, paediatricians and gynaecologists referred few patients. PP referrals contributed to 20% of the sputum smear positive PTB cases detected by RNTCP in Tumkur city (14% were from intervention arm PPs). CONCLUSIONS: We demonstrated the effectiveness of a health system-oriented intervention to improve PP's referrals of presumptive PTB cases to RNTCP.