Vitamin D and Zinc Supplementation to Improve Treatment Outcomes among COVID-19 Patients in India: Results from a Double-Blind Randomized Placebo-Controlled Trial.

Background: There remains a need to identify low-cost interventions to improve coronavirus disease 2019 (COVID-19) outcomes. Vitamin D and zinc play a role in respiratory infections and could hold value as part of therapeutic regimens. Objectives: To determine the effect of vitamin D or zinc supplementation on recovery from COVID-19. Methods: We conducted a double-blind, randomly assigned 2 x 2 factorial placebo-controlled trial with 1:1:1:1 allocation ratio, enrolling nonpregnant adults with COVID-19 from hospitals in Mumbai and Pune, India (NCT04641195). Participants (N = 181) were randomly assigned to vitamin D3 (180,000 IU bolus, then 2000 IU daily), zinc (40 mg daily), vitamin D3 and zinc, or placebo, for 8 wk. Participants were followed until 8 wk. The primary outcome was time to resolution of fever, cough, and shortness of breath. Secondary outcomes were duration of individual symptoms; need for assisted ventilation; duration of hospital stay; all-cause mortality; and blood biomarkers, including nutritional, inflammatory, and immunological markers. Results: We observed no effect of vitamin D or zinc supplementation on time to resolution of all 3 symptoms [vitamin D hazard ratio (HR): 0.92; 95% confidence interval (95% CI): 0.66, 1.30; P = 0.650; zinc HR: 0.94; 95% CI: 0.67, 1.33; P = 0.745)]. Neither vitamin D nor zinc supplementation was associated with secondary outcomes, except for increased endline serum vitamin D with vitamin D supplementation [median (interquartile range) difference between endline and baseline for vitamin D: 5.3 ng/mL (-2.3 to 13.7); for no vitamin D: -1.4 ng/mL (-5.6 to 3.9); P = 0.003]. We observed nonsignificant increases in serum zinc at endline following zinc supplementation. There was no evidence of interaction between vitamin D and zinc supplementation, no effect of either on hypercalcemia, and no adverse events. Conclusions: Results suggest that neither vitamin D nor zinc supplementation improves COVID-19 treatment outcomes in this population. However, much larger-scale evidence, particularly from populations with vitamin D or zinc deficiency and severe infection, is required to corroborate our findings. This trial was registered at ClinicalTrials.gov and the Clinical Trials Registry of India as NCT04641195 and CTRI/2021/04/032593 respectively.

Randomised trial to determine the effect of vitamin D and zinc supplementation for improving treatment outcomes among patients with COVID-19 in India: trial protocol.

INTRODUCTION: Presently, there are few population-level strategies to address SARS-CoV-2 infection except preventive measures such as vaccination. Micronutrient deficiency, particularly vitamin D and zinc deficiency, has been associated with dysregulated host responses, and may play an important role in COVID-19. METHODS AND ANALYSIS: We have designed a 2×2 factorial, randomised, double-blind, multi-centre placebo-controlled trial to evaluate the effect of vitamin D and zinc on COVID-19 outcomes in Maharashtra, India. COVID-19 positive individuals are recruited from hospitals in Mumbai and Pune. Participants are provided (1) vitamin D3 bolus (180 000 IU) maintained by daily dose of 2000 IU and/or (2) zinc gluconate (40 mg daily), versus placebo for 8 weeks. Participants undergo a detailed assessment at baseline and at 8 weeks, and are monitored daily in hospital or every 3 days after leaving the hospital to assess symptoms and other clinical measures. A final follow-up telephone call occurs 12 weeks post-enrolment to assess long-term outcomes. The primary outcome of the study is to time to recovery, defined as time to resolution of all of fever, cough and shortness of breath. Secondary outcomes include: duration of hospital stay, all-cause mortality, necessity of assisted ventilation, change in blood biomarker levels and individual symptoms duration. Participant recruitment commenced on April 2021. ETHICS AND DISSEMINATION: Ethical approval was obtained from institutional ethical committees of all participating institutions. The study findings will be presented in peer-reviewed medical journals. TRIAL REGISTRATION NUMBERS: NCT04641195, CTRI/2021/04/032593, HMSC (GOI)-2021-0060.

Protocol for a case-control study of vitamin D status, adult multidrug-resistant tuberculosis disease and tuberculosis infection in Mumbai, India.

INTRODUCTION: Vitamin D status may be an important determinant of multidrug-resistant tuberculosis (MDR-TB) infection, progression to disease and treatment outcomes. Novel and potentially cost-effective therapies such as vitamin D supplementation are needed to stem the tide of TB and MDR-TB globally, particularly in India, a country that accounts for the largest fraction of the world's TB incidence and MDR-TB incidence, and where vitamin D deficiency is endemic. While vitamin D has shown some promise in the treatment of MDR-TB, its role in the context of MDR-TB infection and progression to disease is largely unknown. METHODS AND ANALYSIS: Through a case-control study in Mumbai, India, we aim to examine associations between vitamin D status and active MDR-TB and to investigate vitamin D status and TB infection among controls. Cases are adult outpatient pulmonary patients with MDR-TB recruited from two public TB clinics. Controls are recruited from the cases' household contacts and from non-respiratory departments of the facilities where cases were recruited. Cases and controls are assessed for serum 25-hydroxyvitamin D concentration, nutrient intake, diet quality, anthropometry and other relevant clinical and sociodemographic parameters. Controls undergo additional clinical assessments to rule out active TB and laboratory assessments to determine presence of TB infection. Statistical analysis investigates associations between vitamin D status and active MDR-TB and between vitamin D status and TB infection among controls, accounting for potential confounding effects of diet, anthropometry and other covariates. ETHICS AND DISSEMINATION: This study has been approved by Harvard T.H. Chan School of Public Health Institutional Review Board; Foundation for Medical Research Institutional Research Ethics Committee and Health Ministry's Screening Committee of the Indian Council for Medical Research. Permission was granted by the Municipal Corporation of Greater Mumbai, India, a collaborating partner on this research. Outcomes will be disseminated through publication and scientific presentation. TRIAL REGISTRATION NUMBER: NCT04342598.

Effect of public-private interface agency in Patna and Mumbai, India: Does it alter durations and delays in care seeking for drug-sensitive pulmonary tuberculosis?

Background: Public-private interface agency (PPIA) intervention models in Patna (E. India) and Mumbai (W. India) for pulmonary drug-sensitive (DS) tuberculosis (TB) patients were evaluated over 2 years after maturity to examine effect on reduction of patient pathways and retention.  The models engaged private providers, diagnostic facilities and pharmacies into an effective network providing free diagnostic tests and treatment. Methods: A population-based retrospective study was undertaken to assess effectiveness of the PPIA model in care pathways of 64 (Patna) and 86 (Mumbai) patients through in-depth interviews conducted within 6 months of initiation treatments to identify types and facilities accessed, duration to diagnosis and treatment. Median durations based on facilities accessed were statistically analysed.  Comparisons were made with baseline values and endline pathways of patients accessing PPIA engaged/non-engaged facilities in private and public sectors. Results: Compared to non-engaged facilities, persons accessing engaged facilities at first point-of-care had shorter pathways (Mumbai: 32 vs 43 days), (Patna: 15 vs 40 days).  Duration for first care-seeking was considerably shorter for patients accessing PPIA in Patna and for both engaged and non-engaged private facilities in Mumbai (4 days).  Whilst PPIA engaged facilities diagnosed more cases than others, the RNTCP in Mumbai provided diagnosis early.  There was good retention of patients by PPIA-engaged (1 st) facilities (90% post-diagnosis in Patna) but this was affected by the hub-spoke referral system in Mumbai (13%). Second diagnosis is a common feature in Mumbai.  The spoke-hub model in Mumbai contributed considerably to treatment delay; PPIA-engaged providers were better at retaining patients post treatment initiation 11/25 (44%). Conclusion: PPIA-engaged facilities, accessed at onset, result in marked reduction in pathway durations.  Such initiatives should engage a critical mass of competent providers, proximal investigation facilities with enhanced disease awareness and literacy efforts amongst communities.  Patient movement should be minimized for early treatment and retention.

Such a long journey: What health seeking pathways of patients with drug resistant tuberculosis in Mumbai tell us.

INTRODUCTION: The Indian Tuberculosis (TB) Programme currently faces the dual challenges of tackling increasing numbers of drug resistant (DR) TB cases and regulating practices of a pluralistic private sector catering to TB patients. A study of health seeking behaviour of DR-TB patients in such a situation, offers an opportunity to understand the problems patients face while interacting with health systems. METHODOLOGY: Forty-six DR-TB patients drawn from 15 high TB burden wards in Mumbai were interviewed using an open ended interview tool. Interviews were audio recorded and transcribed. Pathway schematics developed from analysis of patient records, were linked to transcripts. Open coding was used to analyse these units and themes were derived after collating the codes. RESULTS AND DISCUSSION: The paper presents themes interwoven with narratives in the discussions. These include awareness-action gap among patients, role of neighbourhood providers, responsiveness of health systems, the not-such a 'merry go round' that patients go/are made to go on while seeking care, costs of diagnostics and treatment, and how DR-TB is viewed as the 'big TB'. CONCLUSION: The recommendations are based on a preventative ethos which is sustainable, compared to interventions with top-down approaches, which get piloted, but fail to sustain impact when scaled up.

Pathway to care for drug resistant tuberculosis cases identified during a retrospective study conducted in high TB burden wards in Mumbai.

Background: Mumbai is witnessing a rising incidence of all forms of drug resistant tuberculosis (DR-TB). Methods: A population-based, retrospective study was conducted between April and July 2014, in 15 high TB burden wards in Mumbai, to capture the patient pathways to TB care. A total of 23 DR-TB patients were identified and their pathways to access DR-TB care were recorded using semi-structured interviews. Results: The total DR-TB pathway time of new patients (who did not report any past episode of TB) (180 days; IQR 123,346) was found to be more than twice that of retreatment patients (who reported a past episode of TB) (69 days; IQR 42,128). Conclusions: The unacceptable delay for diagnosis and treatment of DR-TB in Mumbai advocates for consistent implementation of early screening of patients using rapid gene-based technologies.

Mycobacterium Interjectum isolated from an immunocompetent host with lung infection.

Improved molecular diagnostic techniques have resulted in increased reporting of nontuberculous mycobacterial infections. A 40-year-old male immunocompetent individual presented with cough and fever of 2-week duration. His chest X-ray showed cavities in the left upper zone and fibrosis in the right upper zone. His sputum was positive for AFB on Ziehl-Neelsen staining and showed slow-growing mycobacteria in mycobacteria growth indicator tube. The isolate was identified as Mycobacterium interjectum using GenoType® Mycobacterium CM assay (Hain Lifescience, GmBH, Nehren, Germany). At the end of a year's treatment, this first case from India has shown good progress.

Pulmonary tuberculosis in Patna, India: Durations, delays, and health care seeking behaviour among patients identified through household surveys.

BACKGROUND: Delays in accessing effective health care plays a pivotal role in increasing Tuberculosis (TB) transmission within the community. Patna, North India, with high levels of poverty and weak public health system, faces huge challenges for achieving effective TB control. The study aims to determine delays that occur from onset of TB symptoms until initiation of pulmonary TB (PTB) treatment among patients in Patna. METHODS: Of the 109 self-reporting TB patients identified through an active household survey, 64 PTB patients were interviewed. First care seeking, TB diagnostic and treatment initiation durations were calculated and delays defined for new and retreatment patients and minors and adults. Outliers exhibiting extreme delays were additionally identified. RESULTS: A cross sMean total pathway duration for TB care was 40days, with diagnostic duration contributing to 58% of the duration. No significant differences were noted between new and retreatment patients. Minors, comprising of 30% of total PTB patients accessed care faster than adults, but showed significantly higher diagnostic duration (38days vs. 17days). Preference for private sector, chemists and allopaths was seen throughout the pathway. DISCUSSION: Patna requires a more effective harnessing of the private sector augmented with reliable diagnostic investigations and a focus on quality.

Tuberculosis in congregate settings: Policies and practices in various facilities in Mumbai, India.

Congregate settings and correctional facilities have high risk of transmission of tuberculosis. They should have capacity to identify and diagnose cases early and initiate prompt treatment to prevent spread to inmates and staff. Appropriate interventions should ensure completion of treatment, documentation and reporting, and prevention of reactivation of successfully treated cases. This requires support from local health authorities. Although international policies and guidelines for infection control in congregate settings are available, there is very little information on how these are practiced in such settings. Our investigation highlights the policies and practices of various congregate facilities in the city of Mumbai.

Correction: Durations and Delays in Care Seeking, Diagnosis and Treatment Initiation in Uncomplicated Pulmonary Tuberculosis Patients in Mumbai, India.

[This corrects the article DOI: 10.1371/journal.pone.0152287.].

Durations and Delays in Care Seeking, Diagnosis and Treatment Initiation in Uncomplicated Pulmonary Tuberculosis Patients in Mumbai, India.

BACKGROUND: Timely diagnosis and treatment initiation are critical to reduce the chain of transmission of Tuberculosis (TB) in places like Mumbai, where almost 60% of the inhabitants reside in overcrowded slums. This study documents the pathway from the onset of symptoms suggestive of TB to initiation of TB treatment and examines factors responsible for delay among uncomplicated pulmonary TB patients in Mumbai. METHODS: A population-based retrospective survey was conducted in the slums of 15 high TB burden administrative wards to identify 153 self-reported TB patients. Subsequently in-depth interviews of 76 consenting patients that fit the inclusion criteria were undertaken using an open-ended interview schedule. Mean total, first care seeking, diagnosis and treatment initiation duration and delays were computed for new and retreatment patients. Patients showing defined delays were divided into outliers and non-outliers for all three delays using the median values. RESULTS: The mean duration for the total pathway was 65 days with 29% of patients being outliers. Importantly the mean duration of first care seeking was similar in new (24 days) and retreatment patients (25 days). Diagnostic duration contributed to 55% of the total pathway largely in new patients. Treatment initiation was noted to be the least among the three durations with mean duration in retreatment patients twice that of new patients. Significantly more female patients experienced diagnostic delay. Major shift of patients from the private to public sector and non-allopaths to allopaths was observed, particularly for treatment initiation. CONCLUSION: Achieving positive behavioural changes in providers (especially non-allopaths) and patients needs to be considered in TB control strategies. Specific attention is required in counselling of TB patients so that timely care seeking is effected at the time of relapse. Prioritizing improvement of environmental health in vulnerable locations and provision of point of care diagnostics would be singularly effective in curbing pathway delays.

Clinical profile and treatment outcomes of drug-resistant tuberculosis before directly observed treatment strategy plus: Lessons for the program.

BACKGROUND: Characteristics and treatment outcomes of patients with drug-resistant tuberculosis (DR TB) before introduction of directly observed treatment strategy (DOTS) plus are infrequently reported. AIMS: To study clinical characteristics and treatment outcomes of drug-resistant TB patients. SETTING: A TB unit in Mumbai. MATERIALS AND METHODS: A retrospective analysis of DR TB patients attending a TB unit and taking treatment at NGOs was performed. Of the 34 cases, 5 (14%) had mycobacterium other than tuberculosis, 24 were pulmonary TB, 4 extra-pulmonary TB, and one both. Three were HIV-infected, two had diabetes. Two cases were treatment naive. Of the 29 cases studied, 3 (11%) were mono-resistant, 20 (69%) were multidrug-resistant (MDR) TB with E/Z/EZ resistance; 4 were pure MDR TB. One case had XDR TB, 13 (44.8%) had resistance to at least one conventional second-line drug. Seven cases had adverse drug reaction, four requiring drug substitution. Two patients are on treatment; 14 of the remaining 27 (51%) were successfully treated, 5 (18%) died, 2 (7%) failed treatment, 5 (18%) were lost to follow-up, one migrated. CONCLUSION: DST profiles suggest high levels of drug resistance due to amplification which leads to poor outcomes. There is an urgent need for Indian Revised National TB Control Program to introduce daily DOTS for susceptible cases, DST for all new cases, and scaling up DST for second-line drugs. There is also a need to use individualized treatment for DR TB.

TB/ HIV coordination through Public Private Partnership: lessons from the field.

BACKGROUND: Co-infection with tuberculosis adversely affects the quality of life of HIV infected individuals and additionally, HIV testing among TB patients gives an opportunity for prevention and treatment of HIV infection. TB-HIV coordination activities are therefore a good public health intervention. METHODS: It was a three-year Public Private Partnership Project, implemented in four districts of Maharashtra, to improve access to public health facilities through community awareness and motivating referrals. Outreach workers were engaged to motivate patients attending Integrated Counselling and Testing Centres (ICTCs) and Designated Microscopy Centres (DMCs) for cross referrals and adherence to services. Community leaders and private health providers were sensitized to issues around TB and HIV/AIDS. OBSERVATIONS: 357 outreach workers referred 17,200 individuals for HIV testing and 32,549 TB suspects were referred for testing. An average of 18% TB cases (13% to 26%) and 7% (4% to 13%) HIV infected cases were identified. Involvement of PLHA and cured TB patients can better motivate symptomatics to avail of diagnostic services. Erratic funding affects smooth implementation of programmes. CONCLUSION: Public Private Partnerships improve access to care. Constant dialogue between all stake holders is essential for successful implementation of such partnerships.

Drug-resistant tuberculosis: Study of clinical practices of chest physicians, Maharashtra, India.

BACKGROUND: Patients suffering from drug-resistant tuberculosis (DR TB) avail of private care since Programmatic Management of DR TB (PMDT) is not universally available in India. Management of DR TB is challenging and involves great expertise. Chest physicians (CPs) play a major role in this area. The study was undertaken with the objective to see whether the practices of CPs comply with current guidelines and to identify areas where they could be involved to improve access to PMDT. MATERIALS AND METHODS: For this cross-sectional study, CPs from Mumbai and Nagpur, Maharashtra, India, were given pretested questionnaires to be filled in and returned. OBSERVATIONS: Of 70 enlisted CPs, 29 (41%) responded. Twenty-six (89%) respondents used the drug susceptibility test (DST) for diagnosis: private labs and hospitals were preferred; 9 (31%) used standard treatment, 15 (51%) switched to individual treatment after starting standard therapy and 12 (41%) started empirical treatment later switched to individual treatment as per the WHO guidelines. Seven consultants (10%) used in addition drugs from alternative systems of medicine for immune modulation and adverse drug effects. Eighty-six per cent CPs monitored treatment by smear examination, 51% by culture and 93% used X-rays. Reported case holding in the form of regular follow-up consultation visits was around 70%, treatment success estimated to be between 30% and 70%, and deaths around 30%. Adverse drug reactions were reported in around 30% cases. CONCLUSION: This study shows that most private CPs generally comply with current guidelines for management of DR TB. Accreditation of private labs for DST, involving CPs in diagnosis, treatment and monitoring of patients through public private partnerships can improve access to PMDT.

Chest X-rays and associated clinical parameters in pulmonary tuberculosis cases from the National Tuberculosis Programme, Mumbai.

The study was carried out in pulmonary tuberculosis (PTB) patients from the local Tuberculosis control programme, Mumbai, India. It examined features of chest X-rays and their correlation with clinical parameters for possible application in suspected multidrug resistant TB (MDRTB) and to predict outcome in new and treatment failure PTB cases. X-ray features (infiltrate, cavitation, miliary shadows, pleural effusion, mediastinal lymphadenopathy and extent of lesions) were analyzed to identify associations with biological/clinical parameters through univariate and multivariate logistic regression. Failures demonstrated associations between extensive lesions and high glycosylated hemoglobin (GHb) levels (P=0.028) and male gender (P=0.03). An association was also detected between cavitation and MDR (P=0.048). In new cases, bilateral cavities were associated with MDR (P=0.018) and male gender (P=0.01), low body mass index with infiltrates (P=0.008), and smoking with cavitation (P=0.0238). Strains belonging to the Manu1 spoligotype were associated with mild lesions (P=0.002). Poor outcome showed borderline significance with extensive lesions at onset (P=0.053). Furthermore, amongst new cases, smoking, the Central Asian Strain (CAS) spoligotype and high GHb were associated with cavitation, whereas only CAS spoligotypes and high GHb were associated with extensive lesions. The study highlighted associations between certain clinical parameters and X-ray evidence which support the potential of X-rays to predict TB, MDRTB and poor outcome. The use of X-rays as an additional tool to shorten diagnostic delay and shortlist MDR suspects amongst nonresponders to TB treatment should be explored in a setting with limited resources coping with a high MDR case load such as Mumbai.