Immune profiling reveals umbilical cord blood mononuclear cells from South India display an IL-8 dominant, CXCL-10 deficient polyfunctional monocyte response to pathogen-associated molecular patterns (PAMPs) that is distinct from adult blood cells.

Neonate responses to pathogen-associated molecular patterns (PAMPS) differ from adults; such understanding is poor in Indian neonates, despite recognised significant infectious risk. Immune profiling analysis was undertaken of ten secreted mediators contextualised with cellular source induced by six PAMPs in umbilical cord (CB; n=21) and adult-blood (PBMC, n=14) from a tertiary care hospital in South India. Differential cytokine expression analysis (minimum log2-fold difference; adj p-value<0.05) identified bacterial PAMPs induced higher concentrations of IL-1ß, IL-10, TNF-α in adults versus IL-8, GM-CSF, IFN-γ and IL-2 in CB. CB responded to poly I:C and SARS-CoV-2 lysate with a dominant IL-8 response, whereas, in PBMC, CXCL-10 dominated poly I:C, but not SARS-CoV-2, responses, highlighting potential IL-8 importance, in absence of Type I Interferons, in antiviral CB immunity. Candida albicans was the only PAMP to uniformly induce higher secretion of effectors in CB. The predominant source of IL-8/IL-6/TNF-α/IL-1ß in both CB and PBMC was polyfunctional monocytes and IFN-γ /IL-2/IL-17 from innate lymphocytes. Correlation matrix analyses revealed IL-8 to be the most differentially regulated, correlating positively in CB versus negatively in PBMC with IL-6, GM-CSF, IFN-γ, IL-2, consistent with more negatively regulated cytokine modules in adults, potentially linked to higher anti-inflammatory IL-10. Cord and adult blood from India respond robustly to PAMPs with unique effector combinations. These data provide a strong foundation to monitor, explore, mechanisms that regulate such immunity during the life course, an area of significant global health importance given infection-related infant mortality incidence.

Immunogenicity of SARS-CoV-2 vaccines BBV152 (COVAXIN®) and ChAdOx1 nCoV-19 (COVISHIELD™) in seronegative and seropositive individuals in India: a multicentre, nonrandomised observational study.

Background: There are limited global data on head-to-head comparisons of vaccine platforms assessing both humoral and cellular immune responses, stratified by pre-vaccination serostatus. The COVID-19 vaccination drive for the Indian population in the age group 18-45 years began in April 2021 when seropositivity rates in the general population were rising due to the delta wave of COVID-19 pandemic during April-May 2021. Methods: Between June 30, 2021, and Jan 28, 2022, we enrolled 691 participants in the age group 18-45 years across four clinical sites in India. In this non-randomised and laboratory blinded study, participants received either two doses of Covaxin® (4 weeks apart) or two doses of Covishield™ (12 weeks apart) as per the national vaccination policy. The primary outcome was the seroconversion rate and the geometric mean titre (GMT) of antibodies against the SARS-CoV-2 spike and nucleocapsid proteins post two doses. The secondary outcome was the frequency of cellular immune responses pre- and post-vaccination. Findings: When compared to pre-vaccination baseline, both vaccines elicited statistically significant seroconversion and binding antibody levels in both seronegative and seropositive individuals. In the per-protocol cohort, Covishield™ elicited higher antibody responses than Covaxin® as measured by seroconversion rate (98.3% vs 74.4%, p < 0.0001 in seronegative individuals; 91.7% vs 66.9%, p < 0.0001 in seropositive individuals) as well as by anti-spike antibody levels against the ancestral strain (GMT 1272.1 vs 75.4 binding antibody units/ml [BAU/ml], p < 0.0001 in seronegative individuals; 2089.07 vs 585.7 BAU/ml, p < 0.0001 in seropositive individuals). As participants at all clinical sites were not recruited at the same time, site-specific immunogenicity was impacted by the timing of vaccination relative to the delta and omicron waves. Surrogate neutralising antibody responses against variants-of-concern including delta and omicron was higher in Covishield™ recipients than in Covaxin® recipients; and in seropositive than in seronegative individuals after both vaccination and asymptomatic infection (omicron variant). T cell responses are reported from only one of the four site cohorts where the vaccination schedule preceded the omicron wave. In seronegative individuals, Covishield™ elicited both CD4+ and CD8+ spike-specific cytokine-producing T cells whereas Covaxin® elicited mainly CD4+ spike-specific T cells. Neither vaccine showed significant post-vaccination expansion of spike-specific T cells in seropositive individuals. Interpretation: Covishield™ elicited immune responses of higher magnitude and breadth than Covaxin® in both seronegative individuals and seropositive individuals, across cohorts representing the pre-vaccination immune history of most of the vaccinated Indian population. Funding: Corporate social responsibility (CSR) funding from Hindustan Unilever Limited (HUL) and Unilever India Pvt. Ltd. (UIPL).

BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways.

This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6 in HLA-DR+CD16-CD14hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4+ T cell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR+CD16-CD14hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1ß, and IL-6 to "heterologous" fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes: CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.

Polyfunctional CD4 T-cells correlating with neutralising antibody is a hallmark of COVISHIELDTM and COVAXIN® induced immunity in COVID-19 exposed Indians.

Detailed characterisation of immune responses induced by COVID-19 vaccines rolled out in India: COVISHIELDTM (CS) and COVAXIN® (CO) in a pre-exposed population is only recently being discovered. We addressed this issue in subjects who received their primary series of vaccination between November 2021 and January 2022. Both vaccines are capable of strongly boosting Wuhan Spike-specific neutralising antibody, polyfunctional Th1 cytokine producing CD4+ T-cells and single IFN-γ + CD8+ T-cells. Consistent with inherent differences in vaccine platform, the vector-based CS vaccine-induced immunity was of greater magnitude, breadth, targeting Delta and Omicron variants compared to the whole-virion inactivated vaccine CO, with CS vaccinees showing persistent CD8+ T-cells responses until 3 months post primary vaccination. This study provides detailed evidence on the magnitude and quality of CS and CO vaccine induced responses in subjects with pre-existing SARS-CoV-2 immunity in India, thereby mitigating vaccine hesitancy arguments in such a population, which remains a global health challenge.

Feasibility and acceptability pilot of video-based direct observed treatment (vDOT) for supporting antitubercular treatment in South India: a cohort study.

OBJECTIVES: The objective of this study was to assess the feasibility and acceptability of video-based anti-tuberculosis (TB) treatment adherence support in patients with TB (PwTB) in South India. DESIGN: An exploratory cohort. SETTING: Participants were recruited at the TB treatment centre (direct observed treatment short centre) of a tertiary-level teaching facility in Bangalore, Karnataka, South India. PARTICIPANTS: The study enrolled 25 PwTB, with replacement. Adult PwTB who were on drug-sensitive treatment regimens were included, while those who had drug resistant TB were excluded from the study. INTERVENTION: Participants received scheduled adherence reminders and were trained to videorecord themselves swallowing their medication via a mobile application. The application was automated to submit these videos for evaluation. Participants were followed up monthly till treatment completion or withdrawal. OUTCOME MEASURES: Adherence rate and acceptability of video-based directly observed treatment (vDOT). RESULTS: The mean±SD age of the participants was 33±14 years, majority were females (16, 64%), residing in urban areas (24,96%), married (17, 68%) and had access to smart phones (23,92%). A total of 3193 person days of follow-up was completed; of the videos submitted within the first 6 months of enrollment (2501), 94% (2354/2501) were considered 'acceptable' and 16 (64%) participants were optimally adherent (ie, ≥80%). Participant videos improved in quality and a higher proportion met acceptability criteria over time. Twenty-one (84%) participants stated that they found the application easy to learn; 13 (52%) preferred vDOT over DOT. Mixed model logistic regression showed that those who are married are more likely have daily adherence to anti-TB treatment. CONCLUSION: Video-based mobile phone interventions are acceptable to PwTB and the ease of using the application increases with time. To provide patient-centred care, vDOT is a promising option that can be offered to patients for treatment support and adherence monitoring.

Differences in Immune Responses in Individuals of Indian and European Origin: Relevance for the COVID-19 Pandemic.

During the coronavirus disease 2019 (COVID-19) pandemic, large differences in susceptibility and mortality due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported between populations in Europe and South Asia. While both host and environmental factors (including Mycobacterium bovis BCG vaccination) have been proposed to explain this, the potential biological substrate of these differences is unknown. We purified peripheral blood mononuclear cells from individuals living in India and the Netherlands at baseline and 10 to 12 weeks after BCG vaccination. We compared chromatin accessibility between the two populations at baseline, as well as gene transcription profiles and cytokine production capacities upon stimulation. The chromatin accessibility of genes important for adaptive immunity was higher in the Indians than in the Europeans, while the latter had more accessible chromatin regions in genes of the innate immune system. At the transcriptional level, we observed that the Indian volunteers displayed a more tolerant immune response to stimulation, in contrast to a more exaggerated response in the Europeans. BCG vaccination strengthened the tolerance program in the Indians but not in the Europeans. These differences may partly explain the different impact of COVID-19 on the two populations. IMPORTANCE In this study, we assessed the differences in immune responses in individuals from India and Europe. This aspect is of great relevance, because of the described differences in morbidity and mortality between India and Europe during the pandemic. We found a significant difference in chromatin accessibility in immune cells from the two populations, followed by a more balanced and effective response in individuals from India. These exciting findings represent a very important piece of the puzzle for understanding the COVID-19 pandemic at a global level.

Identifying phenotypes of obstructive sleep apnea using cluster analysis.

PURPOSE: Over the last decade, advances in understanding the pathophysiology, clinical presentation, systemic consequences and treatment responses in obstructive sleep apnea (OSA) have made individualised OSA management plausible. As the first step in this direction, this study was undertaken to identify OSA phenotypes. METHODS: Patients diagnosed with OSA on level 1 polysomnography (PSG) were included. Clinical and co-morbidity profile, anthropometry and sleepiness scores were compiled. On PSG, apnea-hypopnea index, positional indices, sleep stages and desaturation indices (T90) were tabulated. Cluster analysis was performed to identify distinct phenotypes among included patients with OSA. RESULTS: One hundred patients (66 males) with a mean age of 49.5 ± 13.3 years were included. Snoring was reported by 94% subjects, and 50% were excessively sleepy. Two-thirds of subjects had co-morbidities, the most frequent being hypertension (55%) and dyslipidemia (53%). Severe OSA was diagnosed on PSG in 42%, while 29% each had mild and moderate OSA, respectively. On cluster analysis, 3 distinct clusters emerged. Cluster 1 consisted of older, obese subjects with no gender predilection, higher neck circumference, severe OSA with more co-morbidities and higher T90. Cluster 2 comprised of younger, less obese males with snoring, witnessed apnea, moderate and supine predominant OSA. Cluster 3 consisted of middle-aged, obese males with lesser co-morbidities, mild OSA and lower T90. CONCLUSIONS: This study revealed three OSA clusters with distinct demographic, anthropometric and PSG features. Further research with bigger sample size and additional parameters may pave the way for characterising distinct phenotypes and individualising OSA management.

Clinical outcomes of bronchiectasis in India: data from the EMBARC/Respiratory Research Network of India registry.

BACKGROUND: Identifying risk factors for poor outcomes can help with risk stratification and targeting of treatment. Risk factors for mortality and exacerbations have been identified in bronchiectasis but have been almost exclusively studied in European and North American populations. This study investigated the risk factors for poor outcome in a large population of bronchiectasis patients enrolled in India. METHODS: The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India (EMBARC-India) registry is a prospective observational study of adults with computed tomography-confirmed bronchiectasis enrolled at 31 sites across India. Baseline characteristics of patients were used to investigate associations with key clinical outcomes: mortality, severe exacerbations requiring hospital admission, overall exacerbation frequency and decline in forced expiratory volume in 1 s. RESULTS: 1018 patients with at least 12-month follow-up data were enrolled in the follow-up study. Frequent exacerbations (≥3 per year) at baseline were associated with an increased risk of mortality (hazard ratio (HR) 3.23, 95% CI 1.39-7.50), severe exacerbations (HR 2.71, 95% CI 1.92-3.83), future exacerbations (incidence rate ratio (IRR) 3.08, 95% CI 2.36-4.01) and lung function decline. Coexisting COPD, dyspnoea and current cigarette smoking were similarly associated with a worse outcome across all end-points studied. Additional predictors of mortality and severe exacerbations were increasing age and cardiovascular comorbidity. Infection with Gram-negative pathogens (predominantly Klebsiella pneumoniae) was independently associated with increased mortality (HR 3.13, 95% CI 1.62-6.06), while Pseudomonas aeruginosa infection was associated with severe exacerbations (HR 1.41, 95% CI 1.01-1.97) and overall exacerbation rate (IRR 1.47, 95% CI 1.13-1.91). CONCLUSIONS: This study identifies risk factors for morbidity and mortality among bronchiectasis patients in India. Identification of these risk factors may support treatment approaches optimised to an Asian setting.

Molecular markers for early stratification of disease severity and progression in COVID-19.

COVID-19 infections have imposed immense pressure on the healthcare system of most countries. While the initial studies have identified better therapeutic and diagnostic approaches, the disease severity is still assessed by close monitoring of symptoms by healthcare professionals due to the lack of biomarkers for disease stratification. In this study, we have probed the immune and molecular profiles of COVID-19 patients at 48-h intervals after hospitalization to identify early markers, if any, of disease progression and severity. Our study reveals that the molecular profiles of patients likely to enter the host-immune response-mediated moderate or severe disease progression are distinct even in the early phase of infection when severe symptoms are not yet apparent. Our data from 37 patients suggest that at hospitalization, interleukins (IL6) (>300 pg/ml) and IL8 levels (>200 pg/ml) identify cytokine-dependent disease progression. Monitoring their levels will facilitate timely intervention using available immunomodulators or precision medicines in those likely to progress due to cytokine storm and help improve outcomes. Additionally, it will also help identify cytokine-independent progressive patients, not likely to benefit from immunomodulators or precision drugs.

Indian Guidelines on Nebulization Therapy.

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

Evidence for the heterologous benefits of prior BCG vaccination on COVISHIELD™ vaccine-induced immune responses in SARS-CoV-2 seronegative young Indian adults.

This proof-of-concept study tested if prior BCG revaccination can qualitatively and quantitively enhance antibody and T-cell responses induced by Oxford/AstraZeneca ChAdOx1nCoV-19 or COVISHIELD™, an efficacious and the most widely distributed vaccine in India. We compared COVISHIELD™ induced longitudinal immune responses in 21 BCG re-vaccinees (BCG-RV) and 13 BCG-non-revaccinees (BCG-NRV), all of whom were BCG vaccinated at birth; latent tuberculosis negative and SARS-CoV-2 seronegative prior to COVISHIELD™ vaccination. Compared to BCG-NRV, BCG-RV displayed significantly higher and persistent spike-specific neutralizing (n) Ab titers and polyfunctional CD4+ and CD8+ T-cells for eight months post COVISHIELD™ booster, including distinct CD4+IFN-γ+ and CD4+IFN-γ- effector memory (EM) subsets co-expressing IL-2, TNF-α and activation induced markers (AIM) CD154/CD137 as well as CD8+IFN-γ+ EM,TEMRA (T cell EM expressing RA) subset combinations co-expressing TNF-α and AIM CD137/CD69. Additionally, elevated nAb and T-cell responses to the Delta mutant in BCG-RV highlighted greater immune response breadth. Mechanistically, these BCG adjuvant effects were associated with elevated markers of trained immunity, including higher IL-1ß and TNF-α expression in CD14+HLA-DR+monocytes and changes in chromatin accessibility highlighting BCG-induced epigenetic changes. This study provides first in-depth analysis of both antibody and memory T-cell responses induced by COVISHIELD™ in SARS-CoV-2 seronegative young adults in India with strong evidence of a BCG-induced booster effect and therefore a rational basis to validate BCG, a low-cost and globally available vaccine, as an adjuvant to enhance heterologous adaptive immune responses to current and emerging COVID-19 vaccines.

Mortality Associated with Ambient PM2.5 Exposure in India: Results from the Million Death Study.

BACKGROUND: Studies on the extent to which long-term exposure to ambient particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5) contributes to adult mortality in India are few, despite over 99% of Indians being exposed to levels that the World Health Organization (WHO) considers unsafe. OBJECTIVE: We conducted a retrospective cohort study within the Million Death Study (MDS) to provide the first-ever quantification of national mortality from exposure to PM2.5 in India from 1999 to 2014. METHODS: We calculated relative risks (RRs) by linking a total of ten 3-y intervals of satellite-based estimated PM2.5 exposure to deaths 3 to 5 y later in over 7,400 small villages or urban blocks covering a total population of 6.8 million. We applied using a model-based geostatistical model, adjusted for individual age, sex, and year of death; smoking prevalence, rural/urban residency, area-level female illiteracy, languages, and spatial clustering and unit-level variation. RESULTS: PM2.5 exposure levels increased from 1999 to 2014, particularly in central and eastern India. Among 212,573 deaths at ages 15-69 y, after spatial adjustment, we found a significant RR of 1.09 [95% credible interval (CI): 1.04, 1.14] for stroke deaths per 10-µg/m3 increase in PM2.5 exposure, but no significant excess for deaths from chronic respiratory disease and ischemic heart disease (IHD), all nonaccidental causes, and total mortality (after excluding stroke). Spatial adjustment attenuated the RRs for chronic respiratory disease and IHD but raised those for stroke. The RRs were consistent in various sensitivity analyses with spatial adjustment, including stratifying by levels of solid fuel exposure, by sex, and by age group, addition of climatic variables, and in supplementary case-control analyses using injury deaths as controls. DISCUSSION: Direct epidemiological measurements, despite inherent limitations, yielded associations between mortality and long-term PM2.5 inconsistent with those reported in earlier models used by the WHO to derive estimates of PM2.5 mortality in India. The modest RRs in our study are consistent with near or null mortality effects. They suggest suitable caution in estimating deaths from PM2.5 exposure based on MDS results and even more caution in extrapolating model-based associations of risk derived mostly from high-income countries to India. https://doi.org/10.1289/EHP9538.

SARS-CoV-2 infection of human-induced pluripotent stem cells-derived lung lineage cells evokes inflammatory and chemosensory responses by targeting mitochondrial pathways.

The COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the lung, particularly the proximal airway and distal alveolar cells. NKX2.1+ primordial lung progenitors of the foregut (anterior) endoderm are the developmental precursors to all adult lung epithelial lineages and are postulated to play an important role in viral tropism. Here, we show that SARS-CoV-2 readily infected and replicated in human-induced pluripotent stem cell-derived proximal airway cells, distal alveolar cells, and lung progenitors. In addition to the upregulation of antiviral defense and immune responses, transcriptomics data uncovered a robust epithelial cell-specific response, including perturbation of metabolic processes and disruption in the alveolar maturation program. We also identified spatiotemporal dysregulation of mitochondrial heme oxygenase 1 (HMOX1), which is associated with defense against antioxidant-induced lung injury. Cytokines, such as TNF-α, INF-γ, IL-6, and IL-13, were upregulated in infected cells sparking mitochondrial ROS production and change in electron transport chain complexes. Increased mitochondrial ROS then activated additional proinflammatory cytokines leading to an aberrant cell cycle resulting in apoptosis. Notably, we are the first to report a chemosensory response resulting from SARS-CoV-2 infection similar to that seen in COVID-19 patients. Some of our key findings were validated using COVID-19-affected postmortem lung tissue sections. These results suggest that our in vitro system could serve as a suitable model to investigate the pathogenetic mechanisms of SARS-CoV-2 infection and to discover and test therapeutic drugs against COVID-19 or its consequences.

BCG revaccination qualitatively and quantitatively enhances SARS-CoV-2 spike-specific neutralizing antibody and T cell responses induced by the COVISHIELD™ vaccine in SARS-CoV-2 seronegative young Indian adults.

This study tested if prior BCG revaccination can further boost immune responses subsequently induced by a widely distributed and otherwise efficacious Oxford/AstraZeneca ChAdOx1nCoV-19 vaccine, referred to as COVISHIELD™, in India. We compared COVISHIELD™ induced longitudinal immune responses in 21 BCG re-vaccinees (BCG-RV) and 13 BCG-non-revaccinees (BCG-NRV), all of whom were BCG vaccinated at birth and latent tuberculosis negative, after COVISHIELD™ prime and boost with baseline samples that were collected pre-pandemic and pre-BCG revaccination. Compared to BCG-NRV, BCG-RV displayed significantly higher magnitude of spike-specific Ab and T cell responses, including a greater proportion of high responders; better quality polyfunctional CD4 and CD8 T cells that persisted and a more robust Ab and T cell response to the Delta mutant of SARS-CoV-2 highlighting greater breadth. Mechanistically, BCG adjuvant effects on COVISHIELD™ induced adaptive responses was associated with more robust innate responses to pathogen-associated-molecular-patterns through TNF-α and IL-1ß secretion. This study provides first in-depth analysis of immune responses induced by COVISHIELD™ in India and highlights the potential of using a cheap and globally available vaccine, BCG, as an adjuvant to enhance heterologous adaptive immune responses induced by COVIDSHIELD™ and other emerging vaccines.

Pulmonary Rehabilitation in the Management of Chronic Obstructive Pulmonary Disease among Asian Indians- Current Status and Moving Forward.

Chronic Obstructive Pulmonary Disease (COPD) is a significant public health concern in India with high prevalence and associated disability, morbidity, mortality. The progression of COPD is not confined to the lungs but includes extrapulmonary involvement that reduces the functional capacity and quality of life. Pulmonary Rehabilitation (PR) is an evidence-based intervention, targeting multiple domains of pulmonary and extrapulmonary manifestations, and therefore, is recommended as an integral part of COPD management. The practical implementation of PR in India is poor. In this review, we have summarized the latest pieces of evidence in support of PR and highlight the challenges and potential solutions for PR implementation in India.

A century of BCG: Impact on tuberculosis control and beyond.

BCG turns 100 this year and while it might not be the perfect vaccine, it has certainly contributed significantly towards eradication and prevention of spread of tuberculosis (TB). The search for newer and better vaccines for TB is an ongoing endeavor and latest results from trials of candidate TB vaccines such as M72AS01 look promising. However, recent encouraging data from BCG revaccination trials in adults combined with studies on mucosal and intravenous routes of BCG vaccination in non-human primate models have renewed interest in BCG for TB prevention. In addition, several well-demonstrated non-specific effects of BCG, for example, prevention of viral and respiratory infections, give BCG an added advantage. Also, BCG vaccination is currently being widely tested in human clinical trials to determine whether it protects against SARS-CoV-2 infection and/or death with detailed analyses and outcomes from several ongoing trials across the world awaited. Through this review, we attempt to bring together information on various aspects of the BCG-induced immune response, its efficacy in TB control, comparison with other candidate TB vaccines and strategies to improve its efficiency including revaccination and alternate routes of administration. Finally, we discuss the future relevance of BCG use especially in light of its several heterologous benefits.

Effect of Indoor Air Pollution on Chronic Obstructive Pulmonary Disease (COPD) Deaths in Southern Asia-A Systematic Review and Meta-Analysis.

BACKGROUND: About half of the population in developing countries are exposed to indoor pollution such as combustion fuels at present. Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality globally and the primary cause of COPD in women is indoor air pollution exposure, while tobacco smoking is the leading cause in men. The aim of this systematic review and meta-analysis is to evaluate the correlation between the indoor air pollution and deaths related to COPD and COPD prevalence in South Asia. METHODS: A systematic search on studies with sufficient statistical power has been conducted from 1985 until 30 June 2020, in English electronic databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in MEDLINE and PubMed databases with the terms Chronic Obstructive Pulmonary disease COPD or Chronic Bronchitis or Emphysema or COPD Deaths or Chronic Obstructive Lung Disease or Airflow Obstruction or Chronic Airflow Obstruction or Airflow Obstruction, Chronic or Bronchitis, Chronic and Mortality or Death or Deceased was conducted. Studies were eligible if they were Prospective controlled or non-controlled trials conducted in Southern Asia/ Asia and Retrospective studies conducted in Southern Asia/ Asia. RESULTS: The results have concluded that long term exposure to indoor pollution had a significant effect on COPD deaths as well as its symptoms. Odd's ratio was in a range of 1.05 (Randomized controlled trials) to 7.87 (Cross sectional studies) for all the studies mentioned. Meta-analysis observed a significantly higher Odds Ratio of 2.13 for COPD mortality and 2.08 for COPD prevalence on exposure to indoor air pollution. CONCLUSION: Exposure to solid fuel smoke is consistently and significantly correlated with COPD mortality and COPD prevalence in South Asian countries, in spite of heterogeneity observed in the studies included. For performing domestic tasks, initiatives are to be taken to reduce dependency on solid fuel by using cleaner alternatives or comparatively cleaner technology.

A simple x-ray scoring system for the diagnosis of chronic pulmonary aspergillosis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is a severe form of post-tuberculosis lung disease (PTBLD). Considering the high burden of TB in India, it can be concluded that the prevalence of CPA is also high. Chest x-ray though most feasible, interpretation is subjective. Therefore, decision on evaluation for CPA cannot be based on x-ray alone. OBJECTIVE: Present study evaluated an x-ray score as a marker for extent of lung damage in patients with PTBLD presenting with haemoptysis and its utility to predict Aspergillus serum IgG levels. METHODS: We used a modified scoring system developed by Anna Ralph et al X-ray score cut-offs of >71 and 40, with or without history of massive haemoptysis, were compared with serum IgG levels. RESULTS: With a chest x-ray score cut-off of 71, specificity was 88%. With an x-ray score of >71 combined with history of massive haemoptysis, 86% cases were found to be IgG positive. The specificity of this combination was 96%. CONCLUSION: This study concluded that a simple chest x-ray scoring system in addition to the symptom of massive haemoptysis helped in the decision on further evaluation of the subject for CPA, especially in resource constrained settings.

The effect of CPAP therapy on excessive daytime sleepiness and quality of life in subjects with obstructive sleep apnoea: an AB design study.

BACKGROUND: Obstructive sleep apnoea (OSA) is a disorder characterized by apnoeas and hypopnoeas due to repetitive upper airway collapse during sleep. So far, there are no published data regarding quality of life (QoL) and adherence to CPAP among patients with OSA in India. This study aims to measure sleepiness and QoL of patients before and after effective CPAP use in patients with OSA. METHOD: Newly diagnosed subjects with OSA were included, and socio-demographic risk factors and anthropomorphic measures were collected. Epworth sleepiness scale (ESS) and short sleep apnoea quality of life index (SAQLI) were administered before and after a minimum of 4 weeks of domiciliary CPAP use. While short SAQLI is a disease-specific questionnaire, ESS measures excessive daytime sleepiness. RESULTS: In 92 subjects age range was 28-74 years, mean age 49.7 ± 11.3 years, and male:female ratio was 70:22. Mean BMI was 32.1 ± 6.4 kg/sq.m; mean neck circumference was 39.4 ± 3.4 cm; 56 subjects had Mallampati score of 3 or 4. One-month follow-up was completed by 34 subjects who reported a mean of 5.8 ± 1.1 hours/night usage of CPAP. Mean ESS score was 11.31 ± 5.6 at baseline vs 6.9 ± 3.3 after 1 month (p = 0.02), and baseline short SAQLI score was at 2.54 ± 1.26 vs 1.38 ± 0.87 after 1 month (p = 0.0001). CONCLUSIONS: Subjects reported adequate compliance with CPAP at 1 month, and both ESS and short SAQLI showed a significant improvement in these patients. CPAP compliance improved both QoL and sleepiness in patients with OSA.

HIV Skews a Balanced Mtb-Specific Th17 Response in Latent Tuberculosis Subjects to a Pro-inflammatory Profile Independent of Viral Load.

HIV infection predisposes latent tuberculosis-infected (LTBI) subjects to active TB. This study is designed to determine whether HIV infection of LTBI subjects compromises the balanced Mycobacterium tuberculosis (Mtb)-specific T helper 17 (Th17) response of recognized importance in anti-TB immunity. Comparative analysis of Mtb- and cytomegalovirus (CMV)-specific CD4+ T cell responses demonstrates a marked dampening of the Mtb-specific CD4+ T cell effectors and polyfunctional cells while preserving CMV-specific response. Additionally, HIV skews the Mtb-specific Th17 response in chronic HIV-infected LTBI progressors, but not long-term non-progressors (LTNPs), with preservation of pro-inflammatory interferon (IFN)-γ+/interleukin-17+ (IL-17+) and significant loss of anti-inflammatory IL-10+/IL-17+ effectors that is restored by anti-retroviral therapy (ART). HIV-driven impairment of Mtb-specific response cannot be attributed to preferential infection as cell-associated HIV DNA and HIV RNA reveal equivalent viral burden in CD4+ T cells from different antigen specificities. We therefore propose that beyond HIV-induced loss of Mtb-specific CD4+ T cells, the associated dysregulation of Mtb-specific T cell homeostasis can potentially enhance the onset of TB in LTBI subjects.