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The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has prompted a massive global vaccination campaign, leading to the rapid development and deployment of several vaccines. Various COVID-19 vaccines are under different phases of clinical trials and include the whole virus or its parts like DNA, mRNA, or protein subunits administered directly or through vectors. Beginning in 2020, a few mRNA (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) and adenovirus-based (AstraZeneca ChAdOx1-S and the Janssen Ad26.COV2.S) vaccines were recommended by WHO for emergency use before the completion of the phase 3 and 4 trials. These vaccines were mostly administered in two or three doses at a defined frequency between the two doses. While these vaccines, mainly based on viral nucleic acids or protein conferred protection against the progression of SARS-CoV-2 infection into severe COVID-19, and prevented death due to the disease, their use has also been accompanied by a plethora of side effects. Common side effects include localized reactions such as pain at the injection site, as well as systemic reactions like fever, fatigue, and headache. These symptoms are generally mild to moderate and resolve within a few days. However, rare but more serious side effects have been reported, including allergic reactions such as anaphylaxis and, in some cases, myocarditis or pericarditis, particularly in younger males. Ongoing surveillance and research efforts continue to refine the understanding of these adverse effects, providing critical insights into the risk-benefit profile of COVID-19 vaccines. Nonetheless, the overall safety profile supports the continued use of these vaccines in combating the pandemic, with regulatory agencies and health organizations emphasizing the importance of vaccination in preventing COVID-19’s severe outcomes. In this review, we describe different types of COVID-19 vaccines and summarize various adverse effects due to autoimmune and inflammatory response(s) manifesting predominantly as cardiac, hematological, neurological, and psychological dysfunctions. The incidence, clinical presentation, risk factors, diagnosis, and management of different adverse effects and possible mechanisms contributing to these effects are discussed. The review highlights the potential ambivalence of human response post-COVID-19 vaccination and necessitates the need to mitigate the adverse side effects.

Introduction: Early initiation of drug susceptibility testing (DST) guided anti-tuberculosis treatment benefits the patient in terms of better treatment outcomes and possibly reduces the transmission of tuberculosis (TB) disease in the community. To determine the status of universal DST (UDST) coverage in smear-positive pulmonary TB patients (PTB) initiated on treatment under the TB program in Greater Chennai Corporation. In addition, the barriers and facilitators for UDST were explored. Material and Methods: The data of PTB patients who were initiated on anti-TB treatment from July to December 2019 was abstracted from the NI-KSHAY database of TB Program. The barriers and facilitators for UDST were explored in 5 focus group discussions (FGDs) among the TB program healthcare workers (HCW). UDST coverage was based on the availability of Cartridge-based Nucleic Acid Amplification test (CBNAAT) results in the NI-KSHAY database. Results: The CBNAAT result was available for 1628 (82.6%) of the 1970 smear-positive PTB patients. Non-availability of CBNAAT results was significantly higher among the older age group (>50 years), in female PTB patients, and the Private Sector. Issues with sputum collection, transport of specimens, and receipt of results were highlighted by the HCWs for the non-availability of UDST results. Conclusion: Universal DST coverage in smear-positive PTB patients initiated on treatment in 2019 in Chennai was optimal as per National Strategic Plan for TB elimination UDST target of 80% for the year 2020 but with scope for improvement. The low UDST coverage in the private sector, among female patients and older age groups, needs to be addressed.

IntroductionTruenat MTB-RIF assay (Truenat), a nucleic acid amplification test (NAAT), is a real-time polymerase chain reaction (RT-PCR) chip-based assay that can detect Mycobacterium tuberculosis (Mtb) and rifampicin (RIF) drug resistance using portable, battery-operated devices. The National TB Elimination Program (NTEP) in India introduced this novel tool at the district and subdistrict level in 2020. This study aimed to assess the level and causes of inconclusive results (invalid results, errors, and indeterminate results) in MTB and RIF testing at NTEP sites and the root causes of these in the programmatic setting.MethodsTruenat testing data from 1,690 functional Truenat sites under the NTEP from April to June 2021 were analyzed to assess the rates of errors, invalid MTB results, and indeterminate RIF results. Following this analysis, 12 Truenat sites were selected based on site performance in Truenat testing, diversity of climatic conditions, and geographical terrain. These sites were visited to assess the root causes of their high and low rates of inconclusive results using a structured checklist.ResultsA total of 327,649 Truenat tests performed for MTB and RIF testing were analyzed. The rate of invalid MTB results was 5.2% [95% confidence interval (CI): 5.11–5.26; n = 16,998] and the rate of errors was 2.5% (95% CI: 2.46–2.57; n = 8,240) in Truenat MTB chip testing. For Mtb-positive samples tested using the Truenat RIF chip for detection of RIF resistance (n = 40,926), the rate of indeterminate results was 15.3% (95% CI: 14.97–15.67; n = 6,267) and the rate of errors was 1.6% (95% CI: 1.53–1.78; n = 675). There was a 40.1% retesting gap for Mtb testing and a 78.2% gap for inconclusive RR results. Among the inconclusive results retested, 27.9% (95% CI: 27.23–28.66; n = 4,222) were Mtb-positive, and 9.2% (95% CI: 7.84–10.76; n = 139) were detected as RR.ConclusionThe main causes affecting Truenat testing performance include suboptimal adherence to standard operating procedures (SOPs), inadequate training, improper storage of testing kits, inadequate sputum quality, lack of quality control, and delays in the rectification of machine issues. Root cause analysis identified that strengthening of training, external quality control, and supervision could improve the rate of inconclusive results. Ensuring hands-on training of technicians for Truenat testing and retesting of samples with inconclusive results are major recommendations while planning for Truenat scale-up. The recommendations from the study were consolidated into technical guidance documents and videos and disseminated to laboratory staff working at the tiered network of TB laboratories under the NTEP in order to improve Truenat MTB-RIF testing performance.

Pathogenic Mycobacterium tuberculosis complex organisms (MTBC) primarily cause pulmonary tuberculosis (PTB); however, MTBC are also capable of causing disease in extrapulmonary (EP) organs, which pose a significant threat to human health worldwide. Extrapulmonary tuberculosis (EPTB) accounts for about 20–30% of all active TB cases and affects mainly children and adults with compromised immune systems. EPTB can occur through hematogenous, lymphatic, or localized bacillary dissemination from a primary source, such as PTB, and affects the brain, eye, mouth, tongue, lymph nodes of neck, spine, bones, muscles, skin, pleura, pericardium, gastrointestinal, peritoneum, and the genitourinary system as primary and/or disseminated disease. EPTB diagnosis involves clinical, radiological, microbiological, histopathological, biochemical/immunological, and molecular methods. However, only culture and molecular techniques are considered confirmatory to differentiate MTBC from any non-tuberculous mycobacteria (NTM) species. While EPTB due to MTBC responds to first-line anti-TB drugs (ATD), drug susceptibility profiling is an essential criterion for addressing drug-resistant EPTB cases (DR-EPTB). Besides antibiotics, adjuvant therapy with corticosteroids has also been used to treat specific EPTB cases. Occasionally, surgical intervention is recommended, mainly when organ damage is debilitating to the patient. Recent epidemiological studies show a striking increase in DR-EPTB cases ranging from 10–15% across various reports. As a neglected disease, significant developments in rapid and accurate diagnosis and better therapeutic interventions are urgently needed to control the emerging EPTB situation globally. In this review, we discuss the recent advances in the clinical diagnosis, treatment, and drug resistance of EPTB.

Background: Patients with first-line drug resistance (DR) to rifampicin (RIF) or isoniazid (INH) as a first-line (FL) line probe assay (LPA) were subjected to genotypic DST using second-line (SL) LPA to identify SL-DR (including pre-XDR) under the National TB Elimination Program (NTEP), India. SL-DR patients were initiated on different DR-TB treatment regimens and monitored for their outcomes. The objective of this retrospective analysis was to understand the mutation profile and treatment outcomes of SL-DR patients. Materials and Methods: A retrospective analysis of mutation profile, treatment regimen, and treatment outcome was performed for SL-DR patients who were tested at ICMR-NIRT, Supra-National Reference Laboratory, Chennai between the years 2018 and 2020. All information, including patient demographics and treatment outcomes, was extracted from the NTEP Ni-kshay database. Results: Between 2018 and 2020, 217 patients out of 2557 samples tested were identified with SL-DR by SL-LPA. Among them, 158/217 were FQ-resistant, 34/217 were SLID-resistant, and 25/217 were resistant to both. D94G (Mut3C) of gyrA and a1401g of rrs were the most predominant mutations in the FQ and SLID resistance types, respectively. Favorable (cured and treatment complete) and unfavorable outcomes (died, lost to follow up, treatment failed, and treatment regimen changed) were recorded in a total of 82/217 and 68/217 patients in the NTEP Ni-kshay database. Conclusions: As per the testing algorithm, SL- LPA is used for genotypic DST following identification of first-line resistance, for early detection of SL-DR in India. The fluoroquinolone resistance pattern seen in this study population corelates with the global trend. Early detection of fluoroquinolone resistance and monitoring of treatment outcome can help achieve better patient management.

Pulmonary disease due to Mycobacterium abscessus (Mab) has become an increasing cause of health concern, particularly among individuals infected with nontuberculous mycobacteria. Since Mab is intrinsically resistant to many antibiotics, it is very challenging to treat patients with symptomatic disease. In this case series, we report four patients with symptomatic pulmonary Mab who had prior history of antituberculosis treatment intake and declared cured at the end of treatment. The current episode was confirmed to be due to Mab infection by molecular and clinical diagnosis and received species specific-antibiotics therapy. All were periodically monitored for the sputum smear and culture conversions throughout the treatment period. The clinical course was variable though all received similar antibiotic regimen and showed varied treatment outcomes. The time of diagnosis and the treatment outcome indicate that a better understanding of host-pathogen interactions is essential for the successful treatment of pulmonary Mab infection.

Abstract Pulmonary diseases due to mycobacteria cause significant morbidity and mortality to human health. In addition to tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), recent epidemiological studies have shown the emergence of non-tuberculous mycobacteria (NTM) species in causing lung diseases in humans. Although more than 170 NTM species are present in various environmental niches, only a handful, primarily Mycobacterium avium complex and M. abscessus, have been implicated in pulmonary disease. While TB is transmitted through inhalation of aerosol droplets containing Mtb, generated by patients with symptomatic disease, NTM disease is mostly disseminated through aerosols originated from the environment. However, following inhalation, both Mtb and NTM are phagocytosed by alveolar macrophages in the lungs. Subsequently, various immune cells are recruited from the circulation to the site of infection, which leads to granuloma formation. Although the pathophysiology of TB and NTM diseases share several fundamental cellular and molecular events, the host-susceptibility to Mtb and NTM infections are different. Striking differences also exist in the disease presentation between TB and NTM cases. While NTM disease is primarily associated with bronchiectasis, this condition is rarely a predisposing factor for TB. Similarly, in Human Immunodeficiency Virus (HIV)-infected individuals, NTM disease presents as disseminated, extrapulmonary form rather than as a miliary, pulmonary disease, which is seen in Mtb infection. The diagnostic modalities for TB, including molecular diagnosis and drug-susceptibility testing (DST), are more advanced and possess a higher rate of sensitivity and specificity, compared to the tools available for NTM infections. In general, drug-sensitive TB is effectively treated with a standard multi-drug regimen containing well-defined first- and second-line antibiotics. However, the treatment of drug-resistant TB requires the additional, newer class of antibiotics in combination with or without the first and second-line drugs. In contrast, the NTM species display significant heterogeneity in their susceptibility to standard anti-TB drugs. Thus, the treatment for NTM diseases usually involves the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical and not entirely successful. In general, the treatment duration is much longer for NTM diseases, compared to TB, and resection surgery of affected organ(s) is part of treatment for patients with NTM diseases that do not respond to the antibiotics treatment. Here, we discuss the epidemiology, diagnosis, and treatment modalities available for TB and NTM diseases of humans.

Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

COVID-19, caused by a novel coronavirus, SARS-CoV-2, contributes significantly to the morbidity and mortality in humans worldwide. In the absence of specific vaccines or therapeutics available, COVID-19 cases are managed empirically with the passive immunity approach and repurposing of drugs used for other conditions. Recently, a concept that bacilli Calmette–Guerin (BCG) vaccination could confer protection against COVID-19 has emerged. The foundation for this widespread attention came from several recent articles, including the one by Miller et al. submitted to MedRxiv, a pre-print server. The authors of this article suggest that a correlation exists between countries with a prolonged national BCG vaccination program and the morbidity/mortality due to COVID-19. Further, clinical BCG vaccination trials are currently ongoing in the Netherlands, Australia, the UK, and Germany with the hope of reducing mortality due to COVID-19. Although BCG vaccination helps protect children against tuberculosis, experimental studies have shown that BCG can also elicit a non-specific immune response against viral and non-mycobacterial infections. Here, we summarize the pros and cons of BCG vaccination and critically analyze the evidence provided for the protective effect of BCG against COVID-19 and highlight the confounding factors in these studies.

Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of HOS2 (HighOsmolarity Sensitive), a gene coding for fungal histone deacetylase from C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This in vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.

Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of HOS2 (High Osmolarity Sensitive) , a gene coding for fungal histone deacetylase from C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This in vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.

Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of HOS2 (High Osmolarity Sensitive) , a gene coding for fungal histone deacetylase from C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This in vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.

Candida albicans is a mucosal commensal organism in normal individuals, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of HOS2 (High Osmolarity Sensitive) , a gene coding for fungal histone deacetylase from C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such MS-275. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. This in vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.