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Background: Multidrug-Resistant Tuberculosis (MDR-TB) in children is a significant public health concern, mirroring the burden seen in adults. This study aims to evaluate the clinical and demographic characteristics of pediatric MDR-TB cases at a tertiary care center in South India, highlighting the need for improved diagnostic and treatment strategies. Methods: A combined prospective and retrospective cross-sectional study was conducted on 40 pediatric MDR-TB cases from September 2022 to August 2024. Data were collected from case sheets and the district tuberculosis center in Kurnool. Statistical analysis was performed using SPSS version 20.0 to identify key clinical and demographic characteristics. Results: The study included 40 children with MDR-TB, with a mean age of 16.63±2.13 years and a median age of 17 years. There was a noticeable female preponderance, with a female- to-male ratio of 13:7. Most patients belonged to the upper-lower socioeconomic class. The predominant symptoms were fever (100%) and cough (100%). Additionally, 87.5% of the children knew their BCG vaccination status, and 22.5% had a history of contact with TB patients. A significant proportion of the children, 77.5%, were malnourished, and 55% had abnormal chest X-rays. Furthermore, 82.5% tested positive in the Mantoux test, and 12.5% were positive for Acid-Fast Bacilli (AFB). Conclusion: The prevalence of MDR-TB among the pediatric population in the study was 10.92%. The findings underscore the critical need for enhanced diagnostic and treatment strategies for pediatric MDR-TB in India. The high rates of malnutrition and abnormal chest X-rays among affected children highlight the importance of comprehensive care approaches that address both the disease and associated comorbidities. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) arising within scar tissue is a rare but clinically significant phenomenon. This comprehensive review aims to provide a succinct overview of the current state of knowledge regarding the etiological factors, pathogenesis, clinical presentation, and management of BCC. This study constitutes a literature review pertaining to BCC, with a particular emphasis on BCC developing within scar tissue. It also provides a clinical case presentation of a patient who had developed BCC in a BCG post-vaccination scar and a review of analogous findings available in the existing literature. Despite the fact that an array of mechanisms play a role in injury-related BCC growth, the main mechanism remains ambiguous and yet to be elucidated. The review also includes a detailed description of the various therapeutic options available for BCC, ranging from surgical interventions to novel pharmacological treatments. By examining these intersections, the review seeks to elucidate the potential mechanisms, identify risk factors, and suggest considerations for clinical practice. The findings underscore the importance of vigilant dermatological assessment in patients with scar tissue and those recently vaccinated, aiming to improve early detection and optimize management strategies for BCC. [ABSTRACT FROM AUTHOR]

BCG vaccination affects other diseases beyond tuberculosis by unknown—potentially immunomodulatory—mechanisms. Recent studies have shown that BCG vaccination administered during overt type 1 diabetes (T1D) improved glycemic control and affected immune and metabolic parameters. Here, we comprehensively characterized Ghanaian T1D patients with or without routine neonatal BCG vaccination to identify vaccine-associated alterations. Ghanaian long-term T1D patients (n = 108) and matched healthy controls (n = 214) were evaluated for disease-related clinical, metabolic, and immunophenotypic parameters and compared based on their neonatal BCG vaccination status. The majority of study participants were BCG-vaccinated at birth and no differences in vaccination rates were detected between the study groups. Notably, glycemic control metrics, i.e., HbA1c and IDAA1c, showed significantly lower levels in BCG-vaccinated as compared to unvaccinated patients. Immunophenotype comparisons identified higher expression of the T cell activation marker CD25 on CD8+ T cells from BCG-vaccinated T1D patients. Correlation analysis identified a negative correlation between HbA1c levels and CD25 expression on CD8+ T cells. In addition, we observed fractional increases in glycolysis metabolites (phosphoenolpyruvate and 2/3-phosphoglycerate) in BCG-vaccinated T1D patients. These results suggest that neonatal BCG vaccination is associated with better glycemic control and increased activation of CD8+ T cells in T1D patients. [ABSTRACT FROM AUTHOR]

Background The BCG (Bacillus Calmette-Guérin) vaccine can induce nonspecific protection against unrelated infections. We aimed to test the effect of BCG on absenteeism and health of Danish health care workers (HCWs) during the coronavirus disease 2019 (COVID-19) pandemic. Methods A single-blinded randomized controlled trial included 1221 HCWs from 9 Danish hospitals. Participants were randomized 1:1 to standard dose BCG or placebo. Primary outcome was days of unplanned absenteeism. Main secondary outcomes were incidence of COVID-19, all-cause hospitalization, and infectious disease episodes. Results There was no significant effect of BCG on unplanned absenteeism. Mean number of days absent per 1000 workdays was 20 in the BCG group and 17 in the placebo group (risk ratio, 1.23; 95% credibility interval, 0.98–1.53). BCG had no effect on incidence of COVID-19 or all-cause hospitalization overall. In secondary analyses BCG revaccination was associated with higher COVID-19 incidence (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.07–5.71), but also reduced risk of hospitalization (HR, 0.28; 95% CI,.09–.86). The incidence of infectious disease episodes was similar between randomization groups (HR, 1.09; 95% CI,.96–1.24). Conclusions In this relatively healthy cohort of HCWs, there was no overall effect of BCG on any of the study outcomes. Clinical Trials Registration NCT0437329 and EU Clinical Trials Register (EudraCT number 2020-001888-90). [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) contact tracing and TB preventive treatment are key tools in preventing the transmission of TB with the aim of eliminating the disease. Our study seeks to demonstrate how the infection spread from an individual patient to the entire community and how proactive contact tracing facilitated prompt diagnosis and treatment. Our work was conducted as a retrospective analysis of the spread of TB infection within the Roma community in the Czech Republic, following the case of an index patient who succumbed to pulmonary TB. Several levels of care and preventive and treatment measures are outlined. Confirming the identity of the Mycobacterium tuberculosis strain was achieved using molecular methods. Among the 39 individuals examined, TB disease was detected in eight patients and TB infection was detected in six patients. The investigation of contacts within this group yielded positive results in 36% of cases, necessitating treatment. The study's findings provide evidence that actively tracing individuals at risk can lead to early detection of cases, prompt treatment, and prevention of further disease transmission. The study also indicates that the highest risk of infection occurs within the sick person's household and that young children under the age of 5 are most susceptible to falling ill. [ABSTRACT FROM AUTHOR]

Abstract Background A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity. Methods This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models. Discussion It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic. Trial registration ClinicalTrials.gov NCT04348370. Registered on April 16, 2020.

Basal cell carcinoma (BCC) arising within scar tissue is a rare but clinically significant phenomenon. This comprehensive review aims to provide a succinct overview of the current state of knowledge regarding the etiological factors, pathogenesis, clinical presentation, and management of BCC. This study constitutes a literature review pertaining to BCC, with a particular emphasis on BCC developing within scar tissue. It also provides a clinical case presentation of a patient who had developed BCC in a BCG post-vaccination scar and a review of analogous findings available in the existing literature. Despite the fact that an array of mechanisms play a role in injury-related BCC growth, the main mechanism remains ambiguous and yet to be elucidated. The review also includes a detailed description of the various therapeutic options available for BCC, ranging from surgical interventions to novel pharmacological treatments. By examining these intersections, the review seeks to elucidate the potential mechanisms, identify risk factors, and suggest considerations for clinical practice. The findings underscore the importance of vigilant dermatological assessment in patients with scar tissue and those recently vaccinated, aiming to improve early detection and optimize management strategies for BCC.

BCG vaccination has beneficial off-target ("nonspecific") effects on nonmycobacterial infections. On this premise, trials set out to investigate whether BCG provides off-target protection against coronavirus disease 2019 (COVID-19). A literature search identified 11 randomized "BCG COVID-19" trials, with conflicting results. These trials and the differences in their study design are discussed using the PICOT (participants, intervention, control, outcome, and timing) framework to highlight the factors that likely explain their inconsistent findings. These include participant age, sex and comorbid conditions, BCG vaccination strain and dose, outcome measure and duration of follow-up. Understanding how to control these factors to best exploit BCG's off-target effects will be important in designing future trials and intervention strategies. [ABSTRACT FROM AUTHOR]

Background: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity. Methods: This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models. Discussion: It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic. Trial registration: ClinicalTrials.gov NCT04348370. Registered on April 16, 2020. [ABSTRACT FROM AUTHOR]

BCG vaccination affects other diseases beyond tuberculosis by unknown—potentially immunomodulatory—mechanisms. Recent studies have shown that BCG vaccination administered during overt type 1 diabetes (T1D) improved glycemic control and affected immune and metabolic parameters. Here, we comprehensively characterized Ghanaian T1D patients with or without routine neonatal BCG vaccination to identify vaccine-associated alterations. Ghanaian long-term T1D patients (n = 108) and matched healthy controls (n = 214) were evaluated for disease-related clinical, metabolic, and immunophenotypic parameters and compared based on their neonatal BCG vaccination status. The majority of study participants were BCG-vaccinated at birth and no differences in vaccination rates were detected between the study groups. Notably, glycemic control metrics, i.e., HbA1c and IDAA1c, showed significantly lower levels in BCG-vaccinated as compared to unvaccinated patients. Immunophenotype comparisons identified higher expression of the T cell activation marker CD25 on CD8+ T cells from BCG-vaccinated T1D patients. Correlation analysis identified a negative correlation between HbA1c levels and CD25 expression on CD8+ T cells. In addition, we observed fractional increases in glycolysis metabolites (phosphoenolpyruvate and 2/3-phosphoglycerate) in BCG-vaccinated T1D patients. These results suggest that neonatal BCG vaccination is associated with better glycemic control and increased activation of CD8+ T cells in T1D patients.

We aimed to determine potential risk factors for COVID-19 severity including serum vitamin D levels and latent TB infection among Mongolian inpatients diagnosed with COVID-19, and to study the effects of disease complications and treatment outcomes. This study included patients admitted to the Mongolian National Center for Communicable Disease, a main referral center for infectious disease in Mongolia, with COVID-19 ascertained by a positive PCR test. Patients' demographic, clinical, and laboratory data were analyzed. Of the 270 patients enrolled, 125 (46%) had mild-to-moderate illness, 86 (32%) had severe illness, and 59 (22%) had critical illness. Ten (91%) of the 11 patients who had active TB were hospitalized with severe or critical COVID-19, suggesting that they had a higher risk of falling into the severe category (OR = 10.6 [1.2; 92.0] 95% CI). Severe vitamin D deficiency (25(OH)D < 10 ng/mL) was present in 32% of the patients, but was not significantly associated with the severity of illness (p = 0.65). Older age, being male, having active TB and/or COPD were associated with greater COVID-19 severity, whereas a history of COVID-19 vaccination and the presence of a BCG vaccination scar were protective in terms of disease severity. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for M. abscessus. This study provides evidence that routine BCG vaccination may reduce M. abscessus colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4+ T cells recognising M. abscessus in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF. [ABSTRACT FROM AUTHOR]

• Bacille Calmette-Guérin (BCG) vaccination did not modulate myeloid functional responses to BCG. • BCG vaccination induced natural killer (NK) cell functional responses to BCG. • NK responses correlate with pro-inflammatory mediators only in vaccinated infants. • BCG-induced NK cell responses may contribute to immunity against mycobacteria. The bacille Calmette-Guérin (BCG) vaccine is usually administered at birth to protect against severe forms of tuberculosis in children. BCG also confers some protection against other infections, possibly mediated by innate immune training. We investigated whether newborn BCG vaccination modulates myeloid and natural killer (NK) cell responses to mycobacteria. BCG vaccination was either administered at birth or delayed to 6 or 10 weeks of age in 130 South African infants. Whole blood was stimulated with BCG and clusters of differentiation (CD)4+ T, myeloid, and NK cell responses were measured by flow cytometry; the levels of secreted cytokines were measured by a multiplex bead array. Newborn BCG vaccination was associated with significantly higher frequencies of BCG-reactive, cytokine-expressing CD4+ T cells, and interferon (IFN)-γ-expressing NK cells than in unvaccinated infants but no differences in cytokine-expressing CD33+ myeloid cells were observed. The induction of BCG-reactive IFN-γ-expressing NK cells was not associated with the markers of NK cell maturation, differentiation, or cytokine receptor expression. BCG-reactive NK cell responses correlated directly with the levels of secreted interleukin (IL)-2 and IFN-γ and the innate pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor (TNF) in BCG-vaccinated infants only. We showed that BCG-reactive IFN- γ -expressing NK cells are strongly induced by BCG vaccination in infants and are likely amplified through bystander cytokines. [ABSTRACT FROM AUTHOR]

Background: The cross-protective nature of Bacillus Calmette-Guerin (BCG) vaccine against SARS-CoV-2 virus was previously suggested, however its effect in COVID-19 patients with type 2 diabetes (T2D) and the underlying metabolic pathways has not been addressed. This study aims to investigate the difference in the metabolomic patterns of type 2 diabetic patients with BCG vaccination showing different severity levels of COVID-19 infection. Methods: Sixty-seven COVID-19 patients were categorized into diabetic and non-diabetic individuals who had been previously vaccinated or not with BCG vaccination. Targeted metabolomics were performed from serum samples from all patients using tandem mass spectrometry. Statistical analysis included multivariate and univariate models. Results: Data suggested that while BCG vaccination may provide protection for individuals who do not have diabetes, it appears to be linked to more severe COVID-19 symptoms in T2D patients (p = 0.02). Comparing the metabolic signature of BCG vaccinated T2D individuals to non-vaccinated counterparts revealed that amino acid (sarcosine), cholesterol esters (CE 20:0, 20:1, 22:2), carboxylic acid (Aconitic acid) were enriched in BCG vaccinated T2D patients, whereas spermidine, glycosylceramides (Hex3Cer(d18:1_22:0), Hex2Cer(d18:1/22:0), HexCer(d18:1/26:1), Hex2Cer(d18:1/24:0), HexCer(d18:1/22:0) were higher in BCG vaccinated non- T2D patients. Furthermore, data indicated a decrease in sarcosine synthesis from glycine and choline and increase in spermidine synthesis in the BCG vaccinated cohort in T2D and non-T2D groups, respectively. Conclusion: This pilot study suggests increased severity of COVID-19 in BCG vaccinated T2D patients, which was marked by decreased sarcosine synthesis, perhaps via lower sarcosine-mediated removal of viral antigens. [ABSTRACT FROM AUTHOR]

Mycobacterium (M.) bovis BCG vaccination is recommended for healthy babies after birth in several countries with a high prevalence of tuberculosis, including Ghana. Previous studies showed that BCG vaccination prevents individuals from developing severe clinical manifestations of tuberculosis, but BCG vaccination effects on the induction of IFN-γ after M. tuberculosis infection have hardly been investigated. Here, we performed IFN-γ-based T-cell assays (i.e., IFN-γ Release Assay, IGRA; T-cell activation and maturation marker assay, TAM-TB) in children who had contact with index tuberculosis patients (contacts). These contacts were classified as either being BCG vaccinated at birth (n = 77) or non-BCG-vaccinated (n = 17) and were followed up at three timepoints for a period of one year to determine immune conversion after M. tuberculosis exposure and potential infection. At baseline and month 3, BCG-vaccinated contacts had significantly lower IFN-γ levels after stimulation with M. tuberculosis-specific proteins as compared to non-BCG-vaccinated contacts. This resulted in decreased proportions of positive IGRA results (BCG-vaccinated: 60% at baseline, 57% at month 3; non-BCG-vaccinated: 77% and 88%, respectively) at month 3. However, until month 12, immune conversion in BCG-vaccinated contacts led to balanced proportions in IGRA responders and IFN-γ expression between the study groups. TAM-TB assay analyses confirmed higher proportions of IFN-γ-positive T-cells in non-BCG-vaccinated contacts. Low proportions of CD38-positive M. tuberculosis-specific T-cells were only detected in non-BCG-vaccinated contacts at baseline. These results suggest that BCG vaccination causes delayed immune conversion as well as differences in the phenotype of M. tuberculosis-specific T-cells in BCG-vaccinated contacts of tuberculosis patients. These differences are immune biomarker candidates for protection against the development of severe clinical tuberculosis manifestations. [ABSTRACT FROM AUTHOR]

Plain Language Summary The Bacillus Calmette–Guérin (BCG) vaccine has been studied previously in several settings, including reducing childhood mortalities due to viral infections and induction of trained immunity and reducing upper respiratory tract infections and pneumonia in older adults. This multi-centre trial has tried to evaluate the efficacy of BCG revaccination in reducing the incidence and severity of COVID-19 infections in adults between 18 and 60 years of age belonging to the high-risk group owing to the presence of comorbidities including diabetes, chronic kidney disease, chronic liver disease and chronic lung diseases. A single dose of BCG vaccine produced significantly high titres of BCG antibodies lasting for six months. While there was no significant reduction in the incidence of COVID-19 infection, there was an 8.4% reduction in the incidence of symptomatic COVID-19 disease at the end of 9 months of follow-up. In addition, there were significantly fewer severe COVID-19 infections requiring hospital stay and oxygen support. However, the overall numbers of severe COVID-19 infections were low. Thus, the study shows that BCG can protect against symptomatic and severe COVID-19 disease. However, it might not reduce the incidence of new infections. The study results are significant for low- and middle-income countries without adequate coverage of primary doses of COVID-19 vaccination, let alone the booster doses. Future studies should evaluate the BCG vaccine’s efficacy as a booster compared with routine COVID-19 vaccine boosters.

Introduction: Tuberculosis is currently one of the planet's most serious healthy issues. Search the effect of BCG vaccine on tuberculin skin test results. Patients and methods: From January 2018 to January 2019, 1109 patients were enrolled in the trial, which took place at the Tuberculosis Center in Babylon Province. Tuberculin skin testing was done using the mantoux method, which involved injecting 0.1 unit of pure tuberculin protein intradermally and reading the result after 48 hours (mm). Result: This cross-sectional revision of 1109 patients aged 1 to 85 years old in Babylon province who had BCG immunization at birth. Females outnumbered males in terms of percentage (52 percent versus 48 percent). The BCG vaccinated cases were 966 (87%) while the number of non-BCG vaccinated cases was 143 (13%). The quantity of tuberculin skin test diameters (0-5mm) are1007 (90.8%) patients in non-vaccinated patients 129 (12.8%) and vaccinated patients 878 (87.2%), diameter (6-10mm) 33 (3%) patients in non-vaccinated 6 (18.2%) and vaccinated 27 (81.8%) and tuberculin skin diameter (> 11mm) 69 (6.2%) patients in non-vaccinated 8 (11.6%) and vaccinated patients 61 (88.1%). Vaccinated subjects had a larger skin test diameter than not received vaccine, and the difference was critical (p value=0.029). Conclusion: There is a statistically significant link between the BCG vaccine, positivity and the diameter of the tuberculin test. [ABSTRACT FROM AUTHOR]

Problem: Long‐lived mycobacterial L‐forms (mL‐forms) could be detected in the blood of BCG‐vaccinated people. We have previously found mL‐forms in term placentas and blood of neonates, delivered by healthy BCG‐vaccinated mothers as first formal demonstration that BCG vaccination in the childhood of the woman could affect her placentobiome during pregnancy. Of note, the isolated mL‐forms reverted to the cell‐walled state of the parental BCG bacilli in vitro. Method of study: Here, we analyzed triple samples of blood, decidua and chorion taken from BCG‐vaccinated pregnant women, directed to elective abortions (6‐12 gestation weeks). The colonization of the primary samples with mycobacterial L‐forms (mL‐forms) was evaluated using microbiological isolation and subsequent identification by real time PCR and morphological characterization by light microscopy and SEM. The potential of early placenta‐derived mL‐forms to expand mycobacteria‐reactive γδ T cells in vitro was assessed using FACS, whereas their immunogenicity in vivo was followed up after i.p. inoculation in rats. Results: Our results showed two important findings: 1) viable filterable mL‐forms varying in size, shape and proliferation modes are capable of colonizing the gestational tissues of BCG‐vaccinated women early in pregnancy and 2) early placenta‐derived mL‐forms are not as immunogenic as walled M. bovis BCG bacilli, shown by lack of stimulation of mycobacteria‐reactive γδ T cells co‐cultured with early placenta‐derived mL‐forms and inefficient internalization of mL‐forms by rat's peritoneal phagocytes in vivo. Conclusion: Although generally thought to be reduced in virulence, mL‐forms could provide a reservoir, hidden from the immune system especially in an immune privileged niche like placenta. [ABSTRACT FROM AUTHOR]

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Objectives: The bacille Calmette-Guérin (BCG) vaccine is usually administered at birth to protect against severe forms of tuberculosis in children. BCG also confers some protection against other infections, possibly mediated by innate immune training. We investigated whether newborn BCG vaccination modulates myeloid and natural killer (NK) cell responses to mycobacteria. Methods: BCG vaccination was either administered at birth or delayed to 6 or 10 weeks of age in 130 South African infants. Whole blood was stimulated with BCG and clusters of differentiation (CD)4+ T, myeloid, and NK cell responses were measured by flow cytometry; the levels of secreted cytokines were measured by a multiplex bead array. Results: Newborn BCG vaccination was associated with significantly higher frequencies of BCG-reactive, cytokine-expressing CD4+ T cells, and interferon (IFN)-γ-expressing NK cells than in unvaccinated infants but no differences in cytokine-expressing CD33+ myeloid cells were observed. The induction of BCG-reactive IFN-γ-expressing NK cells was not associated with the markers of NK cell maturation, differentiation, or cytokine receptor expression. BCG-reactive NK cell responses correlated directly with the levels of secreted interleukin (IL)-2 and IFN-γ and the innate pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor (TNF) in BCG-vaccinated infants only. Conclusion: We showed that BCG-reactive IFN-γ-expressing NK cells are strongly induced by BCG vaccination in infants and are likely amplified through bystander cytokines.

BackgroundThe cross-protective nature of Bacillus Calmette-Guerin (BCG) vaccine against SARS-CoV-2 virus was previously suggested, however its effect in COVID-19 patients with type 2 diabetes (T2D) and the underlying metabolic pathways has not been addressed. This study aims to investigate the difference in the metabolomic patterns of type 2 diabetic patients with BCG vaccination showing different severity levels of COVID-19 infection.MethodsSixty-seven COVID-19 patients were categorized into diabetic and non-diabetic individuals who had been previously vaccinated or not with BCG vaccination. Targeted metabolomics were performed from serum samples from all patients using tandem mass spectrometry. Statistical analysis included multivariate and univariate models.ResultsData suggested that while BCG vaccination may provide protection for individuals who do not have diabetes, it appears to be linked to more severe COVID-19 symptoms in T2D patients (p = 0.02). Comparing the metabolic signature of BCG vaccinated T2D individuals to non-vaccinated counterparts revealed that amino acid (sarcosine), cholesterol esters (CE 20:0, 20:1, 22:2), carboxylic acid (Aconitic acid) were enriched in BCG vaccinated T2D patients, whereas spermidine, glycosylceramides (Hex3Cer(d18:1_22:0), Hex2Cer(d18:1/22:0), HexCer(d18:1/26:1), Hex2Cer(d18:1/24:0), HexCer(d18:1/22:0) were higher in BCG vaccinated non- T2D patients. Furthermore, data indicated a decrease in sarcosine synthesis from glycine and choline and increase in spermidine synthesis in the BCG vaccinated cohort in T2D and non-T2D groups, respectively.ConclusionThis pilot study suggests increased severity of COVID-19 in BCG vaccinated T2D patients, which was marked by decreased sarcosine synthesis, perhaps via lower sarcosine-mediated removal of viral antigens.

Objective To analyze the clinical characteristics of pulmonary tuberculosis in children, and provide the basis for improving the diagnosis and treatment of pulmonary tuberculosis in children. Methods The general data, laboratory examination and imaging examination of 45 children with pulmonary tuberculosis admitted to our hospital were retrospectively analyzed. The results of chest CT and chest X-ray were compared and analyzed. The fiberoptic bronchoscopy and treatment of endobronchial tuberculosis were reviewed. Results There were 28 males and 17 females in the 45 patients. Forty-two cases (93.3%) were definitely vaccinated with Bacille Calmette-Guérin (BCG) vaccine. There were 11 cases (24.4%) with definite recent contact history of active tuberculosis, and 33 cases (73.3%) with past family history of tuberculosis. There were 37 cases (82.2%) with simple pulmonary tuberculosis. Tuberculous pleurisy was more common in patients with extrapulmonary tuberculosis. The common symptoms were fever, cough, wheezing and tuberculosis poisoning symptoms. Pulmonary tuberculosis occurred in different forms in children. There were 29 cases (64.4%) with bronchitis and pneumonia, 3 cases (6.7%) with bronchial asthma, 5 cases (11.1%) with chronic cough, 6 cases (13.3%) with fever, and 2 cases (4.4%) with postoperative trauma. The tuberculin test was moderately positive in 38 cases (84.4%). Chest CT scan can detect tubercular lesions better than chest X-ray examination. Among the 45 cases, 42 cases underwent fiberoptic bronchoscopy, and 13 cases (31.0%) were found to have endobronchial tuberculosis. Patients (n=42) were treated with freezing and linezolid lavage. The endobronchial wall became smooth after 2-3 times of treatment. Conclusion The diagnostic value of chest CT scan is superior to chest X-ray examination. Bronchoscopic freezing and linezolid lavage are effective methods for the treatment of endobronchial tuberculosis. [ABSTRACT FROM AUTHOR]

Introduction: Universal coverage of vaccines alone cannot be relied upon to protect at-risk populations in lower- and middle-income countries against the impact of the coronavirus disease 2019 (COVID-19) pandemic and newer variants. Live vaccines, including Bacillus Calmette–Guérin (BCG), are being studied for their effectiveness in reducing the incidence and severity of COVID-19 infection. Methods: In this multi-centre quadruple-blind, parallel assignment randomised control trial, 495 high-risk group adults (aged 18–60 years) were randomised into BCG and placebo arms and followed up for 9 months from the date of vaccination. The primary outcome was the difference in the incidence of COVID-19 infection at the end of 9 months. Secondary outcomes included the difference in the incidence of severe COVID-19 infections, hospitalisation rates, intensive care unit stay, oxygen requirement and mortality at the end of 9 months. The primary analysis was done on an intention-to-treat basis, while safety analysis was done per protocol. Results: There was no significant difference in the incidence rates of cartridge-based nucleic acid amplification test (CB-NAAT) positive COVID-19 infection [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.54–2.14] in the two groups, but the BCG arm showed a statistically significant decrease in clinically diagnosed (symptomatic) probable COVID-19 infections (OR 0.38, 95% CI 0.20–0.72). Compared with the BCG arm, significantly more patients developed severe COVID-19 pneumonia (CB-NAAT positive) and required hospitalisation and oxygen in the placebo arm (six versus none; p = 0.03). One patient belonging to the placebo arm required intensive care unit (ICU) stay and died. BCG had a protective efficacy of 62% (95% CI 28–80%) for likely symptomatic COVID-19 infection. Conclusions: BCG is protective in reducing the incidence of acute respiratory illness (probable symptomatic COVID-19 infection) and severity of the disease, including hospitalisation, in patients belonging to the high-risk group of COVID-19 infection, and the antibody response persists for quite a long time. A multi-centre study with a larger sample size will help to confirm the findings in this study. Clinical Trials Registry: Clinical Trials Registry India (CTRI/2020/07/026668). Plain Language Summary: The Bacillus Calmette–Guérin (BCG) vaccine has been studied previously in several settings, including reducing childhood mortalities due to viral infections and induction of trained immunity and reducing upper respiratory tract infections and pneumonia in older adults. This multi-centre trial has tried to evaluate the efficacy of BCG revaccination in reducing the incidence and severity of COVID-19 infections in adults between 18 and 60 years of age belonging to the high-risk group owing to the presence of comorbidities including diabetes, chronic kidney disease, chronic liver disease and chronic lung diseases. A single dose of BCG vaccine produced significantly high titres of BCG antibodies lasting for six months. While there was no significant reduction in the incidence of COVID-19 infection, there was an 8.4% reduction in the incidence of symptomatic COVID-19 disease at the end of 9 months of follow-up. In addition, there were significantly fewer severe COVID-19 infections requiring hospital stay and oxygen support. However, the overall numbers of severe COVID-19 infections were low. Thus, the study shows that BCG can protect against symptomatic and severe COVID-19 disease. However, it might not reduce the incidence of new infections. The study results are significant for low- and middle-income countries without adequate coverage of primary doses of COVID-19 vaccination, let alone the booster doses. Future studies should evaluate the BCG vaccine's efficacy as a booster compared with routine COVID-19 vaccine boosters. [ABSTRACT FROM AUTHOR]

Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1β secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity. [Display omitted] • BCG persistently alters gene expression in human hematopoietic stem cells (HSCs) • HSCs maintain a differentiation bias toward the myeloid lineage after 90 days • BCG alters chromatin accessibility (CA), but not gene expression, of progenitors • CA changes in myeloid progenitors correlate with IL-1β secretion by paired PBMCs The BCG vaccine for tuberculosis protects against non-mycobacterial infections, but the mechanisms are unclear. Sun et al. found that BCG alters gene expression and chromatin accessibility in hematopoietic stem and progenitor cells (HSPCs), predicting cytokine secretion in peripheral blood mononuclear cells. This research highlights BCG's lasting, multimodal effects on HSPCs and the regulation of innate immune responses. [ABSTRACT FROM AUTHOR]

We aimed to determine potential risk factors for COVID-19 severity including serum vitamin D levels and latent TB infection among Mongolian inpatients diagnosed with COVID-19, and to study the effects of disease complications and treatment outcomes. This study included patients admitted to the Mongolian National Center for Communicable Disease, a main referral center for infectious disease in Mongolia, with COVID-19 ascertained by a positive PCR test. Patients’ demographic, clinical, and laboratory data were analyzed. Of the 270 patients enrolled, 125 (46%) had mild-to-moderate illness, 86 (32%) had severe illness, and 59 (22%) had critical illness. Ten (91%) of the 11 patients who had active TB were hospitalized with severe or critical COVID-19, suggesting that they had a higher risk of falling into the severe category (OR = 10.6 [1.2; 92.0] 95% CI). Severe vitamin D deficiency (25(OH)D < 10 ng/mL) was present in 32% of the patients, but was not significantly associated with the severity of illness (p = 0.65). Older age, being male, having active TB and/or COPD were associated with greater COVID-19 severity, whereas a history of COVID-19 vaccination and the presence of a BCG vaccination scar were protective in terms of disease severity.

Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for M. abscessus. This study provides evidence that routine BCG vaccination may reduce M. abscessus colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4+ T cells recognising M. abscessus in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF.

Japan amended the recommended age for the Bacille Calmette–Guérin (BCG) vaccination to less than 6 months after 2005, but subsequently amended the recommended age to 5–8 months (latest amendment, <1 year) in April 2013 due to the increasing incidence of BCG-associated osteitis/osteomyelitis since 2005. We collected data on BCG-associated vaccine adverse events (VAEs) in the population aged <1 year between April 2013 and March 2017. The incidence of BCG-associated VAE was analyzed using census and vaccine coverage data from the government website. We compared the incidence of VAEs in patients vaccinated at less than 6 months with those vaccinated at 6 months or older. Among the 581 BCG-associated VAEs recorded during the study period, 354 (61%) were male, and the average age at vaccination was 5.7 months. The incidence of VAEs per million population aged <1 year at vaccination was highest for suppurative lymphadenitis (63.7), followed by skin lesions (38.4), and BCG-associated osteitis/osteomyelitis (3.1). Disseminated BCG and anaphylaxis were rare (1.1 and 1.6%, respectively). The incidence of VAEs in the population vaccinated at <6 months of age was higher for BCG-associated osteitis/osteomyelitis (3.8) and disseminated BCG (1.3) than in the population vaccinated at ≥6 months. The population vaccinated at <6 months of age was more likely to develop BCG-associated osteitis/osteomyelitis than the population vaccinated at ≥6 months of age, indicating that the change in the recommended vaccination age in 2013 might have contributed to the subsequent decrease in the incidence of BCG-associated osteitis/osteomyelitis. [ABSTRACT FROM AUTHOR]

Bovine tuberculosis (bTB) challenges intensive dairy production in Ethiopia and implementation of the test and slaughter control strategy is not economically acceptable in the country. Vaccination of cattle with Bacillus Calmette–Guerin (BCG) could be an important adjunct to control, which would require a diagnostic test to differentiate Mycobacterium bovis (M. bovis)‐infected and BCG‐vaccinated animals (DIVA role). This study describes an evaluation of a DIVA skin test (DST) that is based on a cocktail (DSTc) or fusion (DSTf) of specific (ESAT‐6, CFP‐10 and Rv3615c) M. bovis proteins in Zebu–Holstein–Friesians crossbred cattle in Ethiopia. The study animals used were 74 calves (35 BCG vaccinated and 39 unvaccinated) aged less than 3 weeks at the start of experiment and 68 naturally infected 'TB reactor' cows. Six weeks after vaccination, the 74 calves were tested with the DSTc and the single intradermal cervical comparative tuberculin (SICCT) test. The TB reactor cows were tested with the DSTc and the SICCT test. Reactions to the DSTc were not observed in BCG‐vaccinated and unvaccinated calves, while SICCT test reactions were detected in vaccinated calves. DSTc reactions were detected in 95.6% of the TB reactor cows and single intradermal tuberculin positive reactions were found in 98.2% (95% confidence interval, CI, 92.1–100%). The sensitivity of the DSTc was 95.6% (95% CI, 87.6–99.1%), and significantly (p <.001) higher than the sensitivity (75%, 95% CI, 63.0–84.7%) of the SICCT test at 4 mm cut‐off. DSTf and DSTc reactions were correlated (r = 0.75; 95% CI = 0.53–0.88). In conclusion, the DSTc could differentiate M. bovis‐infected from BCG‐vaccinated cattle in Ethiopia. DST had higher sensitivity than the SICCT test. Hence, the DSTc could be used as a diagnostic tool for bTB if BCG vaccination is implemented for the control of bTB in Ethiopia and other countries. [ABSTRACT FROM AUTHOR]

Background Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19. Methods In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses. Results The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval,.65–2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval,.71–1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine. Conclusions BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection. Clinical trials registration EU Clinical Trials Register 2020-001591-15 ClinicalTrials.gov NCT04417335. [ABSTRACT FROM AUTHOR]

Background: Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner., Methods: We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis. Validation of the identified CpG sites was conducted using three independent cohorts., Results: 215 CpG sites were associated with serum urate in males, while 5 CpG sites were associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increased after BCG vaccination, and baseline DNA methylation was associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males were enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites were related to lipid and glucose metabolism., Conclusion: Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights have significant implications for the diagnosis, prevention, and treatment of various urate-related diseases and highlight the importance of personalized and sex-specific approaches in medicine., Competing Interests: Additional Declarations: There is NO Competing Interest.

Mycobacterium (M.) bovis BCG vaccination is recommended for healthy babies after birth in several countries with a high prevalence of tuberculosis, including Ghana. Previous studies showed that BCG vaccination prevents individuals from developing severe clinical manifestations of tuberculosis, but BCG vaccination effects on the induction of IFN-γ after M. tuberculosis infection have hardly been investigated. Here, we performed IFN-γ-based T-cell assays (i.e., IFN-γ Release Assay, IGRA; T-cell activation and maturation marker assay, TAM-TB) in children who had contact with index tuberculosis patients (contacts). These contacts were classified as either being BCG vaccinated at birth (n = 77) or non-BCG-vaccinated (n = 17) and were followed up at three timepoints for a period of one year to determine immune conversion after M. tuberculosis exposure and potential infection. At baseline and month 3, BCG-vaccinated contacts had significantly lower IFN-γ levels after stimulation with M. tuberculosis-specific proteins as compared to non-BCG-vaccinated contacts. This resulted in decreased proportions of positive IGRA results (BCG-vaccinated: 60% at baseline, 57% at month 3; non-BCG-vaccinated: 77% and 88%, respectively) at month 3. However, until month 12, immune conversion in BCG-vaccinated contacts led to balanced proportions in IGRA responders and IFN-γ expression between the study groups. TAM-TB assay analyses confirmed higher proportions of IFN-γ-positive T-cells in non-BCG-vaccinated contacts. Low proportions of CD38-positive M. tuberculosis-specific T-cells were only detected in non-BCG-vaccinated contacts at baseline. These results suggest that BCG vaccination causes delayed immune conversion as well as differences in the phenotype of M. tuberculosis-specific T-cells in BCG-vaccinated contacts of tuberculosis patients. These differences are immune biomarker candidates for protection against the development of severe clinical tuberculosis manifestations.

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is an infectious disease that poses severe threats to global public health and significant economic losses. The COVID-19 global burden is rapidly increasing, with over 246.53 million COVID-19 cases and 49.97 million deaths reported in the WHO 2021 report. People with compromised immunity, such as tuberculosis (TB) patients, are highly exposed to severe COVID-19. Both COVID-19 and TB diseases spread primarily through respiratory droplets from an infected person to a healthy person, which may cause pneumonia and cytokine storms, leading to severe respiratory disorders. The COVID-19-TB coinfection could be fatal, exacerbating the current COVID-19 pandemic apart from cellular immune deficiency, coagulation activation, myocardial infarction, and other organ dysfunction. This study aimed to assess the pathogenesis of SARS-CoV-2- Mycobacterium tuberculosis coinfections. We provide a brief overview of COVID19-TB coinfection and discuss SARS-CoV-2 host cellular receptors and pathogenesis. In addition, we discuss M. tuberculosis host cellular receptors and pathogenesis. Moreover, we highlight the impact of SARS-CoV-2 on TB patients and the pathological pathways that connect SARS-CoV-2 and M. tuberculosis infection. Further, we discuss the impact of BCG vaccination on SARS-CoV-2 cases coinfected with M. tuberculosis , as well as the diagnostic challenges associated with the coinfection. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is one of the top 10 leading causes of death worldwide. The recombinant BCG strain expressing the genetically detoxified A subunit of the thermolabile toxin from Escherichia coli (LTAK63) adjuvant (rBCG-LTAK63) has previously been shown to confer superior protection and immunogenicity compared to BCG in a murine TB infection model. To further investigate the immunological mechanisms induced by rBCG-LTAK63, we evaluated the immune responses induced by rBCG-LTAK63, BCG, and Mycobacterium tuberculosis (Mtb) H37Rv strains in experimental infections of primary human M1 and M2 macrophages at the transcriptomic and cytokine secretion levels. The rBCG-LTAK63-infected M1 macrophages more profoundly upregulated interferon-inducible genes such as IFIT3, OAS3, and antimicrobial gene CXCL9 compared to BCG, and induced higher levels of inflammatory cytokines such as IL-12(p70), TNF-β, and IL-15. The rBCG-LTAK63-infected M2 macrophages more extensively upregulated transcripts of inflammation-related genes, TAP1, GBP1, SLAMF7, TNIP1, and IL6, and induced higher levels of cytokines related to inflammation and tissue repair, MCP-3 and EGF, as compared to BCG. Thus, our data revealed an important signature of immune responses induced in human macrophages by rBCG-LTAK63 associated with increased inflammation, activation, and tissue repair, which may be correlated with a protective immune response against TB. [ABSTRACT FROM AUTHOR]

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Objective: To study the prevalence of Mycobacterium tuberculosis at the infection reservoirs in the Republic of Tajikistan among children and the impact of BCG vaccination assessed by tuberculin skin test. Methods: The results of tuberculin skin test in children from Mycobacterium tuberculosis seedbeds in the Republic of Tajikistan were analyzed in the city of Bokhtar (n=176) and the village of Dusti, Khatlon region (n=124). The impact of BCG vaccination in children under 6 years of age was considered in interpretation of the tuberculin skin test results. Results: The positive result of the tuberculin skin test in children aged 0-6 years was found in 64.7% of cases, 7-14 years – in 47.0% and 15-17 years – in 61.5% respectively. It was shown that rate of high degree of tuberculin sensitivity in children from Mycobacterium tuberculosis reservoirs increased with age. The highest rate of tuberculin sensitivity was observed in 15-17 years old children, and among them in the city – 22.2%, in the village – 27.3%; followed by the age group 7-14 years: in the city – 20%, in the village – 25%. In the age group 0-6 years, this indicator was 2.4% and 3% respectively. Conclusion: The analysis shows that the situation with tuberculosis in the reservoirs of infection, especially in children aged 7 years and over, is challenging. For the correct interpretation of tuberculin test results in children under 6 years of age, it is important to consider the effect of BCG vaccination. Prevalence of the tuberculosis among the children at the infection reservoirs is high, which requires special attention and measures for comprehensive prevention of tuberculosis in its seedbeds. Insufficient monitoring of contact children residing in the reservoirs of infection is an important factor contributing to the late detection of severe and complicated forms of tuberculosis in children.

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is an infectious disease that poses severe threats to global public health and significant economic losses. The COVID-19 global burden is rapidly increasing, with over 246.53 million COVID-19 cases and 49.97 million deaths reported in the WHO 2021 report. People with compromised immunity, such as tuberculosis (TB) patients, are highly exposed to severe COVID-19. Both COVID-19 and TB diseases spread primarily through respiratory droplets from an infected person to a healthy person, which may cause pneumonia and cytokine storms, leading to severe respiratory disorders. The COVID-19-TB coinfection could be fatal, exacerbating the current COVID-19 pandemic apart from cellular immune deficiency, coagulation activation, myocardial infarction, and other organ dysfunction. This study aimed to assess the pathogenesis of SARS-CoV-2-Mycobacterium tuberculosis coinfections. We provide a brief overview of COVID19-TB coinfection and discuss SARS-CoV-2 host cellular receptors and pathogenesis. In addition, we discuss M. tuberculosis host cellular receptors and pathogenesis. Moreover, we highlight the impact of SARS-CoV-2 on TB patients and the pathological pathways that connect SARS-CoV-2 and M. tuberculosis infection. Further, we discuss the impact of BCG vaccination on SARS-CoV-2 cases coinfected with M. tuberculosis, as well as the diagnostic challenges associated with the coinfection.

• The BCG vaccine provides variable protection against tuberculosis. • Correlates of protection remain elusive, but IFNγ can measure immunogenicity. • BCG vaccination induces innate immune training as well as antigen-specific immunity. • Many factors may contribute to the variable responses to BCG vaccination. • Prior BCG vaccination or factors modulating its efficacy may affect new TB vaccines. • Innate training may also provide non-specific protection against infectious diseases. • New TB vaccines should not lose BCG's beneficial non-specific effects. The BCG vaccine will, in 2021, have been in use for 100 years. Much remains to be understood, including the reasons for its variable efficacy against pulmonary tuberculosis in adults. This review will discuss what has been learnt about the BCG vaccine in the last two decades, and whether this new information can be exploited to improve its efficacy, by enhancing its ability to induce either antigen-specific and/or non-specific effects. Many factors affect both the immunogenicity of BCG and its protective efficacy, highlighting the challenges of working with a live vaccine in man, but new insights may enable us to exploit better what BCG can do. [ABSTRACT FROM AUTHOR]

In order to assess the possible protective potential of BCG vaccination as regards to COVID-19, we have analyzed BCG vaccination status and SARS CoV-2 morbidity and mortality in China and we have also examined other studies performed in other countries to assess the potential of booster doses of BCG vaccination for adults. We have concluded that BCG vaccination early in life is highly unlikely to be a tool that might prevent SARS CoV-2 infection in adults. Furthermore, we have suggested that BCG vaccination potential benefit to decrease COVID-19 morbidity and mortality in children is confounded by many factors, e.g. age limitations of exposure and other vaccines. However, BCG vaccination booster doses in adults might be of protective value until the results of well-designed clinical trials are published to confirm, or refute, this potential.

Summary: Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism.

Dear Editor, COVID-19 is a new type of respiratory infection and might lead to serious pneumonia causing acute respiratory distress syndrome (ARDS). Most people infected with SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) manifest as having asymptomatic or mild to moderate upper respiratory tract disease. However, a minority of all can have severe course and even death, especially elderly patients.1 Here, one of the possible reasons, BCG vaccination and its impact, causing this difference in a population is delineated more. Can BCG vaccine reprogram natural (innate) immunity and decrease spread of COVID-19? Since the first use of BCG vaccine in Europe in the 1920s, a serious decrease in infant mortality has been reported. It is not likely to explain this decline only with the decrease in tuberculosis frequency. The reason for this decrease in infant mortality was reported to be associated with decline in neonatal sepsis and respiratory infections. In another study, this hypothesis was supported by showing that the frequency of respiratory syncytial virus (RSV) infection reduced in population after BCG vaccine.2 In a South African study, 70 percent of BCG vaccinated adolescents had a decrease in respiratory infections as well. BCG application also reduced influenza A viral load in mice through affecting macrophages. Similarly, BCG vaccine increased the cytokines and peritoneal macrophages against many unrelated pathogens in mice. In the healthy population, BCG vaccination increased the release of proinflammatory cytokines (eg. IL-1β, TNF-α and IL-6).3 Could BCG vaccine be a weapon in reducing the morbidity and mortality of COVID-19? The countries such as Italy, Holland and USA applying non-universal BCG vaccination policies, it is noteworthy that COVID-19 progresses more severely, compared to the countries following the universal policy. In epidemiological studies, the rate and death of COVID-19 in countries where BCG vaccination applied was also quite lower than non-vaccinated countries. Statistical evaluation of the current data of both European countries and countries in the Northern and Southern Hemisphere, the incidence and mortality of COVID-19 per population was also found lower in BCG-vaccinated countries. If same countries were separately assessed, BCG vaccination has not been performed in Italy, England and France where mortality of COVID-19 was higher. Nevertheless the mortality rates were relatively lower in the countries (Qatar, Saudi Arabia and China); whose BCG vaccination rates in 2018 were very high at 99%, 98%, 99%; respectively.4,5 Although there are differences in genetic, demographic, non-pharmacological measures, diagnosis and reporting between nations, possible inverse direct relation between BCG vaccination and COVID-19 looks interesting. Severity of SARS-CoV-2 infection in elderly might be due to long time past after the BCG’s positive effect on innate immunity. Consistently, COVID-19 often manifests as asymptomatic/mildly symptomatic since shorter time passed in younger than in the elderly after BCG vaccination.

We investigated whether countries with higher coverage of childhood live vaccines [BCG or measles-containing-vaccine (MCV)] have reduced risk of coronavirus disease 2019 (COVID-19)-related mortality, while accounting for known systems differences between countries. In this ecological study of 140 countries using publicly available national-level data, higher vaccine coverage, representing estimated proportion of people vaccinated during the last 14 years, was associated with lower COVID-19 deaths. The associations attenuated for both vaccine variables, and MCV coverage became no longer significant once adjusted for published estimates of the Healthcare access and quality index (HAQI), a validated summary score of healthcare quality indicators. The magnitude of association between BCG coverage and COVID-19 death rate varied according to HAQI, and MCV coverage had little effect on the association between BCG and COVID-19 deaths. While there are associations between live vaccine coverage and COVID-19 outcomes, the vaccine coverage variables themselves were strongly correlated with COVID-19 testing rate, HAQI and life expectancy. This suggests that the population-level associations may be further confounded by differences in structural health systems and policies. Cluster randomised studies of booster vaccines would be ideal to evaluate the efficacy of trained immunity in preventing COVID-19 infections and mortality in vaccinated populations and on community transmission. [ABSTRACT FROM AUTHOR]

Abstract Background The observations of some recent epidemiological studies offer hope for a reduced impact of COVID-19 for countries which practice universal BCG vaccination policy. Main body This report provides a correlation between the case fatality rates of COVID-19 and the percentage of BCG vaccination coverage in 183 most affected countries. The main objective of this observational ecologic report is to evaluate possible effects of the previous BCG vaccination in different populations and the epidemic outcomes specially the rates of severe/critical cases and case fatalities. The analysis is preliminary since it is based on constantly rolling data while the COVID-19 pandemic is still unfolding. Conclusion Our findings seem to support the fact that an older BCG vaccine may have a protective role in avoiding severe/critical SARS-CoV2 pneumonia and relatively decrease its fatalities.

The live BCG vaccine, causing a complex response of both innate and cellular as well as humoral adaptive immunity, is a biological adjuvant. It serves as a trigger for a "trained" immune system response, characterized by the activation of monocytes, macrophages, natural killer cells, and lymphoid elements of inborn populations, all contribute to the early activation of non-antigen-specific protective programmes of the body fight against a number of viral, fungal, protozoan infections and neoplastic clones. One of the infections, altered by BCG vaccination, may be COVID-19. The pathogenesis of the development of acute interstitial pneumonia/respiratory distress syndrome caused by COVID-19 is characterized by the triggering of excessive systemic action of inflammatory mediators, in particular, cytokines, due to violation of the focal inflammatory barriers. Gamma-interferon, produced by lymphocytes after BCG vaccination, modulates the activity of a number of interleukins, which in turn may attenuate course of COVID-19 by reducing the activity of IL-12 and IL-18 -dependent reactions. There is an antigenic cross-reaction between the peptides from causative agents of mycobacterioses and SARS-CoV2 because of their proteins’ homology. Unlike many adjuvants, BCG decreases the incidence of lymphoid malignancies and its effect on various autoimmunopathies is different, not necessarily harmful. The peculiar character of BCG vaccination effect may be related to its very early impact on immature immune system and symbiotic character of host-BCG interactions. Geo-epidemiological data on the relationship between the historical practice of using BCG vaccination in different countries and the current incidence of new coronavirus infection and mortality from it are presented. Historically, the medical and social reasons for the different national policies of health authorities regarding the use of the BCG vaccine are considered.

Abstract Background To investigate the association between parameters indicating immunity from BCG at country level (presence of BCG vaccination policy, BCG coverage, age-specific incidence of tuberculosis (TB)) and the morbidity and mortality of COVID-19. Methods Country-specific data for COVID-19 cases and deaths, demographic details, BCG coverage and policy, age-specific TB incidence and income level were obtained. The crude COVID-19 cases and deaths per 100,000 population were calculated and assessed against the parameters indicating immunity from BCG using linear regression analysis. Results Univariate analysis identified higher income level of a country to be significantly associated with COVID-19 cases (p 65-years (Cases (rs = − 0.785,p = 0.0001)) and deaths (rs = − 0.647,p = 0.0001). Multivariate analysis identified the higher income level of a country and not having a universal BCG vaccination policy to affect the COVID-19 cases. The deaths were inversely affected by the presence of BCG vaccination policy and coverage; and positively by the TB incidence in patients > 65-years. Conclusion Significant inverse correlations observed between cases and deaths of COVID-19 and BCG related parameters highlights immunity from BCG as a likely explanation for the variation in COVID-19 across countries.