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The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient's awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly affects MoCA testing when administered by the intravesical route. MoCA scores were lower with increasing age and higher in more formally educated individuals. Patients receiving BCG tended to maintain their MoCA scores, whereas almost half the control cases tended to show reduced scores. This benefit is supported by reduced pre-amyloid biomarkers in BCG-injected healthy volunteers and a favorable effect on neuronal dendritic development in animal models. Our results suggest that BCG has a beneficial impact on the cognitive status of older individuals. [ABSTRACT FROM AUTHOR]

Bacille Calmette–Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries. Disseminated BCG vaccine disease is a classic feature of children with human immunodeficiency virus (HIV) or primary immunodeficiency disorders (PIDs) and is associated with high mortality. We report a case of a 6-month-old infant with disseminated BCG disease and hemophagocytic lymphohistiocytosis mimicking juvenile myelomonocytic leukemia with no demonstrable features of HIV or PID even after extensive laboratory work-up and succumbed to progressive disease. Disseminated BCG disease is a rare and potentially fatal complication of BCG vaccine, and prompt immunological evaluation complemented by initiation of 4-drug antitubercular therapy and definitive treatment with antiretroviral therapy or hematopoietic stem cell transplant is warranted.

The persistent threat of tuberculosis (TB) on a global scale hasprompted a reevaluation of preventive strategies, with a particular focus onthe Bacille Calmette‐Guérin (BCG) vaccine's role in revaccination. Theresurgence underscores an urgent need for enhanced measures, prompting acritical examination of BCG revaccination strategies. Drawing from the researchof Paulo Cesar Pereira dos Santos and a synthesis of randomized controlledtrials (RCTs), this review identifies key considerations for refining BCGrevaccination's efficacy against Mycobacterium tuberculosis (MTB) andTB. The main body of this review integrates four principal domains essentialfor optimizing BCG revaccination: the timing of revaccination, the assessmentof various BCG strains, the evaluation of the vaccine's effectiveness on MTBand non‐tuberculous mycobacteria (NTM) strains, and the enhancement of RCTmethodologies. Determining the optimal revaccination timing is paramount forbolstering immunity, especially in regions with high TB prevalence. Theanalysis of different BCG strains provides insights into strain‐specificimmunogenicity, informing vaccine deployment strategies. Additionally,understanding the vaccine's impact on a range of mycobacterial infections iscrucial for its broader application in various microbial contexts. The reviewemphasizes the refinement of RCT designs to ensure robust and consistentoutcomes, facilitating the reproducibility of results in diverse settings. Itproposes a strategy that not only suggests modifications to revaccinationpractices to increase global TB prevention effectiveness but also calls forcontinuous research to improve BCG revaccination methodologies. The paperadvocates for a standardized, evidence‐driven approach to global TB preventionthat takes into account regional epidemiological differences. In conclusion,this review significantly contributes to the discourse on TB prevention,advocating for evidence‐based, standardized approaches that could potentiallytransform the role of BCG revaccination in global TB prevention efforts. Thefindings support current initiatives aimed at developing policies based onsolid evidence, ensuring the scientific integrity and practical relevance ofBCG revaccination strategies. [ABSTRACT FROM AUTHOR]

Bacille Calmette–Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries. Disseminated BCG vaccine disease is a classic feature of children with human immunodeficiency virus (HIV) or primary immunodeficiency disorders (PIDs) and is associated with high mortality. We report a case of a 6-month-old infant with disseminated BCG disease and hemophagocytic lymphohistiocytosis mimicking juvenile myelomonocytic leukemia with no demonstrable features of HIV or PID even after extensive laboratory work-up and succumbed to progressive disease. Disseminated BCG disease is a rare and potentially fatal complication of BCG vaccine, and prompt immunological evaluation complemented by initiation of 4-drug antitubercular therapy and definitive treatment with antiretroviral therapy or hematopoietic stem cell transplant is warranted. [ABSTRACT FROM AUTHOR]

Can Hu,1,2,* Yan Qiu,1,2,* Jiajun Guo,1,2 Yuchao Cao,1,2 Dairong Li,3 Yonghong Du1,2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dairong Li, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012745, Fax +86-23-68485021, Email lidairong@hospital.cqmu.edu.cn Yonghong Du, State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel/Fax +86-23-68485021, Email duyonghong@cqmu.edu.cnPurpose: Tuberculosis (TB) is a chronic disease caused by Mycobacterium tuberculosis (MTB) that remains a major global health challenge. One of the main obstacles to effective treatment is the heterogeneous microenvironment of TB granulomas. This study aimed to investigate the potential of a hypoxic remission-based strategy to enhance the outcome of tuberculosis treatment when implemented in combination with ultrasound.Methods: A PLGA nanoparticle (LEV@CAT-NPs) loaded with levofloxacin (LEV) and catalase (CAT) was fabricated by a double emulsification method, and its physical characteristics, oxygen production capacity, drug release capacity, and biosafety were thoroughly investigated. The synergistic therapeutic effects of ultrasound (US)-mediated LEV@CAT-NPs were evaluated using an experimental mouse model of subcutaneous tuberculosis granuloma induced by Bacille Calmette-Guérin (BCG) as a substitute for MTB.Results: LEV@CAT-NPs exhibited excellent oxygen production capacity, biosafety, and biocompatibility. Histological analysis revealed that ultrasound-mediated LEV@CAT-NPs could effectively remove bacteria from tuberculous granulomas, significantly alleviate the hypoxia state, reduce the necrotic area and inflammatory cells within the granuloma, and increase the penetration of dyes in granuloma tissues. The combined treatment also reduced the serum levels of inflammatory cytokines (eg, TNF-α, IL-6, and IL-8), and significantly downregulated the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). These results suggested that the synergistic treatment of ultrasound-mediated LEV@CAT-NPs effectively eradicated the bacterial infection and reversed the hypoxic microenvironment of tuberculous granulomas, further promoting tissue repair.Conclusion: This study provides a non-invasive and new avenue for treating refractory tuberculosis infections. The potential role of regulating hypoxia within infected lesions as a therapeutic target for infection deserves further exploration in future studies.Keywords: tuberculosis granulomatous, hypoxia, catalase, sonodynamic therapy, Bacille Calmette-Guérin

There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette–Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia. [ABSTRACT FROM AUTHOR]

Vaccines such as Bacille Calmette–Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive interleukin (IL)-12p40 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). It has been described in ∼50 patients, usually with onset at childhood with Bacille Calmette-Guérin (BCG) and Salmonella infections. Case Presentation: A male patient born to consanguineous parents was diagnosed with presumed lymph node MSMD at the age of 13 years after ocular symptoms. A positive history of inborn error of immunity was present: BCG reaction, skin abscess, and recurrent oral candidiasis. Abnormal measurements of cytokine levels, IL-12p40 and interferon-gamma (IFN-γ), lead to the diagnosis of MSMD. Genetic analysis showed a mutation in exon 7 of the IL12B gene. Currently, the patient is alive under prophylactic antibiotics. Conclusion: We report a rare case of IL-12p40 deficiency in a Latin American patient. Medical history was crucial for immune defect suspicion, as confirmed by precision diagnostic medicine tools. [ABSTRACT FROM AUTHOR]

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PurposeThe coronavirus disease 2019 (COVID-19) pandemic has spread to all countries in the world, and different countries have been impacted differently. The study aims to understand what factors contribute to different COVID-19 impacts at the country level.MethodsMultivariate statistical analyses were used to evaluate COVID-19 deaths and cases relative to nine other demographic and socioeconomic factors in all countries and regions of the world using data as of August 1, 2020. The factors analyzed in the study include a country's total COVID-19 deaths and cases per million population, per capita gross domestic product (GDP), population density, virus tests per million population, median age, government response stringency index, hospital beds availability per thousand population, extreme poverty rate, Bacille Calmette-Guérin (BCG) vaccination rate, and diphtheria-tetanus-pertussis (DTP3) immunization rate.ResultsThe study reveals that COVID-19 deaths per million population in a country most significantly correlates, inversely, with the country's BCG vaccination rate (r =  - 0.50, p = 5.3e-5), and also significantly correlates a country's per capita GDP (r = 0.39, p = 7.4e-3) and median age (r = 0.30, p = 0.042), while COVID-19 cases per million population significantly correlate with per capita GDP and tests per thousand population. To control for possible confounding effects of age, the correlation was assessed in countries propensity score matched for age. The inverse correlation between BCG vaccination rates and COVID-19 case (r =  - 0.30, p = 0.02) and death (r =  - 0.42, p = 0.0007) remained significant among the top 61 countries with the highest median age.ConclusionThis study contributes to a growing body of evidence supporting the notion that BCG vaccination may be protective against COVID-19 mortality.

The coronavirus disease 2019 (COVID-19) pandemic has spread to all countries in the world after more than half a year since it was first reported in late 2019, and different countries have been impacted differently. Multivariate statistical analyses were used to evaluate COVID-19 deaths and cases relative to nine other demographic and socioeconomic factors in all countries and regions of the world using data as of August 1, 2020. The factors analyzed in the study include a country's total COVID-19 deaths and cases per million population, per capita gross domestic product (GDP), population density, virus tests per million population, median age, government response stringency index, hospital beds availability per thousand population, extreme poverty rate, Bacille Calmette-Guérin (BCG) vaccination rate, and diphtheria-tetanus-pertussis (DTP3) immunization rate. The study reveals that COVID-19 deaths per million population in a country most significantly correlates, inversely, with the country's BCG vaccination rate, and also significantly correlates a country's per capita GDP and median age, while COVID-19 cases per million population significantly correlate with per capita GDP and tests per thousand population. This study contributes to a growing body of evidence supporting the notion that BCG vaccination may be protective against COVID-19 mortality.

ABSTRACTThe bacille Calmette-Guérin (BCG) vaccine is administered in many countries as part of their vaccination schedules. Epidemiologic studies have suggested a possible benefit of this vaccine in the context of the COVID-19 pandemic and other respiratory infections. We aimed to assess the safety of this intervention in BCG-primed adults. Adult health care workers (n = 451) received a single intradermal application of the BCG vaccine (Tokyo 172 strain) in the deltoid region of the right arm. Follow-up (30 days) calls and clinical inspections were guided using a standardized data sheet to assess local and systemic reactions. Early local reactions were common at 24 h and 7 days, such as erythema (74.9%, 69.2%), induration (55.7%, 59%), a papule (53.4%, 47.7%), and edema (48.3%, 38.1). Local symptoms (pruritus 44.8%, heat 16.2%, and pain 34.8%) were less frequent at day 7. Late expected reactions (14 and 30 days) included the formation of crusts (39.6% and 63.9%), a pustule (36.6% and 17%), or ulcers (28.8% and 17.7%). Severe reactions were limited to subcutaneous abscesses (2%) and lymphadenitis (

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Purpose: Summarize the characteristics of a large cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and patients without identified genetic etiology. Methods: We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID), and gene negative group. Results: A total of 134 patients were reviewed, and most of them had PID. A total of 111 (82.8%) patients had 18 different types of pathogenic gene mutations, most of whom (91.0%) were classified with CGD, MSMD, and SCID. CYBB was the most common gene mutation (52/111). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P < 0.001), age at diagnosis (P = 0.013), frequency of recurrent fever (P = 0.007), and vaccination-homolateral axillary lymph node enlargement (P = 0.039) and infection severity (P = 0.006) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (48.3%). The course of anti-tuberculosis treatment and the survival time between patients with PID and without identified genetic etiology were similar. Conclusion: Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Patients without identified genetic etiology had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered. [ABSTRACT FROM AUTHOR]

Purpose: To examine the effect of an aqueous infusion of Plectranthus amboinicus (AIP) on the immunological development of rats in response to Bacille Calmette-Guerin (BCG) antigen induction. Methods: Twenty-four male rats, aged 3 months, were separated into six groups. Group 1 was normal control group without treatment, whereas groups 2 and 3 were the treatment groups induced with 100 µL BCG on days 7 and 14, followed by oral administration of AIP at doses of 19 and 31.5 g/kg, respectively. Groups 4 and 5 were treated only with AIP at doses of 19 and 31.5 g/kg respectively. Group 6 was a negative control group induced with 100 µL BCG on days 7 and 14. On day 31, IgG activity, antibody titer, lysozyme activity, relative organ weight, and lung histology were determined. Results: The results showed that IgG levels, antibody titers, and lysozyme activity were significantly elevated in groups 4, 5, and 6 compared to normal control group (p < 0.05). Aqueous infusion of Plectranthus amboinicus and BCG had no effect on the relative weight of spleen. However, the therapy administered to rats in group 3 significantly increased their liver and lung mass (p < 0.05). Conclusion: Aqueous infusion of Plectranthus amboinicus leaves stimulates the immune system in BCG-induced rats. [ABSTRACT FROM AUTHOR]

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats' health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4+, CD8+, and γδ T cells showed that CD4+ T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats. [ABSTRACT FROM AUTHOR]

Helminth infections are among the neglected tropical diseases affecting billions of people globally, predominantly in developing countries. Helminths' effects are augmented by coincident tuberculosis disease, which infects a third of the world's population. The role of helminth infections on the pathogenesis and pathology of active tuberculosis (T.B.) remains controversial. Parasite-induced suppression of the efficacy of Bacille Calmette-Guerin (BCG) has been widely reported in helminth-endemic areas worldwide. T.B. immune response is predominantly proinflammatory T-helper type 1 (Th1)-dependent. On the other hand, helminth infections induce an opposing anti-inflammatory Th2 and Th3 immune-regulatory response. This review summarizes the literature focusing on host immune response profiles during single-helminth, T.B. and dual infections. It also aims to necessitate investigations into the complexity of immunity in helminth/T.B. coinfected patients since the research data are limited and contradictory. Helminths overlap geographically with T.B., particularly in Sub-Saharan Africa. Each disease elicits a response which may skew the immune responses. However, these effects are helminth species-dependent, where some parasites have no impact on the immune responses to concurrent T.B. The implications for the complex immunological interactions that occur during coinfection are highlighted to inform government treatment policies and encourage the development of high-efficacy T.B. vaccines in areas where helminths are prevalent. [ABSTRACT FROM AUTHOR]

The development of heterologous prime-boost regimens utilizing Bacille Calmette-Guerin (BCG) as the priming vaccine is a promising approach to improve the efficacy of vaccination against tuberculosis (TB). In this study, we examined the ability of a DNA vaccine that expressed a fusion of antigens Rv2299c and Ag85A to boost BCG immunity and protection against Mycobacterium tuberculosis (Mtb) in Balb/c mice. The fusion DNA vaccine was moderately immunogenic and afforded some protection when used on its own. After a priming BCG vaccination, the DNA boost significantly amplified Th1-type cell-mediated immunity compared to that resulting from either BCG or DNA immunization. In the DNA-boosted mice, Ag-specific CD4+ and CD8+ T cells that were mono-positive for IFN-γ alone were the most prominently expanded in infected lungs. The protective efficacy afforded by BCG against challenge infection was greatly improved by the DNA boost; bacterial loads were significantly reduced in both spleen and lung and histological damage in the lung was less. The use of a DNA vaccine containing the fusion antigens Rv2299c and Ag85A to boost BCG may be a good choice for the rational design of an efficient vaccination strategy against TB. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non‐muscle‐invasive bladder cancer (NMIBC) treated with adequate bacille Calmette–Guérin (BCG). Patients and Methods: We performed an Institutional Review Board‐approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence‐ and progression‐free survival were analysed using Kaplan–Meier methods and Cox proportional hazard models. Results: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence‐ or progression‐free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. Conclusion: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The Bacille Calmette-Guérin (BCG) vaccine, given as a single dose, offers variable protection against Tuberculosis (TB). It is plausible that repeat doses could improve the effectiveness of the BCG vaccine in settings where the population remain at risk of the disease. Objective: To assess the effectiveness of BCG revaccination as a booster dose in preventing TB in Low- and Middle- Income Countries (LMICs). Methods: We searched the electronic databases without language or publication restrictions and followed the procedures for preparing systematic reviews, including assessing the risk of bias as outlined in the Cochrane handbook. We included randomised controlled trials (RCTs) conducted in LMICs involving children and adults receiving one or more BCG vaccine doses after the primary BCG vaccination. The incidence of severe forms of TB, active TB and adverse events were the primary outcomes. Results: Five RCTs were included in this systematic review. Revaccination with BCG probably makes little or no difference to the risk of active TB measured after five years (Relative risk (RR) 1.16, 95% CI 0.88 to 1.51; 348,083 participants; one study, moderate certainty evidence) or nine years post-revaccination (RR 0.96, 95% CI 0.82 to 1.12; 348,083 participants; one study, moderate certainty evidence). In populations with HIV co-infection, revaccination probably increases the risk of pulmonary tuberculosis compared to placebo (RR 1.74, 95% CI 1.00 to 3.01; 46,764 participants; one study, moderate certainty evidence). Conclusion: The available evidence suggests that BCG revaccination probably makes little or no difference in preventing tuberculosis disease in LMICs.

Objective: To explore whether all individuals with diabetes are at an increased risk of tuberculosis or whether there are high-risk groups of diabetes patients. Methods: A population-based census was conducted in China, including 27 807 individuals. Risk factors for incident tuberculosis were investigated and participants included in the study were linked to the Tuberculosis Management Information System. Cox proportional hazards models adjusting for several variables were constructed in two steps. First, the incident rate of tuberculosis in individuals with/without diabetes was compared without any stratification by high body mass index (BMI). Second, two groups stratified by BMI were compared. Results: Over 7 years of follow-up, 108 individuals progressed to tuberculosis. In the multivariable Cox regression analysis, participants with diabetes had a 2.26 higher hazard (P = 0.017) of tuberculosis when compared to participants without diabetes. However, participants with a BMI >24 kg/m2 and diagnosed with diabetes had a similar risk as overweight participants without diabetes (P = 0.953), while diabetes with a BMI

Purpose: Bacille Calmette-Guerin (BCG) is considered the most effective agent for non-muscle invasive bladder cancer (NMIBC). However, due to BCG-related toxicity, multiple studies have suggested the role of newer chemotherapeutic drugs. The aim of our study was to evaluate intravesical gemcitabine + docetaxel (Gem/Doce) versus BCG with respect to quality of life (QOL), safety, and efficacy in NMIBC. Methods: A total of 60 patients with NMIBC were evaluated between July 2019 and December 2020 in a prospective manner. The sample size calculation was done, keeping in mind the incidence of intravesical BCG-related complications of up to 50–60% and 20–30% for Gem/Doce combination. The p value of 0.05 was kept as statistically significant. The enrollment ratio was kept at 1, and power of study was aimed at 80%. The study population was alternatively assigned to two groups (BCG vs. Gem/Doce) of 30 patients each. Both the groups received 6 weekly doses of induction therapy followed by 6 monthly doses of maintenance therapy if no recurrence was noted at interim follow-up. QOL scores, safety, and efficacy were assessed at beginning of intravesical therapy, end of induction, and 6 months of maintenance therapy. Cystoscopy examination and cytology were performed at the end of induction therapy and 3-monthly thereafter. Result: The preliminary results at the end of 6 months following maintenance therapy showed that the demographic profile, histological stage, and grade were comparable between two groups. The QOL scores using QLQ-30 and QLQ-BLS-24 showed statistically significant differences with the Gem/Doce arm showing better outcomes. There were no progressions to higher stage, while one recurrence each was seen in both groups. Patient-related side effects measured by CTCAE (Common Terminology Criteria for Adverse Events)version 5 showed that the BCG group had higher toxicity profile as compared to Gem/Doce group. Conclusion: Gem/Doce combination intravesical therapy is a promising alternative to BCG for treatment of NMIBC, showing better QOL measures and lesser side effects. [ABSTRACT FROM AUTHOR]

Cutaneous Tuberculosis (TB) is a chronic bacterial infection. It is difficult to diagnose these lesions since they mimic various other dermatological conditions. Cutaneous tuberculosis has a wide range of variations in morphology, histopathology, immunology and treatment response and a diagnosis of cutaneous tuberculosis is very much common in developing countries like India. Cutaneous tuberculosis can be exogenous; endogenous: caused by contiguity or autoinoculation and by haematogenous spread; induced by the Calmette-Guérin bacillus and manifest as a tuberculoid. The diagnosis of the infection is supported through the direct test, culture, histopathology, tuberculin skin test, polymerase chain reaction, interferon-gamma release assay, and genotyping. Drugs used for treatment comprises of isoniazid, rifampicin, pyrazinamide and ethambutol. The authors hereby present a case series (six cases) of various types of lupus vulgaris and scrofuloderma that came to Dermatology Outpatient Department with similar findings. [ABSTRACT FROM AUTHOR]

Background and Objectives: The enigma COVID-19 pandemic already involved major parts of globe with toll of 2,074,529 victims and 139,378 deaths from 213 countries/territories as on April 14, 2020. It cripples nations by the loss of human resources, economic decline, hunger, unemployment insecurities giving way to mental morbidities, and still many others to be discovered. Till it completes its trajectory, a systematic investigation, a prerequisite of any epidemic control, is warranted. Materials and Methods: A cross-sectional survey over 2 weeks (April 15, 2020–April 28, 2020) has been conducted at a teaching institution at Kolkata aiming to describe the magnitude, pattern, severity, and correlates of coronavirus pandemic 2020. Data pertaining to COVID-19 cases, deaths of affected countries, and their reported and or potential correlates were retrieved from various public domains, for example, https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports, worldpopulationreview.com, data.worldbank.org. Results: Multiple linear regression analysis revealed a maximum R2 of 32.3% (P = 0.013) with a significant model fit (P = 0.000) for COVID-19 incidence rate per million which is associated positively with the proportion of the urban population (b = 0.024) and the percentage of the population aged 65 years or higher (b = 0.112) and negatively with current universal Bacille Calmette-Guérin vaccination (b = −1.021) policy of countries. Conclusion: Against this viral catastrophe evidence-based classical public health measures are underway. Notwithstanding variations in testing and reporting policy, the findings of this research ignite further study.

Diagnosis of Kawasaki disease in infants under 3 months of age is challenging. This study aimed to confirm the diagnostic efficacy of BCGitis in patients with Kawasaki disease aged <3 months. Overall, 473 children were enrolled; they were grouped by age into group 1 (≤3 months, n = 19) and group 2 (>3 months, n = 454). Data, including clinical features and laboratory results, were analyzed and compared between the groups. In group 1, 89% of patients showed Bacille Calmette-Guérin site reactivation. In group 1, total duration of fever and fever duration before initial treatment were significantly shorter than in group 2 (p = 0.001). The incidences of conjunctival injection, changes in extremities (erythema and edema), and cervical lymphadenopathy were significantly lower (p = 0.006, p = 0.040, and p < 0.001, respectively), and desquamation was higher in group 1 (p = 0.004). The incidences of incomplete Kawasaki disease, coronary artery complications, and resistance to intravenous immunoglobulin did not differ between the groups. Kawasaki disease should be suspected in infants aged <3 months with unexplained fever and BCGitis, even if the principal clinical symptoms are not fully presented. BCGitis in infantile Kawasaki disease is a useful sign and can help in the diagnosis of Kawasaki disease. [ABSTRACT FROM AUTHOR]

Background: Intravesical Bacille Calmette-Guérin (BCG) therapy is a widely adopted treatment for non-muscle-invasive bladder cancer (NMIBC). Despite its extensive use, the historical origins of BCG therapy remain under-appreciated by many practitioners. Initially developed as a tuberculosis vaccine by Albert Calmette and Camille Guérin in the early 20 th century, BCG's immunomodulatory potential was later harnessed for cancer treatment. The unintended discovery of its attenuated virulence, combined with extensive subsequent research, laid the foundation for its clinical application in bladder cancer. Currently, BCG is a cornerstone treatment for NMIBC, particularly in high-risk cases, and has significantly influenced the evolution of modern immunotherapies, including checkpoint inhibitors., Objective: This paper was written with the intent of exploring the origins of BCG and historically significant research that led to it's use and acceptance as a treatment for NMIBC while highlighting it's impact on the development of immunotherapy as a whole., Conclusion: The BCG vaccine's journey from a tuberculosis preventive to a groundbreaking cancer treatment underscores the interconnected nature of scientific discovery and its enduring impact on modern medicine., Competing Interests: The authors declare no conflict of interest., (© 2024 Bladder, All rights reserved.)

Vaccines such as bacille Calmette-Guérin (BCG) are known for their heterologous effects mediated through a number of mechanisms, including trained immunity constituted by monocyte-macrophage based innate immunity. Other events such as direct hematogenous spread and induction of autoimmunity are also described. There has been a resurgent interest in harnessing some of the benefits of trained immunity in the management of COVID-19, even as several specific vaccines have been approved. We summarize the current knowledge of ocular effects of BCG. Potential effect of granulomatous inflammation on angiotensin converting enzyme activity and accentuation of cytokine storm that may result in undesirable ocular and systemic effects are also discussed. [ABSTRACT FROM AUTHOR]

Objectives: To investigate bacille Calmette–Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan–Meier and log‐rank tests analysed differences in recurrence‐free (RFS) and progression‐free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. Results: A total of 518 patients received adequate BCG at a median (range) of 26 (6–188) days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7‐33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P = 0.966), RFS (P = 0.632) or PFS (P = 0.789). On both uni‐ and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99–1.00, P = 0.449; and for PFS was 0.99, 95% CI 0.98–1.00, P = 0.074). Conclusion: The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response. [ABSTRACT FROM AUTHOR]

The pandemic of coronavirus disease 2019 (COVID-19) has impacted many health service systems including tuberculosis (TB) control in India. As of October 19, 2020, India has the second highest number of COVID cases globally, amounting to 7.55 million reported COVID-19 cases and 114,640 deaths. Indian Council of Medical Research's Bacille Calmette-Guérin vaccine study among elderly individuals in COVID-19 hotspots involves the following strategy such as COVID screening by antibody testing and real-time reverse-transcriptase-polymerized chain reaction, TB screening by symptom and chest X-ray, and those who are tested positive will be linked to the national tuberculosis elimination programme for the management, this could be a sustainable new strategy in combating the two pandemic diseases, especially in India with high TB and COVID-19 disease burden. To ensure no one is left behind, the paradigm shift of screening for TB and COVID should be in place to sustain the progress made toward TB elimination. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis in children is still found in East Java Province at 2017 with 2,749 cases of paediatric tuberculosis. The Bacille Calmette-Guérin (BCG) immunisation coverage and healthy houses in East Java Province increase every year. Purpose: This study aims to analyse the correlation between BCG immunisation and healthy houses with paediatric tuberculosis discovery in East Java Province during 2015–17. Methods: This study is observational with a correlation study design. The population in this study were children aged 0–14 years who suffered from tuberculosis in a district or city in East Java Province in 2015–17. Sampling of this study uses aggregate data on paediatric tuberculosis discovered in children aged 0–14 years, coverage of BCG immunisation and coverage of healthy houses in districts/cities in East Java in 2015–17 found in Health Profile of East Java Province 2015–17. The variables studied were paediatric tuberculosis in children aged 0–14 years, BCG immunisation coverage and healthy house; the analysis techniques were the Kolmogorov-Smirnov normality test and Pearson correlation. Results: This study shows that there is correlation between BCG immunisation and paediatric tuberculosis (p = 0.01, p

Background: Live attenuated vaccines have been observed to have particularly beneficial effects for child survival when given in the presence of maternally transferred immunity (priming). We aimed to test this finding and furthermore explore the role of paternal priming. Methods: In an exploratory, retrospective cohort study in 2017, parental Bacillus Calmette-Guérin (BCG) scars were assessed for infants from the Bandim Health Project (BHP) who had participated in a 2008–2013 trial of neonatal BCG vaccination. Parental scar effects on mortality were estimated from birth to 42 days, the age of the scheduled diphtheria-tetanus-pertussis (DTP) vaccination, in Cox proportional hazard models adjusted with Inverse Probability of Treatment Weighting. Findings: For 66% (510/772) of main trial infants that were still registered in the BHP area, at least one parent was located. BCG scar prevalence was 77% (353/461) among mothers and 63% (137/219) among fathers. In the first six weeks of life, maternal scars were associated with a mortality reduction of 60% (95%CI, 4% to 83%) and paternal scars with 49% (-68% to 84%). The maternal scar association was most beneficial among infants that had received BCG vaccination at birth (73% (-1% to 93%)). Although priming was less evident for paternal scars, having two parents with scars reduced mortality by 89% (13% to 99%) compared with either one or none of the parents having a scar. Interpretation: Parental BCG scars were associated with strongly increased early-life survival. These findings underline the importance of future studies into the subject of inherited non-specific immunity and parental priming. Funding: Danish National Research Foundation; European Research Council; Novo Nordisk Foundation; University of Southern Denmark.

Background and Objectives: The enigma COVID-19 pandemic already involved major parts of globe with toll of 2,074,529 victims and 139,378 deaths from 213 countries/territories as on April 14, 2020. It cripples nations by the loss of human resources, economic decline, hunger, unemployment insecurities giving way to mental morbidities, and still many others to be discovered. Till it completes its trajectory, a systematic investigation, a prerequisite of any epidemic control, is warranted. Materials and Methods: A cross-sectional survey over 2 weeks (April 15, 2020–April 28, 2020) has been conducted at a teaching institution at Kolkata aiming to describe the magnitude, pattern, severity, and correlates of coronavirus pandemic 2020. Data pertaining to COVID-19 cases, deaths of affected countries, and their reported and or potential correlates were retrieved from various public domains, for example, https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports , worldpopulationreview.com, data.worldbank.org. Results: Multiple linear regression analysis revealed a maximum R2 of 32.3% (P = 0.013) with a significant model fit (P = 0.000) for COVID-19 incidence rate per million which is associated positively with the proportion of the urban population (b = 0.024) and the percentage of the population aged 65 years or higher (b = 0.112) and negatively with current universal Bacille Calmette-Guérin vaccination (b = −1.021) policy of countries. Conclusion: Against this viral catastrophe evidence-based classical public health measures are underway. Notwithstanding variations in testing and reporting policy, the findings of this research ignite further study. [ABSTRACT FROM AUTHOR]

ObjectiveTo assess the effect of fibrin clot inhibitors (aspirin, clopidogrel, and warfarin) and statins on intravesical BCG therapy.MethodA systematic literature search was carried out through PubMed, Embase, and the Cochrane Central Search Library in March 2020. Accumulative analyses of odds ratios (ORs), hazard ratio (HR), and corresponding 95% confidence intervals (CIs) were performed. All analyses were performed by using Review Manager software version 5.3 and Stata 15.1.ResultsFour cohort studies and nine case–control studies containing 3,451 patients were included. The pooled analysis indicated that statins (HR = 1.00; 95%CI, 0.82 to 1.22; p = 1.00) and fibrin clot inhibitors (HR = 1.01; 95%CI, 0.64 to 1.59; p = 0.98) did not affect the efficacy of BCG on recurrence-free survival. The cumulative analysis showed that statins (HR = 0.79; 95%CI, 0.41 to 1.49; p = 0.46) and fibrin clot inhibitors (HR = 1.62; 95%CI, 0.90 to 2.91; p = 0.11) did not affect the efficacy of BCG on progression-free survival. There were no differences on cancer-specific survival (HR = 1.68; 95%CI, 0.64 to 4.40; p = 0.29) and overall survival (HR = 1.13; 95%CI, 0.73 to 1.78; p = 0.58) after taking statins.ConclusionThe present study shows that the application of fibrin clot inhibitors and statins do not influence the efficacy of BCG on oncological prognosis. Consequently, we do not need to stop using them or change to other drugs during intravesical BCG treatment. However, large-scale multi-center prospective research is still needed to confirm the above conclusions.

Objective: To assess the effect of fibrin clot inhibitors (aspirin, clopidogrel, and warfarin) and statins on intravesical BCG therapy. Method: A systematic literature search was carried out through PubMed, Embase, and the Cochrane Central Search Library in March 2020. Accumulative analyses of odds ratios (ORs), hazard ratio (HR), and corresponding 95% confidence intervals (CIs) were performed. All analyses were performed by using Review Manager software version 5.3 and Stata 15.1. Results: Four cohort studies and nine case–control studies containing 3,451 patients were included. The pooled analysis indicated that statins (HR = 1.00; 95%CI, 0.82 to 1.22; p = 1.00) and fibrin clot inhibitors (HR = 1.01; 95%CI, 0.64 to 1.59; p = 0.98) did not affect the efficacy of BCG on recurrence-free survival. The cumulative analysis showed that statins (HR = 0.79; 95%CI, 0.41 to 1.49; p = 0.46) and fibrin clot inhibitors (HR = 1.62; 95%CI, 0.90 to 2.91; p = 0.11) did not affect the efficacy of BCG on progression-free survival. There were no differences on cancer-specific survival (HR = 1.68; 95%CI, 0.64 to 4.40; p = 0.29) and overall survival (HR = 1.13; 95%CI, 0.73 to 1.78; p = 0.58) after taking statins. Conclusion: The present study shows that the application of fibrin clot inhibitors and statins do not influence the efficacy of BCG on oncological prognosis. Consequently, we do not need to stop using them or change to other drugs during intravesical BCG treatment. However, large-scale multi-center prospective research is still needed to confirm the above conclusions. [ABSTRACT FROM AUTHOR]

Despite of the rapid development of the vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it will take several months to have enough doses and the proper infrastructure to vaccinate a good proportion of the world population. In this interim, the accessibility to the Bacille Calmette-Guerin (BCG) may mitigate the pandemic impact in some countries and the BCG vaccine offers significant advantages and flexibility in the way clinical vaccines are administered. BCG vaccination is a highly cost-effective intervention against tuberculosis (TB) and many low-and lower-middle-income countries would likely have the infrastructure, and health care personnel sufficiently familiar with the conventional TB vaccine to mount full-scale efforts to administer novel BCG-based vaccine for COVID-19. This suggests the potential for BCG to overcome future barriers to vaccine roll-out in the countries where health systems are fragile and where the effects of this new coronavirus could be catastrophic. Many studies have reported cross-protective effects of the BCG vaccine toward non-tuberculosis related diseases. Mechanistically, this cross-protective effect of the BCG vaccine can be explained, in part, by trained immunity, a recently discovered program of innate immune memory, which is characterized by non-permanent epigenetic reprogramming of macrophages that leads to increased inflammatory cytokine production and consequently potent immune responses. In this review, we summarize recent work highlighting the potential use of BCG for the treatment respiratory infectious diseases and ongoing SARS-CoV-2 clinical trials. In situations where no other specific prophylactic tools are available, the BCG vaccine could be used as a potential adjuvant, to decrease sickness of SARS-CoV-2 infection and/or to mitigate the effects of concurrent respiratory infections.

Sjogren’s syndrome (SS) is a common, systemic autoimmune disorder primarily affecting the exocrine glands resulting in xerostomia and xerophthalmia. SS may also manifest with polyarthralgia, polyarthritis, polymyalgia, cutaneous/other organ vasculitis, interstitial lung disease, and/or various other disorders. The primary autoantibodies associated with SS and used as adjuncts to diagnosis are anti-Ro (SSA) and anti-La (SSB). The pathogenesis of SS is considered to involve genetic susceptibility and environmental triggers. An identified genetic susceptibility for SS lies in variants of the tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene, the product of which is known as A20. Deficiency or dysfunction of A20 is known to induce macrophage inflammatory response to mycobacteria, potentially increasing the repertoire of mycobacterial antigens available and predisposing to autoimmunity via the paradigm of molecular mimicry; i.e., providing a mechanistic link between genetic susceptibility to SS and exposure to environmental non-tuberculous mycobacteria (NTM). Mycobacterium avium ss. paratuberculosis (MAP) is an NTM that causes Johne’s disease, an enteritis of ruminant animals. Humans are broadly exposed to MAP or its antigens in the environment and in food products from infected animals. MAP has also been implicated as an environmental trigger for a number of autoimmune diseases via cross reactivity of its heat shock protein 65 (hsp65) with host-specific proteins. In the context of SS, mycobacterial hsp65 shares epitope homology with the Ro and La proteins. A recent study showed a strong association between SS and antibodies to mycobacterial hsp65. If and when this association is validated, it would be important to determine whether bacillus Calmette-Guerin (BCG) vaccination (known to be protective against NTM likely through epigenetic alteration of innate and adaptive immunity) and anti-mycobacterial drugs (to decrease mycobacterial antigenic load) may have a preventive or therapeutic role against SS. Evidence to support this concept is that BCG has shown benefit in type 1 diabetes mellitus and multiple sclerosis, autoimmune diseases that have been linked to MAP via hsp65 and disease-specific autoantibodies. In conclusion, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and SS, including the presence of antibodies to mycobacterial hsp65 in SS, the homology of hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases. Furthermore, given that BCG may protect against NTM, has immune modifying effects, and has a strong safety record of billions of doses given, BCG and/or anti-mycobacterial therapeutics should be studied in SS.

Summary: Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p

Diagnosis of Kawasaki disease in infants under 3 months of age is challenging. This study aimed to confirm the diagnostic efficacy of BCGitis in patients with Kawasaki disease aged n = 19) and group 2 (>3 months, n = 454). Data, including clinical features and laboratory results, were analyzed and compared between the groups. In group 1, 89% of patients showed Bacille Calmette-Guérin site reactivation. In group 1, total duration of fever and fever duration before initial treatment were significantly shorter than in group 2 (p = 0.001). The incidences of conjunctival injection, changes in extremities (erythema and edema), and cervical lymphadenopathy were significantly lower (p = 0.006, p = 0.040, and p < 0.001, respectively), and desquamation was higher in group 1 (p = 0.004). The incidences of incomplete Kawasaki disease, coronary artery complications, and resistance to intravenous immunoglobulin did not differ between the groups. Kawasaki disease should be suspected in infants aged

Despite of the rapid development of the vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it will take several months to have enough doses and the proper infrastructure to vaccinate a good proportion of the world population. In this interim, the accessibility to the Bacille Calmette-Guerin (BCG) may mitigate the pandemic impact in some countries and the BCG vaccine offers significant advantages and flexibility in the way clinical vaccines are administered. BCG vaccination is a highly cost-effective intervention against tuberculosis (TB) and many low-and lower-middle-income countries would likely have the infrastructure, and health care personnel sufficiently familiar with the conventional TB vaccine to mount full-scale efforts to administer novel BCG-based vaccine for COVID-19. This suggests the potential for BCG to overcome future barriers to vaccine roll-out in the countries where health systems are fragile and where the effects of this new coronavirus could be catastrophic. Many studies have reported cross-protective effects of the BCG vaccine toward non-tuberculosis related diseases. Mechanistically, this cross-protective effect of the BCG vaccine can be explained, in part, by trained immunity, a recently discovered program of innate immune memory, which is characterized by non-permanent epigenetic reprogramming of macrophages that leads to increased inflammatory cytokine production and consequently potent immune responses. In this review, we summarize recent work highlighting the potential use of BCG for the treatment respiratory infectious diseases and ongoing SARS-CoV-2 clinical trials. In situations where no other specific prophylactic tools are available, the BCG vaccine could be used as a potential adjuvant, to decrease sickness of SARS-CoV-2 infection and/or to mitigate the effects of concurrent respiratory infections. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) is recommended at birth in TB-endemic areas. Currently, BCG vaccination programmes use "BCG vaccination coverage by 12 months of age" as the performance indicator. Previous studies suggest that BCG-vaccinated children, who develop a scar, have better overall survival compared with BCG-vaccinated children, who do not develop a scar. We summarized the available studies of BCG scarring and child survival. A structured literature search for studies with original data and analysis of BCG scarring and mortality were performed. Combined analyses on the effect of BCG scarring on overall mortality. We identified six studies covering seven cohorts, all from Guinea-Bissau, West Africa, with evaluation of BCG scarring amongst BCG-vaccinated children and follow-up for mortality. Determinants of BCG scarring were BCG strain, intradermal injection route, size of injection wheal, and co-administered vaccines and micronutrients. In a combined analysis, having a BCG scar vs. no BCG scar was associated with a mortality rate ratio (MRR) of 0.61 (95% CI: 0.51-0.74). The proportion with a BCG scar varied from 52 to 93%; the estimated effect of a BCG scar was not associated with the scar prevalence. The effect was strongest in the first (MRR = 0.48 (0.37-0.62)) and second (MRR = 0.63 (0.44-0.92)) year of life, and in children BCG-vaccinated in the neonatal period (MRR = 0.45 (0.36-0.55)). The effect was not explained by protection against TB. Confounding and genetic factors are unlikely to explain the strong association between BCG scarring and subsequent survival. Including "BCG scar prevalence" as a BCG vaccination programme performance indicator should be considered. The effect of revaccinating scar-negative children should be studied. [ABSTRACT FROM AUTHOR]

Since its introduction in 1976, Bacille Calmette-Guerin (BCG) has become the standard of care in high risk non-muscle-invasive bladder cancer. Apart from its efficacy, BCG immunotherapy is also considered to be safe. However, in addition to its common adverse effects, which are mild, it can rarely cause serious adverse effects, which can be life threatening. In this report, the case of an 85-year old male, who developed tuberculous cervical lymphadenitis and abscess after BCG immunotherapy is described. the patient pre- sented with acute renal failure. During his hospitalization he also developed hepatitis because of the anti-tuberculous therapy and eventually passed away, probably by septic emboli originated from his right jugular vein which was infiltrated by his abscess. tubercu- lous cervical lymphadenitis accompanied with abscess is a quite rare complication of BCG immunotherapy, but clinicians should be aware of it, as it can be proved fatal. [ABSTRACT FROM AUTHOR]

Bacille Calmette–Guérin (BCG) vaccination, widely used throughout the world to protect against infant tuberculous meningitis and miliary tuberculosis (TB), can provide broad non-specific protection against infectious respiratory diseases in certain groups. Interest in BCG has seen a resurgence within the scientific community as the mechanisms for non-specific protection have begun to be elucidated. The impact of the COVID-19 pandemic on nearly every aspect of society has profoundly illustrated the pressure that respiratory infections can place on a national healthcare system, further renewing interest in BCG vaccination as a public health policy to reduce the burden of those illnesses. However, the United States does not recommend BCG vaccination due to its variable effectiveness against adult TB, the relatively low risk of Mycobacterium tuberculosis infection in most of the United States, and the vaccine’s interference with tuberculin skin test reactivity that complicates TB screening. In this review, we explore the broad immune training effects of BCG vaccination and literature on the effects of BCG vaccination on COVID-19 spread, disease severity, and mortality. We further discuss barriers to scheduled BCG vaccination in the United States and how those barriers could potentially be overcome.

The non-specific beneficial effects of Bacille Calmette-Guérin (BCG) vaccination suggest that this vaccine might play a role in protecting individuals against severe coronavirus disease 2019 (COVID-19). Several studies propose that BCG vaccination may increase the body's immunity, thereby preventing respiratory infections caused by other respiratory pathogens. As the number of deaths due to COVID-19 is increasing rapidly and there is no specific treatment available to date, scientists are evaluating the effectiveness of already approved drugs as therapies against COVID-19, and the results were found to vary widely: from no significant effect being observed to a reduction in the time taken for clinical improvement. This study thus aims to evaluate whether it is worth performing clinical trials to examine the effects of the BCG vaccine on COVID-19. We herein emphasize the need to conduct phase III randomized controlled trials with adequate sample size and quality to investigate the effects of the BCG vaccine on COVID-19. In the event that BCG vaccination provides non-specific protection against COVID-19, administering it could be helpful in controlling the transmission of COVID-19 and other infectious diseases during future pandemics.

Bacterial glycoproteins have been investigated as vaccine candidates as well as diagnostic biomarkers. However, they are poorly understood in Mycobacterium bovis strain bacille Calmette-Guérin (BCG), a non-pathogenic model of Mycobacterium tuberculosis. To understand the roles of secreted O-mannosylated glycoproteins in BCG, we conducted a ConA lectin-affinity chromatography and mass spectra analysis to identify O-mannosylated proteins in BCG culture filtrate. Subsequent screening of antigens was performed using polyclonal antibodies obtained from a BCG-immunized mouse, with 15 endogenous O-mannosylated proteins eventually identified. Of these, BCG_0470 and BCG_0980 (PstS3) were revealed as the immunodominant antigens. To examine the protective effects of the antigens, recombinant antigens proteins were first expressed in Mycobacterium smegmatis and Escherichia coli, with the purified proteins then used to boost BCG primed-mice. Overall, the treated mice showed a greater delayed-type hypersensitivity response in vivo, as well as stronger Th1 responses, including higher level of IFN-γ, TNF-α, and specific-IgG. Therefore, mannosylated proteins BCG_0470 and BCG_0980 effectively amplified the immune responses induced by BCG in mice. Together, our results suggest that the oligosaccharide chains containing mannose are the antigenic determinants of glycoproteins, providing key insight for future vaccine optimization and design.

Tuberculosis (TB) remains a major health threat. Although a vaccine has been available for almost 100 years termed Bacille Calmette-Guérin (BCG), it is insufficient and better vaccines are urgently needed. This treatise describes first the basic immunology and pathology of TB with an emphasis on the role of T lymphocytes. Better understanding of the immune response to Mycobacterium tuberculosis (Mtb) serves as blueprint for rational design of TB vaccines. Then, disease epidemiology and the benefits and failures of BCG vaccination will be presented. Next, types of novel vaccine candidates are being discussed. These include: (i) antigen/adjuvant subunit vaccines; (ii) viral vectored vaccines; and (III) whole cell mycobacterial vaccines which come as live recombinant vaccines or as dead whole cell or multi-component vaccines. Subsequently, the major endpoints of clinical trials as well as administration schemes are being described. Major endpoints for clinical trials are prevention of infection (PoI), prevention of disease (PoD), and prevention of recurrence (PoR). Vaccines can be administered either pre-exposure or post-exposure with Mtb. A central part of this treatise is the description of the viable BCG-based vaccine, VPM1002, currently undergoing phase III clinical trial assessment. Finally, new approaches which could facilitate design of refined next generation TB vaccines will be discussed.

Bacterial glycoproteins have been investigated as vaccine candidates as well as diagnostic biomarkers. However, they are poorly understood in Mycobacterium bovis strain bacille Calmette-Guérin (BCG), a non-pathogenic model of Mycobacterium tuberculosis. To understand the roles of secreted O-mannosylated glycoproteins in BCG, we conducted a ConA lectin-affinity chromatography and mass spectra analysis to identify O-mannosylated proteins in BCG culture filtrate. Subsequent screening of antigens was performed using polyclonal antibodies obtained from a BCG-immunized mouse, with 15 endogenous O-mannosylated proteins eventually identified. Of these, BCG_0470 and BCG_0980 (PstS3) were revealed as the immunodominant antigens. To examine the protective effects of the antigens, recombinant antigens proteins were first expressed in Mycobacterium smegmatis and Escherichia coli , with the purified proteins then used to boost BCG primed-mice. Overall, the treated mice showed a greater delayed-type hypersensitivity response in vivo , as well as stronger Th1 responses, including higher level of IFN-γ, TNF-α, and specific-IgG. Therefore, mannosylated proteins BCG_0470 and BCG_0980 effectively amplified the immune responses induced by BCG in mice. Together, our results suggest that the oligosaccharide chains containing mannose are the antigenic determinants of glycoproteins, providing key insight for future vaccine optimization and design. [ABSTRACT FROM AUTHOR]

• A microparticulated adjuvant based on starch is proposed for BCG vaccine. • The protection of BCG vaccine was improved whit the co-administration of this adjuvant by s.c. route to Balb/c mice. • The better protection was observed against infection with virulent H37Rv M. tuberculosis strain. The persistence of tuberculosis (TB) as one of the top 10 causes of death worldwide, the growing incidence of multidrug-resistant tuberculosis and the controversial efficacy of the Bacille Calmette-Guérin (BCG) vaccine drives the development of new generation multistage vaccines against this disease that can boost BCG-primed immunity. The use of polymeric microparticles for this purpose increases due to their advantages, especially their good safety levels and intrinsic immunostimulant properties. We recently explored and demonstrated the reinforcing and adjuvant potential of starch microparticles (SMPs) that administered intranasally to BCG-primed BALB/c mice, alone or in combination with a recombinant antigen, increased survival rates and induced a reduction of bacterial load in the lungs of mice infected with tuberculosis. Here, we tested the effect of SMPs added to the BCG vaccine as adjuvant to the whole-cell vaccine and investigated their contribution to the improvement of the protective efficacy of subcutaneous vaccination in mice challenged with virulent strains of Mycobacterium tuberculosis. As expected, our results were dependent on the infection strains, showing that virulence is a crucial factor that affects the adjuvant activity of SMPs. Our results also confirm the adjuvant activity of this carbohydrate and its usefulness in diverse vaccination strategies not only for mucosal but also for parenteral administration. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette-Guerin (BCG) is included in the routine vaccination program in Gaza and the West Bank. Although safe, complications can occur and include local, extra-regional and disseminated BCG infection. Therefore it is contraindicated in immunodeficiencies. However, most infants are immunized prior to diagnosis of immunodeficiency. We report clinical and immunological characteristics of patients referred with severe combined immunodeficiency (SCID) who suffered from BCG complications. Methods: Files of patients referred for evaluation of immunodeficiency from January 2008 to February 2016 were retrieved. All patients have received BCG. Cell surface markers of peripheral blood mononuclear cells (PBMCs) were measured by immunofluorescent staining and flow cytometry. Serum concentrations of immunoglobulins were measured using nephelometry. Genetic diagnosis of SCID was made by direct Sanger sequencing of candidate genes. BCG complications were classified as: a) local; b) regional; c) distant; and d) disseminated disease. Results: Twenty-one children were diagnosed with SCID. BCG complications were diagnosed in 12 (57.1%). Eight patients developed local and regional disease (67%) and 4 (33%) had disseminated infection. Patients received at least three drugs: isoniazid, ethambutol and rifampicin. Outcome was relatively favorable with eight patients surviving (66.6%). No death related to BCG infection was observed. Disseminated disease was associated with reduced numbers of total lymphocytes, CD3 and CD8 levels (p <.05). Conclusions: Although high rates of BCG complications were observed, mortality was not increased and outcomes were good. Increased awareness in countries where BCG vaccine is not routinely administered and newborn screening programs for SCID could reduce complication rates. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette–Guérin (BCG) is the world’s most widely distributed vaccine, used against tuberculosis (TB), in cancer immunotherapy, and in autoimmune diseases due to its immunomodulatory properties. To date, the effect of BCG vaccination on antibody responses to host proteins has not been reported. High-content peptide microarrays (HCPM) offer a unique opportunity to gauge specific humoral immune responses. Methods: The sera of BCG-vaccinated healthy adults were tested on a human HCPM platform (4953 randomly selected epitopes of human proteins) to detect specific immunoglobulin gamma (IgG) responses. Samples were obtained at 56, 112, and 252 days after vaccination. Immunohistology was performed on lymph node tissue from patients with TB lymphadenitis. Results were analysed with a combination of existing and novel statistical methods. Results: IgG recognition of host peptides exhibited a peak at day 56 post BCG vaccination in all study subjects tested, which diminished over time. Primarily, IgG responses exhibited increased reactivity to ion transporters (sodium, calcium channels), cytokine receptors (interleukin 2 receptor β (IL2Rβ), fibroblast growth factor receptor 1 (FGFR1)), other cell surface receptors (inositol, somatostatin, angiopoeitin), ribonucleoprotein, and enzymes (tyrosine kinases, phospholipase) on day 56. There was decreased IgG reactivity to transforming growth factor-beta type 1 receptor (TGFβR1) and, in agreement with the peptide microarray findings, immunohistochemical analysis of TB-infected lymph node samples revealed an overexpression of TGFβR in granulomatous lesions. Moreover, the vesicular monoamine transporter (VMAT2) showed increased reactivity on days 112 and 252, but not on day 56 post-vaccination. IgG to interleukin 4 receptor (IL4R) showed increased reactivity at 112 days post-vaccination, while IgG to IL2Rβ and FGFR1 showed decreased reactivity on days 112 and 252 as compared to day 56 post BCG vaccination. Conclusions: BCG vaccination modifies the host’s immune landscape after 56 days, but this imprint changes over time. This may influence the establishment of immunological memory in BCG-vaccinated individuals.