BCG-vaccinated Children Research Articles

Determinants of tuberculosis disease development in children in central Ethiopia: A matched case-control study.

The risk factors for tuberculosis (TB) disease development in children remained understudied, particularly in low-income countries like Ethiopia. The objective of this study was to identify determinants of TB disease development in general and in relation to BCG vaccination in children in central Ethiopia. We employed a 1:1 age-matched case-control design to compare the characteristics of children who developed TB (cases) with those who did not (controls). Data were collected in healthcare facilities in Addis Ababa city, Adama, and Bishoftu towns between September 25, 2021, and June 24, 2022. Two hundred and fifty-six cases were drawn at random from a list of childhood TB patients entered into SPSS software, and 256 controls were selected sequentially at triage from the same healthcare facilities where the cases were treated. A bivariate conditional logistic regression analysis was performed first to select candidate variables with p-values less than or equal to 0.20 for the multivariable model. Finally, variables with a p-value less than 0.05 for a matched adjusted odds ratio (mORadj) were reported as independent determinants of TB disease development. The mean age of the cases was nine years, while that of the controls was 10 years. Males comprised 126 cases (49.2%) and 119 controls (46.5%), with the remainder being females. Ninety-nine (38.7%) of the cases were not BCG-vaccinated, compared to 58 (22.7%) of the controls. Household TB contact was experienced by 43 (16.8%) of the cases and 10 (3.9%) of the controls. Twenty-two (8.6%) of the cases and six (2.3%) of the controls were exposed to a cigarette smoker in their household. Twenty-two (8.6%) of the cases and three (1.2%) of the controls were positive for HIV. Children who were not vaccinated with BCG at birth or within two weeks of birth had more than twice the odds (mORadj = 2.11, 95% CI = 1.28-3.48) of developing TB compared to those who were. Children who ever lived with a TB-sick family member (mORadj = 4.28, 95% CI = 1.95-9.39), smoking family members (mORadj = 3.15, 95% CI = 1.07-9.27), and HIV-infected children (mORadj = 8.71, 95% CI = 1.96-38.66) also had higher odds of developing TB disease than their counterparts. Being BCG-unvaccinated, having household TB contact, having a smoker in the household, and being HIV-infected were found to be independent determinants of TB disease development among children.

Nonspecific Effects of the Bacillus Calmette-Guérin Vaccine in Portuguese Children Under 5 Years of Age: Protocol for a Population-Based Historical Birth Cohort Study.

The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis (TB) shows beneficial nonspecific effects, which are likely related to innate immune training. Until 2016, a single BCG dose was administered to all newborns in Portugal. In July 2016, a clinical guideline established that only children under 6 years belonging to high-risk groups should receive BCG. This might have prevented nonvaccinated children from developing trained immunological responses as effectively as BCG-vaccinated children. This study aims to investigate if there is variation in TB-related and all-cause mortality, and severe, moderate, or mild morbidity in children under 5 years of age, and whether such variation might be explained by the BCG vaccination policy change in 2016. This population-based historical birth cohort study includes children under 5 years of age born in Portugal between July 1, 2010, and June 30, 2021. Newborns with low birth weight, premature status, or known or suspected HIV infection are excluded. The follow-up period is until the completion of 5 years of age or the end of follow-up (June 30, 2021). The study will use secondary data from the National Health Service user registry, death certificate database, vaccination registry, communicable diseases surveillance system, TB surveillance system, diagnosis-related group information system for hospital admissions and emergency department visits, and primary health care information system. The data will be linked. Primary outcomes include person-time incidence rates of death (all causes and TB), TB diagnosis, and all causes and some specific causes of severe, moderate, or mild morbidity, and the incidence rate ratio of nonvaccinated to BCG-vaccinated children. We will compare the probability of surviving the first and fifth years of life or of not having severe, moderate, or mild morbidity during the follow-up period according to exposure (BCG vaccinated or nonvaccinated, number of doses, and time from birth until the first dose), using the log-rank test for assessing differences in survival rates between exposed and nonexposed children and hazard ratios for quantifying the differences. Moreover, we will perform a proportional hazards regression analysis. Ethics approval has been obtained. In March 2022, database owners were contacted to present the project and discuss the request for data. A unique identifier will be used. In July 2023, a process of redefinition of the variables per database was initiated. Data were received in October and November 2023. In November 2023, further work was conducted. By April 2024, we expect to start analyzing the full data set. The results will contribute to the accumulating body of knowledge and might have relevance to guide global BCG vaccination policy. Data linkage can contribute to a swifter mechanism to use available health data to conduct population-based studies and inform policy decision-making. ClinicalTrials.gov NCT05471167; https://clinicaltrials.gov/study/NCT05471167. DERR1-10.2196/55332.

Tuberculosis among children visiting friends & relatives.

Most paediatric tuberculosis (TB) cases in low-TB-incidence countries involve children born to migrant families. This may be partially explained by trips to their countries of origin for visiting friends and relatives (VFR). We aimed to estimate the risk of latent TB infection (LTBI) and TB in children VFR. We conducted a prospective multicentric observational study in Catalonia (Spain) from June 2017 to December 2019. We enrolled children aged < 15years with a negative tuberculin skin test (TST) at baseline and at least one parent from a high-TB-incidence country, and who had travelled to their parent's birth country for ≥21days. TST and QuantiFERON-TB Gold Plus (QFT-Plus) were performed within 8-12weeks post-return. LTBI was defined as a TST ≥5mm and/or a positive QFT-Plus. Five hundred children completed the study, equivalent to 78.2 person-years of follow-up (PYFU). Thirteen children (2.6%) were diagnosed with LTBI (16.6/per100 PYFU, 95%CI = 8.8-28.5), including two cases (0.4%) of TB (2.5/per100 PYFU, 95%CI = 0.3-9.3). LTBI incidence rates remained high after excluding BCG-vaccinated children (9.7/per100 PYFU, 95%CI = 3.9-20.0). Household tobacco smoke exposure was associated with LTBI (aOR = 3.9, 95%CI = 1.1-13.3). The risk of LTBI in children VFR in high-TB-incidence countries may equal, or perhaps even exceed, the infection risk of the native population. The primary associated risk factor was the presence of smokers in the household. Furthermore, the incidence rate of active TB largely surpassed that of the countries visited. Children VFR in high-TB-incidence countries should be targeted for diagnostic and preventive interventions.

Frequency of BCG vaccination among children with pulmonary tuberculosis at a tertiary care hospital.

Introduction: There are more instances of tuberculosis in children than the World Health Organization predicts. Most TB cases (95%) are found in low-income nations. Neonate BCG immunization is recommended by the WHO in countries with a "high prevalence" of tuberculosis.Objective: To determine the frequency of BCG vaccination in children diagnosed with pulmonary Tuberculosis at a tertiary care hospital.Methodology: From June 2019 to December 2019, researchers examined the prevalence of pulmonary TB in children aged 2-12 using a cross-sectional descriptive research design. Pulmonary TB was diagnosed in 273 people who had a cough and fever for more than 2 weeks and had a PPA score of 7 or above on the Pakistan Pe-diatric Association (PPA) grading table. Patients were checked for BCG immunization status. The analysis of the data performed using SPSS version 23.Results: Patients from rural regions contributed 68.86%, while those from metro-politan areas made up 33.14. Contact with tuberculosis patients was reported by 17.22% of patients.74.3% of kids got the BCG shot.Conclusion: BCG is the sole effective method of preventing tuberculosis in children and young adults. Children who received the BCG vaccine had a 74.36% increased risk of developing TB in the lungs, according to the current study.Keywords: BCG vaccine, pulmonary tuberculosis, vaccine efficacy.

"Trained Immunity" from Mycobacterium spp. exposure (BCG vaccination and environmental) may have an impact on the incidence of early childhood leukemia.

Preventive variables for childhood leukemia incidence (LI) remain unknown. Past assertions that childhood vaccinations, especially BCG, may be potentially protective have remained disputed for over five decades because of the lack of a unifying framework to explain variable outcomes in different studies. An examination of the early childhood LI for 2020 in European Region countries with supposedly similar underlying confounders but differential childhood vaccination coverage displays negative covariation with prevailing Mycobacterium spp. exposure in BCG-vaccinated children. The childhood LI in 0-4-year-old populations with >90% childhood BCG vaccination coverage is found to be strongly but negatively correlated with prevailing tuberculin immunoreactivity [r(24): -0.7868, p-value: < 0.0001]. No such correlation existed for the LI in 0-4-year-old populations without BCG vaccinations, though weak associations are hinted at by the available data for MCV2, PCV3, and DTP3 vaccinations. We hypothesize that early childhood BCG vaccination "priming" and subsequent "trained immunity" augmentation by "natural" boosting from Mycobacterium spp. exposure play a preventive and protective role in childhood LI. The non-consideration of prevailing "trained immunity" could have been a cause behind the conflicting outcomes in past studies. Exploratory studies, preferably performed in high-burden countries and controlling for the trained-immunity correlate and other potential confounders, would be warranted in order to establish a role for BCG vaccination and early-life immune training (or lack thereof) in childhood LI and help put the current controversy to rest.

BCG-Vaccinated Children with Contact to Tuberculosis Patients Show Delayed Conversion of Mycobacterium tuberculosis-Specific IFN-γ Release.

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.

The Interferon-Gamma Release Assay versus the Tuberculin Skin Test in the Diagnosis of Mycobacterium tuberculosis Infection in BCG-Vaccinated Children and Adolescents Exposed or Not Exposed to Contagious TB.

Children have an increased risk of developing active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (M.tb), and they are more likely to develop the most severe forms of TB. Rapid diagnosis and treatment of latent M.tb infection (LTBI) is essential to lessen the devastating consequences of TB in children. The aim of the study was to evaluate TST (tuberculin skin test) and IGRA (interferon-gamma release assay) utility in identifying LTBI in a cohort of Bacille Calmette-Guérin (BCG)-vaccinated Polish children and adolescents exposed or not exposed to contagious TB. In addition, we asked whether quantitative assessment of IGRA results could be valuable in predicting active TB disease. Of the 235 recruited volunteers, 89 (38%) were TST-positive (TST+), 74 (32%) were IGRA-positive (IGRA+), and 62 (26%) were both TST+ and IGRA+. The frequency of TST positivity was significantly higher in the group with (59%) than without TB contact (18%). The percentage of TST+ subjects increased with age from 36% in the youngest children (<2 years) to 47% in the oldest group (>10 years). All positive IGRA results were found solely in the group of children with TB contact. There was a significant increase in the rate of positive IGRA results with age, from 9% in the youngest to 48% in the oldest group. The 10 mm TST cutoff showed good sensitivity and specificity in both TB exposed and nonexposed children and was associated with excellent negative predictive value, especially among nonexposed volunteers. Mean IFN-γ concentrations in IGRA cultures were significantly higher in the group of LTBI compared to the children with active TB disease, both TST+ and TST-. Both TST and IGRA can be used as screening tests for BCG-vaccinated children and adolescents exposed to contagious TB.

Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients.

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille‐Calmette‐Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion.We tested whether RISK6 and Sweeney3, validated immune‐based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults.Transcripts were measured by RT‐qPCR in BCG‐vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS.In children, RISK6 and Sweeney3 discriminated IRIS cases from non‐IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half‐week on ART and at TB‐IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB‐IRIS onset.Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.

The spectrum of tuberculosis in BCG-vaccinated and unvaccinated children

Introduction: Tuberculosis remains a very important communicable disease in many parts of the world and a major health problem in developing countries. The international controversy surrounding the use and effectiveness of the Bacillus Calmette-Guérin vaccine. The aim the study is to evaluate the spectrum of tuberculosis among Bacillus Calmette-Guérin vaccinated and non-vaccinated children’s. Method: A retrospective study depending on data from flow sheet of each patient which include: age, sex, weight, residence, date of diagnosis, Bacillus Calmette-Guérin vaccination status ,the presence of scar or not, intra or extra familial contact, pattern of disease (pulmonary or extra pulmonary), investigations and associated risk factors. Results: 74 (46.8%) patients were males and 84 (53.2%) were females, they were divided into 2 groups: - group 1 those equal or less than 5 years old who 70 (44.3%) patients, and group 2 those more than 5 year old who 88 (55.7%) patients. The BCG vaccinated patients were 124 (78.5%),9 (7.3%) of them were not developed scar. Distribution of total 158 of TB patients according to the years as following: in 2007 were 46 (29.1%) patients, in 2008 were 51 (32.3%) patients, and in 2009 were 61 (38.6%) patients. 60 (38%) patients, Hashimiyah 43 (27.2%) patients.

Bacillus Calmette-Guerin Vaccine-Associated Lymphadenitis in Children

Background: Tuberculosis (TB) is one of the most important infectious diseases worldwide. Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine, entered into the childhood immunization program by the World Health Organization (WHO) in 1974 to prevent TB. One of the relatively common complications of BCG vaccination is regional lymphadenitis. Objectives: This study aimed to determine the lymphadenitis incidence in BCG-vaccinated children in southwest Iran. Methods: In a prospective descriptive study, infants born from March to June 2017 were evaluated for BCG vaccine complications at two, four, six, nine, and 12 months of age in Ahvaz, southwestern Iran. Results: The study enrolled 1,506 infants (794 males and 712 females). Among the vaccinated infants, four (0.26%) had injection site reactions, and 106 (7.03%) presented lymphadenitis (66 males and 40 females). The lymphadenitis rate was significantly higher in males than in females (P = 0.024). The mean age at presentation was 4.28 ± 0.79 months. Suppurative lymphadenitis was seen in 53 (50%) cases and nonsuppurative lymphadenitis in 53 (50%) cases. About 80% of nonsuppurative lymphadenitis resolved entirely or partially after a one-year follow-up. Of 53 cases with suppurative lymphadenitis, 46 (43.4%) developed spontaneous drainage, and seven (6.6%) were drained by needle aspiration. No significant relationship was found between the BCG inoculation site and lymphadenitis rate. No other complications such as osteomyelitis or disseminated BCG infection were observed after one year of follow-up. Conclusions: The relatively high incidence of BCG lymphadenitis in this study may be due to the vaccine strain, young vaccinees, and improper vaccination techniques. In most cases, nonsuppurative lymphadenitis regressed spontaneously, and suppurative lymphadenitis was drained spontaneously or by needle aspiration.

Local complications and lymphadenitis after BCG–M vaccination in children – сhoosing the right tactics

Тhe aim: to analyze the cases of complications of BCGvaccination in children, potential risk factors, patient management tactics.Materials and methods: The statistical data on local complications of BCG-M vaccination in Saint Petersburg (Russia) from 2012 to 2019 was studied. To verify the diagnosis of post-vaccinal complication the Mantoux test, diaskintest or QuantiFERON-TB, X-ray examination, morphological and bacteriological examination were used in cases of indication. Observations of 22 children aged from 1,5 months to 1,5 years with complications after vaccination with BCG-M were analyzed.Results. Since 2010, the sparing BCG-M vaccine has been used in St. Petersburg for primary immunization. The incidence of local complications over the past 8 years was 0,002% – 0,012% of the number of vaccinated children. A cold abscess was diagnosed in 11 (50,0%), BCG-lymphadenitis in 9 (40,9%), an ulcer in 2 (9,1%) children. In 14 (63,6%) of 22 children complications of vaccination were detected in the phase of abscess formation. Fore children underwent surgery with diagnoses of nonspecific lymphadenitis (3), soft tissue abscess (1). In these cases, diagnoses of BCG-M complications was established only after morphological examination of the surgical material. In children with complications while the results of Mantoux test were positive, results of diaskintest and QuantiFERON-TB were negative. The detection of Mycobacterium bovis BCG was possible in 5 patients by culture and polymerase chain reaction methods. 2 clinical cases are given.Conclusion: It is necessary to increase the knowledge of pediatricians, pediatric surgeons, nurses of BCG vaccination techniques, diagnosis and treatment of post-vaccination complication, indications for dispensary observation.

Accuracy and agreement of the Tuberculin Skin Test (TST) and the QuantiFERON-TB Gold In-tube test (QFT) in the diagnosis of tuberculosis in Indian children

PurposeAccurate diagnosis of TB in children is hampered by poor specificity of symptoms in endemic countries and the paucibacillary nature of childhood TB. This study was done to compare the accuracy and agreement of the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-tube test (QFT) in diagnosing tuberculosis (TB) in a predominantly BCG-vaccinated population of children. MethodsThis retrospective cohort study enrolled all children aged 1–15 years who underwent TST and QFT testing as part of screening for TB. Children were classified according to the 2014 WHO case definition of TB, and statistical analysis was done to generate data on concordance between the TST and the QFT as well as sensitivity and specificity within WHO-defined groups. ResultsTST and QFT concordance was 83.9% overall (kappa 0.51), 79% in those with WHO-defined TB and 89% in those without TB. TST+/QFT-discordance was commoner than QFT+/TST- discordance across groups. The sensitivity of the TST vs. the QFT was 70.8% vs. 50% for WHO-defined TB, with comparable specificity at 89% vs. 90% respectively. ConclusionsThe higher sensitivity of the cheaper and simpler TST supports its use for TB diagnosis in a normally nourished population of BCG-vaccinated children.

The introduction of BCG vaccination to neonates in Northern Sweden, 1927–31: Re-analysis of historical data to understand the lower mortality among BCG-vaccinated children

BackgroundFollowing the introduction of oral Bacille Calmette-Guérin (BCG) a century ago, Albert Calmette suggested that BCG both provided protection against death from tuberculosis (TB) and other causes. The findings were not pursued. Today, there is considerable evidence that intradermal BCG have beneficial non-specific effects (NSEs). We re-analyzed data from BCG’s introduction 1927–1931 in Sweden hypothesizing that BCG reduced infectious deaths. MethodsIn three papers published by Dr Carl Näslund, the progress of oral neonatal BCG rollout provided free-of-charge and the effects on child mortality in the highly TB-prevalent region Norrbotten was sequentially updated. We analyzed cause-specific post-neonatal mortality by vaccination status excluding deaths from congenital conditions. Due to apparent differences in effects during study years, effects were assessed overall and separately in two periods (1927–1929, 1930–1931). ResultsAccording to Näslund, TB households were slightly more likely to accept vaccination; fewer newborns that were sick or had congenital problems were vaccinated. BCG coverage was 28.3% (5659/20,012); 8.7% (1746/20,012) died. The BCG/unvaccinated Risk Ratio (RR) of post-neonatal childhood death was 0.53 (0.45–0.62). BCG was associated with 80% (49–92%) reduced mortality from TB. From 1927 to 29, BCG appeared to protect strongly against deaths from all diseases, including the non-infectious, RR = 0.09 (0.02–0.36), presumably reflecting selection bias. From 1930 to 1931, there was no protection against non-infectious deaths, RR = 0.92 (0.49–1.70) indicating less bias (p = 0.004 for same effect). During 1930–1931, BCG was associated with reductions in non-TB infectious deaths (RR = 0.75 (0.58–0.97)); 2/3 were caused by respiratory infections, against which the BCG/unvaccinated RR was 0.61 (0.43–0.84). Other causes of death were less frequent and provided no clear pattern, except that BCG was associated with more meningitis deaths, RR = 6.85 (2.20–21.4). ConclusionHealthy vaccinee bias, particularly in 1927–1929, resulted in strongly beneficial overall BCG effects. However, the 1930–1931 data provided some support that BCG both protected against TB deaths and deaths from respiratory infections.

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children.

None of the currently used diagnostic tools are efficient enough in diagnosing Mycobacterium tuberculosis (M.tb) infection in children. The study was aimed to identify cytokine biosignatures characterizing active and latent tuberculosis (TB) in children. Using a multiplex bead-based technology, we analyzed the levels of 53 Th17-related cytokines and inflammatory mediators in sera from 216 BCG-vaccinated children diagnosed with active TB (TB) or latent TB (LTBI) as well as uninfected controls (HC). Children with active TB, compared to HC children, showed reduced serum levels of IL-17A, MMP-2, OPN, PTX-3, and markedly elevated concentrations of APRIL/TNFSF13. IL-21, sCD40L, MMP-2, and IL-8 were significantly differentially expressed in the comparisons between groups: (1) HC versus TB and LTBI (jointly), and (2) TB versus LTBI. The panel consisting of APRIL/TNFSF13, sCD30/TNFRSF8, IFN-α2, IFN-γ, IL-2, sIL-6Rα, IL-8, IL-11, IL-29/IFN-λ1, LIGHT/TNFSF14, MMP-1, MMP-2, MMP-3, osteocalcin, osteopontin, TSLP, and TWEAK/TNFSF12 possessed a discriminatory potential for the differentiation between TB and LTBI children. Serum-based host biosignatures carry the potential to aid the diagnosis of childhood M.tb infections. The proposed panels of markers allow distinguishing not only children infected with M.tb from uninfected individuals but also children with active TB from those with latent TB.

Specific Host Signatures for the Detection of Tuberculosis Infection in Children in a Low TB Incidence Country.

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined M. tuberculosis infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days in vitro stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the M. tuberculosis-infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 M. tuberculosis infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2–4 cytokines induced by three different mycobacterial antigens allows an excellent identification of M. tuberculosis-infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.

BCG: new life for a centenarian vaccine

In The Lancet Infectious Diseases, Sarah Prentice and colleagues1 report that the tuberculosis vaccine BCG protects against non-tuberculous infectious diseases. In a randomised controlled trial (RCT), 560 neonates in Uganda were randomly allocated 1:1 to receive BCG-Denmark at birth or at age 6 weeks. The primary outcome was physician-diagnosed non-tuberculous infectious disease. Between birth and age 6 weeks, the BCG-vaccinated children in the early vaccination group had lower incidence (98 presentations) than those in the delayed vaccination group who had not yet received BCG (129 presentations; hazard ratio [HR] 0·71 [95% CI 0·53–0·95], p=0·023).

Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly

BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%–53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%–36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423).

Determination of tuberculin skin test for isoniazid prophylaxis in BCG vaccinated children who are using anti-TNF agents for rheumatologic diseases.

The use of tumor necrosis factor inhibitors (anti-TNF) has a risk of activating latent tuberculosis infection (LTBI). This study was performed to investigate LTBI according to tuberculin skin test (TST) size and to determine the frequency of tuberculosis (TB) in bacillus Calmette-Guerin (BCG)-vaccinated children receiving anti-TNF treatment for rheumatological disease. The study consisted of 559 children. Information on demographics, anti-TNF agents, TST size, and isoniazid (INH) prophylaxis was recorded. Patients (n = 254) with TST size ≥5 mm were divided into three groups according to TST size and INH prophylaxis: group 1, TST size 5 to 9 mm and no INH prophylaxis; group 2, TST size 5 to 9 mm with INH prophylaxis; and group 3, TST size ≥10 mm with INH prophylaxis. The 559 patients comprised 314 (56.3%) females and 245 (43.6%) males; they had a mean age of 13.1 ± 4.1 years. The mean TST size in all patients was 4.2 ± 4.7 mm. Group 1 consisted of 76 (29.9%) patients, group 2 consisted of 88 (34.6%) patients, and group 3 consisted of 90 (35.4%) patients. The mean TST sizes for the three groups were 6.8 ± 3.1 mm, 7.2 ± 3.2 mm, and 13.9 ± 2.8 mm, respectively. New TB was diagnosed in only two (0.35%) patients. Both of them were in group 3. A TST size of ≥10 mm in BCG-vaccinated children receiving anti-TNF treatment may distinguish children at high risk for reactivation of LTBI.

BCG scarring and improved child survival: a combined analysis of studies of BCG scarring.

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 12months 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.

Corrigendum: BCG Vaccination at Birth and Rate of Hospitalization for Infection Until 15 Months of Age in Danish Children: A Randomized Clinical Multicenter Trial.

Background The bacillus Calmette-Guerin (BCG) vaccine against tuberculosis might reduce the non-tuberculosis-related child mortality rate in low-income settings. We tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalization for infection in Denmark, a high-income setting. Hospitalization for infection was a secondary outcome in a randomized trial with the primary aim to estimate the potential non-specific effects of BCG vaccination at birth on all-cause hospitalization. Methods A total of 4262 children included in the Danish Calmette Study were assigned randomly to either receive the BCG vaccine or not and were followed through the Danish National Patient Register. The outcome was number of hospitalizations for infection until the age of 15 months. Data were analyzed by Cox regression in intention-to-treat (ITT) and per-protocol (PP) analyses. Results In the ITT analysis, we observed 588 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2129 children allocated to receive the BCG vaccine and 595 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2133 children allocated to the control group (hazard ratio [HR], 0.99 [95% confidence interval (CI), 0.85-1.15]). The PP analysis yielded an HR of 1.00 (95% CI, 0.86-1.16).Predefined interaction ITT analyses showed that among 740 children with a BCG-vaccinated mother, the HR for BCG-vaccinated children was 0.65 (95% CI, 0.45-0.94); the HR for children who had a non-BCG-vaccinated mother was 1.10 (95% CI, 0.93-1.29) (P = .01, test of no interaction). Cesarean delivery modified the effect of BCG vaccination (HRs, 0.73 [95% CI, 0.54-0.99] in children born by cesarean section vs 1.10 [95% CI, 0.92-1.30] in other children; P = .02). When the outcome was defined as time to first hospitalization, the HR for premature children after BCG vaccination was 1.81 (95% CI, 0.95-3.43), whereas the HR was 0.94 (95% CI, 0.82-1.08) for children born at term (P = .05). Conclusion BCG vaccination did not affect the rate of hospitalization for infection up to the age of 15 months in Danish children. In future studies, the role of maternal BCG-vaccination, premature birth, and cesarean delivery needs further exploration.