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• Infant BCG immunisation induces M. ulcerans -specific immune responses. • M. ulcerans - and M. tuberculosis -specific immune responses are qualitatively similar. • Magnitude of M. ulcerans -specific immune responses was not influenced by BCG strain. • These in-vitro findings support the protective effect observed epidemiologically. Bacillus Calmette–Guérin (BCG) vaccine provides partial protection against Buruli ulcer caused by Mycobacterium ulcerans in epidemiological studies. This study aimed to quantify M. ulcerans -specific immune responses induced by BCG immunisation. Intracellular cytokine analysis of in-vitro experiments done 10 weeks after BCG immunisation in 130 Australian infants randomised to one of three BCG vaccine strains given either at birth (BCG-Denmark, BCG-Japan, or BCG-Russia) or at two months of age (BCG-Denmark). Proportions of polyfunctional CD4+ T-cells were higher in M. ulcerans -stimulated compared to unstimulated control samples. These proportions were not influenced by the vaccine strain or timing of the immunisation. The M. ulcerans -specific immune responses showed similar patterns to those observed in M. tuberculosis -stimulated samples, although they were of lower magnitude. Our data show that BCG immunisation induces M. ulcerans -specific immune responses in infants, likely explaining the cross-protective effect observed in epidemiological studies. (ACTRN12608000227392) [ABSTRACT FROM AUTHOR]

Abstract Objective Accurate and timely diagnosis of tuberculosis (TB) is essential to control the global pandemic. Currently available immunodiagnostic tests cannot discriminate between latent tuberculosis infection (LTBI) and active tuberculosis. This study aimed to determine whether candidate mycobacterial antigen-stimulated cytokine biomarkers can discriminate between TB-uninfected and TB-infected adults, and additionally between LTBI and active TB disease. Methods 193 adults were recruited, and categorised into four unambiguous diagnostic groups: microbiologically-proven active TB, LTBI, sick controls (non-TB lower respiratory tract infections) and healthy controls. Whole blood assays were used to determine mycobacterial antigen (CFP-10, ESAT-6, PPD)-stimulated cytokine (IL-1ra, IL-2, IL-10, IL-13, TNF-α, IFN-γ, IP-10 and MIP-1β) responses, measured by Luminex multiplex immunoassay. Results The background-corrected mycobacterial antigen-stimulated cytokine responses of all eight cytokines were significantly higher in TB-infected participants compared with TB-uninfected individuals, with IL-2 showing the best performance characteristics. In addition, mycobacterial antigen-stimulated responses with IL-1ra, IL-10 and TNF-α were higher in participants with active TB compared those with LTBI, reaching statistical significance with PPD stimulation, although there was a degree of overlap between the two groups. Conclusion Mycobacterial antigen-stimulated cytokine responses may prove useful in future immunodiagnostic tests to discriminate between tuberculosis-infected and tuberculosis-uninfected individual, and potentially between LTBI and active tuberculosis. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether there are seasonal changes in the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays, an interferon-gamma release assay widely used for the diagnosis of tuberculosis infection. Results of 31,932 QFT-GIT assays performed at a large independent, accredited diagnostic service provider in London, UK over a 4.5-year-period were analysed. The proportion of positive results was significantly lower in autumn (14.8%) than in spring (16.0%; p = 0.0366) and summer (17.5%; p < 0.0001), but similar to winter (15.2%; p = 0.4711). The proportion of indeterminate results was significantly higher in autumn (8.2%) than in spring (6.2%; p < 0.0001), summer (4.8%; p < 0.0001), and winter (6.2%; p < 0.0001). The highest proportions of indeterminate results were observed in October (8.4%) and November (8.8%), the lowest in June (4.5%). Our data show that significant seasonal variation occurs in the performance of QFT-GIT assays in a temperate climate setting. Potential underlying mechanisms, including host and environmental factors, are discussed. [ABSTRACT FROM AUTHOR]

Objectives: A biomarker indicating successful tuberculosis (TB) therapy would assist in determining appropriate length of treatment. This study aimed to determine changes in mycobacteria-specific antigen-induced cytokine biomarkers in patients receiving therapy for latent or active TB, to identify biomarkers potentially correlating with treatment success.Methods: A total of 33 adults with active TB and 36 with latent TB were followed longitudinally over therapy. Whole blood stimulation assays using mycobacteria-specific antigens (CFP-10, ESAT-6, PPD) were done on samples obtained at 0, 1, 3, 6 and 9 months. Cytokine responses (IFN-γ, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1β, and TNF-α) in supernatants were measured by Luminex xMAP immunoassay.Results: In active TB cases, median IL-1ra (with CFP-10 and with PPD stimulation), IP-10 (CFP-10, ESAT-6), MIP-1β (ESAT-6, PPD), and TNF-α (ESAT-6) responses declined significantly over the course of therapy. In latent TB cases, median IL-1ra (CFP-10, ESAT-6, PPD), IL-2 (CFP-10, ESAT-6), and IP-10 (CFP-10, ESAT-6) responses declined significantly.Conclusions: Mycobacteria-specific cytokine responses change significantly over the course of therapy, and their kinetics in active TB differ from those observed in latent TB. In particular, mycobacteria-specific IL-1ra responses are potential correlates of successful therapy in both active and latent TB. [ABSTRACT FROM AUTHOR]

Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4 + /CD8 + iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8 + iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is caused by Mycobacterium tuberculosis ( Mtb ) and provided original proof that an infectious agent can cause human disease. However, key steps in TB pathogenesis remain poorly understood. We propose that autoimmunity is a critical and overlooked process driving pathology in TB, and present clinical and experimental observations supporting this hypothesis. [ABSTRACT FROM AUTHOR]

Summary Background Recent reports indicate an ongoing BCG shortage that may influence immunisation practice. This study aimed to determine current availability of BCG vaccine across Europe, and implications on immunisation practices and policies in Europe. Methods Web-based survey among Paediatric Tuberculosis Network European Trials Group (ptbnet) members, between May and October 2015. Results Twenty individuals from 13 European countries participated. Ongoing shortages were reported in eight countries routinely using BCG (8/11, 73%). As a consequence of the shortage, BCG was not given as completely unavailable in some countries (2/8, 25%), was given only whenever available (1/8, 13%), or only in certain regions of the country (1/8, 13%). Strategies reported to reduce loss of immunisation were administration to selected high-risk individuals (2/8, 25%), or cohorting vaccinees on specific days to maximise the use of multi-dose vials (3/8, 38%). Authorities in two countries each were considering a change of manufacturer/supplier (2/8, 25%). Conclusions The BCG shortage in Europe leads to significant changes in immunisation policies including changes of BCG vaccine strain and manufacturer. In addition, infants and children eligible for immunisation are at risk of not receiving BCG. To ensure necessary BCG immunisations, collaboration between national health agencies and vaccine manufacturers is crucial. [ABSTRACT FROM AUTHOR]

Background The incidence of tuberculosis (TB) and the use of Bacille Calmette-Guérin (BCG) vaccines differ significantly worldwide. Information regarding recent changes in BCG use and immunisation policies is difficult to access. Therefore, this study aimed to systematically collect up-to-date data on the use of BCG in Europe. Methods A web-based survey of members of the Paediatric Tuberculosis Network European Trials group (ptbnet) and Tuberculosis Network European Trials group (TBnet) was conducted between October 2012 and May 2013. Results A total of 89 individuals from 31 European countries participated. Participants from 27/31 (87%) countries reported to have a national BCG immunisation policy/guideline. Reported indications for BCG immunisation were: universally at birth (14/31; 45%), universally at older age (2/31; 6%), at birth for high-risk groups (12/31; 39%), at older age for high-risk groups (6/31; 19%), at older age for Mantoux-negative individuals (6/31;19%), for immigrants (4/31; 13%) and as a travel vaccine (10/31; 32%). Members from 11 (35%) countries reported changes in BCG policies in the previous 5 years: discontinuation of universal immunisation of infants/children (6/11), reintroduction of immunisation of high-risk children (3/11), and change in BCG vaccine strain (2/11). Members from 24/31 (77%) countries reported using BCG Denmark. Conclusions Immunisation policies regarding BCG vaccine exist in the majority of European countries. Indications for BCG immunisation varied considerably, likely reflecting national TB incidence rates, immigration and other factors influencing TB control strategies. Importantly, the considerable number of recent policy changes highlights the need for regular collection of up-to-date information to inform public health planning. [ABSTRACT FROM AUTHOR]

Objectives: Cervicofacial lymphadenitis is the most common manifestation of infection with non-tuberculous mycobacteria (NTM) in immunocompetent children. Although complete excision is considered standard management, the optimal treatment remains controversial. This study reviews the evidence for different management options for NTM lymphadenitis.Methods: A systematic literature review and meta-analysis were performed including 1951 children from sixty publications. Generalised linear mixed model regressions were used to compare treatment modalities.Results: The adjusted mean cure rate was 98% (95% CI 97.0-99.5%) for complete excision, 73.1% (95% CI 49.6-88.3%) for anti-mycobacterial antibiotics, and 70.4% (95% CI 49.6-88.3%) for 'no intervention'. Compared to 'no intervention', only complete excision was significantly associated with cure (OR 33.1; 95% CI 10.8-102.9; p < 0.001). Complete excision was associated with a 10% risk of facial nerve palsy (2% permanent). 'No intervention' was associated with delayed resolution.Conclusions: Complete excision is associated with the highest cure rate in NTM cervicofacial lymphadenitis, but also had the highest risk of facial nerve palsy. In the absence of large, well-designed RCTs, the choice between surgical excision, anti-mycobacterial antibiotics and 'no intervention' should be based on the location and extent of the disease, and acceptability of prolonged time to resolution. [ABSTRACT FROM AUTHOR]

Summary Introduction The ability to monitor and confirm adequate treatment of latent TB infection (LTBI) would be a major advance. The potential immunomodulatory effects of anti-tuberculous drugs and steroids need to be considered in assessing the utility of cytokine-based assays for this purpose. Methods We determined whether anti-tuberculous antibiotics or dexamethasone affect the production of IFN-γ and other potential cytokine biomarkers (TNF-α, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1β) in the QuantiFERON-TB Gold In-Tube (QFT-IT) assay. Blood from ten adults with LTBI was added to one standard set of QFT-IT tubes and five further sets containing therapeutic concentrations of either isoniazid, rifampicin, isoniazid and rifampicin, ciprofloxacin or dexamethasone. Resulting supernatants were analysed by ELISA (QFT-IT assay IFN-γ) and xMAP- Luminex assays (all cytokines). Results Anti-tuberculous antibiotics had only a limited effect on categorical QFT-IT assay results and the production of cytokines. In contrast, dexamethasone resulted in a change in categorical results from positive to negative in four of ten patients, and caused a marked reduction in IL-13 and IL-1ra responses. Conclusion Substantial changes in TB-antigen-induced IFN-γ and other cytokine responses during treatment likely primarily reflect host immunological changes rather than immunomodulatory effects of anti-tuberculous antibiotics. Results from cytokine-based assays in patients on corticosteroids should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Summary The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment. [ABSTRACT FROM AUTHOR]

Summary: Enteroviruses, which include echoviruses, coxsackie A and B viruses, polioviruses and the ‘numbered’ enteroviruses, are among the most common viruses causing disease in humans. A large proportion of enteroviral infections occur in neonates and infants. There is a wide spectrum of clinical manifestations that can be caused by enterovirus infection with varying degrees of severity. In the neonatal age group, enteroviral infections are associated with significant morbidity and mortality, particularly when infection occurs antenatally. This review provides a detailed overview of the epidemiology and clinical features of enterovirus infections in the neonatal period. In addition, laboratory features and diagnostic investigations are discussed. A review of the currently available data for prophylactic and therapeutic interventions, including antiviral therapy, is also presented. [Copyright &y& Elsevier]

Objectives: To assess the performance of interferon-gamma release assays (IGRAs) in the differential diagnosis between Mycobacterium avium complex (MAC) and tuberculosis (TB) in children affected with subacute/chronic submandibular/cervical lymphadenitis.Study Design: Multicenter observational study comparing children with microbiologically confirmed MAC lymphadenitis from the European NontuberculouS MycoBacterial Lymphadenitis in childrEn study with children with TB lymphadenitis from the Spanish Network for the Study of Pediatric TB database.Results: Overall, 78 patients with MAC and 34 with TB lymphadenitis were included. Among MAC cases, 44 out of 74 (59.5%) had positive tuberculin skin test (TST) results at the 5-mm cut-off, compared with 32 out of 33 (97%) TB cases (P < .001); at the 10-mm cut-off TST results were positive in 23 out of 74 (31.1%) vs 26 out of 31 (83.9%), respectively (P < .001). IGRA results were positive in only 1 out of 32 (3.1%) patients with MAC who had undergone IGRA testing, compared with 21 out of 23 (91.3%) TB cases (P < .001). Agreement between TST and IGRA results was poor in MAC (23.3%; κ = 0.017), but good in TB cases (95.6%; κ = 0.646). IGRAs had a specificity of 96.9% (95% CI 84.3%-99.8%), positive predictive value of 95.4% (95% CI 78.2%-99.8%), and negative predictive value of 93.9% (95% CI 80.4%-98.9%) for TB lymphadenitis.Conclusions: In contrast to TST, IGRAs have high specificity, negative predictive value, and positive predictive value for TB lymphadenitis in children with subacute/chronic lymphadenopathy, and consequently can help to discriminate between TB and MAC disease. Therefore, IGRAs are useful tools in the diagnostic work-up of children with lymphadenopathy, particularly when culture and polymerase chain reaction results are negative. [ABSTRACT FROM AUTHOR]

Abstract: Bacille Calmette-Guérin (BCG) vaccine is one of the most commonly administered vaccines worldwide. In countries with high tuberculosis (TB) prevalence, it is generally given shortly after birth. In a number of low TB prevalence countries, BCG is used as a travel vaccine, typically given to children outside the neonatal period prior to visiting regions where TB is common. In this setting, it is recommended that latent TB infection (LTBI) resulting from prior exposure to Mycobacterium tuberculosis is excluded by a tuberculin skin test (TST) before BCG immunisation. This is to avoid the risk of an accelerated local reaction that is more common in individuals who have LTBI. In addition, BCG immunisation in individuals with LTBI is unnecessary, as it does not provide protection against progression to active TB disease. We review and discuss current international guidelines and recommendations on the need to screen children for LTBI prior to BCG immunisation. Guidelines vary significantly regarding age-related cut-offs and additional selection criteria. This variation primarily reflects the lack of evidence on which to base recommendations. We suggest an alternative strategy using a risk assessment questionnaire to identify children who should have a TST before BCG immunisation. This targeted approach will reduce the number of children unnecessarily screened, whilst allowing the identification of those with LTBI, who need further evaluation and treatment. [Copyright &y& Elsevier]

Abstract: A 14-year-old girl was inadvertently immunised with an excessively large dose of BCG-Connaught vaccine (1.0ml instead of 0.1ml). Examination of the patient a few hours later revealed a subcutaneous fluctuant tender lump at the injection site. This was surgically excised within 12h of immunisation and she was treated with isoniazid and rifampicin for six weeks. The patient developed no complications, other than a minor surgical scar. This case highlights the importance of the correct administration and dosing of BCG vaccine and suggests a management option that may prevent the severe local and systemic complications that are frequently associated with BCG overdose. [Copyright &y& Elsevier]

In 2016, a new interferon-gamma release assay, QuantiFERON-TB Gold Plus, was introduced. We conducted a cross-sectional multicenter study, involving 158 children and adolescents with tuberculosis disease. The overall sensitivity of the assay was 82.9% (IQR 77.0%-88.8%), indicating that in children this test does not have higher sensitivity than previous generation interferon-gamma release assays. [ABSTRACT FROM AUTHOR]

Recent studies suggest that the incidence of nontuberculous mycobacterial infections in children may be increasing. Nontuberculous mycobacterial lymphadenitis, skin and soft tissue infection, and pulmonary disease each present unique challenges in relation to diagnosis and treatment. In this update, we critically review the recent literature on the epidemiology, clinical features, diagnostic approaches and treatment of nontuberculous mycobacterial disease in children. In addition, we outline key areas warranting further research. [ABSTRACT FROM AUTHOR]

Background More than 120 million doses of BCG vaccine are administered worldwide each year. Most infants are given BCG at birth in accordance with WHO recommendations. However, the effect of the maturing neonatal immune system on the immune response and protection conferred by BCG remains uncertain. Previous studies investigating the influence of age at immunisation on the immune response induced by BCG have reported conflicting results. This study compared BCG given at birth and at two months of age in infants in Australia. Methods Infants born in Melbourne were randomly allocated to immunisation with BCG-Denmark at birth or two months of age. Ten weeks after immunisation, anti-mycobacterial immune responses were measured in a whole blood assay using intracellular cytokine assays and xMAP multiplex cytokine analysis. Results Result from 98 BCG-immunised infants were included in the final analysis. BCG immunisation at birth ( n = 54) and at 2 months of age ( n = 44) induced comparable proportions of mycobacteria-specific cytokine-producing CD4 and CD8 T cells, as well as comparable proportions of polyfunctional (TNF + IL-2 + IFN-γ + ) CD4 T cells. Concentrations of cytokines in supernatants were also similar in both groups. Conclusions Cellular immunity measured 10 weeks after BCG immunisation was similar in infants given BCG at birth and in those given BCG at 2 months of age. Although definitive correlates of protection against TB remain uncertain, these results suggest that delaying BCG immunisation does not confer any immunological advantage in cellular immunity. [ABSTRACT FROM AUTHOR]