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276 results found
Jarvis H, Thwaites R, Tunstall T, et al., 2017, Isolated mediastinal lymph node tuberculosis (IMLNTB) is characterised by elevation in systemic and bronchial IL-12 pathway mediators compared to pulmonary TB
Berrocal-Almanza LC, OConnell AM, Muzyamba MC, et al., 2017, IS THE NEW NATIONAL LTBI SCREENING PROGRAM REACHING THE TARGET POPULATION? A POPULATION-BASED COHORT STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A21-A22, ISSN: 0040-6376
Abubakar I, Drobniewski F, Southern J, et al., 2017, PROGNOSTIC VALUE OF INTERFERON GAMMA RELEASE ASSAYS AND TUBERCULIN SKIN TEST IN PREDICTING THE DEVELOPMENT OF ACTIVE TUBERCULOSIS: THE UK PREDICT TB COHORT STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A22-A22, ISSN: 0040-6376
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Reuschl AK, Edwards MR, Parker R, et al., 2017, Innate activation of human primary epithelial cells broadens the host response to Mycobacterium tuberculosis in the airways, PLoS Pathogens, Vol: 13, ISSN: 1553-7366
Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1β and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100-family members and epithelial-myleoid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb.
Singanayagam A, Zambon M, Lalvani A, et al., 2017, Urgent challenges in implementing live attenuated influenza vaccine., Lancet Infectious Diseases, Vol: 18, Pages: e25-e32, ISSN: 1473-3099
Conflicting reports have emerged about the effectiveness of the live attenuated influenza vaccine. The live attenuated influenza vaccine appears to protect particularly poorly against currently circulating H1N1 viruses that are derived from the 2009 pandemic H1N1 viruses. During the 2015-16 influenza season, when pandemic H1N1 was the predominant virus, studies from the USA reported a complete lack of effectiveness of the live vaccine in children. This finding led to a crucial decision in the USA to recommend that the live vaccine not be used in 2016-17 and to switch to the inactivated influenza vaccine. Other countries, including the UK, Canada, and Finland, however, have continued to recommend the use of the live vaccine. This policy divergence and uncertainty has far reaching implications for the entire global community, given the importance of the production capabilities of the live attenuated influenza vaccine for pandemic preparedness. In this Personal View, we discuss possible explanations for the observed reduced effectiveness of the live attenuated influenza vaccine and highlight the underpinning scientific questions. Further research to understand the reasons for these observations is essential to enable informed public health policy and commercial decisions about vaccine production and development in coming years.
Shaikh N, Gupte A, Dharmshale S, et al., 2017, Novel interferon-gamma assays for diagnosing tuberculosis in young children in India., Int J Tuberc Lung Dis, Vol: 21, Pages: 412-419
SETTING: The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are used as supportive evidence to diagnose active tuberculosis (TB). Novel IGRAs could improve diagnosis, but data are lacking in young children. DESIGN: Children (age 5 years) with suspected TB were prospectively screened at a tertiary hospital in Pune, India; the children underwent TST, and standard (early secretory antigenic target 6 and culture filtrate protein 10) and enhanced (five additional novel antigens) enzyme-linked immunospot (ELISpot) assays. RESULTS: Of 313 children (median age 30 months) enrolled, 92% had received bacille Calmette-Guérin vaccination, 53% were malnourished and 9% were coinfected with the human immunodeficiency virus (HIV); 48 (15%) had TB, 128 (41%) did not, and TB could not be ruled out in 137 (44%). The sensitivity of enhanced (45%) and standard (42%) ELISpot assays for diagnosing TB was better than that of TST (20%) (P 0.03); however, enhanced ELISpot was not more sensitive than the standard ELISpot assay (P = 0.50). The specificity of enhanced ELISpot, standard ELISpot and TST was respectively 82% (95%CI 74-89), 88% (95%CI 81-94) and 98% (95%CI 93-100). Rv3879c and Rv3615c, previously reported to be promising antigens, failed to improve the diagnostic performance of the ELISpot assay. CONCLUSION: The TST and the standard and novel ELISpot assays performed poorly in diagnosing active TB among young children in India.
Halliday A, Whitworth H, Hermagild Kottoor S, et al., 2017, Stratification of latent tuberculosis infection by cellular immune profiling., Journal of Infectious Diseases, Vol: 215, Pages: 1480-1487, ISSN: 1537-6613
Background: Recently-acquired and remotely-acquired latent tuberculosis (TB) infection (LTBI) are clinically indistinguishable, yet recent acquisition of infection is the greatest risk factor for progression to active TB (ATB) in immunocompetent individuals. We aimed to evaluate the ability of cellular immune signatures which differ between ATB and LTBI, to distinguish recently from remotely acquired LTBI. Methods: Fifty-nine individuals were recruited: ATB (n=20); recent LTBI (n=19); remote LTBI (n=20). The proportion of mycobacteria-specific TNFα+IFNγ-IL-2-- secreting CD4+ T cells with a differentiated effector phenotype (TNFα-only TEFF), and the level of CD27 expression on IFNγ-producing CD4+ T cells, were detected by flow-cytometry. Results: The TNFα-only TEFF signature was significantly higher in recent compared to remote LTBI (p<0.0001), and discriminated between these groups with high sensitivity and specificity, with an area under the curve (AUC) = 0.87. Two signatures incorporating CD27 expression did not distinguish between recent and remote LTBI. Interestingly, the TNFα-only TEFF signature in recent LTBI was more similar to ATB than remote LTBI, suggesting that recent LTBI is immunologically more similar to ATB than remote LTBI. Conclusions: These findings reveal marked biological heterogeneity underlying the clinically homogeneous phenotype of LTBI, providing a rationale for immunological risk-stratification for improved targeting of LTBI treatment.
Eberhardt C, Thillai M, Parker R, et al., 2017, Proteomic analysis of Kveim reagent identifies targets of cellular immunity in sarcoidosis, PLOS ONE, Vol: 12, ISSN: 1932-6203
Background:Kveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4–6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins.Methods:Kv extracts were separated by 1D-SDS-PAGE and 2D-DIGE and then underwent mass spectrometric analysis for protein identification. Sarcoidosis and control PBMCs were first stimulated with Kv and then with three selected recombinant protein candidates which were identified from the proteomic analysis. PBMC secreted cytokines were subsequently measured by Multiplex Cytokine Assay.Results:We observed significantly increased IFN-γ and TNF-α secretion from Kv-stimulated PBMCs of sarcoidosis patients vs. PBMCs from healthy volunteers (IFN-γ: 207.2 pg/mL vs. 3.86 pg/mL, p = 0.0018; TNF-α: 2375 pg/mL vs. 42.82 pg/mL, p = 0.0003). Through proteomic approaches we then identified 74 sarcoidosis tissue-specific proteins. Of these, 3 proteins (vimentin, tubulin and alpha-actinin-4) were identified using both 1D-SDS-PAGE and 2D-DIGE. Data are available via ProteomeXchange with identifier PXD005150. Increased cytokine secretion was subsequently observed with vimentin stimulation of sarcoidosis PBMCs vs. tuberculosis PBMCs (IFN-γ: 396.6 pg/mL vs 0.1 pg/mL, p = 0.0009; TNF-α: 1139 pg/mL vs 0.1 pg/mL, p<0.0001). This finding was also observed in vimentin stimulation of sarcoidosis PBMCs compared to PBMCs from healthy controls (IFN-γ: 396.6 pg/mL vs. 0.1 pg/mL, p = 0.014; TNF-α: 1139 pg/mL vs 42.29 pg/mL, p = 0.027). No difference was found in cytokine secretion between sarcoidosis and contr
Singanayagam A, Manalan K, Connell DW, et al., 2016, Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis, International Journal of Tuberculosis and Lung Disease, Vol: 20, Pages: 1653-1660, ISSN: 1815-7920
OBJECTIVE: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB).METHODS: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months.RESULTS: There were 226 patients included in the study. Serum globulin >45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.59–7.32, P < 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P < 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.23–16.80, P < 0.001).CONCLUSIONS: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.
O'Donoghue M, Jarvis H, Drey N, et al., 2016, THE IMPACT OF TB NICE GUIDANCE ON RESOURCE CAPACITY AND CONTACT SCREENING OUTCOMES: A RETROSPECTIVE, OBSERVATIONAL STUDY WITHIN A CENTRAL LONDON TB CENTRE, THORAX, Vol: 71, Pages: A142-A142, ISSN: 0040-6376
Ritchie A, Singanayagam A, Manalan K, et al., 2016, SERUM INFLAMMATORY BIOMARKERS AS PREDICTORS OF TREATMENT OUTCOME IN PULMONARY TUBERCULOSIS, THORAX, Vol: 71, Pages: A143-A144, ISSN: 0040-6376
Ritchie A, Singanayagam A, Manalan K, et al., 2016, Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Marriott AC, Dennis M, Kane JA, et al., 2016, Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection, PLOS One, Vol: 11, ISSN: 1932-6203
Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.
Pollock KM, Montamat-Sicotte D, Grass L, et al., 2016, PD-1 expression and cytokine secretion profiles of Mycobacterium tuberculosis-specific CD4+ T-cell subsets; potential correlates of containment in HIV-TB co-infection, PLOS One, Vol: 11, ISSN: 1932-6203
HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.
Sridhar S, Lalvani A, 2015, Smoking and the Transmission of Tuberculosis <i>Reply</i>, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 34, Pages: 1138-1138, ISSN: 0891-3668
Lalvani A, Pareek M, Sridhar S, et al., 2015, Vitamin d deficiency and tuberculosis disease phenotype, Thorax, Vol: 70, Pages: 1171-1180, ISSN: 1468-3296
Background Extrapulmonary TB is increasinglycommon, yet the determinants of the wide clinicalspectrum of TB are poorly understood.Methods We examined surveillance data (Birmingham,UK: 1980–2009 and USA Centers for Disease Control:1993–2008) to identify demographic factorsassociated with extrapulmonary TB. We then directlytested association of these factors and serum 25-hydroxycholecalciferol (25(OH)D) concentration withextrapulmonary TB by multivariable analysis in aseparate UK cohort.Results Data were available for 10 152 and 277 013TB cases for Birmingham and US, respectively.Local-born individuals of white ethnicity had a lowerproportion of extrapulmonary disease when comparedwith local-born non-whites (p<0.0001); both groupshad a lower proportion of extrapulmonary disease whencompared with foreign-born non-whites (p<0.0001). Ina separate UK cohort (n=462), individuals withextrapulmonary TB had lower mean serum 25(OH)Dconcentration than those with pulmonary TB (11.4 vs15.2 nmol/L, respectively, p=0.0001). On multivariableanalysis, vitamin D deficiency was strongly associated withextrapulmonary TB independently of ethnicity, gender andother factors. Doubling in serum 25(OH)D concentrationconferred substantially reduced risk of extrapulmonarydisease (OR 0.55, 95% CI 0.41 to 0.73).Conclusions We identify vitamin D deficiency as aprobable risk factor for extrapulmonary dissemination inTB, which may account for the associations of darkskinnedethnicity and female gender with extrapulmonarydisease. Our findings implicate vitamin D status inMycobacterium tuberculosis containment in vivo and, given the high prevalence of deficiency, may informdevelopment of novel TB prevention strategies.
Nooredinvand HA, Connell DW, Asgheddi M, et al., 2015, Viral hepatitis prevalence in patients with active and latent tuberculosis, World Journal of Gastroenterology, Vol: 21, Pages: 8920-8926, ISSN: 1007-9327
AIM: To assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and association with drug induced liver injury (DILI) in patients undergoing anti-tuberculosis (TB) therapy.METHODS: Four hundred and twenty nine patients with newly diagnosed TB - either active disease or latent infection - who were due to commence anti-TB therapy between September 2008 and May 2011 were included. These patients were prospectively tested for serological markers of HBV, HCV and human immunodeficiency virus (HIV) infections - hepatitis B core antigen (HBcAg), hepatitis B surface antigen (HBsAg), hepatitis B e antigen, IgG and IgM antibody to HBcAg (anti-HBc), HCV IgG antibody and HIV antibody using a combination of enzyme-linked immunosorbent assay, Western blot assay and polymerase chain reaction techniques. Patients were reviewed at least monthly during the TB treatment initiation phase. Liver function tests were measured prior to commencement of anti-TB therapy and 2-4 wk later. Liver function tests were also performed at any time the patient had significant nausea, vomiting, rash, or felt non-specifically unwell. Fisher’s exact test was used to measure significance in comparisons of proportions between groups. A P value of less than 0.05 was considered statistically significant.RESULTS: Of the 429 patients, 270 (62.9%) had active TB disease and 159 (37.1%) had latent TB infection. 61 (14.2%) patients had isolated anti-HBc positivity, 11 (2.6%) were also HBsAg positive and 7 (1.6%) were HCV-antibody positive. 16/270 patients with active TB disease compared to 2/159 patients with latent TB infection had markers of chronic viral hepatitis (HBsAg or HCV antibody positive; P = 0.023). Similarly the proportion of HBsAg positive patients were significantly greater in the active vs latent TB infection group (10/43 vs 1/29, P = 0.04). The prevalence of chronic HBV or HCV was significantly higher than the estimated United Kingdom prevalence of 0.3% for each
Behr M, Ellis R, Ernst J, et al., 2015, Developing vaccines to prevent sustained infection with <i>Mycobacterium tuberculosis</i>: Conference proceedings National Institute of Allergy and Infectious Diseases, Rockville, Maryland USA, November 7, 2014, VACCINE, Vol: 33, Pages: 3056-3064, ISSN: 0264-410X
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Pollock KM, Montamat-Sicotte DJ, Cooke GS, et al., 2015, Differences in antigen-specific CD4+ responses to opportunistic infections in HIV infection, Immunity, Inflammation and Disease, Vol: 3, Pages: 141-153, ISSN: 2050-4527
HIV-infected individuals with severe immunodeficiency are at risk of opportunistic infection (OI). Tuberculosis (TB) may occur without substantial immune suppression suggesting an early and sustained adverse impact of HIV on Mycobacterium tuberculosis (MTB)-specific cell mediated immunity (CMI). This prospective observational cohort study aimed to observe differences in OI-specific and MTB-specific CMI that might underlie this. Using polychromatic flow cytometry, we compared CD4+ responses to MTB, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Candida albicans in individuals with and without HIV infection. MTB-specific CD4+ T-cells were more polyfunctional than virus specific (CMV/EBV) CD4+ T-cells which predominantly secreted IFN-gamma (IFN-γ) only. There was a reduced frequency of IFN-γ and IL-2 (IL-2)-dual-MTB-specific cells in HIV-infected individuals, which was not apparent for the other pathogens. MTB-specific cells were less differentiated especially compared with CMV-specific cells. CD127 expression was relatively less frequent on MTB-specific cells in HIV co-infection. MTB-specific CD4+ T-cells PD-1 expression was infrequent in contrast to EBV-specific CD4+ T-cells. The variation in the inherent quality of these CD4+ T-cell responses and impact of HIV co-infection may contribute to the timing of co-infectious diseases in HIV infection.
Lalvani A, Pareek M, Almanza LCB, 2015, Pre-entry screening for tuberculosis: the need for better evidence, PATHOGENS AND GLOBAL HEALTH, Vol: 109, Pages: 44-45, ISSN: 2047-7724
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Sridhar S, Begom S, Hoschler K, et al., 2015, Longevity and Determinants of Protective Humoral Immunity after Pandemic Influenza Infection, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 191, Pages: 325-332, ISSN: 1073-449X
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Kow KJH, Connell DW, Singanayagam A, et al., 2014, INTRATHORACIC LYMPH NODE TUBERCULOSIS - A COMPREHENSIVE CLINICAL DESCRIPTION, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A157-A158, ISSN: 0040-6376
Lalvani A, 2014, Preventing infectious disease pandemics with T cells, IMMUNOLOGY, Vol: 143, Pages: 23-23, ISSN: 0019-2805
Sridhar S, Karnani N, Connell DW, et al., 2014, INCREASED RISK OF <i>MYCOBACTERIUM TUBERCULOSIS</i> INFECTION IN HOUSEHOLD CHILD CONTACTS EXPOSED TO PASSIVE TOBACCO SMOKE, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 33, Pages: 1303-1306, ISSN: 0891-3668
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Abubakar I, Sridhar S, Eisenhut M, et al., 2014, BCG VACCINATION AND TB IN CHILDREN Authors' reply to Turner and colleagues, BMJ-BRITISH MEDICAL JOURNAL, Vol: 349, ISSN: 1756-1833
Roy A, Eisenhut M, Harris R, et al., 2014, The protective effect of BCG vaccination against mycobacterium tuberculosis infection in children: A systematic review, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Zhang L, Li Q, Zhang Y, et al., 2014, Dynamic changes of Thi-cell immune response to ESAT-6 and CFP-10 during anti-tuberculosis treatment, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Zhang L, Song Y, Zhang Y, et al., 2014, Utility of Th1-cell immune responses in differentiating active tuberculosis from latent tuberculosis infection, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Roy A, Eisenhut M, Harris RJ, et al., 2014, Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis, BMJ: British Medical Journal, Vol: 349, ISSN: 0959-535X
Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children.Design Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts.Setting Community congregate settings and households.Inclusion criteria Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays.Data extraction Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis.Results The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77).Conclusions BCG protects against M tuberculosis infection as well as progression from infection to disease.
Hingley-Wilson SM, Connell D, Pollock K, et al., 2014, ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans, TUBERCULOSIS, Vol: 94, Pages: 262-270, ISSN: 1472-9792
Mycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells.
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