#Effectiveness of pre-entry active #tuberculosis and post-entry latent tuberculosis #screening in new entrants to the #UK: a retrospective, population-based cohort study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study

Luis C Berrocal-Almanza, PhD, Ross Harris, MSc, Maeve K Lalor, PhD, Morris C Muzyamba, PhD, John Were, MPH, Anne-Marie O’Connell, MSc, Adil Mirza, MSc, Prof Onn-Min Kon, MD, Prof Ajit Lalvani, DM  †, Dominik Zenner, MD †

Published: August 27, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30260-9

 

Summary

Background

Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population.

Methods

We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System.

Findings

Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166–182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33–1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62–0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59–3·38; p<0·0001).

Interpretation

Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants.

Funding

National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre.

Keywords: Tuberculosis; Migrants; UK.

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Live-attenuated Mycobacterium #tuberculosis #vaccine MTBVAC versus #BCG in #adults and #neonates: a randomised controlled, double-blind dose-escalation trial (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Michele Tameris, MBChB *, Helen Mearns, PhD *, Adam Penn-Nicholson, PhD, Yolande Gregg, NDip, Nicole Bilek, PhD, Simbarashe Mabwe, BSc, Hennie Geldenhuys, MBChB, Justin Shenje, MBChB, Angelique Kany Kany Luabeya, MBChB, Ingrid Murillo, BD, Juana Doce, PhD, Nacho Aguilo, PhD, Dessislava Marinova, PhD, Eugenia Puentes, PhD, Esteban Rodríguez, VD, Jesús Gonzalo-Asensio, PhD, Bernard Fritzell, MD, Jelle Thole, PhD, Prof Carlos Martin, MD, Prof Thomas J Scriba, DPhil †, Prof Mark Hatherill, MD  † and theMTBVAC Clinical Trial Team

Published: August 12, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30251-6

 

Summary

Background

Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high.

Methods

We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-γ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 10 5colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 10 5 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 10 5 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 10 3 CFU, 2·5 × 10 4 CFU, and 2·5 × 10 5 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571.

Findings

Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 10 3 CFU MTBVAC group, nine to the 2·5 × 10 4 CFU group, and ten to the 2·5 × 10 5 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 10 5 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 10 3 CFU MTBVAC group, two in the 2·5 × 10 4 CFU MTBVAC group, and two in the 2·5 × 10 5 CFU MTBVAC group), including one infant in the 2·5 × 10 3 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 10 5 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 10 3 CFU MTBVAC group, six (75%) of eight in the 2·5 × 10 4 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 10 3 CFU MTBVAC group, four (67%) of the six in the 2·5 × 10 4 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 10 5 CFU MTBVAC group.

Interpretation

MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition.

Funding

Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri.

Keywords: Tuberculosis; Vaccines; BCG.

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#Global #burden of #latent #MDR #tuberculosis: #trends and #estimates based on mathematical modelling (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling

Gwenan M Knight, PhD, C Finn McQuaid, PhD, Peter J Dodd, PhD †, Rein M G J Houben, PhD †

Open Access / Published: July 04, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30307-X

 

Summary

Background

To end the global tuberculosis epidemic, latent tuberculosis infection needs to be addressed. All standard treatments for latent tuberculosis contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is resistant. We aimed to estimate the global burden of multidrug-resistant latent tuberculosis infection to inform tuberculosis elimination policy.

Methods

By fitting a flexible statistical model to tuberculosis drug resistance surveillance and survey data collated by WHO, we estimated national trends in the proportion of new tuberculosis cases that were caused by MDR strains. We used these data as a proxy for the proportion of new infections caused by MDR M tuberculosis and multiplied trends in annual risk of infection from previous estimates of the burden of latent tuberculosis to generate trends in the annual risk of infection with MDR M tuberculosis. These estimates were used in a cohort model to estimate changes in the global and national prevalence of latent infection with MDR M tuberculosis. We also estimated recent infection levels (ie, in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis in 2035 and 2050.

Findings

19·1 million (95% uncertainty interval [UI] 16·4 million–21·7 million) people were latently infected with MDR tuberculosis in 2014—a global prevalence of 0·3% (95% UI 0·2–0·3). MDR strains accounted for 1·2% (95% UI 1·0–1·4) of the total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6–3·1) of the burden among children younger than 15 years (risk ratio for those younger than 15 years vsthose aged 15 years or older 2·65 [95% UI 2·11–3·25]). Recent latent infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million–2·3 million) people globally were at high risk of active MDR tuberculosis in 2015.

Interpretation

We estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence is around ten times higher among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis—a cornerstone of tuberculosis elimination strategies.

Funding

UK Medical Research Council, Bill & Melinda Gates Foundation, and European Research Council.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; Worldwide.

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Acquisition of cross- #resistance to #Bedaquiline and #Clofazimine following #treatment for #Tuberculosis in #Pakistan (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Arash Ghodousi, Alamdar Hussain Rizvi, Aurangzaib Quadir Baloch, Abdul Ghafoor, Faisal Masood Khanzada, Mehmood Qadir, Emanuele Borroni, Alberto Trovato, Sabira Tahseen,Daniela Maria Cirillo

DOI: 10.1128/AAC.00915-19

 

ABSTRACT

We report on the first six cases of acquired-resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC test and by detection of mutations in relevant genes. We documented cases failing therapy developed specific mutations in Rv0678 and increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

Copyright © 2019 Ghodousi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; Pakistan; Bedaquiline; Clofazimine.

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Managing #tuberculosis in the #Baltic states (Lancet Resp Med., summary)

[Source: Lancet Respiratory Medicine, full page: (LINK). Summary, edited.]

Managing tuberculosis in the Baltic states

Vijay Shankar Balakrishnan

Published: June 17, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30219-X

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In March, WHO and the European Centre for Disease Prevention and Control (ECDC) jointly released the latest tuberculosis surveillance and monitoring report. The report included a mixture of good and bad news about the management of tuberculosis in the Baltic states (Estonia, Latvia, and Lithuania), which are in fierce competition to eliminate tuberculosis by 2030.

(…)

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Copyright © 2019 Elsevier Ltd. All rights reserved.

Keywords: Tuberculosis; Public Health; Estonia; Lithuania; Latvia.

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High rate of #transmission in a pulmonary #tuberculosis #outbreak in a primary #school, north-eastern #Italy, 2019 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

High rate of transmission in a pulmonary tuberculosis outbreak in a primary school, north-eastern Italy, 2019

Sandro Cinquetti1, Maria Dalmanzio1, Elisa Ros1, Davide Gentili1,2, Mauro Ramigni3, Adriano Grossi4,5, Xanthi D Andrianou5,6, Leonardo Ermanno La Torre7, Roberto Rigoli8, Pier Giorgio Scotton9, Angela Taraschi10, Vincenzo Baldo11, Giuseppina Napoletano12, Francesca Russo12, Patrizio Pezzotti5, Giovanni Rezza5, Antonietta Filia5

Affiliations: 1 Public Health Office , Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 2 Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 3 Epidemiology Office, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 4 University Cattolica del Sacro Cuore, Rome, Italy; 5 Department of Infectious Diseases, National Health Institute (Istituto Superiore di Sanità), Rome, Italy; 6 European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden; 7 Department of Radiology, Oderzo Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 8 Department of Microbiology, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 9 Department of Infectious Diseases, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 10 Department of Pediatrics, Oderzo Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 11 Hygiene and Public Health Unit, University of Padua, Padua, Italy; 12 Prevention Department, Veneto Regional Health Authority, Venice, Italy

Correspondence: Antonietta Filiaantonietta.filiaiss.it

Citation style for this article: Cinquetti Sandro, Dalmanzio Maria, Ros Elisa, Gentili Davide, Ramigni Mauro, Grossi Adriano, Andrianou Xanthi D, La Torre Leonardo Ermanno, Rigoli Roberto, Scotton Pier Giorgio, Taraschi Angela, Baldo Vincenzo, Napoletano Giuseppina, Russo Francesca, Pezzotti Patrizio, Rezza Giovanni, Filia Antonietta. High rate of transmission in a pulmonary tuberculosis outbreak in a primary school, north-eastern Italy, 2019. Euro Surveill. 2019;24(24):pii=1900332. https://doi.org/10.2807/1560-7917.ES.2019.24.24.1900332

Received: 24 May 2019;   Accepted: 13 Jun 2019

 

Abstract

Italy is a low-incidence country for tuberculosis (TB). We describe a TB outbreak in a primary school in north-eastern Italy, involving 10 cases of active pulmonary disease and 42 cases of latent infection. The index case was detected in March 2019, while the primary case, an Italian-born schoolteacher, was likely infectious since January 2018. Administration of a pre-employment health questionnaire to school staff with sustained contact with children should be considered in low-incidence countries.

© This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: TB; Institutional outbreaks; Italy.

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Boosting #BCG with proteins or #rAd5 does not enhance #protection against #tuberculosis in rhesus macaques (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 28 May 2019

Boosting BCG with proteins or rAd5 does not enhance protection against tuberculosis in rhesus macaques

Patricia A. Darrah, Robert M. DiFazio, Pauline Maiello, Hannah P. Gideon, Amy J. Myers, Mark A. Rodgers, Joshua A. Hackney, Thomas Lindenstrom, Thomas Evans, Charles A. Scanga, Victor Prikhodko, Peter Andersen, Philana Ling Lin, Dominick Laddy, Mario Roederer, Robert A. Seder & JoAnne L. Flynn

npj Vaccines 4, Article number: 21 (2019)

 

Abstract

Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

Keywords: Tuberculosis; BCG; Vaccines; Animal models.

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