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1. Measurement of IFN-γ and IL-2 for the assessment of the cellular immunity against SARS-CoV-2

Author: Guillem Safont, Raquel Villar-Hernández, Daria Smalchuk, Zoran Stojanovic, Alicia Marín, Alicia Lacoma, Cristina Pérez-Cano, Anabel López-Martínez, Bárbara Molina-Moya, Alan Jhunior Solis, Fernando Arméstar, Joan Matllo, Sergio Díaz-Fernández, Iris Romero, Irma Casas, Kevin Strecker, Rosemarie Preyer, Antoni Rosell, Irene Latorre, and Jose Domínguez
Subjects: Medicine, Science
Abstract: Abstract The study of specific T-cell responses against SARS-CoV-2 is important for understanding long-term immunity and infection management. The aim of this study was to assess the dual IFN-γ and IL-2 detection, using a SARS-CoV-2 specific fluorescence ELISPOT, in patients undergoing acute disease, during convalescence, and after vaccination. We also evaluated humoral response and compared with T-cells with the aim of correlating both types of responses, and increase the number of specific response detection. Blood samples were drawn from acute COVID-19 patients and convalescent individuals classified according to disease severity; and from unvaccinated and vaccinated uninfected individuals. IgGs against Spike and nucleocapsid, IgMs against nucleocapsid, and neutralizing antibodies were also analyzed. Our results show that IFN-γ in combination with IL-2 increases response detection in acute and convalescent individuals (p = 0.023). In addition, IFN-γ detection can be a useful biomarker for monitoring severe acute patients, as our results indicate that those individuals with a poor outcome have lower levels of this cytokine. In some cases, the lack of cellular immunity is compensated by antibodies, confirming the role of both types of immune responses in infection, and confirming that their dual detection can increase the number of specific response detections. In summary, IFN-γ/IL-2 dual detection is promising for characterizing and assessing the immunization status, and helping in the patient management.
Published: 2024
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2. Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trialResearch in context

Author: Laure F. Pittet, Nicole L. Messina, Ellie McDonald, Francesca Orsini, Simone Barry, Marc Bonten, John Campbell, Julio Croda, Mariana G. Croda, Margareth Dalcolmo, Kaya Gardiner, Amanda Gwee, Bruno Jardim, Marcus V.G. Lacerda, Michaela Lucas, David J. Lynn, Laurens Manning, Kirsten P. Perrett, Jeffrey J. Post, Cristina Prat-Aymerich, Peter C. Richmond, Jorge L. Rocha, Jesus Rodriguez-Baño, Adilia Warris, Nicholas J. Wood, Andrew Davidson, Nigel Curtis, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Rhian Bonnici, Thanh Dang, Susie Germano, Jenny Hua, Rebecca McElroy, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Suellen Nicholson, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O'Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O'Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O'Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O'Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Susan Herrmann, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Bruna Tayara LEOPOLDINA MEIRELES, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, P.M.G. Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, R.C. Pon, Lieke Preijers, J.H. van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, Neil Gow, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O'Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton
Subjects: Bacille Calmette-Guérin (BCG) vaccine, Immunity, Heterologous, Health personnel, Randomised controlled trial, Primary prevention, Medicine (General), R5-920
Abstract: Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.
Published: 2024
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3. Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines—an exploratory sub-study of the BRACE trialResearch in context

Author: Nicole L. Messina, Susie Germano, Rebecca McElroy, Rhian Bonnici, Branka Grubor-Bauk, David J. Lynn, Ellie McDonald, Suellen Nicholson, Kirsten P. Perrett, Laure F. Pittet, Rajeev Rudraraju, Natalie E. Stevens, Kanta Subbarao, Nigel Curtis, Andrew Davidson, Kaya Gardiner, Amanda Gwee, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Francesca Orsini, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Thanh Dang, Jenny Hua, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O’Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O’Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O’Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Simone Barry, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O’Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Laurens Manning, Susan Herrmann, Michaela Lucas, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Bruno Jardim, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Julio Croda, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Larissa Santos Matos, Bruna Tayara Leopoldina Meireles, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Marc Bonten, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Cristina Prat-Aymerich, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, Margreet Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, Roos Pon, Lieke Preijers, Joke van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, John Campbell, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O’Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Adilia Warris, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton
Subjects: Vaccine, Off-target, Immunoregulation, Cytokine, SARS-CoV-2, Heterologous immunity, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.
Published: 2024
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4. Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trialResearch in context

Author: Laure F. Pittet, Cecilia L. Moore, Ellie McDonald, Simone Barry, Marc Bonten, John Campbell, Julio Croda, Margareth Dalcolmo, Andrew Davidson, Mark W. Douglas, Kaya Gardiner, Amanda Gwee, Bruno Jardim, Marcus V.G. Lacerda, Michaela Lucas, David J. Lynn, Laurens Manning, Roberto D. de Oliveira, Kirsten P. Perrett, Cristina Prat-Aymerich, Peter C. Richmond, Jorge L. Rocha, Jesus Rodriguez-Baño, Adilia Warris, Nicholas J. Wood, Nicole L. Messina, Nigel Curtis, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Francesca Orsini, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Rhian Bonnici, Thanh Dang, Susie Germano, Jenny Hua, Rebecca McElroy, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Suellen Nicholson, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O'Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O'Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O'Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O'Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Susan Herrmann, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Larissa Santos Matos, Bruna Tayara Leopoldina Meireles, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, P.M.G. Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, R.C. Pon, Lieke Preijers, J.H. van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O'Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton
Subjects: Herpes simplex virus, Cold sore, Herpes labialis, Bacille Calmette-Guérin, Mycobacterium bovis, Prevention, Medicine (General), R5-920
Abstract: Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.
Published: 2023
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5. Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysisResearch in context

Author: Yohhei Hamada, Rishi K. Gupta, Matteo Quartagno, Abbie Izzard, Carlos Acuna-Villaorduna, Neus Altet, Roland Diel, Jose Dominguez, Sian Floyd, Amita Gupta, Helena Huerga, Edward C. Jones-López, Aarti Kinikar, Christoph Lange, Frank van Leth, Qiao Liu, Wei Lu, Peng Lu, Irene Latorre Rueda, Leonardo Martinez, Stanley Kimbung Mbandi, Laura Muñoz, Elisabeth Sánchez Padilla, Mandar Paradkar, Thomas Scriba, Martina Sester, Kwame Shanaube, Surendra K. Sharma, Rosa Sloot, Giovanni Sotgiu, Kannan Thiruvengadam, Richa Vashishtha, Ibrahim Abubakar, and Molebogeng X. Rangaka
Subjects: LTBI, IGRA, Tuberculin skin test, Prophylaxis, Prevention, Medicine (General), R5-920
Abstract: Summary: Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette–Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69–4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97–8.75). The difference was large in countries with TB incidence rate
Published: 2023
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6. Advances in diagnostic tools for respiratory tract infections: from tuberculosis to COVID-19 – changing paradigms?

Author: Zoran Stojanovic, Filipe Gonçalves-Carvalho, Alicia Marín, Jorge Abad Capa, Jose Domínguez, Irene Latorre, Alicia Lacoma, and Cristina Prat-Aymerich
Subjects: Medicine
Abstract: Respiratory tract infections (RTIs) are one of the most common reasons for seeking healthcare, but are amongst the most challenging diseases in terms of clinical decision-making. Proper and timely diagnosis is critical in order to optimise management and prevent further emergence of antimicrobial resistance by misuse or overuse of antibiotics. Diagnostic tools for RTIs include those involving syndromic and aetiological diagnosis: from clinical and radiological features to laboratory methods targeting both pathogen detection and host biomarkers, as well as their combinations in terms of clinical algorithms. They also include tools for predicting severity and monitoring treatment response. Unprecedented milestones have been achieved in the context of the COVID-19 pandemic, involving the most recent applications of diagnostic technologies both at genotypic and phenotypic level, which have changed paradigms in infectious respiratory diseases in terms of why, how and where diagnostics are performed. The aim of this review is to discuss advances in diagnostic tools that impact clinical decision-making, surveillance and follow-up of RTIs and tuberculosis. If properly harnessed, recent advances in diagnostic technologies, including omics and digital transformation, emerge as an unprecedented opportunity to tackle ongoing and future epidemics while handling antimicrobial resistance from a One Health perspective.
Published: 2022
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7. Study of CD27, CD38, HLA-DR and Ki-67 immune profiles for the characterization of active tuberculosis, latent infection and end of treatment

Author: Sergio Díaz-Fernández, Raquel Villar-Hernández, Zoran Stojanovic, Marco Fernández, Maria Luiza De Souza Galvão, Guillermo Tolosa, Adrián Sánchez-Montalva, Jorge Abad, María Ángeles Jiménez-Fuentes, Guillem Safont, Iris Romero, Josefina Sabrià, Cristina Prat, Jose Domínguez, and Irene Latorre
Subjects: Mycobacterium tuberculosis, T-cells, immune response, activation markers, treatment, flow cytometry, Microbiology, QR1-502
Abstract: BackgroundCurrent blood-based diagnostic tools for TB are insufficient to properly characterize the distinct stages of TB, from the latent infection (LTBI) to its active form (aTB); nor can they assess treatment efficacy. Several immune cell biomarkers have been proposed as potential candidates for the development of improved diagnostic tools.ObjectiveTo compare the capacity of CD27, HLA-DR, CD38 and Ki-67 markers to characterize LTBI, active TB and patients who ended treatment and resolved TB.MethodsBlood was collected from 45 patients defined according to clinical and microbiological criteria as: LTBI, aTB with less than 1 month of treatment and aTB after completing treatment. Peripheral blood mononuclear cells were stimulated with ESAT-6/CFP-10 or PPD antigens and acquired for flow cytometry after labelling with conjugated antibodies against CD3, CD4, CD8, CD27, IFN-γ, TNF-α, CD38, HLA-DR, and Ki-67. Conventional and multiparametric analyses were done with FlowJo and OMIQ, respectively.ResultsThe expression of CD27, CD38, HLA-DR and Ki-67 markers was analyzed in CD4+ T-cells producing IFN-γ and/or TNF-α cytokines after ESAT-6/CFP-10 or PPD stimulation. Within antigen-responsive CD4+ T-cells, CD27− and CD38+ (ESAT-6/CFP-10-specific), and HLA-DR+ and Ki-67+ (PPD- and ESAT-6/CFP-10-specific) populations were significantly increased in aTB compared to LTBI. Ki-67 demonstrated the best discriminative performance as evaluated by ROC analyses (AUC > 0.9 after PPD stimulation). Data also points to a significant change in the expression of CD38 (ESAT-6/CFP-10-specific) and Ki-67 (PPD- and ESAT-6/CFP-10-specific) after ending the anti-TB treatment regimen. Furthermore, ratio based on the CD27 median fluorescence intensity in CD4+ T-cells over Mtb-specific CD4+ T-cells showed a positive association with aTB over LTBI (ESAT-6/CFP-10-specific). Additionally, multiparametric FlowSOM analyses revealed an increase in CD27 cell clusters and a decrease in HLA-DR cell clusters within Mtb-specific populations after the end of treatment.ConclusionOur study independently confirms that CD27−, CD38+, HLA-DR+ and Ki-67+ populations on Mtb-specific CD4+ T-cells are increased during active TB disease. Multiparametric analyses unbiasedly identify clusters based on CD27 or HLA-DR whose abundance can be related to treatment efficacy. Further studies are necessary to pinpoint the convergence between conventional and multiparametric approaches.
Published: 2022
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8. BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)

Author: Donna Legge, Katherine J Lee, Rachel Dixon, Amanda Gwee, Nigel Curtis, Helen Marshall, Fiona McDonald, Nick Evans, Adam Finn, Mark McMillan, Peter Richmond, Joyce Chan, John Carlin, Anthony Byrne, Helen Thomson, Richard Hall, Jesús Rodríguez-Baño, Robert Harrison, Kirsten P Perrett, Michaela Lucas, Sue Evans, Melissa O’Donnell, Justin Waring, Andrew Davidson, Heidi Hutton, Laure F Pittet, Jan Kluytmans, Ana Maria Barriocanal, Emily Fletcher, James Moore, John Campbell, Kate Sidaway-Lee, Alex Harding, Katherine Lee, David Paterson, Juliana Silva, Michael Gibbons, Denise Faustman, Nicole L Messina, Kaya Gardiner, Frank Shann, Veronica Abruzzo, Susie Germano, Laurens Manning, Justin Beardsley, Jason Bell, Francesca Orsini, Jeremy Anderson, Kim Mulholland, Andrew Dunn, Jeffrey Post, Catherine Flynn, Clare Seamark, Andrew Steer, Sigrid Pitkin, Emma Watts, Carlos Garcia, Kristen Overton, Daniel Santos, Christina Guo, Antoni Rosell, Sarah Fowler, Richard Malley, Nicholas J Wood, Wim Boersma, Kanta Subbarao, Karen Jones, Chris Richards, Nigel Crawford, Adilia Warris, Mary Corbett, Pamela Palasanthiran, Cristina Pérez, Esther Calbo, Shelley Rhodes, Brendan McMullan, Jane Jones, Wendy Norton, Luke Stevens, Craig F Munns, Louise Goodchild, Mary Walker, Bridget Knight, Thilanka Morawakage, Josune Goikoetxea, Teresa Rodrigues, Nienke Roescher, David Seamark, Jorge Rocha, Stephanie Reynolds, Lynne Quinn, Harry Tripp, Tobias R Kollmann, Marc Bonten, Steve Wesselingh, Irene Latorre, Maria Esteve, Kate Hamilton, Angela Young, Cristina Prat-Aymerich, NICK WOOD, RAMÓN CASTRO, Ruth Warren, Christopher Martin, Diane Dawson, Lorrie Symons, Ann Krastev, Ellie McDonald, Claudia González Rico, Ester Valls, Julio Croda, Tobias Kollmann, Victoria Gordon, Marcus Vinícius Guimarães Lacerda, Jennifer Kent, Samantha Bannister, Margareth Dalcolmo, Sonja Elia, Casey Goodall, Tenaya Jamieson, Bruno Jardim, David J Lynn, Cristina Prat Aymerich, Eva Sudbury, Paola Villanueva, Katherine Lieschke, Carolinne Abreu, Lynne Addlem, Sophie Agius, Adelita Agripina Barbosa, Ahmed Alamrousi, Ayla Alcoforado Santos, Yasmeen Al-Hindawi, Samyra Almeida Da Silveira, Lais Alves Cruz, Christina Anthony, Andrea Antonia Pereira, Francisco Arnaiz Almajano, Annabelle Arnold, Beth Arrowsmith, Kristy Azzopardi, Cristina Badia Marti, Twinkle Bahaduri, Sarah Barney, Lydia Barrera, Anabel Barriocanal, Dayanne Barros, Adam Bartlett, Lilian Muranaka, Therese Baulman, Morgan Bealing, Ana Belen Gutierrez, Vicki Bennett-Wood, Nikki Bergant, Fabiane Bianca Barbosa, Wouter Bijllaardt, Patricia Bimboese, Camila Bitencourt Andrade, Kitty Blauwendraat, Pilar Bohedo Garcia, Rhian Bonnici, Anne Boon, Anna Bourke, Kirsty Bowes, Larissa Brasil, Clare Brophy, Sandy Buchanan, Jess Bucholc, Alison Burns, Emma Burrell, Natalia Bustos, Bridie Byrne, Jorge Calvo Montes, Beatriz Camesella, Atsegiñe Cangas, Maria Carmen Roque, Roberta Carolina Diogo, Estela Carvalho, Irma Casas, Erika Castro, Helen Catterick, Rodrigo Cezar Escobar, Jo Cheah, Thilakavathi Chengodu, Marianna Ciaverella, Sharon Clark, Marie-Alix Clement Espindola, Annie Cobbledick, Clinton Colaco, Simone Collopy, Patricia Comella, Gabriela Correa Castro, Erlane Costa, Raquel Coya, Alda Cruz, Jac Cushnahan, Anna Czajko, Renato da Silva, Bouchra Daitiri, Karen Dalton, Aiken Dao, Phoebe Dawe, Miriam Jesus Costa, Karina De La Cruz, Almudena de Serna, Fabiani de Morais Batista, Adriely de Oliveira, Rocio del Rey Morillo, Maria Desylva, Helga Dijkstra, Maria Dolores Lopez, Jose Dominguez, Angel Dominguez Castellano, Glauce Dos Santos, Joyce Santos Lencina, Débora Santos Silva, Mark Douglas, Ross Dunn, Jemma Dunnill, Harriet Edmund, Nat Eiffler, Hannah Elborough, Olivia Elkington, Michelle England, Wellyngthon Espindola Ayala, Krist Ewe, María Carmen Álvarez, Kieran Fahey, Jill Fairweather, Erica Fernandes Silva, Monique Fernandez, Galina Fidler, P.M.G. Filius, Carolyn Finucane, Stephanie Firth, Lorraine Flynn, Liam Fouracre, Thamires Freitas, Ana Carolina Furtado, Maria Gabriela Oliveira, Anna Gabriela Santos, Leandro Galdino Gonçalves, Laura Galletta, Larissa Gama, Dinusha Gamage, Radhika Ganpat, Mariana Garcia Croda, Evangeline Gardiner, Grace Gell, Aline Gerhardt Oliveira, Camille Gibson, Alison Gifford, Teresa Giménez Poderos, Ann Ginsberg, Jet Gisolf, Bojana Gladanac, Penny Glenn, Vanessa Godinho, Mayara Góes Santos, Telma Goldenberg, Adriano Gomes, Susana Gonzalez Marcos, Frances Greven, Ana Greyce Capella, David Gutierrez Campos, Manuel Gutierrez Cuadra, Lydia Hall, Matthew Hannan, Houda Harbech, Neil Haker, Robert Jan Hassing, Thaynara Haynara Rosa, Zaheerah Haywood, Nadine Henare, Paulo Henrique Andrade, Susan Herrmann, Erin Hill, Sam Hilton, Danique Huijbens, Axel Janssen, Tyane Jardim, Lance Jarvis, Narelle Jenkins, Jan Jones, Leticia Jorge, Maria Jose Vilegas, Sri Joshi, Rosemary Joyce, Joel Junior, Rama Kandasamy, Anushka Karunanayake, Hana Karuppasamy, Tom Keeble, Paul Kloeg, Tony Korman, Nathan La, Marcus Lacerda, Alicia Lacoma, Renier Lagunday, Debbie Lalich, Erin Latkovic, Paulo Leandro Junior, Toos Lemmers, Titia Leurink, Kee Lim, Gemma Lockhart, Cíntia Lopes Bogéa, Karla Lopes Santos, Reyes Lopez Marques, Maria Luciana Freitas, Norine Ma, Sam Macalister, Cristiane Machado, Matheus Machado Ramos, Francesca Machingaifa, Ivan Maia, Bernardo Maia, Sarah Manton, Jose Manuel Carrerero, Cíntia Maria Alves, Rosa Maria Pereira, Bianca Maria Arruda, Adriana Marins, Katya Martinez Almeida, Wayne Mather, Megan Mathers, Fábio Mauricio Gomes, Mariana Mayumi Tadokoro, Nadia Mazarakis, Kelry Mazurega, Sonia McAlister, Amy McAndrews, Rebecca McElroy, Nick McPhate, Lee Mead, Andrea Meehan, Bob Meek, Rosangela Melo, Guillermo Mena, Daniella Mesquita, Nicole Messina, Isabella Mezzetti, Hugo Miguel Vieira, Skye Miller, Kirsten Mitchell, Marcus Mitchell, Jesutofunmi Mojeed, Kitty Molenaar, Gemma Molina, Barbara Molina, Lisa Montgomery, Cecilia Moore, Simone Moorlag, Julie Moss, Will Moyle, Craig Munns, Elizandra Nascimento, Nicolas Navarrette, Mihai Netea, Juliana Neves, Georgina Newman, Belle Ngien, Jill Nguyen, Khanh Nguyen, Fran Noonan, Jess O’Bryan, Abby O’Connell, Sasha Odoi, Liz O’Donnell, Roberto Oliveira, Marilena Oliveira, Thais Oliveira, Ingrid Oliveira, Nadia Olivier, Ligia Olivio, Benjamin Ong, Jaslyn Ong, Joanne Ong, Jakob Onysk, Isabelle Ooi, Frances Oppedisano, Belinda Ortika, Orygen Group, Arthur Otsuka, Rosie Owens, Rayssa Paes, Virginia Palomo Jiménez, Girlene Pandine, Kimberley Parkin, Alvaro Pascual Hernandez, Nienke Paternotte, Ana Paula Souza, Lisa Pelayo, Casey Pell, Sille Pelser, Handerson Pereira, Gabrielle Pereira, Glady Perez, Tomás Perez Porcuna, Susan Perlen, Kirsten Perrett, Amandine Philippart Floy, Laure Pittet, R.C. Pon, Ines Portillo Calderón, Catherine Power, Christiane Prado, Endriaen Prajitno, Lieke Preijers, Marco Puga, Evelyn Queiroz, Ashleigh Rak, Leticia Ramires Figueiredo, Encarnacion Ramirez de Arellano, Pedro Ramos, Karla Regina Oliveira, Jack Ren, Claudinalva Ribeiro Santos, Holly Richmond, Ana Rita Souza, Laleyska Rodrigues, Bebeto Rodrigues, Iara Rodrigues Fernandes, Sally Rogers, Anke Rol, Jannie Romme, Maria Roser Font, Sonia Sallent, Vanderson Sampaio, Nuria Sanchez, Blanca Sanchez, Tilza Santos, Ariandra Sartim, Amber Sastry, Alice Sawka, Nikki Schultz, Engelien Septer-Bijleveld, Raquel Serrano, Ketaki Sharma, Margaret Shave, Lisa Shen, Adrian Siles Baena, Rafaela Silva, Emanuelle Silva, Mariana Simão, Ronita Singh, Marilda Siqueira, Marciléia Soares Chaves, Thijs Sondag, Enoshini Sooriyarachchi, Antonny Sousa, Leena Spry, Sarah Statton, Dyenyffer Stéffany Santos, Katrina Sterling, Leah Steve, Carolyn Stewart, Lisa Stiglmayer, Lida Stooper, Josephine Studham, Astrid Suiker, Esther Taks, Niki Tan, Bruna Tayara Meireles, Menno te Riele, Jaap ten Oever, Guilherme Teodoro Lima, Jhenyfer Thalyta Angelo, Ryan Toh, Alexandre Trindade, Enriqueta Tristán, Darren Troeman, Alexandra Truelove, Daniel Tsuha, Marlot Uffing, Fernando Val, Olga Valero, Chantal van Ven, Leo Van Heuvel, Sigrid van Veen, Marije van Waal, J.H. van Leusen, Linda van Mook, H. van Onzenoort, Marjoleine van Opdorp, Miranda van Rijen, Nicolette van Sluis, Adria Vasconcelos, Noelia Vega, Sunitha Velagapudi, Louise Vennells, Tamsin Venton, Harald Verheij, P.M. Verhoeven, Caroliny Veron Ramos, Paulo Victor Silva, Sandra Vidal, Patricia Vieira, Matheus Vieira Oliveira, Rosario Vigo Ortega, Raquel Villar, Amanda Vlahos, Ushma Wadia, Kate Wall, Rachael Wallace, Michelle Wearing-Smith, Daniel Webber-Rookes, Jamie Wedderburn, Ashleigh Wee-Hee, Jia Wei Teo, Bethany Whale, Phoebe Williams, Beatrijs Wolters, Ivy Xie, Angela Younes, Felipe Zampieri Batista, Carmen Zhou, Vivian Zwart, Simone Barry, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Catriona Doran, Georgina Eden, Liddy Griffith, Christine Heath, Jane James, Meredith Krieg, David Lynn, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, and Rob ter Heine
Subjects: Medicine
Abstract: Introduction BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysis This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and dissemination Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registration ClinicalTrials.gov NCT04327206
Published: 2021
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9. Cell-Mediated Immune Responses to in vivo-Expressed and Stage-Specific Mycobacterium tuberculosis Antigens in Latent and Active Tuberculosis Across Different Age Groups

Author: Mariateresa Coppola, Raquel Villar-Hernández, Krista E. van Meijgaarden, Irene Latorre, Beatriz Muriel Moreno, Esther Garcia-Garcia, Kees L. M. C. Franken, Cristina Prat, Zoran Stojanovic, Maria Luiza De Souza Galvão, Joan-Pau Millet, Josefina Sabriá, Adrián Sánchez-Montalva, Antoni Noguera-Julian, Annemieke Geluk, Jose Domínguez, and Tom H. M. Ottenhoff
Subjects: IVE-TB antigens, Mycobacterium tuberculosis (Mtb), TB, LTBI, cytokines, cell responses, Immunologic diseases. Allergy, RC581-607
Abstract: A quarter of the global human population is estimated to be latently infected by Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). TB remains the global leading cause of death by a single pathogen and ranks among the top-10 causes of overall global mortality. Current immunodiagnostic tests cannot discriminate between latent, active and past TB, nor predict progression of latent infection to active disease. The only registered TB vaccine, Bacillus Calmette-Guérin (BCG), does not adequately prevent pulmonary TB in adolescents and adults, thus permitting continued TB-transmission. Several Mtb proteins, mostly discovered through IFN-γ centered approaches, have been proposed as targets for new TB-diagnostic tests or -vaccines. Recently, however, we identified novel Mtb antigens capable of eliciting multiple cytokines, including antigens that did not induce IFN-γ but several other cytokines. These antigens had been selected based on high Mtb gene-expression in the lung in vivo, and have been termed in vivo expressed (IVE-TB) antigens. Here, we extend and validate our previous findings in an independent Southern European cohort, consisting of adults and adolescents with either LTBI or TB. Our results confirm that responses to IVE-TB antigens, and also DosR-regulon and Rpf stage-specific Mtb antigens are marked by multiple cytokines, including strong responses, such as for TNF-α, in the absence of detectable IFN-γ production. Except for TNF-α, the magnitude of those responses were significantly higher in LTBI subjects. Additional unbiased analyses of high dimensional flow-cytometry data revealed that TNF-α+ cells responding to Mtb antigens comprised 17 highly heterogeneous cell types. Among these 17 TNF-α+ cells clusters identified, those with CD8+TEMRA or CD8+CD4+ phenotypes, defined by the expression of multiple intracellular markers, were the most prominent in adult LTBI, while CD14+ TNF-α+ myeloid-like clusters were mostly abundant in adolescent LTBI. Our findings, although limited to a small cohort, stress the importance of assessing broader immune responses than IFN-γ alone in Mtb antigen discovery as well as the importance of screening individuals of different age groups. In addition, our results provide proof of concept showing how unbiased multidimensional multiparametric cell subset analysis can identify unanticipated blood cell subsets that could play a role in the immune response against Mtb.
Published: 2020
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10. Serial testing of health care workers for tuberculosis infection: A prospective cohort study.

Author: Irma Casas, Maria Esteve, Rosa Guerola, Irene Latorre, Raquel Villar-Hernández, Guillermo Mena, Cristina Prat-Aymerich, Joan Matllo, and Jose Dominguez
Subjects: Medicine, Science
Abstract: Health Care Workers (HCW) may have an occupational risk of latent tuberculosis infection (LTBI) and TB disease. The objective of this study was to evaluate the performance of the 2-step strategy: tuberculin skin test (TST) followed by confirmation with Interferon (IFN)-γ- release assays (IGRAs) in HCW. A secondary objective was to determine the factors related to conversions and reversions. HCW at risk of occupational exposure who attended the Occupational Department of the Hospital Germans Trias i Pujol were included during the study period (2013-2016). All professionals testing negative for LTBI were included in a cohort study. These workers were followed up with the administration of a TST and an IGRA quantification at least one year after inclusion in the study. Workers with positive TST, regardless of the results of the IGRA tests, were followed-up with an IGRA. 255 workers were enrolled in the study and 108 workers from the same cohort were followed up. During the follow-up period, seven workers presented TST test conversion. One of these conversions was also confirmed by an IGRA test. There were 2 conversions of cases only testing positive with the IGRA. There have been only 2 reversions of cases testing negative with the IGRA. In this study, not all TST conversions were confirmed when using the IGRA test, which highlights the importance of the 2-step strategy. We have detected a low number of conversions and reversions. Our conclusions should be confirmed in studies with a longer follow-up time.
Published: 2020
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11. A Model Based on the Combination of IFN-γ, IP-10, Ferritin and 25-Hydroxyvitamin D for Discriminating Latent From Active Tuberculosis in Children

Author: Patricia Comella-del-Barrio, Rosa Abellana, Raquel Villar-Hernández, Mariette Doresca Jean Coute, Beatriz Sallés Mingels, Lydia Canales Aliaga, Margareth Narcisse, Jacqueline Gautier, Carlos Ascaso, Irene Latorre, Jose Dominguez, and Tomas M. Perez-Porcuna
Subjects: pediatrics, biomarkers, immune response, vitamin D, ferritin, enzyme-linked immunoassays, Microbiology, QR1-502
Abstract: In recent years, pediatric research on tuberculosis (TB) has focused on addressing new biomarkers with the potential to be used as immunological non-sputum-based methods for the diagnosis of TB in children. The aim of this study was to characterize a set of cytokines and a series of individual factors (ferritin, 25-hydroxyvitamin D [25(OH)D], parasite infections, and nutritional status) to assess different patterns for discriminating between active TB and latent TB infection (LTBI) in children. The levels of 13 cytokines in QuantiFERON-TB Gold In-Tube (QFT-GIT) supernatants were analyzed in 166 children: 74 with active TB, 37 with LTBI, and 55 uninfected controls. All cytokines were quantified using Luminex or ELISA. Ferritin and 25(OH)D were also evaluated using CLIA, and Toxocara canis Ig-G antibodies were detected with a commercial ELISA kit. The combination of IP-10, IFN-γ, ferritin, and 25(OH)D achieved the best diagnostic performance to discriminate between active TB and LTBI cases in children in relation to the area under receiver operating characteristic (ROC) curve 0.955 (confidence interval 95%: 0.91–1.00), achieving optimal sensitivity and specificity for the development of a new test (93.2 and 90.0%, respectively). Children with TB showed higher ferritin levels and an inverse correlation between 25(OH)D and IFN-γ levels. The model proposed includes a combination of biomarkers for discriminating between active TB and LTBI in children to improve the accuracy of TB diagnosis in children. This combination of biomarkers might have potential for identifying the onset of primary TB in children.
Published: 2019
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12. Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections

Author: Alicia Lacoma, Lourdes Mateo, Ignacio Blanco, Maria J. Méndez, Carlos Rodrigo, Irene Latorre, Raquel Villar-Hernandez, Jose Domínguez, and Cristina Prat
Subjects: immunogenetics, biological response modifiers, respiratory tract infections, primary immunodeficiencies, inborn errors, Immunologic diseases. Allergy, RC581-607
Abstract: Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.
Published: 2019
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13. Study of CD27 and CCR4 Markers on Specific CD4+ T-Cells as Immune Tools for Active and Latent Tuberculosis Management

Author: Irene Latorre, Marco A. Fernández-Sanmartín, Beatriz Muriel-Moreno, Raquel Villar-Hernández, Sergi Vila, Maria L. De Souza-Galvão, Zoran Stojanovic, María Á. Jiménez-Fuentes, Carmen Centeno, Juan Ruiz-Manzano, Joan-Pau Millet, Israel Molina-Pinargote, Yoel D. González-Díaz, Alicia Lacoma, Lydia Luque-Chacón, Josefina Sabriá, Cristina Prat, and Jose Domínguez
Subjects: CD4 T-cells, CD27, CCR4, flow cytometry, immunity, latent tuberculosis, Immunologic diseases. Allergy, RC581-607
Abstract: The immunological characterization of different cell markers has opened the possibility of considering them as immune tools for tuberculosis (TB) management, as they could correlate with TB latency/disease status and outcome. CD4+ T-cells producing IFN-γ+ with a low expression of CD27 have been described as an active TB marker. In addition, there are unknown homing receptors related to TB, such as CCR4, which might be useful for understanding TB pathogenesis. The aim of our study is focused on the assessment of several T-cell subsets to understand immune-mechanisms in TB. This phenotypic immune characterization is based on the study of the specific immune responses of T-cells expressing CD27 and/or CCR4 homing markers. Subjects enrolled in the study were: (i) 22 adult patients with active TB, and (ii) 26 individuals with latent TB infection (LTBI). Blood samples were drawn from each patient. The expression of CD27 and/or CCR4 markers were analyzed within CD4+ T-cells producing: (i) IFN-γ+, (ii) TNF-α+, (iii) TNF-α+IFN-γ+, and (iv) IFN-γ+ and/or TNF-α+. The percentage of CD27− within all CD4+ T-cell populations analyzed was significantly higher on active TB compared to LTBI after PPD or ESAT-6/CFP-10 stimulation. As previously reported, a ratio based on the CD27 median fluorescence intensity (MFI) was also explored (MFI of CD27 in CD4+ T-cells over MFI of CD27 in IFN-γ+CD4+ T-cells), being significantly increased during disease (p < 0.0001 after PPD or ESAT-6/CFP-10 stimulation). This ratio was also assessed on the other CD4+ T-cells functional profiles after specific stimulation, being significantly associated with active TB. Highest diagnostic accuracies for active TB (AUC ≥ 0.91) were achieved for: (i) CD27 within IFN-γ+TNF-α+CD4+ T-cells in response to ESAT-6/CFP-10, (ii) CD27 and CCR4 markers together within IFN-γ+CD4+ T-cells in response to PPD, and (iii) CD27 MFI ratio performed on IFN-γ+TNF-α+CD4+ T-cells after ESAT-6/CFP-10 stimulation. The lowest diagnostic accuracy was observed when CCR4 marker was evaluated alone (AUC ≤ 0.77). CD27 and CCR4 expression detection could serve as a good method for immunodiagnosis. Moreover, the immunological characterization of markers/subset populations could be a promising tool for understanding the biological basis of the disease.
Published: 2019
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14. Immune-mediated inflammatory diseases differently affect IGRAs' accuracy for latent tuberculosis infection diagnosis in clinical practice.

Author: Irene Latorre, Sonia Mínguez, José-Manuel Carrascosa, Juan Naves, Raquel Villar-Hernández, Beatriz Muriel, Cristina Prat, Esther García-García, Irma Casas, Eugeni Domènech, Carlos Ferrándiz, Lourdes Mateo, and Jose Domínguez
Subjects: Medicine, Science
Abstract: Clinical accuracy of IGRAs remains unclear on patients with immune-mediated inflammatory diseases (IMIDs). Here, we assess the impact of immunosuppressants and IMIDs on QuantiFERON-TB Gold In-Tube (QFN-G-IT) and T-SPOT.TB accuracy.Patients with IMIDs who required latent tuberculosis infection (LTBI) screening were enrolled and classified into: (i) 50 patients with inflammatory rheumatic diseases, (ii) 50 patients with psoriasis and (iii) 30 patients with Crohn's disease. A total of 44 healthy individuals without immunosuppression were also included as controls. Tuberculin skin test (TST), T-SPOT.TB and QFN-G-IT assays were performed. IGRAs were performed following manufacturer's instructions.Immunosuppressant's intake was more frequent on patients with Crohn's disease and psoriasis. Positive IGRAs and TST results were reduced in Crohn's disease patients, whereas rate of indeterminate T-SPOT.TB results was increased in this group with respect to the other IMIDs analysed and controls. When IFN-γ response was studied, the levels of this cytokine after mitogen stimulation were significantly lower in Crohn's and inflammatory rheumatic diseases than in psoriasis. Interestingly, psoriatic patients were the only ones not receiving corticosteroids. Furthermore, a negative correlation was observed between the IFN-γ secreted after mitogen stimulation and corticosteroids dose.IMIDs seem to negatively affect the clinical accuracy of IGRAs, being Crohn's disease patients the most affected individuals due to their concomitant drug-profile and impaired immune response.
Published: 2017
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15. Assessment of the influence of direct tobacco smoke on infection and active TB management.

Author: Neus Altet, Irene Latorre, María Ángeles Jiménez-Fuentes, José Maldonado, Israel Molina, Yoel González-Díaz, Celia Milà, Esther García-García, Beatriz Muriel, Raquel Villar-Hernández, Maisem Laabei, Andromeda-Celeste Gómez, Pere Godoy, Maria Luiza de Souza-Galvão, Segismundo Solano, Carlos A Jiménez-Ruiz, Jose Domínguez, and PII Smoking SEPAR Working Group
Subjects: Medicine, Science
Abstract: Smoking is a risk factor for tuberculosis (TB) infection and disease progression. Tobacco smoking increases susceptibility to TB in a variety of ways, one of which is due to a reduction of the IFN-γ response. Consequently, an impaired immune response could affect performance of IFN-γ Release Assays (IGRAs).In the present study, we assess the impact of direct tobacco smoking on radiological manifestations, sputum conversion and immune response to Mycobacterium tuberculosis, analyzing IFN-γ secretion by IGRAs.A total of 525 participants were studied: (i) 175 active pulmonary TB patients and (ii) 350 individuals coming from contact tracing studies, 41 of whom were secondary TB cases. Clinical, radiological and microbiological data were collected. T-SPOT.TB and QFN-G-IT were processed according manufacturer's instructions.In smoking patients with active TB, QFN-G-IT (34.4%) and T-SPOT.TB (19.5%) had high frequencies of negative results. In addition, by means of an unconditional logistic regression, smoking was a main factor associated with IGRAs' false-negative results (aOR: 3.35; 95%CI:1.47-7.61; p
Published: 2017
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16. Dormancy antigens as biomarkers of latent tuberculosis infection

Author: Irene Latorre and Jose Domínguez
Subjects: Medicine, Medicine (General), R5-920
Published: 2015
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17. Evaluation of interferon-gamma release assays in the diagnosis of recent tuberculosis infection in health care workers.

Author: Irma Casas, Irene Latorre, Maria Esteve, Juan Ruiz-Manzano, Dora Rodriguez, Cristina Prat, Ignasi García-Olivé, Alicia Lacoma, Vicente Ausina, and Jose Domínguez
Subjects: Medicine, Science
Abstract: BACKGROUND:Health care workers (HCWs) are a group at risk of latent tuberculosis infection (LTBI). The aims of this study were to determine IFN-gamma response by QuantiFERON-TB GOLD In Tube (QFN-G-IT) and T-SPOT.TB in HCWs, comparing the results with tuberculin skin test (TST); and to analyze the capacity of IFN-gamma tests to detect recent versus remote LTBI with a prolonged stimulation test (PST). METHODOLOGY/PRINCIPAL FINDINGS:A total of 147 HCWs were enrolled; 23 of whom were BCG vaccinated. 95 HCWs (64.6%) had a previous positive TST and were not retested; and 52 HCWs had a previous negative TST or were tested for the first time. When we analysed individuals without previous positive TST, the number of positive results for T-SPOT.TB was 12/52 (23.1%); and for QFN-G-IT, 9/52 (17.3%). The global concordance (kappa) between T-SPOT.TB and QFN-G-IT with TST was 0.754 and 0.929 respectively. Of individuals with previous positive TST, T-SPOT.TB and QFN-G-IT were negative in 51.6% (49/95) and 62.1% (59/95) respectively, decreasing the concordance to 0.321 and 0.288, respectively. In non-BCG vaccinated HCWs with previous positive TST a positive IFN-gamma test was associated with degree of exposure and diameter of TST. PST was performed in 24 HCW with previous positive TST and negative IFN-gamma tests. PST was developed in 3 cell cultures stimulated with medium alone, ESAT-6 and CFP-10, respectively. In the third and sixth day of incubation period, part of the supernatants were replaced with complete medium supplemented with (rIL)-2. On day 9, ELISPOT assay was performed. In 14 samples PST was not valid due to not having enough cells. In 8 cases, the response was negative, and in 2 cases positive, suggesting that these patients were infected with Mycobacterium tuberculosis in some point in the past. CONCLUSIONS:Both IFN-gamma tests showed a similar number of positive results, and concordance between the tests was excellent. None of the tests was affected by prior BCG vaccination. IFN-gamma tests are a useful tool for detecting recent infection in HCW population.
Published: 2009
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18. Correction: Accuracy of Immunodiagnostic Tests for Active Tuberculosis Using Single and Combined Results: A Multicenter TBNET-Study.

Author: Delia Goletti, Stefania Carrara, Ornella Butera, Massimo Amicosante, Martin Ernst, Ilaria Sauzullo, Vincenzo Vullo, Daniela Cirillo, Emanuele Borroni, Roumiana Markova, Roumiana Drenska, José Dominguez, Irene Latorre, Claudio Angeletti, Assunta Navarra, Nicola Petrosillo, Francesco Nicola Lauria, Giuseppe Ippolito, Giovanni Battista Migliori, Christoph Lange, and Enrico Girardi
Subjects: Medicine, Science
Published: 2009
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19. Accuracy of immunodiagnostic tests for active tuberculosis using single and combined results: a multicenter TBNET-Study.

Author: Delia Goletti, Stefania Carrara, Ornella Butera, Massimo Amicosante, Martin Ernst, Ilaria Sauzullo, Vincenzo Vullo, Daniela Cirillo, Emanuele Borroni, Roumiana Markova, Roumiana Drenska, José Dominguez, Irene Latorre, Claudio Angeletti, Assunta Navarra, Nicola Petrosillo, Francesco Nicola Lauria, Giuseppe Ippolito, Giovanni Battista Migliori, Christoph Lange, and Enrico Girardi
Subjects: Medicine, Science
Abstract: BACKGROUND: The clinical application of IFN-gamma release assays (IGRAs) has recently improved the diagnosis of latent tuberculosis infection. In a multicenter study of the Tuberculosis Network European Trialsgroup (TBNET) we aimed to ascertain in routine clinical practice the accuracy of a novel assay using selected peptides encoded in the mycobacterial genomic region of difference (RD) 1 for the diagnosis of active tuberculosis in comparison with tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (Cellestis Ltd., Carnegie, Australia) and T-SPOT.TB (Oxfordimmunotec, Abingdon, UK). PRINCIPAL FINDINGS: 425 individuals from 6 different European centres were prospectively enrolled. We found that sensitivity of the novel test, TST, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB was respectively 73.1%, 85.3%, 78.1%, and 85.2%; specificity was respectively 70.6%, 48.0%, 61.9% and 44.3%; positive likelihood ratios were respectively 2.48, 1.64, 2.05, and 1.53; negative likelihood ratios were respectively 0.38, 0.31, 0.35, 0.33. Sensitivity of TST combined with the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB increased up to 92.4%, 97.7% and 97.1%, respectively. The likelihood ratios of combined negative results of TST with, respectively, the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB were 0.19, 0.07 and 0.10. CONCLUSIONS: The assay based on RD1 selected peptides has similar accuracy for active tuberculosis compared with TST and commercial IGRAs. Then, independently of the spectrum of antigens used in the assays to elicit mycobacterial specific immune responses, the novel test, IGRAs, and the TST do not allow an accurate identification of active tuberculosis in clinical practice. However, the combined use of the novel assay or commercial IGRAs with TST may allow exclusion of tuberculosis.
Published: 2008
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20. Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis

Author: Hamada, Yohhei, Gupta, Rishi K., Quartagno, Matteo, Izzard, Abbie, Acuna-Villaorduna, Carlos, Altet, Neus, Diel, Roland, Dominguez, Jose, Floyd, Sian, Gupta, Amita, Huerga, Helena, Jones-López, Edward C., Kinikar, Aarti, Lange, Christoph, van Leth, Frank, Liu, Qiao, Lu, Wei, Lu, Peng, Rueda, Irene Latorre, Martinez, Leonardo, Mbandi, Stanley Kimbung, Muñoz, Laura, Padilla, Elisabeth Sánchez, Paradkar, Mandar, Scriba, Thomas, Sester, Martina, Shanaube, Kwame, Sharma, Surendra K., Sloot, Rosa, Sotgiu, Giovanni, Thiruvengadam, Kannan, Vashishtha, Richa, Abubakar, Ibrahim, and Rangaka, Molebogeng X.
Published: 2023
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21. Radioguided detection of a non-palpable occult lesion (ROLL) in a case of abdominal metastasis of a neuroendocrine tumor

Author: Badenes-Romero, Alvaro, Orozco-Cortes, John, Balaguer-Munoz, David, Sanchez, Pedro Abreu, Dolera, Tomas Mut, Gomez-Abril, Segundo Angel, Dolz-Gaiton, Raquel, Calabuig, Elisa Caballero, Canadas, Berta Cueto, Agraz, Irene Latorre, Ojeda, Maria Dolores Reyes, Mansanet, Carmen Plancha, and Hurtado, Angela Esteban
Published: 2020
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22. Measuring T-Cell Responses against SARS-CoV-2 Is of Utility for Disease and Vaccination Management

Author: Guillem Safont, Irene Latorre, Raquel Villar-Hernández, Zoran Stojanovic, Alicia Marín, Cristina Pérez-Cano, Alicia Lacoma, Bárbara Molina-Moya, Alan Jhunior Solis, Fernando Arméstar, Joan Matllo, Sergio Díaz-Fernández, Arnau Cendón, Liliya Sokalchuk, Guillermo Tolosa, Irma Casas, Antoni Rosell, and José Domínguez
Subjects: IFN-gamma, SARS-CoV-2, T-cell response, ELISPOT, General Medicine, humoral response, IFN-γ, vaccination
Abstract: The measurement of specific T-cell responses can be a useful tool for COVID-19 diagnostics and clinical management. In this study, we evaluated the IFN-γ T-cell response against the main SARS-CoV-2 antigens (spike, nucleocapsid and membrane) in acute and convalescent individuals classified according to severity, and in vaccinated and unvaccinated controls. IgG against spike and nucleocapsid were also measured. Spike antigen triggered the highest number of T-cell responses. Acute patients showed a low percentage of positive responses when compared to convalescent (71.6% vs. 91.7%, respectively), but increased during hospitalization and with severity. Some convalescent patients showed an IFN-γ T-cell response more than 200 days after diagnosis. Only half of the vaccinated individuals displayed an IFN-γ T-cell response after the second dose. IgG response was found in a higher percentage of individuals compared to IFN-γ T-cell responses, and moderate correlations between both responses were seen. However, in some acute COVID-19 patients specific T-cell response was detected, but not IgG production. We found that the chances of an IFN-γ T-cell response against SARS-CoV-2 is low during acute phase, but may increase over time, and that only half of the vaccinated individuals had an IFN-γ T-cell response after the second dose.
Published: 2022
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23. Tobacco Smoking and Second-Hand Smoke Exposure Impact on Tuberculosis in Children

Author: Neus, Altet, Irene, Latorre, María Ángeles, Jiménez-Fuentes, Antoni, Soriano-Arandes, Raquel, Villar-Hernández, Celia, Milà, Pablo, Rodríguez-Fernández, Beatriz, Muriel-Moreno, Patricia, Comella-Del-Barrio, Pere, Godoy, Joan-Pau, Millet, Maria Luiza, de Souza-Galvão, Carlos A, Jiménez-Ruiz, Jose, Domínguez, On Behalf Of Pii Smoking Separ Working Group, Institut Català de la Salut, [Altet N] Unitat de Tuberculosi, Drassanes-Vall d’Hebron Hospital Universitari, Barcelona, Spain. Serveis Clínics, Unitat Clínica de Tractament Directament Observat de la Tuberculosi, Barcelona, Spain. [Latorre I, Villar-Hernández R] Institut d’Investigació Germans Trias i Pujol, CIBER Enfermedades Respiratorias, Universitat Autònoma de Barcelona, Badalona, Spain. [Jiménez-Fuentes MÁ, Soriano-Arandes A, Milà C, de Souza-Galvão ML] Unitat de Tuberculosi, Drassanes-Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Tuberculosi, Immunology, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], General Medicine, Mycobacterium tuberculosis, Persons::Age Groups::Child [NAMED GROUPS], infecciones bacterianas y micosis::infecciones bacterianas::infecciones por bacterias grampositivas::infecciones por Actinomycetales::micobacteriosis::tuberculosis [ENFERMEDADES], Cigarette smoking, ambiente y salud pública::salud pública::contaminación ambiental::contaminación del aire::contaminación por humo de tabaco [ATENCIÓN DE SALUD], cigarette smoking, passive smoking, child, immunology, Passive smoking, Environment and Public Health::Public Health::Environmental Pollution::Air Pollution::Tobacco Smoke Pollution [HEALTH CARE], Tabaquisme passiu en els infants, Bacterial Infections and Mycoses::Bacterial Infections::Gram-Positive Bacterial Infections::Actinomycetales Infections::Mycobacterium Infections::Tuberculosis [DISEASES], Child
Abstract: Mycobacterium tuberculosis; Child; Passive smoking Tuberculosis micobacteriana; Niño; Tabaquismo pasivo Tuberculosi micobacteriana; Infant; Tabaquisme passiu Little is known about whether second-hand smoke (SHS) exposure affects tuberculosis (TB). Here, we investigate the association of cigarette smoke exposure with active TB and latent TB infection (LTBI) in children, analyzing Interferon-Gamma Release Assays’ (IGRAs) performance and cytokine immune responses. A total of 616 children from contact-tracing studies were included and classified regarding their smoking habits [unexposed, SHS, or smokers]. Risk factors for positive IGRAs, LTBI, and active TB were defined. GM-CSF, IFN-γ, IL-2, IL-5, IL-10, IL-13, IL-22, IL-17, TNF-α, IL-1RA and IP-10 cytokines were detected in a subgroup of patients. Being SHS exposed was associated with a positive IGRA [aOR (95% CI): 8.7 (5.9–12.8)] and was a main factor related with LTBI [aOR (95% CI): 7.57 (4.79–11.94)] and active TB [aOR (95% CI): 3.40 (1.45–7.98)]. Moreover, IGRAs’ sensitivity was reduced in active TB patients exposed to tobacco. IL-22, GM-CSF, IL-5, TNF-α, IP-10, and IL-13 were less secreted in LTBI children exposed to SHS. In conclusion, SHS is associated with LTBI and active TB in children. In addition, false-negative IGRAs obtained on active TB patients exposed to SHS, together with the decrease of specific cytokines released, suggest that tobacco may alter the immune response. This research was supported by: (i) a grant from the Instituto de Salud Carlos III (PI 13/01546, PI16/01912, and PI18/00411), integrated in the Plan Nacional I+D+I and co-funded by the ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER) and CERCA Programme/Generalitat de Catalunya; and (ii) a grant from the Sociedad Española de Neumología y Cirugía Torácica (SEPAR; Barcelona, Spain) (Smoking Integrated Research Programme Call).
Published: 2022

24. Use of IP-10 detection in dried plasma spots for latent tuberculosis infection diagnosis in contacts via mail

Author: Josep Domínguez, Adela Cantos, Esther García-García, J. Ruiz-Manzano, Maria Angeles Jimenez, M. L. De Souza-Galvão, Raquel Villar-Hernández, Morten Ruhwald, Israel Molina-Pinargote, Irene Latorre, Beatriz Muriel-Moreno, J. Pilarte, Cristina Prat, Yoel Gonzalez-Diaz, N. Altet, Joan Pau Millet, Institut Català de la Salut, [Villar-Hernández R, Latorre I] Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Institut d'Investigació Germans Trias i Pujol, Badalona, Spain. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain. Universitat Autònoma de Barcelona, Badalona, Spain. [De Souza-Galvão ML, Jiménez MA] Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Ruiz-Manzano J] CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain. Universitat Autònoma de Barcelona, Badalona, Spain. Servei de Pneumologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. [Pilarte J, Cantos A] Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Altet N] Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Unidad Clínica de Tratamiento Directamente Observado 'Serveis Clinics', Barcelona, Spain. CIBER de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Badalona, Spain., and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Adult, Male, Tuberculosis, aminoácidos, péptidos y proteínas::péptidos::péptidos y proteínas de señalización intercelular::citocinas::quimiocinas::quimiocinas CXC::quimiocina CXCL10 [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::/diagnóstico [Otros calificadores], Tuberculosi - Diagnòstic, lcsh:Medicine, Enzyme-Linked Immunosorbent Assay, Sensitivity and Specificity, Article, QuantiFERON, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Other subheadings::/diagnosis [Other subheadings], medicine, Humans, Postal Service, Bacterial Infections and Mycoses::Bacterial Infections::Gram-Positive Bacterial Infections::Actinomycetales Infections::Mycobacterium Infections::Tuberculosis::Latent Tuberculosis [DISEASES], lcsh:Science, Whole blood, Multidisciplinary, Chromatography, Latent tuberculosis, Filter paper, Spots, business.industry, infecciones bacterianas y micosis::infecciones bacterianas::infecciones por bacterias grampositivas::infecciones por Actinomycetales::micobacteriosis::tuberculosis::tuberculosis latente [ENFERMEDADES], técnicas de investigación::métodos epidemiológicos::rastreo de contactos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], lcsh:R, Infection diagnosis, Plasma, medicine.disease, Quimiocines, Chemokine CXCL10, 030104 developmental biology, Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Chemokines::Chemokines, CXC::Chemokine CXCL10 [CHEMICALS AND DRUGS], ROC Curve, Cytokines, Female, lcsh:Q, Dried Blood Spot Testing, Investigative Techniques::Epidemiologic Methods::Contact Tracing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], Contact Tracing, business, 030217 neurology & neurosurgery, Interferon-gamma Release Tests
Abstract: The aim of this study was to test the use of IP-10 detection in dried plasma from contact studies individuals (contacts of smear positive patients), by comparing it with IP-10 and IFN-γ detection in direct plasma, to establish IP-10 detection in DPS as a useful assay for LTBI diagnosis. Whole blood samples were collected from 80 subjects: 12 with active tuberculosis (TB), and 68 from contact studies. The amount of IFN-γ produced by sensitized T cells was determined in direct plasma by QuantiFERON Gold In-Tube test. IP-10 levels were determined in direct and dried plasma by an in-house ELISA. For dried plasma IP-10 determination, two 25 µl plasma drops were dried in Whatman903 filter paper and sent by mail to the laboratory. Regarding TB patients, 100.0%, 91.7% and 75.0% were positive for IFN-γ detection and IP-10 detection in direct and dried plasma, respectively. In contacts, 69.1%, 60.3% and 48.5% had positive results after IFN-γ and IP-10 in direct and dried plasma, respectively. The agreement among in vitro tests was substantial and IP-10 levels in direct and dried plasma were strongly correlated (r = 0.897). In conclusion, IP-10 detection in dried plasma is a simple and safe method that would help improve LTBI management.
Published: 2019
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25. Radioguided detection of a non-palpable occult lesion (ROLL) in a case of abdominal metastasis of a neuroendocrine tumor

Author: Segundo Ángel Gómez Abril, Irene Latorre Agraz, Ángela Esteban Hurtado, David Balaguer Muñoz, Elisa Caballero Calabuig, Tomás Mut Dólera, Alvaro Badenes Romero, Berta Cueto Cañadas, Carmen Plancha Mansanet, María Dolores Reyes Ojeda, John Orozco Cortés, Raquel Dolz Gaitón, and Pedro Abreu Sánchez
Subjects: business.industry, Gastroenterology, Breast Neoplasms, General Medicine, medicine.disease, Occult, Metastasis, Lesion, Pancreatic Neoplasms, 03 medical and health sciences, Neuroendocrine Tumors, 0302 clinical medicine, 030220 oncology & carcinogenesis, Lymphatic Metastasis, medicine, Humans, 030211 gastroenterology & hepatology, Female, Non palpable, medicine.symptom, Radiopharmaceuticals, Nuclear medicine, business, Radionuclide Imaging
Abstract: Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms that originate in tissues derived from the neural crest, whose characteristic feature is the expression of neuroendocrine markers and somatostatin receptors. Here, we present the case of a patient with a surgically intervened small bowel NET. Focal uptake was identified in the unresected mesentery in the scintigraphy of somatostatin receptors (99mTc-Tektrotyd). A second intervention was performed with intraoperative radio-guided detection with a gamma probe and a handheld SPECT. An intraoperative radioguided technique allowed the detection of a lesion that was confirmed by histology to be a lymph node metastasis of the NET and a nodule of NET in the anastomosis of the first surgical intervention.
Published: 2020

26. Diagnostic Accuracy of Interferon Gamma-Induced Protein 10 mRNA Release Assay for Tuberculosis

Author: Beatriz Muriel-Moreno, Juan Ruiz-Manzano, Carmen Torres, Yoel Gonzalez-Diaz, Thomas Blauenfeldt, Line Lindebo Holm, Maria Luiza de Souza-Galvão, Maria Angeles Jimenez, Javier Santiago, Raquel Villar-Hernández, Jose Pilarte, Esther García-García, José Domínguez, Fina Sabriá, Carmen Centeno, Adrián Sánchez-Montalvá, Israel Molina-Pinargote, Joan Pau Millet, Morten Ruhwald, Irene Latorre, Adela Cantos, Cristina Prat, and Peter Andersen
Subjects: 0301 basic medicine, Microbiology (medical), Tuberculosis, 030106 microbiology, Enzyme-Linked Immunosorbent Assay, Diagnostic accuracy, Sensitivity and Specificity, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Active tb, medicine, Humans, Interferon gamma, RNA, Messenger, Bradford protein assay, Messenger RNA, business.industry, Mycobacteriology and Aerobic Actinomycetes, Mycobacterium tuberculosis, Plasma levels, medicine.disease, Molecular biology, 030228 respiratory system, Case-Control Studies, Biomarker (medicine), business, Interferon-gamma Release Tests, medicine.drug
Abstract: Interferon gamma (IFN-γ) release assays (IGRAs) are increasingly used to test for latent tuberculosis (TB) infection. Although highly specific, IGRAs have a relatively high false-negative rate in active TB patients. A more sensitive assay is needed. IFN-γ-induced protein 10 (IP-10) is an alternative biomarker with a 100-fold-higher expression level than IFN-γ, allowing for different analysis platforms, including molecular detection. The PCR technique is already an integrated tool in most TB laboratories and, thus, an obvious platform to turn to. In this case-control study, we investigated the diagnostic sensitivity and specificity of a molecular assay detecting IP-10 mRNA expression following antigen stimulation of a blood sample. We included 89 TB patients and 99 healthy controls. Blood was drawn in QuantiFeron-TB gold in-tube (QFT) assay tubes. Eight hours poststimulation, IP-10 mRNA expression was analyzed, and 20 h poststimulation, IP-10 and IFN-γ protein plasma levels were analyzed using an in-house IP-10 enzyme-linked immunosorbent assay (ELISA) and the official QFT ELISA, respectively. The IP-10 mRNA assay provided high specificity (98%), sensitivity (80%), and area under the concentration-time curve (AUC) (0.97); however, the QFT assay provided a higher overall diagnostic potential, with specificity of 100%, sensitivity of 90%, and AUC of 0.99. The IP-10 protein assay performed on par with the QFT assay, with specificity of 98%, sensitivity of 87%, and AUC of 0.98. We have provided proof of high technical performance of a molecular assay detecting IP-10 mRNA expression. As a diagnostic tool, this assay would gain from further optimization, especially on the kinetics of IP-10 mRNA expression.
Published: 2020
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27. Diagnostic benefits of adding EspC, EspF and Rv2348-B to the QuantiFERON Gold In-tube antigen combination

Author: Morten Ruhwald, Maria Angeles Jimenez, Irene Latorre, Carmen Centeno, Cristina Prat, Adrián Sánchez-Montalvá, Esther García-García, Israel Molina-Pinargote, Javier Santiago, Carmen Martos, Fina Sabriá, Josep Domínguez, Adela Cantos, R. M. Guerola, Peter Andersen, Yoel Gonzalez-Diaz, J. Pilarte, Joan Pau Millet, M. L. De Souza-Galvão, Thomas Blauenfeldt, Irma Casas, Raquel Villar-Hernández, Beatriz Muriel-Moreno, and J. Ruiz-Manzano
Subjects: 0301 basic medicine, Adult, Male, lcsh:Medicine, Sensitivity and Specificity, Article, QuantiFERON, 03 medical and health sciences, 0302 clinical medicine, Immune system, Tuberculosis diagnosis, Antigen, Interferon, Latent Tuberculosis, medicine, Tuberculosis, Humans, lcsh:Science, Whole blood, Antigens, Bacterial, Multidisciplinary, Latent tuberculosis, business.industry, Tuberculin Test, lcsh:R, Diagnostic markers, Mycobacterium tuberculosis, Middle Aged, medicine.disease, 030104 developmental biology, Early Diagnosis, Spain, Case-Control Studies, Immunology, lcsh:Q, Female, Interferon-gamma Release Tests, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Interferon (IFN)-γ release assays (IGRAs) are used to diagnose latent tuberculosis (TB) infection (LTBI). To improve the accuracy of these tests, different approaches, such as alternative cytokine detection and using different antigens, are considered. Following this purpose, this study aims to evaluate the addition of EspC, EspF and Rv2348-B to those present in the QuantiFERON-TB Gold In-Tube (QFN-G-IT). We included 115 subjects: 74 active TB patients, 17 LTBI individuals and 24 healthy controls. Whole blood samples were collected in QFN-G-IT and in-house tubes containing different combinations of EspC, EspF and Rv2348-B, together with ESAT-6, CFP-10, and TB7.7. After overnight incubation at 37 ºC, plasma was harvested and IFN-γ quantified. IFN-γ levels in the QFN-G-IT and in-house tubes correlated very good (Spearman Rho(r) > 0.86). In-house antigen combinations distinguished healthy individuals from those with active TB and LTBI (specificities and sensitivities higher than 87.5% and 96.3%, respectively [AUC > 0.938]). Adding EspC, EspF and Rv2348-B, increased the sensitivity of the test, being the addition of EspC and Rv2348-B the combination that yielded a higher sensitivity with no specificity loss. Addition of these antigens could improve diagnosis in patients with impaired or immature immune response who are at high risk of developing TB.
Published: 2020

28. Diagnóstico y abordaje terapéutico de la infección tuberculosa latente

Author: José Domínguez, Miguel Santin, and Irene Latorre
Subjects: Microbiology (medical), 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, 030212 general & internal medicine
Abstract: Resumen La deteccion y tratamiento de la infeccion tuberculosa latente (ITBL) constituye una medida esencial para el control de la tuberculosis (TB) en paises de baja incidencia. Esta estrategia esta limitada, sin embargo, por la falta de capacidad predictiva de las pruebas diagnosticas para el desarrollo de TB activa entre las personas infectadas y la larga duracion y toxicidad de las pautas de tratamiento. Las tecnicas in vitro de liberacion de interferon-gamma son mas especificas y sensibles que la prueba de la tuberculina, y permiten seleccionar mejor los casos que requieren tratamiento. Aun asi, su capacidad para predecir el desarrollo de TB sigue siendo pobre. Ademas, las pautas de tratamiento de ITBL son largas, y las tasas de cumplimiento, bajas. Esta revision discute el uso de las tecnicas diagnosticas disponibles y las nuevas aproximaciones al diagnostico de la ITBL y su abordaje terapeutico en diferentes escenarios clinicos.
Published: 2018
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29. Implementation of Protocol for Image-Guided Resection of Non-Palpable Breast Cancer Tumors

Author: Cortés, Jhon Orozco, primary, Garrigos, Gonzalo, additional, Romero, Alvaro Badenes, additional, Vidagany, Nuria Estelles, additional, Cañadas, Berta Cueto, additional, Vila, Rocio, additional, Agraz, Irene Latorre, additional, Llorente, Carmen Paya, additional, Pelaez, Stella, additional, López, Elias Martinez, additional, Mut, Tomas, additional, Abreu, Pedro, additional, Balaguer, David, additional, Garcia, Rosario Martinez, additional, Plancha, M Carmen, additional, Reyes, Maria Dolores, additional, and Calabuig, Elisa Caballero, additional
Published: 2020
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30. Use of IFN-γ and IP-10 detection in the diagnosis of latent tuberculosis infection in patients with inflammatory rheumatic diseases

Author: Alicia Lacoma, José Domínguez, L. Mateo, Beatriz Muriel-Moreno, Esther García-García, Cristina Prat, Jessica Diaz, Sonia Mínguez, Morten Ruhwald, Raquel Villar-Hernández, Irene Latorre, and A. Olivé
Subjects: Adult, Male, 0301 basic medicine, Microbiology (medical), Tuberculosis, medicine.medical_treatment, Enzyme-Linked Immunosorbent Assay, Immunologic Tests, Diagnostic tools, QuantiFERON, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Rheumatic Diseases, medicine, Humans, In patient, T-SPOT.TB, Inflammation, Latent tuberculosis, Tuberculin Test, business.industry, Immunotherapy, Middle Aged, medicine.disease, Chemokine CXCL10, 030104 developmental biology, Infectious Diseases, Immunosuppressive drug, 030228 respiratory system, Immunology, Female, business, Interferon-gamma Release Tests
Abstract: Summary Objectives Biologic agents are used against rheumatic diseases, however, they increase the risk of developing severe infections and diseases such as tuberculosis. We aimed to determine the benefits of IP-10 detection to diagnose latent tuberculosis infection (LTBI) in patients with inflammatory rheumatic diseases on different immunosuppressive drug regimens, and compare these results with IFN-γ detection. Materials and methods We included 64 patients with inflammatory rheumatic diseases. We used QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB to detect IFN-γ production, and an in-house ELISA for IP-10 detection from the previous QFN-G-IT stimulated samples. We assessed the combined use of IFN-γ release assays (IGRAs) and IP-10 test, and analyzed the influence of immunotherapy on the tests performance. Results We obtained 34.9% positive results by T-SPOT.TB, 25.0% by QFN-G-IT and 31.3% by IP-10 test. The combined use of IGRAs and IP-10 detection increased significantly the amount of positive results ( p in vitro tests ( p > 0.05). Conclusions IP-10 and IFN-γ detection is comparable and their combined use could increase the number of positive results in the diagnosis of LTBI in rheumatic patients. The tested assays were not influenced by rheumatoid immunosuppressive therapy. Thus, IP-10 could be of use in the development of new and improved LTBI diagnostic tools.
Published: 2017
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31. Late Breaking Abstract - Use of non-tuberculous mycobacteria (NTM) specific antigens to detect NTM infection

Author: Nàlia López, Juan Ruiz Manzano, Jordi Puig, José Domínguez, Irma Casas, Alicia C Marin, Neus Altet, Carlos Rodrigo, Beatriz Muriel-Moreno, Marisol Domínguez, María Méndez, Josefina Sabriá, Antonio Soriano-Arandes, Esther García-García, Carmen Martos, Laura Minguell, Irene Latorre, Zoran Stojanovic, María Ángeles Jiménez, Juan Pau Millet, Maria Luiza de Souza-Galvão, Aina Martínez-Planas, Miguel Angel Rodríguez Pérez, José R. Santos, Antoni Noguera-Julian, Yolanda Galea, Jordi B. Torrelles, Cristina Prat, and Raquel Hernández
Subjects: Tuberculosis, business.industry, ELISPOT, bacterial infections and mycoses, medicine.disease, Peripheral blood mononuclear cell, Vaccination, Immune system, IGRA (Interferon g), Antigen, Chronic diseases, Diagnosis, Immunology, Etiology, medicine, Clinical significance, business
Abstract: Diagnosing non-tuberculous mycobacteria (NTM) infection is important to discard tuberculosis (TB) infection when test results are discordant and could be useful to handle patients with pulmonary infectious diseases (PID) with NTM isolations of unclear clinical relevance. This study, describes an immunological NTM-Interferon-gamma (IFN-γ) Release Assay (IGRA) that we have developed using specific NTM antigens to detect NTM sensitization. We enrolled 342 patients: 90 latently TB infected (LTBI), 69 active TB, 60 NTM culture positive, 13 NTM infection suspicion (positive TST, negative IGRA and no BCG vaccination record), 53 HIV positive (4 also LTBI), 32 unknown etiology lymphadenopathies, 3 non-NTM lymphadenopathies, and 22 uninfected controls with no TB exposure record. Peripheral blood mononuclear cells were isolated from whole blood samples. Cells were then stimulated overnight with NTM specific antigens. Detection of IFN-γ producing cells was evaluated by ELISPOT. NTM positive and suspicion groups had a significantly higher count of INF-γ-producing cells after NTM-antigen sensitization. Using ROC curve analysis, a positivity cut-off of 6 spots was determined. NTM suspicion, NTM positive and non-culture confirmed lymphadenopathies groups, had a higher number of positive results than LTBI, HIV positive, and active TB patients (76.9%, 73.3% and 37.5%, 26.7%, 22.6%, 17.4%, respectively). Uninfected individuals and those with non-NTM lymphadenopathies were negative. NTM-IGRA could serve as an NTM infection diagnosis test aiding clinicians in the patient’s clinical evaluation and treatment decision-making. Ongoing studies are focused on characterizing the immune response against these antigens.
Published: 2019
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32. Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections

Author: José Domínguez, Alicia Lacoma, L. Mateo, Irene Latorre, Carlos Rodrigo, Ignacio Blanco, Cristina Prat, Maria J. Méndez, Raquel Villar-Hernández, Institut Català de la Salut, [Lacoma A, Latorre I] Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. Institut d'Investigació Germans Trias i Pujol, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER Enfermedades Respiratorias, Barcelona, Spain. [Mateo L] Servei de Reumatologia, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. Institut d'Investigació Germans Trias i Pujol, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Blanco I] Programa de Genètica Clínica i Atenció Genètica, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. Institut d'Investigació Germans Trias i Pujol, Barcelona, Spain. [Méndez MJ] Servei de Pediatria, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. Institut d'Investigació Germans Trias i Pujol, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Rodrigo C] Servei de Pediatria, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Vall d’Hebron Institut de Recerca, Barcelona, Spain. Facultat de Medicina, Unitat Docent Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain., and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Immunoteràpia, respiratory tract infections, Aspergillosis, medicine.disease_cause, 0302 clinical medicine, Risk Factors, Immunology and Allergy, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], enfermedades respiratorias::infecciones del tracto respiratorio [ENFERMEDADES], Genetics, Síndromes de deficiència immunitària, Respiratory tract infections, Otros calificadores::Otros calificadores::/genética [Otros calificadores], enfermedades del sistema inmune::síndromes de inmunodeficiencia [ENFERMEDADES], Immune System Diseases::Immunologic Deficiency Syndromes [DISEASES], Host-Pathogen Interactions, inborn errors, primary immunodeficiencies, lcsh:Immunologic diseases. Allergy, Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Immunologic Factors [CHEMICALS AND DRUGS], Mini Review, Immunology, Neutropenia, Risk Assessment, 03 medical and health sciences, Immune system, Immunity, Other subheadings::Other subheadings::/immunology [Other subheadings], medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Animals, Humans, Immunologic Factors, Genetic Predisposition to Disease, Biological response modifiers, acciones y usos químicos::acciones farmacológicas::efectos fisiológicos de los fármacos::factores inmunitarios [COMPUESTOS QUÍMICOS Y DROGAS], Infeccions respiratòries - Aspectes genètics, biological response modifiers, business.industry, Immune dysregulation, medicine.disease, immunogenetics, Pneumonia, 030104 developmental biology, lcsh:RC581-607, business, Immunogenètica, 030215 immunology, Respiratory Tract Diseases::Respiratory Tract Infections [DISEASES]
Abstract: Biological response modifiers; Immunogenetics; Inborn errors Modificadors de la resposta biològica; Immunogenètica; Errors congènits Modificadores de la respuesta biológica; Inmunogenética; Errores congénitos Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.
Published: 2019

33. Comparison of NxTAG Respiratory Pathogen Panel and Anyplex II RV16 Tests for Multiplex Detection of Respiratory Pathogens in Hospitalized Children

Author: Pedro Brotons, Antonio Cepillo, Irene Latorre, Cristian Launes, Carmen Muñoz-Almagro, and Desiree Henares
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Adolescent, 030106 microbiology, medicine.disease_cause, Gastroenterology, Microbiology, 03 medical and health sciences, Virology, Nasopharynx, Internal medicine, Multiplex polymerase chain reaction, medicine, Humans, Multiplex, Prospective Studies, Respiratory system, Child, Respiratory Tract Infections, Bacteria, Base Sequence, Respiratory tract infections, business.industry, Respiratory infection, Respiratory Pathogen Panel, Sequence Analysis, DNA, Cross-Sectional Studies, Molecular Diagnostic Techniques, Child, Preschool, Viruses, Enterovirus, Rhinovirus, business, Multiplex Polymerase Chain Reaction
Abstract: Multiplex molecular techniques can detect a diversity of respiratory viruses and bacteria that cause childhood acute respiratory infection rapidly and conveniently. However, currently available techniques show high variation in performance. We sought to compare the diagnostic accuracy of the novel multiplex NxTAG respiratory pathogen panel (RPP) RUO test versus a routine multiplex Anyplex II RV16 assay in respiratory specimens collected from children kappa coefficients were assessed. Bidirectional sequencing was performed for the resolution of discordant results. A total of 319 samples were analyzed by both techniques. A total of 268 (84.0%) of them yielded concordant results. Positive percent agreement values ranged from 83.3 to 100%, while the negative percent agreement was more than 99% for all targets except for enterovirus/rhinovirus (EV/RV; 94.4%). Kappa coefficients ranged from 0.83 to 1.00. Discrepancy analysis confirmed 66.0% of NxTAG RPP RUO results. A total of 260 viruses were detected, with EV/RV ( n = 105, 40.4%) being the most prevalent target. Viral coinfections were found in 44 (14.2%) samples. In addition, NxTAG RPP RUO detected single bacterial and mixed viral-bacterial infections in seven samples. NxTAG RPP RUO showed high positive and negative agreement with Anyplex II RV16 for main viruses that cause acute respiratory infections in children, coupled with an additional capability to detect some respiratory bacteria.
Published: 2016
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34. Serial testing of health care workers for tuberculosis infection: A prospective cohort study

Author: Joan Matllo, José Domínguez, Raquel Villar-Hernández, Maria Esteve, Cristina Prat-Aymerich, Guillermo Mena, Irma Casas, Rosa Guerola, and Irene Latorre
Subjects: Bacterial Diseases, Male, Social Sciences, Cohort Studies, 0302 clinical medicine, Sociology, Medicine and Health Sciences, Prevalence, Mass Screening, Medicine, Public and Occupational Health, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Multidisciplinary, Latent tuberculosis, Vaccination and Immunization, Actinobacteria, Infectious Diseases, Research Design, Cohort, Social Systems, Tuberculosis Diagnosis and Management, Female, Research Article, Cohort study, Adult, medicine.medical_specialty, Tuberculosis, Science, Health Personnel, Immunology, Tuberculin, Research and Analysis Methods, Interferon-gamma, 03 medical and health sciences, Tuberculosis diagnosis, Diagnostic Medicine, Internal medicine, Humans, Mass screening, Health Care Policy, Bacteria, Tuberculin Test, business.industry, Organisms, Biology and Life Sciences, Tropical Diseases, bacterial infections and mycoses, medicine.disease, Health Care, 030228 respiratory system, Preventive Medicine, business, Screening Guidelines, Mycobacterium Tuberculosis, Follow-Up Studies
Abstract: Health Care Workers (HCW) may have an occupational risk of latent tuberculosis infection (LTBI) and TB disease. The objective of this study was to evaluate the performance of the 2-step strategy: tuberculin skin test (TST) followed by confirmation with Interferon (IFN)-γ- release assays (IGRAs) in HCW. A secondary objective was to determine the factors related to conversions and reversions. HCW at risk of occupational exposure who attended the Occupational Department of the Hospital Germans Trias i Pujol were included during the study period (2013-2016). All professionals testing negative for LTBI were included in a cohort study. These workers were followed up with the administration of a TST and an IGRA quantification at least one year after inclusion in the study. Workers with positive TST, regardless of the results of the IGRA tests, were followed-up with an IGRA. 255 workers were enrolled in the study and 108 workers from the same cohort were followed up. During the follow-up period, seven workers presented TST test conversion. One of these conversions was also confirmed by an IGRA test. There were 2 conversions of cases only testing positive with the IGRA. There have been only 2 reversions of cases testing negative with the IGRA. In this study, not all TST conversions were confirmed when using the IGRA test, which highlights the importance of the 2-step strategy. We have detected a low number of conversions and reversions. Our conclusions should be confirmed in studies with a longer follow-up time.
Published: 2020
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35. Implementation of Protocol for Image-Guided Resection of Non-Palpable Breast Cancer Tumors

Author: Jhon Orozco Cortés, Elías Martínez López, Stella Pelaez, Elisa Caballero Calabuig, Nuria Estellés Vidagany, David Balaguer, Berta Cueto Cañadas, Carmen Payá Llorente, Irene Latorre Agraz, Rocio Vila, Rosario Martínez García, Alvaro Badenes Romero, Tomas Mut, M Carmen Plancha, Maria Dolores Reyes, Gonzalo Garrigos, and Pedro Abreu
Subjects: Protocol (science), medicine.medical_specialty, Breast cancer, Oncology, business.industry, Medicine, Surgery, General Medicine, Radiology, Non palpable, business, medicine.disease, Resection
Published: 2020
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36. Performance of Tuberculin Skin Tests and Interferon-γ Release Assays in Children Younger Than 5 Years

Author: Claudia Fortuny, Neus Altet, Antoni Noguera-Julian, Eneritz Velasco-Arnaiz, Antoni Soriano-Arandes, Marc Tebruegge, José Domínguez, Manuel Monsonís, and Irene Latorre
Subjects: Microbiology (medical), Male, medicine.medical_specialty, Tuberculosis, Tuberculin, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Interferon γ, Interquartile range, 030225 pediatrics, Active tb, Internal medicine, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, biology, business.industry, Tuberculin Test, Infant, bacterial infections and mycoses, medicine.disease, biology.organism_classification, Confidence interval, Infectious Diseases, Spain, Child, Preschool, Pediatrics, Perinatology and Child Health, Nontuberculous mycobacteria, Female, business, Interferon-gamma Release Tests, Follow-Up Studies
Abstract: BACKGROUND Available data to assess the optimal diagnostic approach in infants and preschool children at risk of tuberculosis (TB) are limited. METHODS We conducted a prospective observational study in children younger than 5 years undergoing assessment with both tuberculin skin tests (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT) assays at 2 tertiary TB units in Barcelona, Spain. RESULTS A total of 383 children were included. One of 304 participants considered uninfected developed active TB during follow-up {median [interquartile range (IQR)]: 47 [30; 48] months}, compared with none of 40 participants with latent TB infection [follow-up since completion of anti-TB treatment: 42 (32; 45) months]. Overall test agreement between TST and QFT-GIT was moderate (κ = 0.551), but very good in children screened after TB contact (κ = 0.801) and in Bacillus Calmette-Guerin (BCG)-unvaccinated children (κ = 0.816). Discordant results (16.8%, all TST+/QFT-GIT-) were mainly observed in new-entrant screening and in BCG-vaccinated children. Children with indeterminate QFT-GIT results were on average younger than those with determinate results (median age: 12 vs. 30 months; P < 0.001). The sensitivity of TSTs and QFT-GIT assays in children with confirmed active TB was 100% (95% confidence interval: 79.4%-100%) and 93.7% (95% confidence interval: 69.8%-99.8%), respectively. In patients with latent TB infection or active TB, there was no correlation between age and antigen-stimulated interferon-γ responses (r = -0.044; P = 0.714). CONCLUSIONS In young BCG-unvaccinated children with recent TB contact, a dual testing strategy using TST and QFT-GIT in parallel may not be necessary. However, TST+/QFT-GIT- discordance is common, and it remains uncertain if this constellation indicates TB infection or not. In active TB, QFT-GIT assays do not perform better than TSTs.
Published: 2018

37. Aplicación y utilidad actual de las técnicas de interferón-γ en el diagnóstico de la tuberculosis

Author: José Domínguez and Irene Latorre
Subjects: Microbiology (medical), medicine.medical_specialty, Pathology, Tuberculosis, biology, Latent tuberculosis, business.industry, Tuberculin, bacterial infections and mycoses, biology.organism_classification, medicine.disease, QuantiFERON, Mycobacterium tuberculosis, Predictive value of tests, Internal medicine, Medicine, business, Contact tracing, T-SPOT.TB
Abstract: Utility of the in-vitro immunodiagnostic methods, based on the detection of interferon-γ released by T-cells after specific Mycobacterium tuberculosis antigen stimulation (IGRA), has been an improvement in the accuracy of the latent tuberculosis infection diagnosis. IGRA have a well-known higher specificity than the tuberculin skin testing (TST). Moreover, they can obtain a larger number of positive results than the TST in immunocompromised patients. IGRA have shown a high correlation with M. tuberculosis exposure, but their positive and negative predictive value are similar than those obtained by TST. Nevertheless, given their high specificity, they allow reducing number of unnecessary preventive treatments. In addition, these in-vitro techniques are less affected than TST by the different immunosuppressing status. In this review is discussed up-to-date applicability of IGRA in different patient groups: contact studies, pediatric population, immunosuppressed patients, health care workers and active tuberculosis patients. Furthermore, it has been included possible future directions for latent tuberculosis infection and active tuberculosis diagnosis.
Published: 2015
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38. Predicting the Development of Tuberculosis with the Tuberculin Skin Test and QuantiFERON Testing

Author: Maria Luiza de Souza-Galvão, María Dolores Ferrer, Joan A. Caylà, Elisa Lara, Antonio Soriano-Arandes, José Domínguez, Àngels Orcau, Celia Milà, Jordi Solsona, M. Ángeles Jiménez-Fuentes, Juan Ruiz-Manzano, Adela Cantos, Irene Latorre, and Neus Altet
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, Adolescent, Tuberculin, QuantiFERON, Mycobacterium tuberculosis, Young Adult, Latent Tuberculosis, Positive predicative value, medicine, Humans, Child, Retrospective Studies, medicine.diagnostic_test, Latent tuberculosis, biology, Tuberculin Test, business.industry, Incidence, Incidence (epidemiology), Infant, Newborn, Infant, bacterial infections and mycoses, medicine.disease, biology.organism_classification, Dermatology, Spain, Child, Preschool, Immunology, Female, Chest radiograph, business, Interferon-gamma Release Tests, Follow-Up Studies
Abstract: The identification of patients with latent tuberculosis infection, who are at higher risk to develop active disease, is an important component of disease control.We aim to compare the usefulness of the QuantiFERON-TB Gold in-tube assay and the tuberculin skin test to predict the development of active tuberculosis during follow-up, using positive and negative predictive values, positive likelihood ratios, and stratified level of risk.The study included contacts of tuberculosis cases diagnosed between 2007 and 2009. All contacts included were from the first circle of exposure. Tuberculin skin test and QuantiFERON test were performed and a chest radiograph was obtained during the contact's study.A total of 1,335 contacts were followed up for 4 years: a smear-positive index case was identified for 937 contacts, of whom 15 developed active tuberculosis and had initially presented with positive tuberculin skin test/QuantiFERON results, a normal chest radiograph, and no symptoms. The positive predictive value was 4% for QuantiFERON and 2% for the tuberculin skin test (when ≥5 mm). The probability of developing active disease was 2.36 times higher with a positive QuantiFERON, and 1.3 times higher with a positive tuberculin skin test. The positive predictive value was 17%, and the positive likelihood ratio was 7.53 for untreated contacts with a positive QuantiFERON. Stratifying according to initial QuantiFERON results showed a 6.36 times higher risk of developing active tuberculosis for patients with a QuantiFERON result greater than or equal to 10 IU/ml. Among bacillus Calmette-Guérin-vaccinated patients, a tuberculin skin test induration greater than or equal to 15 mm correlated better with a positive QuantiFERON.QuantiFERON results were more accurate than tuberculin skin test results in predicting tuberculosis. Although all contacts with QuantiFERON-positive results are at risk of developing tuberculosis, those with a tuberculin skin test induration greater than or equal to 15 mm and QuantiFERON greater than or equal to 10 IU/ml are at highest risk. This has important implications in the clinical management of tuberculosis contacts.
Published: 2015
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39. A novel whole-blood miRNA signature for a rapid diagnosis of pulmonary tuberculosis

Author: Juan Ruiz-Manzano, Andreas Meyerhans, Maria Luiza de Souza-Galvão, Hernando Knobel, Cristina Prat, José Domínguez, José Maldonado, Petra Leidinger, F. Sánchez, Christina Backes, Andreas Keller, Eckart Meese, Irma Casas, Irene Latorre, Hagen von Briesen, and Publica
Subjects: Pulmonary and Respiratory Medicine, Mirna signature, Tuberculosis, Tuberculosi, business.industry, Case-control study, Bioinformatics, medicine.disease, Text mining, Multicenter study, Pulmonary tuberculosis, medicine, business, Whole blood
Abstract: Background: Deregulation of microRNAs (miRNAs)has been associated with various human pathologies including bacterial infections.Aim: To investigate the role of miRNAs as blood biomarkers for the diagnosis of active pulmonary tuberculosis (TB).Materials and methods: We studied 50 patients, classified into 3 groups:(i) 17individuals with latent tuberculosis infection (LTBI) (ii) 17 active pulmonary TB patients (iii) 16 healthy individuals. Blood was collected in a PAXgene Blood RNA tubefor thelater isolation oftotal RNA. MiRNA quantification was performed with SurePrint G3 8x60K miRNA microarrays (Agilent). Real time-quantitative polymerase chain reaction (RT-qPCR)with the miScript PCR System (Qiagen) was used to validateselectedmiRNAexpression levels.Results: MiRNA expression patternswere comparedin whole blood from active TBpatients, LTBI individuals and healthy controls. Aset of miRNAs differentially deregulated during active pulmonary TB vs.LTBI and healthy controlswas identified. We then selected nine miRNAsfor validation in a larger patient cohort. The set of miRNAs consisting of miR-150, miR-21, miR-29cand miR-194 enabled to rapidly diagnose pulmonary TB with 91.21% sensitivity and 87.95% specificity.Conclusions:Theidentified novel miRNA signature opens the possibility of developinga simple, rapid and cheap TB diagnostic test from blood This work was supported by agrant from the Spanish Ministerio de Ciencia e Innovación SAF2010–21336. Andreas Meyerhans is a researcher founded from the Institucio Catalana de Recerca i Estudis Avancats (ICREA). Irene Latorre wasthe recipient of a joint ERS/SEPAR Long-Term fellowship (LTRF 82-2012)during this work
Published: 2015
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40. False-negative interferon-gamma release assay results in active tuberculosis: a TBNET study

Author: Filippo Bartalesi, Lorenzo Guglielmetti, Martine G. Aabye, Steven Thijsen, Maria Luiza de Souza-Galvão, Asli Gorek Dilektasli, Kristián Brat, Maha Ghanem, Felix C. Ringshausen, Monica Polanova, Aik Bossink, Monica Losi, Delia Goletti, Graham H. Bothamley, Pernille Ravn, Keertan Dheda, Rudolf Rumetshofer, Fusun Oner Eyuboglu, Marleen Bakker, Veerle de Visser, Cynthia B.E. Chee, Won-Jung Koh, Christoph Lange, José Domínguez, Giovanni Sotgiu, Irene Latorre, and Pulmonary Medicine
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, International Cooperation, Interferon-gamma, Interferon γ, SDG 3 - Good Health and Well-being, Risk Factors, Surveys and Questionnaires, Medicine, Humans, Tuberculosis, Risk factor, False Negative Reactions, Retrospective Studies, business.industry, nutritional and metabolic diseases, Genetic Variation, Middle Aged, Active tuberculosis, nervous system diseases, Cross-Sectional Studies, Logistic Models, Immunology, Multivariate Analysis, Regression Analysis, Female, business, Interferon-gamma Release Tests
Abstract: Advanced age was the only risk factor for false-negative IGRAs in this study of active tuberculosis http://ow.ly/Cvp5G
Published: 2015
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41. Diagnosis and therapeutic approach of latent tuberculosis infection

Author: Miguel Santin, José Domínguez, and Irene Latorre
Subjects: medicine.medical_specialty, Tuberculosis, Tuberculin, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, Latent Tuberculosis, Active tb, Diagnosis, Interferon-gamma release assays, medicine, Humans, Latent tuberculosis infection, 030212 general & internal medicine, Intensive care medicine, Latent tuberculosis, Tuberculin skin test, Treatment regimen, business.industry, Diagnostic test, Skin test, bacterial infections and mycoses, medicine.disease, Treatment, 030228 respiratory system, Practice Guidelines as Topic, business
Abstract: Detection and treatment of latent tuberculosis infection (LTBI) is an essential measure for tuberculosis (TB) control in low-incidence countries. However, such strategy is limited by the low predictive ability of the diagnostic tests for the development of active TB among infected people and the long-term and toxic treatment regimens. The in vitro interferon-gamma release assays are more specific and sensitive than the tuberculin skin test (TST), and enable a better selection of cases requiring treatment. Nonetheless, their capacity to predict development of TB is still poor. In addition, treatment regimens for LTBI are long, and compliance rates are low. This review discusses the use of the available diagnostic tests and the new approaches to the diagnosis of LTBI, as well as its management in different clinical scenarios. (C) 2017 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.
Published: 2017

42. Diagnosis of tuberculosis infection by interferon-gamma release assays in patients with psoriasis

Author: Jessica Diaz, Marta Vilavella, Cristina Prat, José Manuel Carrascosa, Carlos Ferrándiz, José Domínguez, and Irene Latorre
Subjects: Adult, Male, Microbiology (medical), medicine.medical_specialty, Tuberculosis, T-Lymphocytes, medicine.medical_treatment, Gastroenterology, Latent Tuberculosis, Internal medicine, Psoriasis, medicine, Humans, Interferon gamma, Prospective Studies, Prospective cohort study, T-SPOT.TB, Immunosuppression Therapy, Latent tuberculosis, Tuberculin Test, business.industry, Immunosuppression, Middle Aged, bacterial infections and mycoses, medicine.disease, Infectious Diseases, Immunology, Female, Interferon-gamma Release Tests, business, medicine.drug
Abstract: Summary Objective In this study, we have performed a direct comparison between both T-cell based assays (QFN-G-IT and T-SPOT.TB) and TST in patients with psoriasis taking different immunosuppressant drug-regimens. Methods We have prospectively studied 103 patients with moderate-to-severe psoriasis who required latent tuberculosis infection (LTBI) screening before starting systemic immunosuppressive treatment or during its sustained use. Results Overall number of positive results was 16.5%, 17.5% and 8.7% using T-SPOT.TB, QFN-G-IT and TST, respectively. Differences in the percentage of positive results between TST with T-SPOT.TB and QFN-G-IT were significant ( p = 0.005 and p = 0.008, respectively). A total of 24.3% of the subjects enrolled were positive for at least one of the three tests performed. Sixteen patients with negative TST (17%) were positive for one of the two IGRAs. We obtained seven indeterminate results by T-SPOT.TB and two by QFN-G-IT. Seven patients with negative TST presented indeterminate results by either of two IFN-γ assays. Positive TST, T-SPOT.TB and QFN-G-IT results were not affected by clinical therapeutic profile. Conclusions Our results reveal that in vitro assays are useful methods for LTBI diagnosis in patients with psoriasis, suggesting that they might be less influenced by immunosuppression than TST.
Published: 2014
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43. Use of Interferon-Gamma Release Assays to Calculate the Annual Risk of Tuberculosis Infection

Author: Francisco-Javier Roig, Alicia Lacoma, Amparo Escribano, Irene Latorre, Irene Mialdea, Nuria Díez, José Domínguez, Mar Serra-Vidal, Jessica Diaz, and Empar Giner
Subjects: Male, Microbiology (medical), medicine.medical_specialty, Tuberculosis, Cross-sectional study, Tuberculin, Risk Assessment, Annual incidence, Cohort Studies, Internal medicine, Prevalence, medicine, Humans, Interferon gamma, Child, Diagnostic Tests, Routine, Tuberculin Test, business.industry, Incidence, Incidence (epidemiology), bacterial infections and mycoses, medicine.disease, Cross-Sectional Studies, Infectious Diseases, Spain, Pediatrics, Perinatology and Child Health, Immunology, Female, business, Risk assessment, Interferon-gamma Release Tests, Cohort study, medicine.drug
Abstract: The objective was to assess the annual risk of tuberculosis infection by means of tuberculin skin testing (TST) in children, evaluating whether QuantiFERON-TB Gold In-Tube (QFN-G-IT) could improve the accuracy. On the basis of the positive TST results, the global annual incidence was estimated at 0.78%, with an increase in the prevalence from 0.64% to 1.68% in 2 years. However, QFN-G-IT was only positive in 6 of the 25 children with positive TST. The confirmation of the positive TST results by QFN-G-IT provided more accurate annual incidence estimation.
Published: 2015
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44. Dried plasma spots in the diagnosis of tuberculosis: IP-10 release assay on filter paper

Author: Jesper Eugen-Olsen, Jessica Diaz, Martine G. Aabye, José Maldonado, Morten Ruhwald, José Domínguez, Irene Latorre, Pernille Ravn, and Irene Mialdea
Subjects: Adult, Male, Paper, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, Adolescent, Denmark, Enzyme-Linked Immunosorbent Assay, Gastroenterology, Cohort Studies, Mycobacterium tuberculosis, Interferon-gamma, Latent Tuberculosis, Internal medicine, medicine, Humans, Antigens, Bacterial, Latent tuberculosis, Filter paper, biology, Spots, Tuberculin Test, business.industry, Reproducibility of Results, Diagnostic algorithms, Middle Aged, medicine.disease, biology.organism_classification, Training cohort, Chemokine CXCL10, Case-Control Studies, Immunology, Original Article, Female, Reagent Kits, Diagnostic, Interferon-gamma Release Tests, business, Algorithms
Abstract: Interferon (IFN)-γ release assays (IGRAs) are probably the most accurate tests for the detection of latent Mycobacterium tuberculosis infection, but IGRAs are labour intensive and the transport of samples over longer distances is difficult. IFN-γ-induced protein (IP)-10 is expressed at 100-fold higher levels than IFN-γ, and IP-10 release assays have comparable performance to IGRAs. The aim of this study was to explore the diagnostic potential of a novel IP-10 release assay based on dried plasma spots (DPS). The presence of IP-10 and IFN-γ was determined in plasma and in DPS by ELISA. Diagnostic algorithms for plasma and DPS tests for IP-10 were developed on a training cohort comprising 60 tuberculosis (TB) patients and 59 healthy controls. Diagnostic accuracy was assessed in a validation cohort comprising 78 TB patients and 98 healthy controls. Plasma was measured in Spain and DPS samples were sent to Denmark using the conventional postal service for analysis. IP-10 was readily detectable in both plasma and DPS, and correlation was excellent (r2 = 0.95). QuantiFERON-TB Gold In-Tube (QFT-TB) and IP-10 in DPS and plasma rendered comparable sensitivity (78%, 82% and 84%, respectively), specificity (100%, 97% and 97%, respectively) and indeterminate rates (p>0.55). The DPS-based IP-10 test has comparable diagnostic accuracy to the QFT-TB and samples can be sent via conventional mail over long distances for analysis without affecting the results.
Published: 2013
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45. Cigarette smoke has a negative impact onM. tuberculosisimmune response

Author: Cristina Prat, Angeles Jimenez, Celia Milà, Maria Altet Gomez, José Domínguez, Yoel Gonzalez-Diaz, Joan Pau Millet, Maria Louiza de Sosa-Galvao, José Maldonado, Irene Latorre, and Israel Molina-Pinargote
Subjects: Tuberculosis, business.industry, Cross-sectional study, medicine.disease, Asymptomatic, Immune system, Immunology, Medicine, Cigarette smoke, Interferon gamma, Risk factor, medicine.symptom, business, Contact tracing, medicine.drug
Abstract: Objectives: To investigate the immune response against M. tuberculosis (MTB) by Interferon Gamma Release Assays (IGRAs) in Tuberculosis (TB) and Latent TB Infected (LTBI) patients exposed to cigarette smoke. Methods: A cross sectional study from two clinics in Barcelona. Subjects included were: (i) 216 active pulmonary TB, (ii) 309 asymptomatic contact tracing individuals. At first visit blood was collected for IGRAs. The impact of cigarette smoke on MTB immune response was analyzed as the median of IFN-γ secreted (UI/mL) in QFN-G-IT and as the number (median) of T-cells producing IFN-γ [spot forming cells (SFC)] in T-SPOT.TB. Results: False-negative results in TB patients were higher in smokers (aOR:4.42; p Conclusions: Tobacco exposure was associated with IGRAs false-negative results in TB patients and was an independent risk factor for LTBI acquisition. A less IFN-γ response was observed in smokers than non-smokers. An increment on tobacco smoking produces a reduction on immune responses observed by both IGRAs. PII –Tabaquismo. 2013 SEPAR grant.
Published: 2016
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46. Thermostability of IFN-gamma and IP-10 release assays for latent infection with Mycobacterium tuberculosis: A TBnet study

Author: Jan Heyckendorf, Clara Morais, Christoph Lange, Otto D. Schoch, Dirk Wagner, Martine G. Aabye, Morten Ruhwald, Irene Latorre, Pernille Ravn, Matthias Hoffmann, Raquel Duarte, Thomas Blauenfeldt, Berit Lange, Martin Ernst, José Domínguez, and Instituto de Saúde Pública
Subjects: Adult, Male, 0301 basic medicine, Microbiology (medical), Tuberculosis, Immunology, IP-10, Microbiology, Specimen Handling, Mycobacterium tuberculosis, IFN-gamma, Interferon-gamma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Predictive Value of Tests, medicine, Humans, Interferon gamma, Prospective Studies, Tuberculosis, Pulmonary, Incubation, Whole blood, biology, Latent tuberculosis, Protein Stability, Temperature, Reproducibility of Results, Middle Aged, biology.organism_classification, medicine.disease, Chemokine CXCL10, Europe, 030104 developmental biology, Infectious Diseases, ROC Curve, 030228 respiratory system, Area Under Curve, Case-Control Studies, Host-Pathogen Interactions, Female, Interferon-gamma Release Tests, Biomarkers, Mycobacterium, medicine.drug
Abstract: Summary Introduction Interferon-γ (IFN-γ) inducible protein 10kD (IP-10) and IFN-γ release assays (IGRAs) are immunodiagnostic tests aiming to identify the presence of specific cellular immune responses, interpreted as markers for latent infection with Mycobacterium tuberculosis. Incubation at higher temperatures could affect IFN-γ and IP-10 responsiveness in order to improve the performance of IP-10 release assays and IGRAs. Aim The aim of this study was to assess the robustness of whole blood based IP-10 release assay and IGRAs and the effect of hyper-thermic incubation (39 °C) on the diagnostic accuracy of IP-10 release assay and IGRAs. Results We included 65 patients with confirmed pulmonary tuberculosis and 160 healthy controls from 6 European centres collaborating in the TBnet. In patients, IP-10 responses increased 1.07 (IQR 0.90–1.36) fold and IFN-γ responses decreased 0.88 (IQR 0.57–1.02) fold, with 39 °C compared to 37 °C incubation temperature. At 37 °C IGRA sensitivity was 85% and IP-10 sensitivity was 82%, whereas specificity was 97% for both tests (p > 0.8). These minor changes observed as a result of hyper-thermic incubation were not sufficient to impact IGRA and IP-10 release assay test performance. Conclusion The performance of IGRA and IP-10 release assays is robust despite variations in the incubation temperature between 37 °C and 39 °C.
Published: 2016

47. Calcineurin and mTOR inhibitors have opposing effects on regulatory T cells while reducing regulatory B cell populations in kidney transplant recipients

Author: Jordi Argilaguet, Ana Esteve-Solé, Andreas Meyerhans, Isabelle Forstmann, Julio Pascual, Marta Crespo, Cristina Peligero, Dolores Redondo, Sandra Giest, Irene Latorre, and Sara Alvarez
Subjects: Male, 0301 basic medicine, Regulatory B cells, Cèl·lules B, Calcineurin Inhibitors, Immunology, Ronyons -- Trasplantació, 030230 surgery, CD38, T-Lymphocytes, Regulatory, CD19, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Transplantation Immunology, Humans, Immunology and Allergy, Medicine, IL-2 receptor, B-Lymphocytes, Regulatory, Transplantation, biology, business.industry, TOR Serine-Threonine Kinases, FOXP3, hemic and immune systems, Kidney Transplantation, Interleukin-10, Calcineurin, Interleukin 10, 030104 developmental biology, Cèl·lules T, biology.protein, Female, Medicaments immunosupressors, business
Abstract: BACKGROUND: Regulatory B (Breg) and T (Treg) cells represent a biomarker for tolerance in transplant patients. Despite the importance of Treg and Breg in transplantation and the suggested crosstalk between both suppressive cell populations, little is known on how they are influenced by long-term immunosuppressive treatment. The aim of the present study was to investigate the effect of different immunosuppressive drugs used in routine clinical practice on Treg and Breg cell numbers. METHODS: Thirty-six kidney transplant recipients with stable graft function were recruited and classified according to their concomitant therapy: 22 patients received calcineurin inhibitors (CNI) and 14 patients received mammalian target of rapamycin (mTOR) inhibitors. A group of 8 healthy untreated subjects was included as control. Absolute numbers of peripheral blood-derived IL10-producing B cells (CD19(+)IL10(+)), CD19(+)CD24(hi)CD38(hi) transitional B cells and Treg cells (CD4(+)CD25(+)FOXP3(+)) were quantified in all KT patients and controls by flow cytometry. RESULTS: CD19(+)CD24(hi)CD38(hi) transitional B cells increased over time and seem to be related with long-term therapeutic graft survival irrespective of the treatment regimen. CNI and mTOR inhibitors significantly reduced numbers of Breg cells when compared with healthy individuals, whereas mTOR inhibitors expanded Treg cells in comparison with CNI drugs. CONCLUSIONS: Bridging the drug-mediated reduction of Breg cell numbers in vivo with the requirements of Breg cells for long-term transplant success remains an as yet unresolved task for therapeutic intervention. Further larger cohort studies that evaluate the effect of different treatment regimen on defined lymphocyte subpopulations are warranted. DR and MC were supported by a grant Marató TV3 137/C/2012. JP was supported by grants/nFIS-ISCIII-FEDER PI13/00598 and RedinRenRD12/0021/0024. AM was supported by a Ministerio de Economía y Competitividad grant SAF2010–21336.
Published: 2016

48. Técnicas basadas en la detección de IFN-γ en el diagnóstico de la infección tuberculosa en pacientes con psoriasis candidatos a terapias biológicas

Author: José Domínguez, Irene Latorre, and Marta Vilavella
Subjects: General Medicine
Abstract: Resumen Las terapias biologicas representan una alternativa de indudable eficacia en la psoriasis moderada y grave. Sin embargo, existe una asociacion entre el tratamiento con anti-TNF-α y la reactivacion de la infeccion tuberculosa. La tuberculina se utiliza como herramienta para el diagnostico de la infeccion tuberculosa, pero presenta una baja especificidad en pacientes vacunados con la BCG (Mycobacterium bovis bacilo de Calmette-Guerin) y una baja sensibilidad en pacientes con alteraciones de la inmunidad celular. En este sentido se han desarrollado diferentes metodologias in vitro que incorporan antigenos especificos de Mycobacterium tuberculosis para estimular celulas T sensibilizadas y detectar posteriormente IFN-γ liberado para el diagnostico in vitro de la infeccion tuberculosa. Los resultados obtenidos hasta ahora muestran a estas como una alternativa real a la tuberculina, ya que presentan una mayor especificidad y sensibilidad. Estas tecnicas, ademas, estan demostrando un elevado valor predictivo negativo que hace que nos podamos plantear a corto-medio plazo su utilizacion sin necesidad de combinarla con la tuberculina.
Published: 2012
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49. Usefulness of mid regional pro-atrial natriuretic peptide in the exacerbations of chronic obstructive pulmonary disease

Author: Miguel Pérez, Irene Latorre, Felipe Andreo, Alicia Lacoma, Luis Lores, José Domínguez, Juan Ruiz-Manzano, Cristina Prat, and Vicente Ausina
Subjects: Male, medicine.medical_specialty, Exacerbation, medicine.drug_class, Clinical Biochemistry, Pulmonary disease, Biochemistry, Pulmonary Disease, Chronic Obstructive, Internal medicine, medicine, Natriuretic peptide, Humans, In patient, Aged, COPD, business.industry, Biochemistry (medical), Pneumonia, General Medicine, Prognosis, medicine.disease, Pro atrial natriuretic peptide, Etiology, Cardiology, Female, business, Atrial Natriuretic Factor, Follow-Up Studies
Abstract: Background A recent approach for the management of chronic obstructive pulmonary disease (COPD) is the measurement of systemic biomarkers. The aim of this study was to evaluate the usefulness of mid regional pro-atrial natriuretic peptide (MR-proANP) to predict short and long term prognosis. Methods We included 318 COPD patients: 46 in a stable phase, 217 undergoing an exacerbation and 55 with pneumonia. Serum samples were collected at admission. For 20 exacerbated patients, we also collected a second sample one month later. MR-proANP was measured by an inmunofluorescent assay. Results Statistically higher levels of MR-proANP were found in patients with pneumonia when comparing to patients in the stable state (p = 0.031). For those patients with paired samples, MR-proANP decreased statistically one month later (p = 0.027). MR-proANP showed significant lower levels in exacerbations with isolation of pathogenic bacteria (p = 0.011). MR-proANP levels were higher in patients that died within one month, decreasing as long as the moment of death occurred later on (p = 0.163). Conclusions The identification of exacerbation etiology by means of MR-proANP is not clinically reliable. Levels of MR-proANP vary depending on the clinical status, being higher during pneumonia in comparison to the stable state. MR-proANP levels were higher in patients that died within one month after the exacerbation episode.
Published: 2011
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50. Diagnosing TB infection in children: analysis of discordances using in vitro tests and the tuberculin skin test

Author: N Altet-Gómez, Celia Milà, Maria Angeles Jimenez, Vicente Ausina, J J Zamora, Juan Ruiz-Manzano, M. L. De Souza-Galvão, Jordi Solsona, Adela Cantos, José Domínguez, and Irene Latorre
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, Adolescent, T-Lymphocytes, Tuberculin, Sensitivity and Specificity, Interferon-gamma, Tuberculosis diagnosis, Internal medicine, Humans, Mass Screening, Medicine, Prospective Studies, Child, Prospective cohort study, Mass screening, Tuberculina, biology, Tuberculin Test, business.industry, bacterial infections and mycoses, medicine.disease, biology.organism_classification, Child, Preschool, Immunology, BCG Vaccine, Female, Contact Tracing, business, Contact tracing, Mycobacterium
Abstract: The aim of the present study was to compare the performance of the interferon (IFN)-γ tests (QuantiFERON®-TB Gold In-Tube (QFT-G-IT) and T-SPOT®.TB) with the tuberculin skin test (TST) in diagnosing tuberculosis (TB) infection in children, and to analyse discordant results. This was a prospective study including 98 children from contact-tracing studies and 68 children with TST indurations ≥ 5 mm recruited during public health screenings. Positive IFN-γ tests results were associated with risk of exposure (p
Published: 2010
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