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1. Host-response transcriptional biomarkers accurately discriminate bacterial and viral infections of global relevance

Author

Emily R. Ko, Megan E. Reller, L. Gayani Tillekeratne, Champica K. Bodinayake, Cameron Miller, Thomas W. Burke, Ricardo Henao, Micah T. McClain, Sunil Suchindran, Bradly Nicholson, Adam Blatt, Elizabeth Petzold, Ephraim L. Tsalik, Ajith Nagahawatte, Vasantha Devasiri, Matthew P. Rubach, Venance P. Maro, Bingileki F. Lwezaula, Wasantha Kodikara-Arachichi, Ruvini Kurukulasooriya, Aruna D. De Silva, Danielle V. Clark, Kevin L. Schully, Deng Madut, J. Stephen Dumler, Cecilia Kato, Renee Galloway, John A. Crump, Geoffrey S. Ginsburg, Timothy D. Minogue, and Christopher W. Woods

Subjects
Medicine, Science
Abstract

Abstract Diagnostic limitations challenge management of clinically indistinguishable acute infectious illness globally. Gene expression classification models show great promise distinguishing causes of fever. We generated transcriptional data for a 294-participant (USA, Sri Lanka) discovery cohort with adjudicated viral or bacterial infections of diverse etiology or non-infectious disease mimics. We then derived and cross-validated gene expression classifiers including: 1) a single model to distinguish bacterial vs. viral (Global Fever-Bacterial/Viral [GF-B/V]) and 2) a two-model system to discriminate bacterial and viral in the context of noninfection (Global Fever-Bacterial/Viral/Non-infectious [GF-B/V/N]). We then translated to a multiplex RT-PCR assay and independent validation involved 101 participants (USA, Sri Lanka, Australia, Cambodia, Tanzania). The GF-B/V model discriminated bacterial from viral infection in the discovery cohort an area under the receiver operator curve (AUROC) of 0.93. Validation in an independent cohort demonstrated the GF-B/V model had an AUROC of 0.84 (95% CI 0.76–0.90) with overall accuracy of 81.6% (95% CI 72.7–88.5). Performance did not vary with age, demographics, or site. Host transcriptional response diagnostics distinguish bacterial and viral illness across global sites with diverse endemic pathogens.

Published
2023
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2. Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trialsResearch in context

Author

Ilias I. Siempos, Andre C. Kalil, Drifa Belhadi, Viviane Cordeiro Veiga, Alexandre Biasi Cavalcanti, Westyn Branch-Elliman, Eleni Papoutsi, Konstantinos Gkirgkiris, Nikoleta A. Xixi, Anastasia Kotanidou, Olivier Hermine, Raphaël Porcher, Xavier Mariette, Philippe Ravaud, Serge Bureau, Maxime Dougados, Matthieu Resche-Rigon, Pierre-Louis Tharaux, Annick Tibi, Elie Azoulay, Jacques Cadranel, Joseph Emmerich, Muriel Fartoukh, Bertrand Guidet, Marc Humbert, Karine Lacombe, Matthieu Mahevas, Frédéric Pene, Valerie Pourchet-Martinez, Frédéric Schlemmer, Yazdan Yazdanpanah, Gabriel Baron, Elodie Perrodeau, Damien Vanhoye, Cécile Kedzia, Lauren Demerville, Anne Gysembergh-Houal, Alexandre Bourgoin, Nabil Raked, Lakhdar Mameri, Claire Montlahuc, Lucie Biard, St.phanie Alary, Samir Hamiria, Thinhinane Bariz, Hala Semri, Dhiaa Meriem Hai, Moustafa Benafla, Mohamed Belloul, Pernelle Vauboin, Saskia Flamand, Claire Pacheco, Anouk Walter-Petrich, Emilia Stan, Souad Benarab, Corine Nyanou, Robin Charreteur, Céline Dupre, Kévin Cardet, Blandine Lehmann, Kamyl Baghli, Claire Madelaine, Eric D'Ortenzio, Oriane Puéchal, Caroline Semaille, Laurent Savale, Anatole Harrois, Samy Figueiredo, Jacques Duranteau, Nadia Anguel, Arthur Pavot, Xavier Monnet, Christian Richard, Jean-Louis Teboul, Philippe Durand, Pierre Tissieres, Mitja Jevnikar, David Montani, Stephan Pavy, Gaétane Nocturne, Samuel Bitoun, Nicolas Noel, Olivier Lambotte, Lelia Escaut, Stephane Jauréguiberry, Elodie Baudry, Christiane Verny, Edouard Lefevre, Mohamad Zaidan, Domitille Molinari, Gaël Leprun, Alain Fourreau, Laurent Cylly, Lamiae Grimaldi, Myriam Virlouvet, Ramdane Meftali, Soléne Fabre, Marion Licois, Asmaa Mamoune, Yacine Boudali, Clotilde Le Tiec, Céline Verstuyft, Anne-Marie Roques, Sophie Georgin-Lavialle, Patricia Senet, Gilles Pialoux, Angele Soria, Antoine Parrot, Helene François, Nathalie Rozensztajn, Emmanuelle Blin, Pascaline Choinier, Juliette Camuset, Jean-Simon Rech, Antony Canellas, Camille Rolland-Debord, Nadege Lemarié, Nicolas Belaube, Marine Nadal, Martin Siguier, Camille Petit-Hoang, Julie Chas, Elodie Drouet, Matthieu Lemoine, Audrey Phibel, Lucie Aunay, Eliane Bertrand, Sylviane Ravato, Marie Vayssettes, Anne Adda, Celine Wilpotte, Pélagie Thibaut, Julie Fillon, Isabelle Debrix, Soraya Fellahi, Jean-Philippe Bastard, Guillaume Lefévre, Jacques-Eric Gottenberg, Yves Hansmann, Frédéric Blanc, Sophie Ohlmann-Caillard, Vincent Castelain, Emmanuel Chatelus, Eva Chatron, Olivier Collange, François Danion, Frédéric De Blay, Pierre Diemunsch, Sophie Diemunsch, Renaud Felten, Bernard Goichot, Valentin Greigert, Aurelien Guffroy, Bob Heger, Charlotte Kaeuffer, Loic Kassegne, Anne Sophie Korganow, Pierrick Le Borgne, Nicolas Lefebvre, Paul-Michel Mertes, Eric Noll, Mathieu Oberlin, Vincent Poindron, Julien Pottecher, Yvon Ruch, François Weill, Nicolas Meyer, Emmanuel Andres, Eric Demonsant, Hakim Tayebi, Gabriel Nisand, Stéphane Brin, Cédric Sublon, Guillaume Becker, Anne Hutt, Tristan Martin, Sophie Bayer, Catherine Metzger, Arsene Mekinian, Noémie Abisror, Amir Adedjouma, Diane Bollens, Marion Bonneton, Nathalie Bourcicaux, Anne Bourrier, Maria Chauchard Thibault Chiarabiani, Doroth.e Chopin, Jonathan Cohen, Ines Devred, Bruno Donadille, Olivier Fain, Geoffrey Hariri, Vincent Jachiet, Patrick Ingliz, Marc Garnier, Marc Gatfosse, Etienne Ghrenassia, Delphine Gobert, Jessica Krause le Garrec, Cecilia Landman, Jean Remy Lavillegrand, Benedicte Lefebvre, Thibault Mahevas, Sandie Mazerand, Jean Luc Meynard, Marjolaine Morgand, Zineb Ouaz.ne, Jerome Pacanowski, S.bastien Riviere, Philippe Seksik, Harry Sokol, Heithem Soliman, Nadia Valin, Thomas Urbina, Chloé McAvoy, Maria Pereira Miranda, Gladys Aratus, Laurence Berard, Tabassome Simon, Anne Daguenel Nguyen, Elise Girault, Cl.mentine Mayala-Kanda, Marie Antignac, Céline Leplay, Jean-Benoit Arlet, Jean-Luc Diehl, Florence Bellenfant, Anne Blanchard, Alexandre Buffet, Bernard Cholley, Antoine Fayol, Edouard Flamarion, Anne Godier, Thomas Gorget, Sophie-Rym Hamada, Caroline Hauw-Berlemont, Jean-Sébastien Hulot, David Lebeaux, Marine Livrozet, Adrien Michon, Arthur Neuschwander, Marie-Aude Pennet, Benjamin Planquette, Brigitte Ranque, Olivier Sanchez, Geoffroy Volle, Sandrine Briois, Mathias Cornic, Virginie Elisee, Jesuthasan Denis, Juliette Djadi-Prat, Pauline Jouany, Ramon Junquera, Mickael Henriques, Amina Kebir, Isabelle Lehir, Jeanne Meunier, Florence Patin, Val.rie Paquet, Anne Tréhan, Véronique Vigna, Brigitte Sabatier, Damien Bergerot, Charléne Jouve, Camille Knosp, Olivia Lenoir, Nassim Mahtal, Léa Resmini, Xavier Lescure, Jade Ghosn, Antoine Bachelard, Anne Rachline, Valentina Isernia, Bao-chau, Phung, Dorothée Vallois, Aurelie Sautereau, Catherine Neukrich, Antoine Dossier, Raphaël Borie, Bruno Crestani, Gregory Ducrocq, Philippe Gabriel Steg, Philippe Dieude, Thomas Papo, Estelle Marcault, Marhaba Chaudhry, Charléne Da Silveira, Annabelle Metois, Ismahan Mahenni, Meriam Meziani, Cyndie Nilusmas, Sylvie Le Gac, Awa Ndiaye, Fran.oise Louni, Malikhone Chansombat, Zelie Julia, Solaya Chalal, Lynda Chalal, Laura Kramer, Jeniffer Le Grand, Kafif Ouifiya, Valentine Piquard, Sarah Tubiana, Yann Nguyen, Vasco Honsel, Emmanuel Weiss, Anais Codorniu, Virginie Zarrouk, Victoire de Lastours, Matthieu Uzzan, Naura Gamany, Agathe Claveirole, Alexandre Navid, Tiffanie Fouque, Yonathan Cohen, Maya Lupo, Constance Gilles, Roza Rahli, Zeina Louis, David Boutboul, Lionel Galicier, Yaël Amara, Gabrielle Archer, Amira Benattia, Anne Bergeron, Louise Bondeelle, Nathalie de Castro, Melissa Clément, Michaël Darmon, Blandine Denis, Clairelyne Dupin, Elsa Feredj, Delphine Feyeux, Adrien Joseph, Etienne Lenglin, Pierre Le Guen, Geoffroy Liégeon, Gwenaël Lorillon, Asma Mabrouki, Eric Mariotte, Grégoire Martin de Frémont, Adrien Mirouse, Jean-Michel Molina, Régis Peffault de Latour, Eric Oksenhendler, Julien Saussereau, Abdellatif Tazi, Jean-Jacques Tudesq, Lara Zafrani, Isabelle Brindele, Emmanuelle Bugnet, Karine Celli Lebras, Julien Chabert, Lamia Djaghout, Catherine Fauvaux, Anne Lise Jegu, Ewa Kozakiewicz, Martine Meunier, Marie-Thérèse Tremorin, Claire Davoine, Isabelle Madelaine, Sophie Caillat-Zucman, Constance Delaugerre, Florence Morin, Damien Sène, Ruxandra Burlacu, Benjamin Chousterman, Bruno Mégarbanne, Pascal Richette, Jean-Pierre Riveline, Aline Frazier, Eric Vicaut, Laure Berton, Tassadit Hadjam, Miguel Alejandro Vazquez-Ibarra, Clément Jourdaine, Olivia Tran, Véronique Jouis, Aude Jacob, Julie Smati, Stéphane Renaud, Claire Pernin, Lydia Suarez, Luca Semerano, Sébastien Abad, Ruben B. nainous, Nicolas Bonnet, Celine Comparon, Yves Cohen, Hugues Cordel, Robin Dhote, Nathalie Dournon, Boris Duchemann, Nathan Ebstein, Thomas Gille, Benedicte Giroux-Leprieur, Jeanne Goupil de Bouille, Hilario Nunes, Johanna Oziel, Dominique Roulot, Lucile Sese, ClaireTantet, Yurdagul Uzunhan, Coralie Bloch-Queyrat, Vincent Levy, Fadhila Messani, Mohammed Rahaoui, Myléne Petit, Sabrina Brahmi, Vanessa Rathoin, Marthe Rigal, Nathalie Costedoat-Chalumeau, Liem Binh Luong, Zakaria Ait Hamou, Sarah Benghanem, Philippe Blanche, Nicolas Carlier, Benjamin Chaigne, Remy Gauzit, Hassan Joumaa, Mathieu Jozwiak, Marie Lachétre, Hélène Lafoeste, Odie Launay, Paul Legendre, Jonathan Marey, Caroline Morbieu, Lola-Jade Palmieri, Tali-Anne Szwebel, Hendy Abdoul, Alexandra Bruneau, Audrey Beclin-Clabaux, Charly Larrieu, Pierre Montanari, Eric Dufour, Ada Clarke, Catherine Le Bourlout, Nathalie Marin, Nathalie Menage, Samira Saleh-Mghir, Mamadou Salif Cisse, Kahina Cheref, Corinne Guerin, Jérémie Zerbit, Marc Michel, Sébastien Gallien, Etienne Crickx, Benjamin Le Vavasseur, Emmanuelle Kempf, Karim Jaffal, William Vindrios, Julie Oniszczuk, Constance Guillaud, Pascal Lim, Elena Fois, Giovanna Melica, Marie Matignon, Maud Jalabert, Jean-Daniel Lelièvre, David Schmitz, Marion Bourhis, Sylia Belazouz, Laetitia Languille, Caroline Boucle, Nelly Cita, Agnés Didier, Fahem Froura, Katia Ledudal, Thiziri Sadaoui, Alaki Thiemele, Delphine Le Febvre De Bailly, Muriel Carvhalo Verlinde, Julien Mayaux, Patrice Cacoub, David Saadoun, Mathieu Vautier, Héléne Bugaut, Olivier Benveniste, Yves Allenbach, Gaëlle Leroux, Aude Rigolet, Perrine Guillaume-Jugnot, Fanny Domont, Anne Claire Desbois, Chloé Comarmond, Nicolas Champtiaux, Segolene Toquet, Amine Ghembaza, Matheus Vieira, Georgina Maalouf, Goncalo Boleto, Yasmina Ferfar, Jean-Christophe Corvol, C.line Louapre, Sara Sambin, Louise-Laure Mariani, Carine Karachi, Florence Tubach, Candice Estellat, Linda Gimeno, Karine Martin, Aicha Bah, Vixra Keo, Sabrine Ouamri, Yasmine Messaoudi, Nessima Yelles, Pierre Faye, Sebastien Cavelot, Cecile Larcheveque, Laurence Annonay, Jaouad Benhida, Aida Zahrate-Ghoul, Soumeya Hammal, Ridha Belilita, Fanny Charbonnier, Claire Aguilar, Fanny Alby-Laurent, Carole Burger, Clara Campos-Vega, Nathalie Chavarot, Benjamin Fournier, Claire Rouzaud, Damien Vimpére, Caroline Elie, Prissile Bakouboula, Laure Choupeaux, Sophie Granville, Elodie Issorat, Christine Broissand, Marie-Alexandra Alyanakian, Guillaume Geri, Nawal Derridj, Naima Sguiouar, Hakim Meddah, Mourad Djadel, Héléne Chambrin-Lauvray, Jean-Charles Duclos-vallée, Faouzi Saliba, Sophie-Caroline Sacleux, Ilias Kounis, Sonia Tamazirt, Eric Rudant, Jean-Marie Michot, Annabelle Stoclin, Emeline Colomba, Fanny Pommeret, Christophe Willekens, Rosa Da Silva, Valérie Dejean, Yasmina Mekid, Ines Ben-Mabrouk, Florence Netzer, Caroline Pradon, Laurence Drouard, Valérie Camara-Clayette, Alexandre Morel, Gilles Garcia, Abolfazl Mohebbi, Férial Berbour, Mélanie Dehais, Anne-Lise Pouliquen, Alison Klasen, Loren Soyez-Herkert, Jonathan London, Younes Keroumi, Emmanuelle Guillot, Guillaume Grailles, Younes El amine, Fanny Defrancq, Hanane Fodil, Chaouki Bouras, Dominique Dautel, Nicolas Gambier, Thierno Dieye, Boris Bienvenu, Victor Lancon, Laurence Lecomte, Kristina Beziriganyan, Belkacem Asselate, Laure Allanic, Elena Kiouris, Marie-Héléne Legros, Christine Lemagner, Pascal Martel, Vincent Provitolo, Félix Ackermann, Mathilde Le Marchand, Aurélie Chan Hew Wai, Dimitri Fremont, Elisabeth Coupez, Mireille Adda, Frédéric Duée, Lise Bernard, Antoine Gros, Estelle Henry, Claire Courtin, Anne Pattyn, Pierre-Grégoire Guinot, Marc Bardou, Agnes Maurer, Julie Jambon, Amélie Cransac, Corinne Pernot, Bruno Mourvillier, Eric Marquis, Philippe Benoit, Damien Roux, Coralie Gernez, Cécile Yelnik, Julien Poissy, Mandy Nizard, Fanette Denies, Helene Gros, Jean-Jacques Mourad, Emmanuelle Sacco, Sophie Renet, F. Ader, Y. Yazdanpanah, F. Mentre, N. Peiffer-Smadja, F.X. Lescure, J. Poissy, L. Bouadma, J.F. Timsit, B. Lina, F. Morfin-Sherpa, M. Bouscambert, A. Gaymard, G. Peytavin, L. Abel, J. Guedj, C. Andrejak, C. Burdet, C. Laouenan, D. Belhadi, A. Dupont, T. Alfaiate, B. Basli, A. Chair, S. Laribi, J. Level, M. Schneider, M.C. Tellier, A. Dechanet, D. Costagliola, B. Terrier, M. Ohana, S. Couffin-Cadiergues, H. Esperou, C. Delmas, J. Saillard, C. Fougerou, L. Moinot, L. Wittkop, C. Cagnot, S. Le Mestre, D. Lebrasseur-Longuet, V. Petrov-Sanchez, A. Diallo, N. Mercier, V. Icard, B. Leveau, S. Tubiana, B. Hamze, A. Gelley, M. Noret, E. D’Ortenzio, O. Puechal, C. Semaille, T. Welte, J.A. Paiva, M. Halanova, M.P. Kieny, E. Balssa, C. Birkle, S. Gibowski, E. Landry, A. Le Goff, L. Moachon, C. Moins, L. Wadouachi, C. Paul, A. Levier, D. Bougon, F. Djossou, L. Epelboin, J. Dellamonica, C.H. Marquette, C. Robert, S. Gibot, E. Senneville, V. Jean-Michel, Y. Zerbib, C. Chirouze, A. Boyer, C. Cazanave, D. Gruson, D. Malvy, P. Andreu, J.P. Quenot, N. Terzi, K. Faure, C. Chabartier, V. Le Moing, K. Klouche, T. Ferry, F, Valour, B. Gaborit, E. Canet, P. Le Turnier, D. Boutoille, F. Bani-Sadr, F. Benezit, M. Revest, C. Cameli, A. Caro, MJ Ngo Um Tegue, Y. Le Tulzo, B. Laviolle, F. Laine, G. Thiery, F. Meziani, Y. Hansmann, W. Oulehri, C. Tacquard, F. Vardon-Bounes, B. Riu-Poulenc, M. Murris-Espin, L. Bernard, D. Garot, O. Hinschberger, M. Martinot, C. Bruel, B. Pilmis, O. Bouchaud, P. Loubet, C. Roger, X. Monnet, S. Figueiredo, V. Godard, J.P. Mira, M. Lachatre, S. Kerneis, J. Aboab, N. Sayre, F. Crockett, D. Lebeaux, A. Buffet, J.L. Diehl, A. Fayol, J.S. Hulot, M. Livrozet, A Mekontso- Dessap, C. Ficko, F. Stefan, J. Le Pavec, J. Mayaux, H. Ait-Oufella, J.M. Molina, G. Pialoux, M. Fartoukh, J. Textoris, M. Brossard, A. Essat, E. Netzer, Y. Riault, M. Ghislain, L. Beniguel, M. Genin, L. Gouichiche, C. Betard, L. Belkhir, A. Altdorfer, V Fraipont Centro, S. Braz, JM Ferreira Ribeiro, R Roncon Alburqueque, M. Berna, M. Alexandre, B. Lamprecht, A. Egle, R. Greil, M. Joannidis, Thomas F. Patterson, Philip O. Ponce, Barbara S. Taylor, Jan E. Patterson, Jason E. Bowling, Heta Javeri, LuAnn Larson, Angela Hewlett, Aneesh K. Mehta, Nadine G. Rouphael, Youssef Saklawi, Nicholas Scanlon, Jessica J. Traenkner, Ronald P. Trible, Jr., Emmanuel B. Walter, Noel Ivey, Thomas L. Holland, Guillermo M. Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Lanny Hsieh, Alpesh N. Amin, Miki Watanabe, Helen S. Lee, Susan Kline, Joanne Billings, Brooke Noren, Hyun Kim, Tyler D. Bold, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Nicole Iovine, Lars K. Beattie, Rebecca Murray Wakeman, Matthew Shaw, Mamta K. Jain, Satish Mocherla, Jessica Meisner, Amneris Luque, Daniel A. Sweeney, Constance A. Benson, Farhana Ali, Robert L. Atmar, Hana M. El Sahly, Jennifer Whitaker, Ann R. Falsey, Angela R. Branche, Cheryl Rozario, Justino Regalado Pineda, José Arturo Martinez-Orozco, David Chien Lye, Sean WX. Ong, Po Ying Chia, Barnaby E. Young, Uriel Sandkovsky, Mezgebe Berhe, Clinton Haley, Emma Dishner, Valeria D. Cantos, Colleen F. Kelley, Paulina A. Rebolledo Esteinou, Sheetal Kandiah, Sarah B. Doernberg, Pierre-Cedric B. Crouch, Hannah Jang, Anne F. Luetkemeyer, Jay Dwyer, Stuart H. Cohen, George R. Thompson, 3rd, Hien H. Nguyen, Robert W. Finberg, Jennifer P. Wang, Juan Perez-Velazquez, Mireya Wessolossky, Patrick E.H. Jackson, Taison D. Bell, Miranda J. West, Babafemi Taiwo, Karen Krueger, Johnny Perez, Triniece Pearson, Catharine I. Paules, Kathleen G. Julian, Danish Ahmad, Alexander G. Hajduczok, Henry Arguinchona, Christa Arguinchona, Nathaniel Erdmann, Paul Goepfert, Neera Ahuja, Maria G. Frank, David Wyles, Heather Young, Myoung-don Oh, Wan Beom Park, Chang Kyung Kang, Vincent Marconi, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Eu Suk Kim, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Seow Yen Tan, Humaira Shafi, MF Jaime Chien, Raymond KC. Fong, Daniel D. Murray, Jens Lundgren, Henrik Nielsen, Tomas Jensen, Barry S. Zingman, Robert Grossberg, Paul F. Riska, Otto O. Yang, Jenny Ahn, Rubi Arias, Rekha R. Rapaka, Naomi Hauser, James D. Campbell, William R. Short, Pablo Tebas, Jillian T. Baron, Susan L.F. McLellan, Lucas S. Blanton, Justin B. Seashore, C. Buddy Creech, Todd W. Rice, Shannon Walker, Isaac P. Thomsen, Diego Lopez de Castilla, Jason W. Van Winkle, Francis X. Riedo, Surinder Kaur Pada, Alvin DY. Wang, Li Lin, Michelle Harkins, Gregory Mertz, Nestor Sosa, Louis Yi Ann Chai, Paul Anantharajah Tambyah, Sai Meng Tham, Sophia Archuleta, Gabriel Yan, David A. Lindholm, Ana Elizabeth Markelz, Katrin Mende, Richard Mularski, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Ryan C. Maves, Gregory C. Utz, Sarah L. George, Daniel F. Hoft, James D. Brien, Roger Paredes, Lourdes Mateu, Cora Loste, Princy Kumar, Sarah Thornton, Sharmila Mohanraj, Noreen A. Hynes, Lauren M. Sauer, Christopher J. Colombo, Christina Schofield, Rhonda E. Colombo, Susan E. Chambers, Richard M. Novak, Andrea Wendrow, Samir K. Gupta, Tida Lee, Tahaniyat Lalani, Mark Holodniy, Aarthi Chary, Nikhil Huprikar, Anuradha Ganesan, Norio Ohmagari, Ayako Mikami, D. Ashley Price, Christopher J.A. Duncan, Kerry Dierberg, Henry J. Neumann, Stephanie N. Taylor, Alisha Lacour, Najy Masri, Edwin Swiatlo, Kyle Widmer, James D. Neaton, Mary Bessesen, David S. Stephens, Timothy H. Burgess, Timothy M. Uyeki, Robert Walker, G. Lynn Marks, Anu Osinusi, Huyen Cao, Anabela Cardoso, Stephanie de Bono, Douglas E. Schlichting, Kevin K. Chung, Jennifer L. Ferreira, Michelle Green, Mat Makowski, Michael R. Wierzbicki, Tom M. Conrad, Jill Ann El-Khorazaty, Heather Hill, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, John H. Beigel, Kay M. Tomashek, Varduhi Ghazaryan, Tatiana Beresnev, Seema Nayak, Lori E. Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, Ruth Florese, Jocelyn D. Voell, Richard Davey, Ruth C. Serrano, Zanthia Wiley, Varun K. Phadke, Paul A. Goepfert, Carlos A. Gomez, Theresa A. Sofarelli, Laura Certain, Hannah N. Imlay, Cameron R. Wolfe, Emily R. Ko, John J. Engemann, Nora Bautista Felix, Claire R. Wan, Sammy T. Elmor, Laurel R. Bristow, Michelle S. Harkins, Nicole M. Iovine, Marie-Carmelle Elie-Turenne, Victor F. Tapson, Pyoeng Gyun Choe, Richard A. Mularski, Kevin S. Rhie, Rezhan H. Hussein, Dilek Ince, Patricia L. Winokur, Jin Takasaki, Sho Saito, Kimberly McConnell, PharmD, David L. Wyles, Ellen Sarcone, Kevin A. Grimes, Katherine Perez, Charles Janak, Jennifer A. Whitaker, Paulina A. Rebolledo, John Gharbin, Allison A. Lambert, Diego F. Zea, Emma Bainbridge, David C. Hostler, Jordanna M. Hostler, Brian T. Shahan, Evelyn Ling, Minjoung Go, Fleesie A. Hubbard, Melony Chakrabarty, Maryrose Laguio-Vila, Edward E. Walsh, Faheem Guirgis, Vincent C. Marconi, Christian Madar, Scott A. Borgetti, Corri Levine, Joy Nock, Keith Candiotti, Julia Rozman, Fernando Dangond, Yann Hyvert, Andrea Seitzinger, Kaitlyn Cross, Stephanie Pettibone, Seema U. Nayak, and Gregory A. Deye

Subjects
Acute respiratory distress syndrome, Acute hypoxemic respiratory failure, Pneumonia, Critically ill, Cancer, Medicine (General), R5-920
Abstract

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Published
2024
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3. Author Correction: Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion

Author

Nicholas S. Giroux, Shengli Ding, Micah T. McClain, Thomas W. Burke, Elizabeth Petzold, Hong A. Chung, Grecia O. Rivera, Ergang Wang, Rui Xi, Shree Bose, Tomer Rotstein, Bradly P. Nicholson, Tianyi Chen, Ricardo Henao, Gregory D. Sempowski, Thomas N. Denny, Maria Iglesias De Ussel, Lisa L. Satterwhite, Emily R. Ko, Geoffrey S. Ginsburg, Bryan D. Kraft, Ephraim L. Tsalik, Xiling Shen, and Christopher W. Woods

Subjects
Medicine, Science
Published
2023
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4. Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion

Author

Nicholas S. Giroux, Shengli Ding, Micah T. McClain, Thomas W. Burke, Elizabeth Petzold, Hong A. Chung, Grecia O. Rivera, Ergang Wang, Rui Xi, Shree Bose, Tomer Rotstein, Bradly P. Nicholson, Tianyi Chen, Ricardo Henao, Gregory D. Sempowski, Thomas N. Denny, Maria Iglesias De Ussel, Lisa L. Satterwhite, Emily R. Ko, Geoffrey S. Ginsburg, Bryan D. Kraft, Ephraim L. Tsalik, Xiling Shen, and Christopher W. Woods

Subjects
Medicine, Science
Abstract

Abstract SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associated with mild or moderate symptoms were already robust and included severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity was marked by upregulation of classical antiviral pathways, including those regulating IRF1 and IRF7, whereas in moderate disease, these classical antiviral signals diminished, suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19.

Published
2022
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5. Systematic comparison of published host gene expression signatures for bacterial/viral discrimination

Author

Nicholas Bodkin, Melissa Ross, Micah T. McClain, Emily R. Ko, Christopher W. Woods, Geoffrey S. Ginsburg, Ricardo Henao, and Ephraim L. Tsalik

Subjects
Biomarkers, Infectious disease, Diagnostics, Gene expression, Machine learning, Medicine, Genetics, QH426-470
Abstract

Abstract Background Measuring host gene expression is a promising diagnostic strategy to discriminate bacterial and viral infections. Multiple signatures of varying size, complexity, and target populations have been described. However, there is little information to indicate how the performance of various published signatures compare to one another. Methods This systematic comparison of host gene expression signatures evaluated the performance of 28 signatures, validating them in 4589 subjects from 51 publicly available datasets. Thirteen COVID-specific datasets with 1416 subjects were included in a separate analysis. Individual signature performance was evaluated using the area under the receiving operating characteristic curve (AUC) value. Overall signature performance was evaluated using median AUCs and accuracies. Results Signature performance varied widely, with median AUCs ranging from 0.55 to 0.96 for bacterial classification and 0.69–0.97 for viral classification. Signature size varied (1–398 genes), with smaller signatures generally performing more poorly (P < 0.04). Viral infection was easier to diagnose than bacterial infection (84% vs. 79% overall accuracy, respectively; P < .001). Host gene expression classifiers performed more poorly in some pediatric populations (3 months–1 year and 2–11 years) compared to the adult population for both bacterial infection (73% and 70% vs. 82%, respectively; P < .001) and viral infection (80% and 79% vs. 88%, respectively; P < .001). We did not observe classification differences based on illness severity as defined by ICU admission for bacterial or viral infections. The median AUC across all signatures for COVID-19 classification was 0.80 compared to 0.83 for viral classification in the same datasets. Conclusions In this systematic comparison of 28 host gene expression signatures, we observed differences based on a signature’s size and characteristics of the validation population, including age and infection type. However, populations used for signature discovery did not impact performance, underscoring the redundancy among many of these signatures. Furthermore, differential performance in specific populations may only be observable through this type of large-scale validation.

Published
2022
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6. An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

Author

Liuyang Wang, Thomas J. Balmat, Alejandro L. Antonia, Florica J. Constantine, Ricardo Henao, Thomas W. Burke, Andy Ingham, Micah T. McClain, Ephraim L. Tsalik, Emily R. Ko, Geoffrey S. Ginsburg, Mark R. DeLong, Xiling Shen, Christopher W. Woods, Elizabeth R. Hauser, and Dennis C. Ko

Subjects
Pleiotropy, Cross-phenotype association, Gout, LD-score, Colocalization, PheWAS, Medicine, Genetics, QH426-470
Abstract

Abstract Background While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Results Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Conclusions Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .

Published
2021
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7. The Host Response to Viral Infections Reveals Common and Virus-Specific Signatures in the Peripheral Blood

Author

Ephraim L. Tsalik, Cassandra Fiorino, Ammara Aqeel, Yiling Liu, Ricardo Henao, Emily R. Ko, Thomas W. Burke, Megan E. Reller, Champica K. Bodinayake, Ajith Nagahawatte, Wasantha K. Arachchi, Vasantha Devasiri, Ruvini Kurukulasooriya, Micah T. McClain, Christopher W. Woods, Geoffrey S. Ginsburg, L. Gayani Tillekeratne, and Klaus Schughart

Subjects
viral respiratory infections, host response (HR), human patients, influenza, enterovirus, rhinovirus (RV), Immunologic diseases. Allergy, RC581-607
Abstract

Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections.

Published
2021
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8. Direct-from-blood RNA sequencing identifies the cause of post-bronchoscopy fever

Author

Emily R. Ko, Casandra W. Philipson, Thomas W. Burke, Regina Z. Cer, Kimberly A. Bishop-Lilly, Logan J. Voegtly, Ephraim L. Tsalik, Christopher W. Woods, Danielle V. Clark, and Kevin L. Schully

Subjects
Transcriptome, Metagenomic sequencing, Early diagnosis, Molecular diagnostics, Bacterial infections, Stenotrophomonas maltophilia, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Antibiotic resistance is rising at disturbing rates and contributes to the deaths of millions of people yearly. Antibiotic resistant infections disproportionately affect those with immunocompromising conditions, chronic colonization, and frequent antibiotic use such as transplant patients or those with cystic fibrosis. However, clinicians lack the diagnostic tools to confidently diagnose and treat infections, leading to widespread use of empiric broad spectrum antimicrobials, often for prolonged duration. Case presentation A 22 year-old Caucasian female with cystic fibrosis received a bilateral orthotopic lung transplantation 5 months prior to the index hospitalization. She underwent routine surveillance bronchoscopy and was admitted for post-procedure fever. A clear cause of infection was not identified by routine methods. Imaging and bronchoscopic lung biopsy did not identify an infectious agent or rejection. She was treated with a prolonged course of antimicrobials targeting known colonizing organisms from prior bronchoalveolar lavage cultures (Pseudomonas, Staphylococcus aureus, and Aspergillus). However, we identified Stenotrophomonas maltophilia in two independent whole blood samples using direct-pathogen sequencing, which was not identified by other methods. Conclusions This case represents a common clinical conundrum: identification of infection in a high-risk, complex patient. Here, direct-pathogen sequencing identified a pathogen that would not otherwise have been identified by common techniques. Had results been clinically available, treatment could have been customized, avoiding a prolonged course of broad spectrum antimicrobials that would only exacerbate resistance. Direct-pathogen sequencing is poised to fill a diagnostic gap for pathogen identification, allowing early identification and customization of treatment in a culture-independent, pathogen-agnostic manner.

Published
2019
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9. Validation of a host response test to distinguish bacterial and viral respiratory infection

Author

Emily C. Lydon, Ricardo Henao, Thomas W. Burke, Mert Aydin, Bradly P. Nicholson, Seth W. Glickman, Vance G. Fowler, Eugenia B. Quackenbush, Charles B. Cairns, Stephen F. Kingsmore, Anja K. Jaehne, Emanuel P. Rivers, Raymond J. Langley, Elizabeth Petzold, Emily R. Ko, Micah T. McClain, Geoffrey S. Ginsburg, Christopher W. Woods, and Ephraim L. Tsalik

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases. Methods: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin. Findings: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85–0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02). Interpretation: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases. Keywords: Biomarkers, Gene expression, Respiratory tract infections, Coinfection, Diagnosis, Precision medicine

Published
2019
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10. A comparison of host response strategies to distinguish bacterial and viral infection.

Author

Melissa Ross, Ricardo Henao, Thomas W Burke, Emily R Ko, Micah T McClain, Geoffrey S Ginsburg, Christopher W Woods, and Ephraim L Tsalik

Subjects
Medicine, Science
Abstract

ObjectivesCompare three host response strategies to distinguish bacterial and viral etiologies of acute respiratory illness (ARI).MethodsIn this observational cohort study, procalcitonin, a 3-protein panel (CRP, IP-10, TRAIL), and a host gene expression mRNA panel were measured in 286 subjects with ARI from four emergency departments. Multinomial logistic regression and leave-one-out cross validation were used to evaluate the protein and mRNA tests.ResultsThe mRNA panel performed better than alternative strategies to identify bacterial infection: AUC 0.93 vs. 0.83 for the protein panel and 0.84 for procalcitonin (PConclusionsA gene expression signature was the most accurate host response strategy for classifying subjects with bacterial, viral, or non-infectious ARI.

Published
2021
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11. A host gene expression approach for identifying triggers of asthma exacerbations.

Author

Emily C Lydon, Charles Bullard, Mert Aydin, Olga M Better, Anna Mazur, Bradly P Nicholson, Emily R Ko, Micah T McClain, Geoffrey S Ginsburg, Chris W Woods, Thomas W Burke, Ricardo Henao, and Ephraim L Tsalik

Subjects
Medicine, Science
Abstract

RationaleAsthma exacerbations often occur due to infectious triggers, but determining whether infection is present and whether it is bacterial or viral remains clinically challenging. A diagnostic strategy that clarifies these uncertainties could enable personalized asthma treatment and mitigate antibiotic overuse.ObjectivesTo explore the performance of validated peripheral blood gene expression signatures in discriminating bacterial, viral, and noninfectious triggers in subjects with asthma exacerbations.MethodsSubjects with suspected asthma exacerbations of various etiologies were retrospectively selected for peripheral blood gene expression analysis from a pool of subjects previously enrolled in emergency departments with acute respiratory illness. RT-PCR quantified 87 gene targets, selected from microarray-based studies, followed by logistic regression modeling to define bacterial, viral, or noninfectious class. The model-predicted class was compared to clinical adjudication and procalcitonin.ResultsOf 46 subjects enrolled, 7 were clinically adjudicated as bacterial, 18 as viral, and 21 as noninfectious. Model prediction was congruent with clinical adjudication in 15/18 viral and 13/21 noninfectious cases, but only 1/7 bacterial cases. None of the adjudicated bacterial cases had confirmatory microbiology; the precise etiology in this group was uncertain. Procalcitonin classified only one subject in the cohort as bacterial. 47.8% of subjects received antibiotics.ConclusionsOur model classified asthma exacerbations by the underlying bacterial, viral, and noninfectious host response. Compared to clinical adjudication, the majority of discordances occurred in the bacterial group, due to either imperfect adjudication or model misclassification. Bacterial infection was identified infrequently by all classification schemes, but nearly half of subjects were prescribed antibiotics. A gene expression-based approach may offer useful diagnostic information in this population and guide appropriate antibiotic use.

Published
2019
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12. A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies

Author

Gregory D. Poore, Emily R. Ko, Ashlee Valente, Ricardo Henao, Kelsey Sumner, Christopher Hong, Thomas W. Burke, Marshall Nichols, Micah T. McClain, Erich S. Huang, Geoffrey S. Ginsburg, Christopher W. Woods, and Ephraim L. Tsalik

Subjects
personalized medicine, micro RNA, transcriptome, respiratory tract infections, molecular diagnostics, host-pathogen interaction, Microbiology, QR1-502
Abstract

Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies.Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection.Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8–100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0–98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling.Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.

Published
2018
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13. Single-cell genome-wide association reveals a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus

Author

Benjamin H. Schott, Liuyang Wang, Xinyu Zhu, Alfred T. Harding, Emily R. Ko, Jeffrey S. Bourgeois, Erica J. Washington, Thomas W. Burke, Jack Anderson, Emma Bergstrom, Zoe Gardener, Suzanna Paterson, Richard G. Brennan, Christopher Chiu, Micah T. McClain, Christopher W. Woods, Simon G. Gregory, Nicholas S. Heaton, Dennis C. Ko, and Defence Advanced Research Projects Agency (UK)

Subjects
Genetics, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract

During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and susceptibility. We applied this method to influenza A virus (IAV), the cause of four pandemics since the start of the 20th century. scHi-HOST leverages single-cell RNA sequencing (scRNA-seq) to simultaneously assign genetic identity to cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral burden, and identify expression quantitative trait loci. Integration of scHi-HOST with human challenge and experimental validation demonstrated that a missense variant in endoplasmic reticulum aminopeptidase 1 (ERAP1; rs27895) increased IAV burden in cells and human volunteers. rs27895 exhibits population differentiation, likely contributing to greater permissivity of cells from African populations to IAV. scHi-HOST is a broadly applicable method and resource for decoding infectious-disease genetics.

Published
2022

14. Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO):a randomised controlled trial

Author

Wesley H. Self, Uriel Sandkovsky, Cavan S. Reilly, David M. Vock, Robert L. Gottlieb, Michael Mack, Kevin Golden, Emma Dishner, Andrew Vekstein, Emily R. Ko, Tatyana Der, John Franzone, Eyad Almasri, Mohamed Fayed, Michael R. Filbin, Kathryn A. Hibbert, Todd W. Rice, Jonathan D. Casey, J. Awori Hayanga, Vinay Badhwar, Bradley G. Leshnower, Milad Sharifpour, Kirk U. Knowlton, Ithan D. Peltan, Elizieta Bakowska, Justyna Kowalska, Michael E. Bowdish, Jeffrey M. Sturek, Angela J. Rogers, D. Clark Files, Jarrod M. Mosier, Michelle N. Gong, David J. Douin, R. Duncan Hite, Barbara W. Trautner, Mamta K. Jain, Edward M. Gardner, Akram Khan, Jens-Ulrik Jensen, Michael A. Matthay, Adit A. Ginde, Samuel M. Brown, Elizabeth S. Higgs, Sarah Pett, Amy C. Weintrob, Christina C. Chang, Daniel D. Murrary, Huldrych F. Günthard, Ellen Moquete, Greg Grandits, Nicole Engen, Birgit Grund, Shweta Sharma, Huyen Cao, Rajesh Gupta, Suzette Osei, David Margolis, Qing Zhu, Mark N. Polizzotto, Abdel G. Babiker, Victoria J. Davey, Virginia Kan, B. Taylor Thompson, Annetine C. Gelijns, James D. Neaton, H. Clifford Lane, Jens D. Jundgren, John Tierney, Kevin Barrett, Betsey R. Herpin, Mary C. Smolskis, Susan E. Voge, Laura A. McNay, Kelly Cahill, Page Crew, Matthew Kirchoff, Ratna Sardana, Sharon Segal Raim, Joseph Chiu, Lisa Hensley, Josua Lorenzo, Rebecca Mock, Katy Shaw-Saliba, Judith Zuckerman, Stacey J. Adam, Judy Currier, Sarah Read, Eric Hughes, Laura Amos, Amy Carlsen, Anita Carter, Bionca Davis, Eileen Denning, Alain DuChene, Merrie Harrison, Payton Kaiser, Joseph Koopmeiners, Sue Meger, Thomas Murray, Kien Quan, Siu Fun Quan, Greg Thompson, Jamie Walski, Deborah Wentworth, Alan J. Moskowitz, Emilia Bagiella, Karen O'Sullivan, Mary E. Marks, Evan Accardi, Emily Kinzel, Gabriela Bedoya, Lopa Gupta, Jessica R. Overbey, Maria L. Padillia, Milerva Santos, Marc A. Gillinov, Marissa A. Miller, Wendy C. Taddei-Peters, Kathleen Fenton, Mezgebe Berhe, Clinton Haley, Christopher Bettacchi, Erin Duhaime, Madison Ryan, Sarah Burris, Felecia Jones, Samantha Villa, Samantha Want, Raven Robert, Tanquinisha Coleman, Laura Clariday, Rebecca Baker, Marian Hurutado-Rodriguez, Nazia Iram, Michelle Fresnedo, Allyson Davis, Kiara Leonard, Noelia Ramierez, Jon Thammavong, Krizia Duque, Emma Turner, Tammy Fisher, Dianna Robinson, Desirae Ransom, Erica Lusk, Aaron Killian, Adriana Palacious, Edilia Solis, Janet Jerrow, Matthew Watts, Heather Whitacre, Elizabeth Cothran, Peter K. Smith, Christina E. Barkauskas, Grace R. Dreyer, Marie Witte, Nilima Mosaly, Ahmad Mourad, Thomas L. Holland, Kathleen Lane, Andrew Bouffler, Lauren M. McGowan, Marry Motta, Gregory Tipton, Ben Stallings, Gennifer Stout, Beth McLendon-Arvik, Beth A. Hollister, Dana M. Giangiacomo, Sunil Sharma, Brian Pappers, Paul McCarthy, Troy Krupica, Arif Sarwari, Rebecca Reece, Lisa Fornaresio, Chad Glaze, Raquel Evans, Katarina Preamble, Lisa Giblin Sutton, Sabrina Buterbaugh, Elizabeth Berry Bartolo, Roger Williams, Robin Bunner, William Bender, Jeffrey Miller, Kim T. Baio, Mary K. McBride, Michele Fielding, Sonya Mathewson, Kristina Porte, Missy Maton, Chari Ponder, Elizabeth Haley, Christine Spainhour, Susan Rogers, Derrick Tyler, Noah Wald-Dickler, Douglass Hutcheon, Amytis Towfighi, May M. Lee, Meghan R. Lewis, Brad Spellberg, Linda Sher, Aniket Sharma, Anna P. Olds, Chris Justino, Edward Lozano, Chris Romero, Janet Leong, Valentina Rodina, Tammie Possemato, Jose Escobar, Charlene Chiu, Kevin Weissman, Andrew Barros, Kyle B. Enfield, Alexandra Kadl, China J. Green, Rachel M. Simon, Ashley Fox, Kara Thornton, Patrick E. Parrino, Stephen Spindel, Aditya Bansal, Katherine Baumgarten, Jonathan Hand, Derek Vonderhaar, Bobby Nossaman, Sylvia Laudun, DeAnna Ames, Shane Broussard, Nilmo Hernandez, Geralyn Isaac, Huan Dinh, Yiling Zheng, Sonny Tran, Hunter McDaniel, Nicolle Crovetto, Leslie Miller, Beth Schelle, Sherry McLean, Howard R. Rothbaum, Michael S. Alvarez, Shivam P. Kalan, Heather H. Germann, Jennifer Hendershot, Karen Maroney, Karen Herring, Sharri Cook, Pam Paul, Ronson J. Madathil, Joseph Rabin, Andrea Levine, Kapil Saharia, Ali Tabatabai, Christine Lau, James S. Gammie, Maya-Loren Peguero, Kimberley McKernan, Matthew Audette, Emily Fleischmann, Freshta Akbari, Maia Lee, Myounghee Lee, Andrew Chi, Hanna Salehi, Alan Pariser, Phuong Tran Nguyen, Jessica Moore, Adrienne Gee, Shelika Vincent, Richard A. Zuckerman, Alexander Iribarne, Sara Metzler, Samantha Shipman, Taylor Caccia, Haley Johnson, Crystallee Newton, Doug Parr, Vicente Rodriguez, Gordon Bokhart, Sharon M. Eichman, Crystal North, Cathryn Oldmixon, Nancy Ringwood, Laura Fitzgerald, Haley D. Morin, Ariela Muzikansky, Richard Morse, Roy G. Brower, Lora A. Reineck, Neil R. Aggarwal, Karen Bienstock, Peter Hou, Jay Steingrub, Mark A. Tidswell, Lori-Ann Kozikowski, Cynthia Kardos, Leslie DeSouza, Sherell Thornton-Thompson, Daniel Talmor, Nathan Shapiro, Valerie Banner-Goodspeed, Katherine L. Boyle, Sharon Hayes, Alan E. Jones, James Galbraith, Utsav Nandi, Rebekah K. Peacock, Blair Alden Parry, Justin D. Margolin, Kelsey Brait, Caroline Beakes, Kirsten N. Kangelaris, Kimberly J. Yee, Kimia Ashktorab, Alejandra E. Jauregui, Hanjing Zhuo, Gregory Hendey, Kinsley A. Hubel, Alyssa R. Hughes, Rebekah L. Garcia, Jennifer G. Wilson, Rosemary Vojnik, Jonasel Roque, Cynthia Perez, George W. Lim, Steven Y. Chang, Rebecca Beutler, Trisha Agarwal, Julia Vargas, Marc Moss, Amiran Baduashvili, Lakshmi Chauhan, Lani L. Finck, Michelle Howell, Robert C. Hyzy, Pauline K. Park, Kristine Nelson, Jake I. McSparron, Ivan N. Co, Bonnie R. Wang, Shijing Jia, Barbara Sullins, Sinan Hanna, Norman Olbrich, Lynne D. Richardson, Rahul Nair, Obiageli Offor, Brenda Lopez, Omowunmi Amosu, Hiwet Tzehaie, Thomas E. Terndrup, Herbert P. Wiedemann, Abhijit Duggal, Nirosshan Thiruchelvam, Kiran Ashok, Alexander H. King, Omar Mehkri, Kristin Hudock, Simra Kiran, Harshada More, Tammy Roads, Jamie Martinkovic, Sarah Kennedy, Bryce H. Robinson, Catherine L. Hough, Olivia F. Krol, Mistry Kinjal, Emmanuel Mills, Madeline McDougal, Rupali Deshmukh, Peter Chen, Sam S. Torbati, Yuri Matusov, June Choe, Niree A. Hindoyan, Susan E. Jackman, Emad Bayoumi, Timothy Wynter, Antonina Caudill, Ethan Pascual, Gregg J. Clapham, Lisa Herrera, Cristabelle Ojukwu, Shaunt Mehdikhani, D. Shane O'Mahony, Sonam T. Nyatsatsang, David M. Wilson, Julie A. Wallick, Chadwick Miller, Keven W. Gibbs, Lori S. Flores, Mary E. LaRose, Leigha D. Landreth, Peter E. Morris, Jamie L. Sturgill, Evan P. Cassity, Sanjay Dhar, Ashley A. Montgomery-Yates, Sara N. Pasha, Kirby P. Mayer, Brittany Bissel, Joseph Bledsoe, Samuel Brown, Michael Lanspa, Lindsey Leither, Brent P. Armbruster, Quinn Montgomery, Darrin Applegate, Naresh Kumar, Melissa Fergus, Erna Serezlic, Karah Imel, Ghazal Palmer, Brandon Webb, Valerie T. Aston, Jakea Johnson, Christopher Gray, Margaret Hays, Megan Roth, Adriana Sánchez, Laura Popielski, Heather Rivasplata, Melissa Turner, Michael Vjecha, Tianna Petersen, Dena Kamel, Laura Hansen, Claudia Sanchez Lucas, Natalie DellaValle, Sonia Gonzales, James Scott, David Wyles, Ivor Douglas, Jason Haukoos, Kevin Kamis, Caitlin Robinson, Jason V. Baker, Anne Frosch, Rachael Goldsmith, Hodan Jibrell, Melanie Lo, Jonathan Klaphake, Shari Mackedanz, Linh Ngo, Kelly Garcia-Myers, Norman Markowitz, Erika Pastor, Mayur Ramesh, Indira Brar, Emanuel Rivers, Princy Kumar, Maximiliano Menna, Kousick Biswas, Cristin Harrington, Alex Delp, Lavannya Pandit, Casey Hines-Munson, John Van, Laura Dillon, Yiqun Want, Paola Lichtenberger, Gio Baracco, Carol Ramos, Lauren Bjork, Melyssa Sueiro, Phyllis Tien, Heather Freasier, Theresa Buck, Hafida Nekach, Stephanie Nagy-Agren, Shikha Vasudeva, Tracy Ochalek, Brentin Roller, Chinh Nguyen, Amani Mikail, Dorthe Raben, Tomas O. Jensen, Bitten Aagaard, Charlotte B. Nielsen, Katharina Krapp, Bente Rosdahl Nykjær, Katja Lisa Kanne, Anne Louise Grevsen, Zillah Maria Joensen, Tina Bruun, Ane Bojesen, Frederik Woldbye, Nick E. Normand, Frederik V.L. Esmann, Clara Lundetoft Clausen, Nichlas Hovmand, Karen Brorup Pedersen, Louise Thorlacius-Ussing, Michaela Tinggaard, Dorthe S. Høgsberg, Ema Rastoder, Thobias Kamstrup, Christina Marisa Bergsøe, Lars Østergaard, Nina Breinholt Stærke, Isik S. Johansen, Fredrikke C. Knudtzen, Lykke Larsen, Mathias A. Hertz, Thilde Fabricius, Marie Helleberg, Jan Gerstoft, Tomas Østergaard Jensen, Birgitte Lindegaard, Thomas Ingemann Pedersen, Birgit Thorup Røge, Sandra Valborg Løfberg, Thomas Michael Hansen, Ariella Denize Nielsen, Sebastian Leicht von Huth, Henrik Nielsen, Rikke Krog Thisted, Daria Podlekareva, Stine Johnsen, Helle Frost Andreassen, Lars Pedersen, Cecilia Ebba Clara Ellinor Lindnér, Lothar Wiese, Lene Surland Knudsen, Nikolaj Julian Skrøder Nytofte, Signe Ravn Havmøller, Roger Paredes, Maria Exposito, Eduardo Fernández-Cruz, José Muñoz, Jose R. Arribas, Vicente Estrada, Juan P. Horcajada, Joaquin Burgos, Jose Luis Morales-Rull, Dominique L. Braun, Emily West, Khadija M'Rabeth-Bensalah, Mareile L. Eichinger, Manuela Grüttner-Durmaz, Christina Grube, Veronika Zink, Andrzej Horban, Agnieszka Bednarska, Natalia Jurek, Gerd Fätkenheuer, Jakob J. Malinm, Gail Matthews, Anthony Kelleher, Gesalit Cabrera, Catherine Carey, Sally Hough, Sophie Virachit, Amy Zhong, Barnaby E. Young, Po Ying Chia, Tau Hong Lee, Ray J. Lin, David Lye, Sean Ong, Ser Hon Puah, Tsin Wen Yeo, Shiau Hui Diong, Juwinda Ongko, Fleur Hudson, Mahesh KB Parmar, Anna Goodman, Jonathan Badrock, Adam Gregory, Nicola Harris, Giota Touloumi, Nikos Pantaz, Vicky Gioukari, Joseph Lutaakome, Cissy M. Kityo, Henry Mugerwa, Francis Kiweewa, Anu Osinusi, Craig Tipple, Angela Willis, Amanda Peppercorn, Helen Watson, Elizabeth Alexander, Erik Mogalian, Leo Lin, Xiao Ding, Li Yan, Jean-Luc Girardet, Ji Ma, Zhi Hong, Amy Adams, Sara Albert, Abby Balde, Michelle Baracz, Beth Baseler, Nancy Becker, Mona Bielica, Shere Billouin-Frazier, Jennifer Cash, Jay Choudhary, Suzanne Dolney, Mary Dixon, Carolyn Eyler, Leanna Frye, Michael Galcik, Jensen Gertz, Lisa Giebeig, Neelam Gulati, Liz Hankinson, Debbie Hissey, Debi Hogarty, Matt Hohn, H Preston Holley, Lisa Hoopengardner, Lynda Huber, Shirley Jankelevich, Gary Krauss, Eileen Lake, Jessica Linton, Leah MacDonald, Meryan Manandhar, Mary Spinelli-Nadzam, Charles Oluremi, Calvin Proffitt, Erin Rudzinski, Jen Sandrus, Marylu Schaffhauser, Adam Schechner, Connie Suders, Norman P. Gerry, Kenneth Smith, Courtney Solomon, Amanda Kubernac, Marium Rashid, Bhakti Patel, Robert Kubernac, Joseph Murphy, Marie L. Hoover, Craig Brown, Nadine DuChateau, Adam Flosi, Les Johnson, Amy Treagus, and Christine Wenner

Subjects
Adult, Male, Adolescent, SARS-CoV-2, Comment, COVID-19, Antibodies, Monoclonal, Articles, Middle Aged, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, COVID-19/drug therapy, COVID-19 Drug Treatment, Hospitalization, Infectious Diseases, Antineoplastic Agents, Immunological, Treatment Outcome, Antibodies, Monoclonal, Humanized/therapeutic use, Double-Blind Method, Humans, Female, Aged
Abstract

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Published
2022

15. Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test

Author

Ricardo Henao, Emily R Ko, Bradly P. Nicholson, Emily Lydon, Charles B. Cairns, Andrew Hemmert, Stephen F. Kingsmore, Vance G. Fowler, Jeff Nawrocki, Emanuel P. Rivers, Elizabeth Petzold, Seth W. Glickman, Raymond J. Langley, Micah T. McClain, Mert Aydin, Christopher W. Woods, Robert J Crisp, Anja Kathrin Jaehne, Geoffrey S. Ginsburg, Ephraim L. Tsalik, Montgomery Jesse Linton, Thomas W. Burke, and Eugenia Quackenbush

Subjects
medicine.medical_specialty, business.industry, Area under the curve, Host gene, Critical Care and Intensive Care Medicine, medicine.disease, Viral infection, Procalcitonin, Article, Salt lake, Sepsis, Internal medicine, Cohort, Coinfection, Medicine, business
Abstract

OBJECTIVES Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test. DESIGN Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results. SETTING Four U.S. emergency departments. PATIENTS Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis. INTERVENTIONS Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes. MEASUREMENTS AND MAIN RESULTS Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance. CONCLUSIONS The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.

Published
2021

16. Validation of a host response test to distinguish bacterial and viral respiratory infection

Author

Ricardo Henao, Emanuel P. Rivers, Stephen F. Kingsmore, Ephraim L. Tsalik, Raymond J. Langley, Eugenia Quackenbush, Elizabeth Petzold, Christopher W. Woods, Seth W. Glickman, Emily Lydon, Thomas W. Burke, Anja Kathrin Jaehne, Charles B. Cairns, Micah T. McClain, Vance G. Fowler, Geoffrey S. Ginsburg, Emily R Ko, Mert Aydin, and Bradly P. Nicholson

Subjects
0301 basic medicine, Adult, Male, Research paper, Host response, lcsh:Medicine, Host gene, Respiratory tract infections, Real-Time Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, Procalcitonin, Workflow, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Diagnosis, medicine, Humans, Respiratory system, Viral respiratory infection, Aged, lcsh:R5-920, business.industry, Coinfection, lcsh:R, Precision medicine, Reproducibility of Results, General Medicine, Bacterial Infections, Middle Aged, medicine.disease, Peripheral blood, 3. Good health, 030104 developmental biology, Virus Diseases, 030220 oncology & carcinogenesis, Immunology, Host-Pathogen Interactions, Female, Gene expression, lcsh:Medicine (General), business, Biomarkers
Abstract

Background: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases. Methods: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin. Findings: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85–0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02). Interpretation: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases. Keywords: Biomarkers, Gene expression, Respiratory tract infections, Coinfection, Diagnosis, Precision medicine

Published
2019

17. Direct-from-blood RNA sequencing identifies the cause of post-bronchoscopy fever

Author

Regina Z. Cer, Emily R Ko, Logan J. Voegtly, Ephraim L. Tsalik, Thomas W. Burke, Danielle V. Clark, Christopher W. Woods, Kimberly A. Bishop-Lilly, Kevin L. Schully, and Casandra W. Philipson

Subjects
0301 basic medicine, Cystic Fibrosis, medicine.medical_treatment, Stenotrophomonas maltophilia, Case Report, Bronchoalveolar Lavage, Cystic fibrosis, 0302 clinical medicine, Medical microbiology, Bronchoscopy, Bacterial infections, 030212 general & internal medicine, medicine.diagnostic_test, biology, High-Throughput Nucleotide Sequencing, Early diagnosis, Anti-Bacterial Agents, Treatment Outcome, Infectious Diseases, Female, Lung Transplantation, Staphylococcus aureus, medicine.medical_specialty, Fever, Clinical Decision-Making, Lung biopsy, lcsh:Infectious and parasitic diseases, Young Adult, 03 medical and health sciences, Antibiotic resistance, Pseudomonas, Internal medicine, Drug Resistance, Bacterial, medicine, Molecular diagnostics, Humans, Lung transplantation, lcsh:RC109-216, Sequence Analysis, RNA, business.industry, biology.organism_classification, medicine.disease, 030104 developmental biology, Bronchoalveolar lavage, Gram-Negative Bacterial Infections, business, Transcriptome, Metagenomic sequencing
Abstract

Background Antibiotic resistance is rising at disturbing rates and contributes to the deaths of millions of people yearly. Antibiotic resistant infections disproportionately affect those with immunocompromising conditions, chronic colonization, and frequent antibiotic use such as transplant patients or those with cystic fibrosis. However, clinicians lack the diagnostic tools to confidently diagnose and treat infections, leading to widespread use of empiric broad spectrum antimicrobials, often for prolonged duration. Case presentation A 22 year-old Caucasian female with cystic fibrosis received a bilateral orthotopic lung transplantation 5 months prior to the index hospitalization. She underwent routine surveillance bronchoscopy and was admitted for post-procedure fever. A clear cause of infection was not identified by routine methods. Imaging and bronchoscopic lung biopsy did not identify an infectious agent or rejection. She was treated with a prolonged course of antimicrobials targeting known colonizing organisms from prior bronchoalveolar lavage cultures (Pseudomonas, Staphylococcus aureus, and Aspergillus). However, we identified Stenotrophomonas maltophilia in two independent whole blood samples using direct-pathogen sequencing, which was not identified by other methods. Conclusions This case represents a common clinical conundrum: identification of infection in a high-risk, complex patient. Here, direct-pathogen sequencing identified a pathogen that would not otherwise have been identified by common techniques. Had results been clinically available, treatment could have been customized, avoiding a prolonged course of broad spectrum antimicrobials that would only exacerbate resistance. Direct-pathogen sequencing is poised to fill a diagnostic gap for pathogen identification, allowing early identification and customization of treatment in a culture-independent, pathogen-agnostic manner.

Published
2019

18. Average Weighted Accuracy: Pragmatic Analysis for a Rapid Diagnostics in Categorizing Acute Lung Infections (RADICAL) Study

Author

Ephraim L. Tsalik, Emily R Ko, Christopher W. Woods, Ying Liu, Scott R. Evans, Ricardo Henao, and Yunyun Jiang

Subjects
Microbiology (medical), Diagnostic information, Population, 030204 cardiovascular system & hematology, Machine learning, computer.software_genre, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, False Positive Reactions, 030212 general & internal medicine, education, False Negative Reactions, Lung, education.field_of_study, business.industry, Diagnostic Tests, Routine, Diagnostic test, Predictive value, Test (assessment), Patient management, Infectious Diseases, Invited Article, Clinical value, Metric (unit), Artificial intelligence, business, computer
Abstract

Patient management relies on diagnostic information to identify appropriate treatment. Standard evaluations of diagnostic tests consist of estimating sensitivity, specificity, positive/negative predictive values, likelihood ratios, and accuracy. Although useful, these metrics do not convey the tests’ clinical value, which is critical to informing decision-making. Full appreciation of the clinical impact of a diagnostic test requires analyses that integrate sensitivity and specificity, account for the disease prevalence within the population of test application, and account for the relative importance of specificity vs sensitivity by considering the clinical implications of false-positive and false-negative results. We developed average weighted accuracy (AWA), representing a pragmatic metric of diagnostic yield or global utility of a diagnostic test. AWA can be used to compare test alternatives, even across different studies. We apply the AWA methodology to evaluate a new diagnostic test developed in the Rapid Diagnostics in Categorizing Acute Lung Infections (RADICAL) study.

Published
2019

19. A host gene expression approach for identifying triggers of asthma exacerbations

Author

Anna Mazur, Micah T. McClain, Emily R Ko, Olga Better, Bradly P. Nicholson, Thomas W. Burke, Geoffrey S. Ginsburg, Ricardo Henao, Charles Bullard, Mert Aydin, Emily Lydon, Christopher W. Woods, and Ephraim L. Tsalik

Subjects
0301 basic medicine, Bacterial Diseases, Male, Critical Care and Emergency Medicine, Pulmonology, Etiology, Antibiotics, Gene Expression, Logistic regression, Pathology and Laboratory Medicine, Procalcitonin, Cohort Studies, 0302 clinical medicine, Community-acquired pneumonia, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Child, Aged, 80 and over, education.field_of_study, Multidisciplinary, Antimicrobials, Drugs, General Medicine, Bacterial Infections, Middle Aged, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, Virus Diseases, Cohort, Female, General Agricultural and Biological Sciences, Emergency Service, Hospital, Research Article, Adult, medicine.medical_specialty, Adolescent, medicine.drug_class, Science, Population, Microbiology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, Internal medicine, Microbial Control, Virology, Genetics, Humans, education, Asthma, Aged, Retrospective Studies, Pharmacology, business.industry, Biology and Life Sciences, medicine.disease, 030104 developmental biology, Respiratory Infections, business, Viral Transmission and Infection
Abstract

RationaleAsthma exacerbations often occur due to infectious triggers, but determining whether infection is present and whether it is bacterial or viral remains clinically challenging. A diagnostic strategy that clarifies these uncertainties could enable personalized asthma treatment and mitigate antibiotic overuse.ObjectivesTo explore the performance of validated peripheral blood gene expression signatures in discriminating bacterial, viral, and noninfectious triggers in subjects with asthma exacerbations.MethodsSubjects with suspected asthma exacerbations of various etiologies were retrospectively selected for peripheral blood gene expression analysis from a pool of subjects previously enrolled in emergency departments with acute respiratory illness. RT-PCR quantified 87 gene targets, selected from microarray-based studies, followed by logistic regression modeling to define bacterial, viral, or noninfectious class. The model-predicted class was compared to clinical adjudication and procalcitonin.ResultsOf 46 subjects enrolled, 7 were clinically adjudicated as bacterial, 18 as viral, and 21 as noninfectious. Model prediction was congruent with clinical adjudication in 15/18 viral and 13/21 noninfectious cases, but only 1/7 bacterial cases. None of the adjudicated bacterial cases had confirmatory microbiology; the precise etiology in this group was uncertain. Procalcitonin classified only one subject in the cohort as bacterial. 47.8% of subjects received antibiotics.ConclusionsOur model classified asthma exacerbations by the underlying bacterial, viral, and noninfectious host response. Compared to clinical adjudication, the majority of discordances occurred in the bacterial group, due to either imperfect adjudication or model misclassification. Bacterial infection was identified infrequently by all classification schemes, but nearly half of subjects were prescribed antibiotics. A gene expression-based approach may offer useful diagnostic information in this population and guide appropriate antibiotic use.

Published
2019

20. Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis

Author

Thomas N. Williams, Raul E. Salinas, Patricia Njuguna, J. W. Thompson, Neema Mturi, Christopher W. Woods, Emily R Ko, James J. Gilchrist, M.A. Moseley, Kelly J. Pittman, Dennis C. Ko, Matti Pirinen, Geoffrey S. Ginsburg, Douglas C. Rouse, Hill Avs., Liuyang Wang, Ephraim L. Tsalik, Laura G. Dubois, Raymond J. Langley, Sarah L. Jaslow, Salim Mwarumba, Anna Rautanen, and Scott Jag.

Subjects
Male, 0301 basic medicine, Adenosine, Adolescent, methylthioadenosine, medicine.medical_treatment, Inflammation, Biology, Models, Biological, Polymorphism, Single Nucleotide, Kenyan Bacteraemia Study Group, Proinflammatory cytokine, sepsis, Machine Learning, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Salmonella, Pathology, cytokine, medicine, SIRS, Humans, Research Articles, Multidisciplinary, pyroptosis, Wellcome Trust Case Control Consortium 2, methionine salvage, Area under the curve, Pyroptosis, SciAdv r-articles, Human Genetics, medicine.disease, APIP, 3. Good health, 030104 developmental biology, Cytokine, inflammation, Bacteremia, Salmonella Infections, Immunology, biomarker, Biomarker (medicine), Female, medicine.symptom, Biomarkers, 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract

The substrate of the methionine salvage pathway, methylthioadenosine, is a predictor of death in sepsis patients., Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway’s substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

Published
2017

21. 2018. Host Gene Expression Classifiers Distinguish Bacterial and Viral Infections in Sri Lankan Patients with Acute Febrile Respiratory Illness

Author

L. Gayani Tillekeratne, Thomas W. Burke, Elizabeth Petzold, Micah T. McClain, Champica K Bodinayake, Sunil Suchindran, Megan E. Reller, Ephraim L. Tsalik, Geoffrey S. Ginsburg, Ruvini Kurukulasooriya, Ajith Nagahawatte, Christopher W. Woods, Emily R Ko, Ricardo Henao, Vasantha Devasiri, and Bradly P. Nicholson

Subjects
Abstracts, Infectious Diseases, Respiratory illness, Oncology, Expression (architecture), B. Poster Abstracts, business.industry, Immunology, Host gene, Medicine, business
Abstract

Background Acute febrile illness is a frequent cause of hospitalization in the tropics and often presents with respiratory symptoms, even when caused by nonrespiratory pathogens. Previously, host-based gene expression signatures accurately identified acute respiratory infections as being bacterial or viral in a U.S. cohort. We determined signature performance in a Sri Lankan cohort with acute febrile respiratory illness (AFRI). Methods We enrolled patients with AFRI in Sri Lanka from July 2012 to May 2013 and collected nasopharygeal swabs, acute/ convalescent sera, and blood in PAXgene RNA tubes. Bacterial (Orientia tsutsugamushi, Leptospira spp.) and viral (influenza A/B, dengue) infections were confirmed using polymerase chain reaction, virus isolation, enzyme immunoassay, and/or microscopic agglutination testing. We extracted total RNA and performed host RNA sequencing (Illumina). We aligned reads to hg38 reference genome using Bowtie2, quantified at isoform level using Express version 1.5.1, and normalized using trimmed-mean normalization. The original model estimated three classes and separate signatures predicted bacterial infections, viral infections, and non-infectious illnesses. Regularized regression was used to predict bacterial and viral infections based on prior signatures. Accuracy was estimated using leave-one-out cross-validation. Results Among 43 patients with viral infections (14 dengue, 29 influenza) and 16 patients with bacterial infections (six Leptospira spp., 10 O. tsutsumagushi), median age was 37 years (IQR 23–51) and 49% were male. Of five respiratory symptoms (cough, sore throat, rhinitis/ congestion, shortness of breath, and pain with breathing), median (IQR) number of symptoms was 2 (1–2) for influenza, 2 (1–2) for dengue, 2 (2–3) for Leptospira spp., and 1.5 (1–2) for O. tsutsumagushi. We observed high predictive accuracy in discriminating bacterial and viral infections: AUROC 0.91 for the bacterial and AUROC 0.81 for the viral model. At enrollment, 65% of viral and 50% of bacterial AFRI patients received antibiotics. Conclusion Host gene expression classifiers performed well in a Sri Lankan population with AFRI, even with nonrespiratory pathogens that may not be readily identified. Host-based diagnostics may play a critical role in improving diagnostic ability and antibiotic use globally. Disclosures E. L. Tsalik, Host Response, Inc.: Founder, Equity. G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth

Published
2018

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