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1. COVID-19–associated Lung Microvascular Endotheliopathy: A “From the Bench” Perspective

Author

Joffre, Jérémie, Rodriguez, Lauren, Matthay, Zachary A, Lloyd, Elliot, Fields, Alexander T, Bainton, Roland J, Kurien, Philip, Sil, Anita, Calfee, Carolyn S, Woodruff, Prescott G, Erle, David J, Hendrickson, Carolyn, Krummel, Matthew F, Langelier, Charles R, Matthay, Michael A, Kornblith, Lucy Z, Hellman, Judith, Bhide, Sharvari, Carrillo, Sidney A, Chak, Suzanna, Fragiadakis, Gabriela K, Ghale, Rajani, Giberson, Jeremy, Glenn, Pat, Gonzalez, Ana, Jauregui, Alejandra, Jones, Norman, Kangelaris, Kirsten, Ke, Serena, Lea, Tasha, Lee, Deanna, Lelidowicz, Aleskandra, Lota, Raphael, Matthay, Michael, Milush, Jeff, Nguyen, Viet, Rashid, Ahmad Sadeed, Rodriguez, Nicklaus, Sigman, Austin, Tang, Kevin, Altamirano, Luz Torres, Ward, Alyssa, Willmore, Andrew, Wilson, Michael, Ambachew, Biniam, Cary, Sarah, Chalwell, Lauren, Colwell, Christopher, Jones, Chayse, Josephy, Clayton, LeGrand, Matthieu, Montoy, Juan Carlos, Kornblith, Aaron E, Nunez-Garcia, Brenda, Park, John J, Prakash, Arun, Robinson, Brittany, Shelley, India, and Wick, Katherine D

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Prevention, Biodefense, Pneumonia & Influenza, Pneumonia, Acute Respiratory Distress Syndrome, Vaccine Related, Infectious Diseases, Lung, Rare Diseases, Clinical Research, Emerging Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Biomarkers, COVID-19, Endothelial Cells, Humans, Inflammation Mediators, Plasminogen Activator Inhibitor 1, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vascular Diseases, Vascular Endothelial Growth Factor A, acute respiratory distress syndrome, endothelial permeability, lung endothelial injury, COVID-19 Multi-Phenotyping for Effective Therapies (COMET) Consortium, COVID-19 Associated Coagulopathy, Inflammation, and Thrombosis (Co-ACIT) Study Group, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

Rationale: Autopsy and biomarker studies suggest that endotheliopathy contributes to coronavirus disease (COVID-19)-associated acute respiratory distress syndrome. However, the effects of COVID-19 on the lung endothelium are not well defined. We hypothesized that the lung endotheliopathy of COVID-19 is caused by circulating host factors and direct endothelial infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objectives: We aimed to determine the effects of SARS-CoV-2 or sera from patients with COVID-19 on the permeability and inflammatory activation of lung microvascular endothelial cells. Methods: Human lung microvascular endothelial cells were treated with live SARS-CoV-2; inactivated viral particles; or sera from patients with COVID-19, patients without COVID-19, and healthy volunteers. Permeability was determined by measuring transendothelial resistance to electrical current flow, where decreased resistance signifies increased permeability. Inflammatory mediators were quantified in culture supernatants. Endothelial biomarkers were quantified in patient sera. Measurements and Main Results: Viral PCR confirmed that SARS-CoV-2 enters and replicates in endothelial cells. Live SARS-CoV-2, but not dead virus or spike protein, induces endothelial permeability and secretion of plasminogen activator inhibitor 1 and vascular endothelial growth factor. There was substantial variability in the effects of SARS-CoV-2 on endothelial cells from different donors. Sera from patients with COVID-19 induced endothelial permeability, which correlated with disease severity. Serum levels of endothelial activation and injury biomarkers were increased in patients with COVID-19 and correlated with severity of illness. Conclusions: SARS-CoV-2 infects and dysregulates endothelial cell functions. Circulating factors in patients with COVID-19 also induce endothelial cell dysfunction. Our data point to roles for both systemic factors acting on lung endothelial cells and viral infection of endothelial cells in COVID-19-associated endotheliopathy.

Published
2022

2. Mass cytometry reveals a conserved immune trajectory of recovery in hospitalized COVID-19 patients

Author

Burnett, Cassandra E, Okholm, Trine Line Hauge, Tenvooren, Iliana, Marquez, Diana M, Tamaki, Stanley, Sandoval, Priscila Munoz, Willmore, Andrew, Consortium, The UCSF COMET, Patel, Ravi, Abe-Jones, Yumiko, Asthana, Saurabh, Beagle, Alexander, Bhide, Sharvari, Cai, Cathy, Calvo, Maria, Carrillo, Sidney A, Chak, Suzanna, Collins, Zachary, Darmanis, Spyros, Fragiadakis, Gabriela K, Ghale, Rajani, Giberson, Jeremy, Glenn, Pat, Gonzalez, Ana, Hiam-Galvez, Kamir, Jauregui, Alejandra, Ke, Serena, Lea, Tasha, Lee, Deanna, Lota, Raphael, Lupin-Jimenez, Leonard, Nguyen, Viet, Nigam, Nishita, Pierce, Logan, Prasad, Priya, Rao, Arjun, Rashid, Sadeed, Rodriguez, Nicklaus, Samad, Bushra, Shaw, Cole, Sigman, Austin, Sinha, Pratik, Tang, Kevin, Altamirano, Luz Torres, Tumurbaatar, Erden, Upadhyay, Vaibhav, Ward, Alyssa, Wong, Kristine, Ye, Chun Jimmie, Yee, Kimberly, Zhou, Mingyue, Hendrickson, Carolyn M, Kangelaris, Kirsten N, Langelier, Charles R, Krummel, Matthew F, Woodruff, Prescott G, Calfee, Carolyn S, Erle, David J, Ansel, K Mark, and Spitzer, Matthew H

Subjects
Biomedical and Clinical Sciences, Immunology, Pneumonia & Influenza, Pneumonia, Clinical Research, Lung, Infectious Diseases, Hematology, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, COVID-19, Disease Progression, Humans, SARS-CoV-2, UCSF COMET Consortium, disease resolution, immune cell signaling, immune response, recovery
Abstract

While studies have elucidated many pathophysiological elements of COVID-19, little is known about immunological changes during COVID-19 resolution. We analyzed immune cells and phosphorylated signaling states at single-cell resolution from longitudinal blood samples of patients hospitalized with COVID-19, pneumonia and/or sepsis, and healthy individuals by mass cytometry. COVID-19 patients showed distinct immune compositions and an early, coordinated, and elevated immune cell signaling profile associated with early hospital discharge. Intra-patient longitudinal analysis revealed changes in myeloid and T cell frequencies and a reduction in immune cell signaling across cell types that accompanied disease resolution and discharge. These changes, together with increases in regulatory T cells and reduced signaling in basophils, also accompanied recovery from respiratory failure and were associated with better outcomes at time of admission. Therefore, although patients have heterogeneous immunological baselines and highly variable disease courses, a core immunological trajectory exists that defines recovery from severe SARS-CoV-2 infection.

Published
2022

3. Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study

Author

Ozonoff, Al, Schaenman, Joanna, Jayavelu, Naresh Doni, Milliren, Carly E., Calfee, Carolyn S., Cairns, Charles B., Kraft, Monica, Baden, Lindsey R., Shaw, Albert C., Krammer, Florian, van Bakel, Harm, Esserman, Denise A., Liu, Shanshan, Sesma, Ana Fernandez, Simon, Viviana, Hafler, David A., Montgomery, Ruth R., Kleinstein, Steven H., Levy, Ofer, Bime, Chris, Haddad, Elias K., Erle, David J., Pulendran, Bali, Nadeau, Kari C., Davis, Mark M, Hough, Catherine L., Messer, William B., Higuita, Nelson I. Agudelo, Metcalf, Jordan P., Atkinson, Mark A., Brakenridge, Scott C., Corry, David, Kheradmand, Farrah, Ehrlich, Lauren I.R., Melamed, Esther, McComsey, Grace A., Sekaly, Rafick, Diray-Arce, Joann, Peters, Bjoern, Augustine, Alison D., Reed, Elaine F., McEnaney, Kerry, Barton, Brenda, Lentucci, Claudia, Saluvan, Mehmet, Chang, Ana C., Hoch, Annmarie, Albert, Marisa, Shaheen, Tanzia, Kho, Alvin T., Thomas, Sanya, Chen, Jing, Murphy, Maimouna D., Cooney, Mitchell, Presnell, Scott, Fragiadakis, Gabriela K., Patel, Ravi, Guan, Leying, Gygi, Jeremy, Pawar, Shrikant, Brito, Anderson, Khalil, Zain, Maguire, Cole, Fourati, Slim, Overton, James A., Vita, Randi, Westendorf, Kerstin, Salehi-Rad, Ramin, Leligdowicz, Aleksandra, Matthay, Michael A., Singer, Jonathan P., Kangelaris, Kirsten N., Hendrickson, Carolyn M., Krummel, Matthew F., Langelier, Charles R., Woodruff, Prescott G., Powell, Debra L., Kim, James N., Simmons, Brent, Goonewardene, I. Michael, Smith, Cecilia M., Martens, Mark, Mosier, Jarrod, Kimura, Hiroki, Sherman, Amy C., Walsh, Stephen R., Issa, Nicolas C., Dela Cruz, Charles, Farhadian, Shelli, Iwasaki, Akiko, Ko, Albert I., Chinthrajah, Sharon, Ahuja, Neera, Rogers, Angela J., Artandi, Maja, Siegel, Sarah A.R., Lu, Zhengchun, Drevets, Douglas A., Brown, Brent R., Anderson, Matthew L., Guirgis, Faheem W., Thyagarajan, Rama V., Rousseau, Justin F., Wylie, Dennis, Busch, Johanna, Gandhi, Saurin, Triplett, Todd A., Yendewa, George, Giddings, Olivia, Anderson, Evan J., Mehta, Aneesh K., Sevransky, Jonathan E., Khor, Bernard, Rahman, Adeeb, Stadlbauer, Daniel, Dutta, Jayeeta, Xie, Hui, Kim-Schulze, Seunghee, Gonzalez-Reiche, Ana Silvia, van de Guchte, Adriana, Farrugia, Keith, Khan, Zenab, Maecker, Holden T., Elashoff, David, Brook, Jenny, Ramires-Sanchez, Estefania, Llamas, Megan, Rivera, Adreanne, Perdomo, Claudia, Ward, Dawn C., Magyar, Clara E., Fulcher, Jennifer A., Abe-Jones, Yumiko, Asthana, Saurabh, Beagle, Alexander, Bhide, Sharvari, Carrillo, Sidney A., Chak, Suzanna, Ghale, Rajani, Gonzalez, Ana, Jauregui, Alejandra, Jones, Norman, Lea, Tasha, Lee, Deanna, Lota, Raphael, Milush, Jeff, Nguyen, Viet, Pierce, Logan, Prasad, Priya A., Rao, Arjun, Samad, Bushra, Shaw, Cole, Sigman, Austin, Sinha, Pratik, Ward, Alyssa, Willmore, Andrew, Zhan, Jenny, Rashid, Sadeed, Rodriguez, Nicklaus, Tang, Kevin, Altamirano, Luz Torres, Betancourt, Legna, Curiel, Cindy, Sutter, Nicole, Paz, Maria Tercero, Tietje-Ulrich, Gayelan, Leroux, Carolyn, Connors, Jennifer, Bernui, Mariana, Kutzler, Michel A., Edwards, Carolyn, Lee, Edward, Lin, Edward, Croen, Brett, Semenza, Nicholas C., Rogowski, Brandon, Melnyk, Nataliya, Woloszczuk, Kyra, Cusimano, Gina, Bell, Mathew R., Furukawa, Sara, McLin, Renee, Marrero, Pamela, Sheidy, Julie, Tegos, George P., Nagle, Crystal, Mege, Nathan, Ulring, Kristen, Seyfert-Margolis, Vicki, Conway, Michelle, Francisco, Dave, Molzahn, Allyson, Erickson, Heidi, Wilson, Connie Cathleen, Schunk, Ron, Sierra, Bianca, Hughes, Trina, Smolen, Kinga, Desjardins, Michael, van Haren, Simon, Mitre, Xhoi, Cauley, Jessica, Li, Xiaofang, Tong, Alexandra, Evans, Bethany, Montesano, Christina, Licona, Jose Humberto, Krauss, Jonathan, Chang, Jun Bai Park, Izaguirre, Natalie, Chaudhary, Omkar, Coppi, Andreas, Fournier, John, Mohanty, Subhasis, Muenker, M. Catherine, Nelson, Allison, Raddassi, Khadir, Rainone, Michael, Ruff, William E., Salahuddin, Syim, Schulz, Wade L., Vijayakumar, Pavithra, Wang, Haowei, Wunder Jr., Elsio, Young, H. Patrick, Zhao, Yujiao, Saksena, Miti, Altman, Deena, Kojic, Erna, Srivastava, Komal, Eaker, Lily Q., Bermúdez-González, Maria C., Beach, Katherine F., Sominsky, Levy A., Azad, Arman R., Carreño, Juan Manuel, Singh, Gagandeep, Raskin, Ariel, Tcheou, Johnstone, Bielak, Dominika, Kawabata, Hisaaki, Mulder, Lubbertus CF, Kleiner, Giulio, Lee, Alexandra S., Do, Evan Do, Fernandes, Andrea, Manohar, Monali, Hagan, Thomas, Blish, Catherine A., Din, Hena Naz, Roque, Jonasel, Yang, Samuel, Brunton, Amanda, Sullivan, Peter E., Strnad, Matthew, Lyski, Zoe L., Coulter, Felicity J., Booth, J. Leland, Sinko, Lauren A., Moldawer, Lyle L., Borresen, Brittany, Roth-Manning, Brittney, Song, Li-Zhen, Nelson, Ebony, Lewis-Smith, Megan, Smith, Jacob, Tipan, Pablo Guaman, Siles, Nadia, Bazzi, Sam, Geltman, Janelle, Hurley, Kerin, Gabriele, Gio, Sieg, Scott, Vaysman, Tatyana, Bristow, Laurel, Hussaini, Laila, Hellmeister, Kieffer, Samaha, Hady, Cheng, Andrew, Spainhour, Christine, Scherer, Erin M., Johnson, Brandi, Bechnak, Amer, Ciric, Caroline R., Hewitt, Lauren, Carter, Erin, Mcnair, Nina, Panganiban, Bernadine, Huerta, Christopher, Usher, Jacob, Ribeiro, Susan Pereira, Altman, Matthew C., Becker, Patrice M., Rouphael, Nadine, Bime, Christian, and Davis, Mark M.

Published
2022
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4. Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Author

Bastard, Paul, Vazquez, Sara, Liu, Jamin, Laurie, Matthew, Wang, Chung, Gervais, Adrian, Le Voyer, Tom, Bizien, Lucy, Zamecnik, Colin, Philippot, Quentin, Rosain, Jérémie, Catherinot, Emilie, Willmore, Andrew, Mitchell, Anthea, Bair, Rebecca, Garçon, Pierre, Kenney, Heather, Fekkar, Arnaud, Salagianni, Maria, Poulakou, Garyphallia, Siouti, Eleni, Sahanic, Sabina, Tancevski, Ivan, Weiss, Günter, Nagl, Laurenz, Manry, Jérémy, Duvlis, Sotirija, Arroyo-Sánchez, Daniel, Paz Artal, Estela, Rubio, Luis, Perani, Cristiano, Bezzi, Michela, Sottini, Alessandra, Quaresima, Virginia, Roussel, Lucie, Vinh, Donald, Reyes, Luis, Garzaro, Margaux, Hatipoglu, Nevin, Boutboul, David, Tandjaoui-Lambiotte, Yacine, Borghesi, Alessandro, Aliberti, Anna, Cassaniti, Irene, Venet, Fabienne, Monneret, Guillaume, Halwani, Rabih, Sharif-Askari, Narjes, Danielson, Jeffrey, Burrel, Sonia, Morbieu, Caroline, Stepanovskyy, Yurii, Bondarenko, Anastasia, Volokha, Alla, Boyarchuk, Oksana, Gagro, Alenka, Neuville, Mathilde, Neven, Bénédicte, Keles, Sevgi, Hernu, Romain, Bal, Antonin, Novelli, Antonio, Novelli, Giuseppe, Saker, Kahina, Ailioaie, Oana, Antolí, Arnau, Jeziorski, Eric, Rocamora-Blanch, Gemma, Teixeira, Carla, Delaunay, Clarisse, Lhuillier, Marine, Le Turnier, Paul, Zhang, Yu, Mahevas, Matthieu, Pan-Hammarström, Qiang, Abolhassani, Hassan, Bompoil, Thierry, Dorgham, Karim, Gorochov, Guy, Laouenan, Cédric, Rodríguez-Gallego, Carlos, Ng, Lisa, Renia, Laurent, Pujol, Aurora, Belot, Alexandre, Raffi, François, Allende, Luis, Martinez-Picado, Javier, Ozcelik, Tayfun, Imberti, Luisa, Notarangelo, Luigi, Troya, Jesus, Solanich, Xavier, Zhang, Shen-Ying, Puel, Anne, Wilson, Michael, Trouillet-Assant, Sophie, Abel, Laurent, Jouanguy, Emmanuelle, Ye, Chun, Cobat, Aurélie, Thompson, Leslie, Andreakos, Evangelos, Zhang, Qian, Anderson, Mark, Casanova, Jean-Laurent, Derisi, Joseph, Achille, Cristian, Aiuti, Alessandro, Al-Muhsen, Saleh, Al-Mulla, Fahd, Angelini, Micol, Arias, Andrés, Aytekin, Gokhan, Baldanti, Fausto, Feldman, Hagit, Bergami, Federica, Biggs, Catherine, Bogunovic, Dusan, Bolze, Alexandre, Bondarenko, Anastasiia, Bousfiha, Ahmed, Brodin, Petter, Bryceson, Yenan, Bustamante, Carlos, Butte, Manish, Casari, Giorgio, Christodoulou, John, Condino-Neto, Antonio, Constantinescu, Stefan, Conti, Francesca, Cooper, Megan, Dalgard, Clifton, Desai, Murkesh, Drolet, Beth, El Baghdadi, Jamila, Ergun, Recai, Ergun, Dilek, Espinosa-Padilla, Sara, Fellay, Jacques, Flores, Carlos, Franco, José, Froidure, Antoine, Ghirardello, Stefano, Gregersen, Peter, Grimbacher, Bodo, Haerynck, Filomeen, Hagin, David, Hammarström, Lennart, Heath, James, Henrickson, Sarah, Hsieh, Elena, Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich, Kanat, Fikret, Karamitros, Timokratis, Kisand, Kai, Kopcha, Vasyl, Korda, Mykhaylo, Ku, Cheng-Lung, Lau, Yu-Lung, Ling, Yun, Lucas, Carrie, Maniatis, Tom, Mansouri, Davood, Maródi, László, Meyts, Isabelle, Milner, Joshua, Mironska, Kristina, Mogensen, Trine, Mojoli, Francesco, Morandeira, Francisco, Morio, Tomohiro, O'Farrelly, Cliona, Okada, Satoshi, Okamoto, Keisuke, Pagani, Michele, Pape, Jean, de Diego, Rebeca, Perlin, David, Pesole, Graziano, Pession, Andrea, Piralla, Antonio, Planas, Anna, Prando, Carolina, Quintana-Murci, Lluis, Ramaswamy, Sathishkumar, Resnick, Igor, Rigo-Bonnin, Raúl, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänen, Mikko, Shahrooei, Mohammed, Shcherbina, Anna, Slaby, Ondrej, Snow, Andrew, Soler-Palacín, Pere, Spaan, András, Tangye, Stuart, Abou Tayoun, Ahmad, Tulek, Baykal, Turvey, Stuart, Uddin, K, Uddin, Mohammed, Clément, Bénédicte, Abe-Jones, Yumiko, Asthana, Saurabh, Bhide, Sharvari, Calfee, Carolyn, Carrillo, Sidney, Chak, Suzanna, Collins, Zachary, Erle, David, Fragiadakis, Gabriela, Ghale, Rajani, Hendrickson, Carolyn, Jauregui, Alejandra, Kangelaris, Kirsten, Krummel, Matthew, Langelier, Charles, Lea, Tasha, Lee, Deanna, Leligdowicz, Aleksandra, Leroux, Carolyn, Lota, Raphael, Matthay, Michael, Nguyen, Viet, Patel, Ravi, Pierce, Logan, Prasad, Priya, Rao, Arjun, Rashid, Ahmad, Rodriguez, Nicklaus, Samad, Bushra, Shaw, Cole, Sigman, Austin, Tang, Kevin, Altamirano, Luz, Ward, Alyssa, Woodruff, Prescott, Allavena, Clotilde, Andrejak, Claire, Angoulvant, François, Azoulay, Cecile, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behilill, Sylvie, Beluze, Marine, Benech, Nicolas, Benkerrou, Dehbia, Bhavsar, Krishna, Bitker, Laurent, Bouadma, Lila, Bouscambert, Maude, Paz, Pauline, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Cordel, Hugues, Couffignal, Camille, Couffin-Cadiergues, Sandrine, D’ortenzio, Eric, de Montmollin, Etienne, Debard, Alexa, Debray, Marie-Pierre, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diehl, Jean-Luc, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Eloy, Philippine, Enouf, Vincent, Epaulard, Olivier, Esperou, Hélène, Esposito-Farese, Marina, Etienne, Manuel, Garot, Denis, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Goehringer, François, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kafif, Ouifiya, Kaguelidou, Florentia, Kali, Sabrina, Kerroumi, Younes, Khalil, Antoine, Khan, Coralie, Kimmoun, Antoine, Laine, Fabrice, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Bris, Cyril, Le Gac, Sylvie, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lemaignen, Adrien, Lemee, Véronique, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean, Machado, Moïse, Malvy, Denis, Mambert, Marina, Manuel, Aldric, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Peigne, Vincent, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Piquard, Valentine, Poissy, Julien, Puéchal, Oriane, Rosa-Calatrava, Manuel, Rossignol, Bénédicte, Rossignol, Patrick, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Tellier, Marie-Capucine, Téoulé, François, Terrier, Olivier, Timsit, Jean-François, Tual, Christelle, Tubiana, Sarah, van der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], Grand Hôpital de l'Est Francilien (GHEF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 4th Department of Internal Medicine, ATTIKON University General Hospital, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Goce Delchev University (UGD), Génétique Evolutive Humaine - Human Evolutionary Genetics, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Basic medicine, Settore MED/03, [SDV]Life Sciences [q-bio], Immunology, COVID-19, Pneumònia, Pneumonia, General Medicine
Abstract

International audience; Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Published
2022

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