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3. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Zatz, Mayana, Beudel, Martijn, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Bulle, Esther, Dijkstra, Mirjam, Dongelmans, Dave A., Dujardin, Romein W. G., Goorhuis, Bram, Grobusch, Martin P., Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hollmann, Markus, Horn, Janneke, Hovius, Joppe W., de Jong, Menno D., Lim, Endry H. T., van Mourik, Niels, Paulus, Frederique, Pina-Fuentes, Dan A. I., Prins, Jan M., Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits C. F. J., Schultz, Marcus J., Schrauwen, Femke A. P., Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen A., Smit, Marry, Stijnis, Cornelis S., Stilma, Willemke, van der Valk, Marc, Veelo, Denise, Volleman, Carolien, van Vugt, Michèle, Zwinderman, A. H., Wiersinga, W. Joost, Vlaar, Alexander P. J., Neurology, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, Center of Experimental and Molecular Medicine, Graduate School, ANS - Neurodegeneration, Pulmonology, ACS - Pulmonary hypertension & thrombosis, AII - Inflammatory diseases, Intensive Care Medicine, ACS - Heart failure & arrhythmias, Infectious diseases, APH - Aging & Later Life, APH - Global Health, ACS - Amsterdam Cardiovascular Sciences, Laboratory Specialized Diagnostics & Research, APH - Quality of Care, Anesthesiology, AII - Amsterdam institute for Infection and Immunity, Experimental Immunology, Global Health, APH - Health Behaviors & Chronic Diseases, Radiology and Nuclear Medicine, AMS - Musculoskeletal Health, AMS - Sports, ACS - Microcirculation, Medical Microbiology and Infection Prevention, ANS - Amsterdam Neuroscience, Nursing, Central Diagnostic Laboratory, ACS - Diabetes & metabolism, APH - Digital Health, APH - Personalized Medicine, Epidemiology and Data Science, APH - Methodology, and AII - Cancer immunology

Abstract

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Published
2023

5. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Abou Tayoun, Ahmad, Aiuti, Alessandro, Alavi Darazam, Ilad, Allende, Luis M., Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T., Bustos, Ingrid G., Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E., Delmonte, Ottavia M., El Zein, Loubna, Flores, Carlos, Gregersen, Peter K., Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Metin Akcan, Ozge, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E., Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G., Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M., Baris-Feldman, Hagit, Butte, Manish J., Constantinescu, Stefan N., Cooper, Megan A., Dalgard, Clifton L., Fellay, Jacques, Heath, James R., Lau, Yu-Lung, Lifton, Richard P., Maniatis, Tom, Mogensen, Trine H., von Bernuth, Horst, Lermine, Alban, Vidaud, Michel, Boland, Anne, Deleuze, Jean-François, Nussbaum, Robert, Kahn-Kirby, Amanda, Mentre, France, Tubiana, Sarah, Gorochov, Guy, Tubach, Florence, Hausfater, Pierre, Abel, Laurent, Al-Muhsen, Saleh, Al-Mulla, Fahd, Anderson, Mark S., Andreakos, Evangelos, Arias, Andrés A., Feldman, Hagit Baris, Belot, Alexandre, Biggs, Catherine M., Bogunovic, Dusan, Bondarenko, Anastasiia, Bousfiha, Ahmed A., Brodin, Petter, Bryceson, Yenan, Bustamante, Carlos D., Chakravorty, Samya, Christodoulou, John, Desai, Murkesh, Drolet, Beth A., Baghdadi, Jamila El, Espinosa-Padilla, Sara, Franco, José Luis, Froidure, Antoine, Hagin, David, Henrickson, Sarah E., Hsieh, Elena W. Y., Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich D., Karamitros, Timokratis, Kisand, Kai, Ku, Cheng-Lung, Ling, Yun, Lucas, Carrie L., Maródi, László, Meyts, Isabelle, Milner, Joshua D., Mironska, Kristina, Morio, Tomohiro, Ng, Lisa F. P., Notarangelo, Luigi D., O’Farrelly, Cliona, Okada, Satoshi, Planas, Anna M., Quintana-Murci, Lluis, Renia, Laurent, Resnick, Igor, Rodríguez-Gallego, Carlos, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänen, Mikko R. J., Shcherbina, Anna, Slaby, Ondrej, Snow, Andrew L., Soler-Palacín, Pere, Spaan, András N., Tancevski, Ivan, Tangye, Stuart G., Ramaswamy, Sathishkumar, Turvey, Stuart E., Uddin, Furkan, Uddin, Mohammed J., Vinh, Donald C., Su, Helen C., Casanova, Jean-Laurent, Bureau, Serge, Vacher, Yannick, Gysembergh-Houal, Anne, Demerville, Lauren, Chachoua, Abla, Abad, Sebastien, Abassi, Radhiya, Abdellaoui, Abdelrafie, Abdelmalek, Abdelkrim, Abdoul, Hendy, Abergel, Helene, Abeud, Fariza, Abgrall, Sophie, Abisror, Noemie, Adechian, Marylise, Aderdour, Nordine, Admane, Hakeem Farid, Adnet, Frederic, Afritt, Sara, Agostini, Helene, Aguilar, Claire, Agut, Sophie, Aiello, Tommaso Francesco, Kaci, Marc Ait, Oufella, Hafid Ait, Ajeenthiravasan, Gokula, Alauzy, Virginie, Alby-Laurent, Fanny, Allard, Lucie, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amam, Sabrina, Amrouche, Lucile, Andronikof, Marc, Anglicheau, Dany, Anguel, Nadia, Annane, Djillali, Aounzou, Mohammed, Aparicio, Caroline, Aratus, Gladys, Arlet, Jean-Benoit, Arzoine, Jeremy, Aslangul, Elisabeth, Assefi, Mona, Aubry, Adeline, Audiffred, Laetitia, Audureau, Etienne, Auger, Christelle Nathalie, Auregan, Jean-Charles, Awotar, Celine, Milla, Sonia Ayllon, Azan, Delphine, Azemar, Laurene, Azzouguen, Billal, Elrufaai, Marwa Bachir, Badsi, Aïda, Bakouboula, Prissile, Balcerowiak, Coline, Balde, Fanta, Baldivia, Elodie, Bangamingo, Eliane-Flore, Baptiste, Amandine, Baran-Marszak, Fanny, Barau, Caroline, Barget, Nathalie, Baronnet, Flore, Barthelemy, Romain, Baudel, Jean-Luc, Baudry, Camille, Baudry, Elodie, Beaugerie, Laurent, Belamri, Adel, Belaube, Nicolas, Belilita, Rhida, Bellassen, Pierre, Belmokhtar, Rawan, Beltran, Isabel, Benainous, Ruben, Benallaoua, Mourad, Benamouzig, Robert, Benbara, Amélie, Benhida, Jaouad, Benkhelouf, Anis, Benlagha, Jihene, Benmostafa, Chahinez, Benothmane, Skander, Bentifraouine, Miassa, Berard, Laurence, Bernier, Quentin, Berti, Enora, Bertier, Astrid, Berton, Laure, Bessis, Simon, Beurton, Alexandra, Bianco, Celine, Bianquis, Clara, Bidar, Frank, Blanche, Philippe, Blayau, Clarisse, Bleibtreu, Alexandre, Blin, Emmanuelle, Bloch-Queyrat, Coralie, Boissier, Marie-Christophe, Bollens, Diane, Bolzoni, Marion, Bompard, Rudy pierre, Bonnet, Nicolas, Bonnouvrier, Justine, Botha, Shirmonecrystal, Boucenna, Wissam, Bouchama, Fatiha, Bouchaud, Olivier, Bouchghoul, Hanane, Boudjebla, Taoueslylia, Boudjema, Noel, Bouffard, Catherine, Bougle, Adrien, Bouguerra, Meriem, Bouras, Leila, Bourcier, Agnes, Durand, Anne Bourgarit, Bourrier, Anne, Bouscarat, Fabrice, Bouvry, Diane, Bouziri, Nesrine, Bouzrara, Ons, Bribier, Sarah, Brugier, Delphine, Brunel, Melanie, Bui, Eida, Buisson, Anne, Bukreyeva, Iryna, Bureau, Côme, Cadranel, Jacques, Cailhol, Johann, Calin, Ruxandra, Vega, Clara Campos, Canavaggio, Pauline, Cancella, Marta, Cantin, Delphine, Cao, Albert, Carbillon, Lionel, Carlier, Nicolas, Cassard, Clementine, Castor, Guylaine, Cauchy, Marion, Cha, Olivier, Chaigne, Benjamin, Challal, Salima, Champion, Karine, Chariot, Patrick, Chas, Julie, Chauveau, Simon, Chauvin, Anthony, Chauvin, Clement, Chavarot, Nathalie, Chebbout, Kamélia, Cherai, Mustapha, Cherubini, Ilaria, Chevalier, Amelie, Chiarabini, Thibault, Chinet, Thierry, Chocron, Richard, Choinier, Pascaline, Chommeloux, Juliette, Choquet, Christophe, Choupeaux, Laure, Chousterman, Benjamin, Ciocan, Dragosmarius, Clarke, Ada, Clavere, Gaëlle, Clavier, Florian, Clement, Karine, Clerc, Sebastien, Cohen, Yves, Cohen, Fleur, Cohen, Adrien, Coilly, Audrey, Colboc, Hester, Colin, Pauline, Collet, Magalie, Comarmond, Chloé, Combacon, Emeline, Combes, Alain, Comparon, Celine, Constantin, Jean-Michel, Cordel, Hugues, Cordier, Anne-Gael, Costantini, Adrien, Chalumeau, Nathalie Costedoat, Couffignal, Camille, Coupeau, Doriane, Creange, Alain, Lamarre, Yannie Cuvillier, Da Silveira, Charlène, Kayani, Sandrine Dautheville Guibal El, De Castro, Nathalie, De Rycke, Yann, Del Pozo, Lucie, Delannoy, Quentin, Delay, Mathieu, Deleris, Robin, Delforge, Juliette, Delphine, Laëtitia, Demare, Noemie, Demeret, Sophie, Demoule, Alexandre, Deniau, Aurore, Depret, François, Derolez, Sophie, Derradji, Ouda, Derridj, Nawal, Descamps, Vincent, Deschamps, Lydia, Desconclois, Celine, Desnos, Cyrielle, Desongins, Karine, Dhote, Robin, Diallo, Benjamin, Didier, Morgane, Diemer, Myriam, Diez, Stephane, Djadi-Prat, Juliette, Monnory, Fatima-Zohra Djamouri, Djebara, Siham, Djebra, Naoual, Djietcheu, Minette, Djillali, Hadjer, Djouadi, Nouara, Donneger, Severine, Dos Santos, Catarina, Dournon, Nathalie, Dres, Martin, Droctove, Laura, Drogrey, Marie, Dropy, Margot, Drouet, Elodie, Dubosq, Valérie, Dubreucq, Evelyne, Dubus, Estelle, Duchemann, Boris, Duchenoy, Thibault, Dudoignon, Emmanuel, Dufau, Romain, Dumas, Florence, Duran, Clara, Duron, Emmanuelle, Durrbach, Antoine, Duvivier, Claudine, Ebstein, Nathan, Khalifa, Jihane El, Elabbadi, Alexandre, Elie, Caroline, Ernotte, Gabriel, Esling, Anne, Etienne, Martin, Eyer, Xavier, Fartoukh, Muriel sarah, Fayali, Takoua, Fermaut, Marion, Fiorentino, Arianna, Fliss, Souha, Fournier, Marie-Céline, Fournier, Benjamin, Francois, Hélène, Freynet, Olivia, Frigout, Yvann, Fromont, Isaure, Fuentes, Axelle, Furet, Thomas, Galand, Joris, Garnier, Marc, Gaubert, Agnes, Gaudry, Stéphane, Gaugain, Samuel, Gauthier, Damien, Gautier, Maxime, Georgin-Lavialle, Sophie, Geromin, Daniela, Ghalayini, Mohamed, Ghaleh, Bijan, Ghezal, Myriam, Gibelin, Aude, Gimeno, Linda, Girard, Benoit, Leprieur, Bénédicte Giroux, Gomes, Doryan, Gomes-Pires, Elisabete, Gouge, Anne, Gouja, Amel, Goulet, Helene, Goupil, Sylvain, De Bouille, Jeanne Goupil, Gras, Julien, Greffe, Segolene, Grimaldi, Lamiae, Guedeney, Paul, Guidet, Bertrand, Guillo, Matthias, Gulczynski, Mariechristelle, Hadjam, Tassadit, Haguenauer, Didier, Hammal, Soumeya, Hammoudi, Nadjib, Hanon, Olivier, Harrois, Anarole, Hautem, Coraline, Hekimian, Guillaume, Heming, Nicholas, Hermine, Olivier, Ho, Sylvie, Houllier, Marie, Huot, Benjamin, Huscenot, Tessa, Saied, Wafa Ibn, Ikherbane, Ghilas, Imarazene, Meriem, Ingiliz, Patrick, Iratni, Lina, Jaureguiberry, Stephane, Jean-Marc, Jean-Francois, Jeyarajasingham, Deleena, Jouany, Pauline, Jouis, Veronique, Jourdaine, Clement, Kafif, Ouifiya, Kallala, Rim, Katsahian, Sandrine, Kelesyan, Lilit, Keo, Vixra, Ketz, Flora, Khamis, Warda, Khelili, Enfel, Khellaf, Mehdi, Youkou, Christy Gaëlla Kotokpo, Kounis, Ilias, Kpalma, Gaelle, Krause, Jessica, Labbe, Vincent, Lacombe, Karine, Lacorte, Jean-Marc, Lafont, Anne Gaelle, Lafont, Emmanuel, Lagha, Lynda, Lamhaut, Lionel, Lancelot, Aymeric, Landman, Cecilia, Lanternier, Fanny, Larcheveque, Cecile, Combe, Caroline Lascoux, Lassel, Ludovic, Laverdant, Benjamin, Lavergne, Christophe, Lavillegrand, Jean-Rémi, Lazureanu, Pompilia, Le Guennec, Loïc, Leberre, Lamia, Leblanc, Claire, Leboyer, Marion, Lecomte, Francois, Lecorre, Marine, Leenhardt, Romain, Lefebvre, Marylou, Lefebvre, Bénédicte, Legendre, Paul, Leger, Anne, Legros, Laurence, Legrosse, Justyna, Lehuunghia, Sébastien, Lemarec, Julien, Leporrier-Ext, Jeremie, Lesein, Manon, Lesur, Hubert, Levy, Vincent, Levy, Albert, Lopes, Edwige, Lopes, Amanda, Lopez, Vanessa, Lopinto, Julien, Lortholary, Olivier, Louadah, Badr, Loze, Bénédicte, Lucas, Marie-Laure, Lucasamichi, Axelle, Luong, Liem Binh, Magazimama-Ext, Arouna, Maingret, David, Mameri, Lakhdar, Manivet, Philippe, Mansouri, Cylia, Marcault, Estelle, Marey, Jonathan, Marin, Nathalie, Marois, Clémence, Martin, Olivier, Martineau, Lou, Martinez-Lopez, Cannelle, Martyniuck, Pierre, De Farcy, Pauline Mary, Marzouk, Nessrine, Masmoudi, Rafik, Mebazaa, Alexandre, Mechai, Frédéric, Mecozzi, Fabio, Mediouni, Chamseddine, Megarbane, Bruno, Meghadecha, Mohamed, Mejean, Élodie, Mekinian, Arsene, Abdelhadi, Nour Mekki, Mekni, Rania, Meliti, Thinhinan Sabrina, Lima, Breno Melo, Meng, Paris, Merbah, Soraya, Messani, Fadhila, Messaoudi, Yasmine, Mewasing, Baboo-Irwinsingh, Meziane, Lydia, Michelot-Burger, Carole, Mignot, Françoise, Minka, Fadi Hillary, Miyara, Makoto, Moine, Pierre, Molina, Jean-Michel, Montegnies-Boulet, Anaïs, Monti, Alexandra, Montlahuc, Claire, Montout, Anne-Lise, Moores, Alexandre, Morbieu, Caroline, Mortelette, Helene, Mouly, Stéphane, Muzaffar, Rosita, Nacerddine, Cherifa Iness, Nadal, Marine, Nadif, Hajer, Nassarmadji, Kladoum, Natella, Pierre, Ndingamondze, Sandrine, Neraal, Stefan, Nguyen, Caroline, N’Guyen, Bao, Larmurier, Isabelle Nion, Nlomenyengue, Luc, Noel, Nicolas, Nunes, Hilario, Omar, Edris, Ouazene, Zineb, Ouedraogo, Elise, Ouelaa, Wassila, Oukhedouma, Anissa, Amara, Yasmina Ould, Oya, Herve, Oziel, Johanna, Padilla, Thomas, Paillaud, Elena, Paiva, Solenne, Parfait, Beatrice, Parize, Perrine, Parizot, Christophe, Parrot, Antoine, Pavot, Arthur, Peaudecerf, Laetitia, Pene, Frédéric, Pepin, Marion, Pernet, Julie, Pernin, Claire, Petit, Mylène, Peyrony, Olivier, Pietri, Marie-Pierre, Pietri, Olivia, De Chambrun, Marc Pineton, Pinson, Michelle, Pintado, Claire, Piquard, Valentine, Pires, Christine, Planquette, Benjamin, Poirier, Sandrine, Pomel, Anne-Laure, Pons, Stéphanie, Ponscarme, Diane, Pourcelot, Annegaelle, Pourcher, Valérie, Pouvaret, Anne, Prever, Florian, Previlon, Miresta, Prevost, Margot, Provoost, Marie-Julie, Quemeneur, Cyril, Rafat, Cédric, Rami, Agathe, Ranque, Brigitte, Raphael, Maurice, Raphalen, Jean Herle, Rastoin, Anna, Raux, Mathieu, Rebai, Amani, Reby, Michael, Regent, Alexis, Regrag, Asma, Resche-Rigon, Matthieu, Ressaire, Quentin, Richard, Christian, Richard, Mariecaroline, Robert, Maxence, Rohaut, Benjamin, Rolland-Debord, Camille, Ropers, Jacques, Roque-Afonso, Anne-Marie, Rosso, Charlotte, Rousseaux, Mélanie, Rousseaux, Nabila, Roux, Swasti, Roux, Lorène, Rouzaud, Claire, Rozes, Antoine, Rubenstein, Emma, Sabate, Jean-Marc, Sabet, Sheila, Sacleux, Sophie-Caroline, Kermanach, Nathalie Saidenberg, Saliba, Faouzi, Salmon, Dominique, Savale, Laurent, Savary, Guillaume, Sberro, Rebecca, Scemla, Anne, Schlemmer, Frederic, Schwartz, Mathieu, Sedfi, Saïd, Sefir-Kribel, Samia, Seksik, Philippe, Sellier, Pierre, Selves, Agathe, Sembach, Nicole, Semerano, Luca, Senat, Marie-Victoire, Sene, Damien, Serris, Alexandra, Sese, Lucile, Sghiouar, Naima, Sigaux, Johanna, Siguier, Martin, Silvain, Johanne, Simon, Noémie, Simon, Tabassome, Skandri, Lina Innes, Slimani, Miassa, Snauwaert, Aurélie, Sokol, Harry, Soliman, Heithem, Soltani, Nisrine, Soyer, Benjamin, Steg, Gabriel, Suarez, Lydia, Szwebel, Tali-Anne, Taffame, Kossi, Tantet, Claire, Tateo, Mariagrazia, Theodose, Igor, Thiebaud, Pierre clement, Thomas, Caroline, Tiercelet, Kelly, Tisserand, Julie, Tomczak, Carole, Torelino, Krystel, Touam-Ext, Fatima, Toumi, Lilia, Toury, Gustave, Toy-Miou, Mireille, Lien, Olivia Tran Dinh Thanh, Trandinh, Alexy, Treluyer, Jean-Marc, Trinque, Baptiste, Truchot, Jennifer, Tunesi, Simone, Turpin, Matthieu, Turpin, Agathe, Urbina, Tomas, Narvaez, Rafael Usubillaga, Uzunhan, Yurdagul, Vaittinadaayar, Prabakar, Valent, Arnaud, Valentian, Maelle, Valin, Nadia, Vallet, Hélène, Vaz, Marina, Vazquezibarra, Miguel-Alejandro, Vedie, Benoit, Velly, Laetitia, Verstuyft, Celine, Viallette, Cedric, Vicaut, Eric, Vignes, Dorothee, Vimpere, Damien, Virlouvet, Myriam, Voiriot, Guillaume, Voisot, Lena, Weiss, Emmanuel, Weiss, Nicolas, Winchenne, Anaïs, Yordanov, Youri, Zafrani, Lara, Zaidan, Mohamad, Zaidi, Wissem, Zak, Cathia, Zarhrate-Ghoul, Aida, Zatout, Ouassila, Zeino, Suzanne, Zeitouni, Michel, Zemirli, Naïma, Zerah, Lorene, Zia, Ounsa, Ziol, Marianne, Zolario, Oceane, Zuber, Julien, Andrejak, Claire, Angoulvant, François, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behilill, Sylvie, Beluze, Marine, Benkerrou, Dehbia, Bhavsar, Krishna, Bouadma, Lila, Bouchez, Sabelline, Bouscambert, Maude, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Couffin-Cadiergues, Sandrine, d’Ortenzio, Eric, Debray, Marie-Pierre, Deconinck, Lauren, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Elharrar, Brigitte, Eloy, Philippine, Enouf, Vincent, Esperou, Hélène, Esposito-Farese, Marina, Etienne, Manuel, Devouge, Eglantine Ferrand, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kaguelidou, Florentia, Kali, Sabrina, Khalil, Antoine, Khan, Coralie, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean Christophe, Malvy, Denis, Mambert, Marina, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Nseir, Saad, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Perpoint, Thomas, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Puéchal, Oriane, Rabaud, Christian, 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, Van Der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, Alavoine, Loubna, Behillil, Sylvie, Burdet, Charles, Charpentier, Charlotte, Dechanet, Aline, Ecobichon, Jean-Luc, Frezouls, Wahiba, Houhou, Nadhira, Lehacaut, Jonathan, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Quintin, Caroline, Thy, Michael, van der Werf, Sylvie, Vignali, Valérie, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Laine, Fabrice, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Goas, Carole L. E., Montagne, Samatha, Richard, Lucie, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Bourgeon, Marilou, Lefévre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Christelle, Kouakam, Nicolas, Leturque, Roufai, Layidé, Amat, Karine, Espérou, Hélène, Hendou, Samia, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Albisures, Jonathan Antonio Roblero, Aldave, Juan C., Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, AlKhater, Suzan A., Allardet-Servent, Jerome, Alshahrani, Mohammed S., Alsina, Laia, Amoura, Zahir, Antolí, Arnau, Arrestier, Romain, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Barrou, Benoit, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Boyarchuk, Oksana, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P., Bukhari, Huda, Bustamante, Jacinta, Agra, Juan José Cáceres, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus V., Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew P., Clavé, Père, Clotet, Bonaventura, Codina, Anna, Comarmond, Cloé, Comoli, Patrizia, Corsico, Angelo G., Sozeri, Betul, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Dalmau, David, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, De Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa H., Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Francois, Bruno, Fumadó, Victoria, Fung, Kitty S. C., Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Garçon, Pierre, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gilardin, Laurent, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Godínez, Karen Alejandra Cifuentes, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis I., González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Hadjadj, Jérôme, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-ki, Holanda-Peña, María Soledad, Horcajada, Juan P., Hraiech, Sami, Humbert, Linda, Hung, Ivan F. N., Iglesias, Alejandro D., Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Yüksek, Saliha Kanık, Kara, Yalcin Burak, Karahan, Aydın, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Klocperk, Adam, Koutsoukou, Antonia, Król, Zbigniew J., Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur M. C., Kwan, Yat Wah M., Kwok, Janette S. Y., Lagier, Jean-Christophe, Lam, David S. Y., Lampropoulou, Vicky, Le Bourgeois, Fleur, Leo, Yee-Sin, Lopez, Rafael Leon, Leung, Daniel, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Lima, Edson Jose Adrian Bolanos, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José M., Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Luyt, Charles-Edouard, Lye, David C., Magnone, Cinthia, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa R. B., Matthews, Gail V., Mayaux, Julien, McLaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi P., Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morandeira, Francisco, Mordacq, Cléemence, Mouly, Stéphane J., Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Yuk-Yung, Nielly, hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. Gonzalo, Okamoto, Keisuke, Oualha, Mehdi, Ouedrani, Amani, Özçelik, Tayfun, Ozkaya-Parlakay, Aslinur, Pagani, Michele, Papadaki, Maria, Parola, Philippe, Pascreau, Tiffany, Paul, Stéphane, Paz-Artal, Estela, Pedraza, Sigifredo, Pellecer, Nancy Carolina González, Pellegrini, Silvia, Pérez-Fernández, Xosé Luis, Philippe, Aurélien, Philippot, Quentin, Picod, Adrien, de Chambrun, Marc Pineton, Piralla, Antonio, Ploin, Dominique, Poissy, Julien, Poncelet, Géraldine, Poulakou, Garyphallia, Pouletty, Marie S., Pourshahnazari, Persia, Qiu-Chen, Jia Li, Quentric, Paul, Rambaud, Thomas, Raoult, Didier, Raoult, Violette, Rebillat, Anne-Sophie, Redin, Claire, Resmini, Léa, Ricart, Pilar, Richard, Jean-Christophe, Rigo-Bonnin, Raúl, rivet, Nadia, Rocamora-Blanch, Gemma, Rodero, Mathieu P., Rodrigo, Carlos, Rodriguez, Luis Antonio, Rodriguez-Palmero, Agustí, Romero, Carolina Soledad, Rothenbuhler, Anya, Roux, Damien, Rovina, Nikoletta, Rozenberg, Flore, Ruch, Yvon, Ruiz, Montse, del Prado, Maria Yolanda Ruiz, Ruiz-Rodriguez, Juan Carlos, Sabater-Riera, Joan, Saks, Kai, Salagianni, Maria, Sanchez, Oliver, Sánchez-Montalvá, Adrián, Sánchez-Ramón, Silvia, Schidlowski, Laire, Schluter, Agatha, Schmidt, Julien, Schmidt, Matthieu, Schuetz, Catharina, Schweitzer, Cyril E., Scolari, Francesco, Seijo, Luis, Seminario, Analia Gisela, Seng, Piseth, Senoglu, Sevtap, Seppänen, Mikko, Llovich, Alex Serra, Siguret, Virginie, Siouti, Eleni, Smadja, David M., Smith, Nikaia, Solanich, Xavier, Solé-Violán, Jordi, Soler, Catherine, Sözeri, Betül, Stella, Giulia Maria, Stepanovskiy, Yuriy, Stoclin, Annabelle, Taccone, Fabio, Taupin, Jean-Luc, Tavernier, Simon, Tello, Loreto Vidaur, Terrier, Benjamin, Thiery, Guillaume, Thorball, Christian, Thorn, Karolina, Thumerelle, Caroline, Tolstrup, Martin, Tomasoni, Gabriele, Toubiana, Julie, Alvarez, Josep Trenado, Triantafyllia, Vasiliki, Trouillet-Assant, Sophie, Troya, Jesús, Tsang, Owen T. Y., Tserel, Liina, Tso, Eugene Y. K., Tucci, Alessandra, Öz, Şadiye Kübra Tüter, Ursini, Matilde Valeria, Utsumi, Takanori, Vabres, Pierre, Valencia-Ramos, Juan, Van Den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Veliz, Silvia Patricia Zuniga, Vidigal, Mateus C., Viel, Sébastien, Villain, Cédric, Vilaire-Meunier, Marie E., Villar-García, Judit, Vincent, Audrey, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wauters, Joost, Wu, Alan K. L., Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby E., Yükselmiş, Ufuk, Zecca, Marco, Zuccaro, Valentina, Van Praet, Jens, Lambrecht, Bart, Van Braeckel, Eva, Bosteels, Cedric, Hoste, Levi, Hoste, Eric, Bauters, Fre, Heijmans, Catherine, Slabbynck, Hans, Naesens, Leslie, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Berkell, Matilda, Carelli, Valerio, Fiorentino, Alessio, Malhotra, Surbi, Mattiaccio, Alessandro, Pippucci, Tommaso, Seri, Marco, Tacconelli, Evelina, van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Bogaard, Harm Jan, Bomers, Marije, Bonta, Peter, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Buis, David T. P., Bugiani, Marianna, Bulle, Esther, Cloherty, Osoul Chouchane Alex, Dijkstra, Mirjam, Dongelmans, Dave A., Dujardin, Romein W. G., Elbers, Paul, Fleuren, Lucas, Geijtenbeek, Suzanne Geerlings Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin P., Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Heunks, Sabine M. Hermans Leo, Hollmann, Markus, Horn, Janneke, Hovius, Joppe W., de Jong, Menno D., Koning, Rutger, Lim, Endry H. T., van Mourik, Niels, Nellen, Jeaninne, Nossent, Esther J., Paulus, Frederique, Peters, Edgar, Pina-Fuentes, Dan A. I., van der Poll, Tom, Preckel, Bennedikt, Prins, Jan M., Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits C. F. J., Schinkel, Michiel, Schultz, Marcus J., Schrauwen, Femke A. P., Schuurmans, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen A., Smeele, Patrick, Smit, Marry, Stijnis, Cornelis S., Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa M., Tuinman, Pieter R., van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, Vught, Lonneke A., van Vugt, Michèle, Wouters, Dorien, Zwinderman, A. H., Brouwer, Matthijs C., Wiersinga, W. Joost, Vlaar, Alexander P. J., Tompkins, Miranda F., Alba, Camille, Hupalo, Daniel N., Rosenberger, John, Sukumar, Gauthaman, Wilkerson, Matthew D., Zhang, Xijun, Lack, Justin, Oler, Andrew J., Dobbs, Kerry, Danielson, Jeffrey J., Biondi, Andrea, Bettini, Laura Rachele, D’Angio’, Mariella, Beretta, Ilaria, Imberti, Luisa, Sottini, Alessandra, Quaresima, Virginia, Quiros-Roldan, Eugenia, Rossi, Camillo, Zhang, Shen-Ying, Declercq, Jozefien, Puel, Anne, Boisson-Dupuis, Stephanie, Boisson, Bertrand, Jouanguy, Emmanuelle, Zhang, Qian, Cobat, Aurélie, COVID Human Genetic Effort, [missing], COVIDeF Study Group, [missing], French COVID Cohort Study Group, [missing], CoV-Contact Cohort, [missing], COVID-STORM Clinicians, [missing], COVID Clinicians, [missing], Orchestra Working Group, [missing], Amsterdam UMC Covid-19 Biobank, [missing], and NIAID-USUHS COVID Study Group, [missing]

Subjects
Medicine and Health Sciences, Genetics, Molecular Medicine, Molecular Biology, Genetics (clinical)
Published
2023

6. Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial

Author

Lim, Endry H. T., Vlaar, Alexander P. J., Bos, Lieuwe D. J., van Vught, Lonneke A., Boer, Anita M. Tuip-de, Dujardin, Romein W. G., Habel, Maria, Xu, Zhongli, Brouwer, Matthijs C., van de Beek, Diederik, de Bruin, Sanne, van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Floor, Beudel, Martijn, Bogaard, Harm Jan, Bomers, Marije, Bonta, Peter, Botta, Michela, de Brabander, Justin, Bree, Godelieve, Bugiani, Marianna, Bulle, Esther, Chouchane, Osoul, Cloherty, Alex, Buis, David T. P., de Rotte, Maurits C. F. J., Dijkstra, Mirjam, Dongelmans, Dave A., Elbers, Paul, Fleuren, Lucas, Geerlings, Suzanne, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin P., Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine M., Heunks, Leo, Hollmann, Markus, Horn, Janneke, Hovius, Joppe W., de Jong, Menno D., Koning, Rutger, van Mourik, Niels, Nellen, Jeannine, Nossent, Esther J., Paulus, Frederique, Peters, Edgar, Piña-Fuentes, Dan A. I., van der Poll, Tom, Preckel, Bennedikt, Prins, Jan M., Raasveld, Jorinde, Reijnders, Tom, Schinkel, Michiel, Schrauwen, Femke A. P., Schultz, Marcus J., Schuurman, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen A., Smeele, Patrick, Smit, Marry, Stijnis, Cornelis S., Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa M., Tuinman, Pieter R., van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, van Vugt, Michèle, Wouters, Dorien, Zwinderman, Aeilko H., Wiersinga, W. Joost, Graduate School, Intensive Care Medicine, ANS - Amsterdam Neuroscience, AII - Amsterdam institute for Infection and Immunity, ACS - Microcirculation, AII - Inflammatory diseases, ACS - Heart failure & arrhythmias, AII - Infectious diseases, ACS - Diabetes & metabolism, APH - Personalized Medicine, Neurology, ANS - Neuroinfection & -inflammation, ACS - Pulmonary hypertension & thrombosis, Center of Experimental and Molecular Medicine, ANS - Neurodegeneration, Pulmonology, ACS - Amsterdam Cardiovascular Sciences, Experimental Immunology, Infectious diseases, Laboratory for General Clinical Chemistry, Genetic Metabolic Diseases, APH - Quality of Care, APH - Aging & Later Life, APH - Global Health, Global Health, Radiology and Nuclear Medicine, AMS - Musculoskeletal Health, AMS - Sports, APH - Methodology, Anesthesiology, Medical Microbiology and Infection Prevention, Nursing, Epidemiology and Data Science, AII - Cancer immunology, APH - Digital Health, and APH - Health Behaviors & Chronic Diseases

Subjects
C5a, Complement inhibition, SARS-CoV-2, Vilobelimab, Complement, COVID-19
Abstract

We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted.

Published
2022

8. Neurofilament light increases over time in severe COVID-19 and is associated with delirium

Author

Smeele, Patrick J., Vermunt, Lisa, Blok, Siebe, Duitman, Jan Willem, Nossent, Esther J., van Agtmael, Michiel A., Heunks, Leo M. A., Horn, Janneke, Bogaard, Harm Jan, Teunissen, Charlotte E., van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Bomers, Marije, Bonta, Peter, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Buis, David T. P., Bugiani, Marianna, Bulle, Esther, Chekrouni, Nora, Chouchane, Osoul, Cloherty, Alex, Dijkstra, Mirjam, Dongelmans, Dave A., Duijvelaar, Erik, Dujardin, Romein W. G., Elbers, Paul, Fleuren, Lucas, Geerlings, Suzanne, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin P., Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine M., Heunks, Leo, Hollmann, Markus, Hovius, Joppe W., de Jong, Menno D., Koning, Rutger, Lim, Endry H. T., van Mourik, Niels, Nellen, Jeaninne, Olie, Sabine, Paulus, Frederique, Peters, Edgar, Pina-Fuentes, Dan A. I., van der Poll, Tom, Preckel, Bennedikt, Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits C. F. J., Schippers, Job R., Schinkel, Michiel, Schultz, Marcus J., Schrauwen, Femke A. P., Schuurman, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen A., Smeele, Patrick, Smit, Marry, Stijnis, Cornelis S., Stilma, Willemke, Thoral, Patrick, Tsonas, Anissa M., Tuinman, Pieter R., van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, Vught, Lonneke A., van Vugt, Michéle, Wouters, Dorien, Zwinderman, A. H., Brouwer, Matthijs C., Wiersinga, W. Joost, Vlaar, Alexander P. J., van de Beek, Diederik, Clinical chemistry, Amsterdam Neuroscience - Neurodegeneration, Pulmonary medicine, CCA - Cancer Treatment and quality of life, ACS - Pulmonary hypertension & thrombosis, Amsterdam Neuroscience - Neuroinfection & -inflammation, Internal medicine, AII - Infectious diseases, AII - Inflammatory diseases, Intensive care medicine, ACS - Diabetes & metabolism, Medical Microbiology and Infection Control, Graduate School, Intensive Care Medicine, Pulmonology, 01 Internal and external specialisms, Experimental Immunology, ANS - Neuroinfection & -inflammation, Center of Experimental and Molecular Medicine, Neurology, ANS - Neurodegeneration, ACS - Heart failure & arrhythmias, Infectious diseases, APH - Aging & Later Life, APH - Global Health, ACS - Amsterdam Cardiovascular Sciences, Genetic Metabolic Diseases, APH - Quality of Care, AII - Amsterdam institute for Infection and Immunity, Global Health, APH - Health Behaviors & Chronic Diseases, Radiology and Nuclear Medicine, AMS - Musculoskeletal Health, AMS - Sports, APH - Methodology, Anesthesiology, ACS - Microcirculation, Medical Microbiology and Infection Prevention, ANS - Amsterdam Neuroscience, Nursing, Laboratory for General Clinical Chemistry, APH - Digital Health, APH - Personalized Medicine, Epidemiology and Data Science, and Laboratory Medicine

Subjects
delirium, TNF-α, neurofilament light, General Engineering, COVID-19, SOFA
Abstract

Neurological monitoring in sedated Intensive Care Unit patients is constrained by the lack of reliable blood-based biomarkers. Neurofilament light is a cross-disease biomarker for neuronal damage with potential clinical applicability for monitoring Intensive Care Unit patients. We studied the trajectory of neurofilament light over a month in Intensive Care Unit patients diagnosed with severe COVID-19 and explored its relation to clinical outcomes and pathophysiological predictors. Data were collected over a month in 31 Intensive Care Unit patients (166 plasma samples) diagnosed with severe COVID-19 at Amsterdam University Medical Centre, and in the first week after emergency department admission in 297 patients with COVID-19 (635 plasma samples) admitted to Massachusetts General hospital. We observed that Neurofilament light increased in a non-linear fashion in the first month of Intensive Care Unit admission and increases faster in the first week of Intensive Care Unit admission when compared with mild-moderate COVID-19 cases. We observed that baseline Neurofilament light did not predict mortality when corrected for age and renal function. Peak neurofilament light levels were associated with a longer duration of delirium after extubation in Intensive Care Unit patients. Disease severity, as measured by the sequential organ failure score, was associated to higher neurofilament light values, and tumour necrosis factor alpha levels at baseline were associated with higher levels of neurofilament light at baseline and a faster increase during admission. These data illustrate the dynamics of Neurofilament light in a critical care setting and show associations to delirium, disease severity and markers for inflammation. Our study contributes to determine the clinical utility and interpretation of neurofilament light levels in Intensive Care Unit patients.

Published
2021
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12. Compliance with the guidelines for laboratory monitoring of patients treated with lithium: A retrospective follow-up study among ambulatory patients in the Netherlands

Author

Nederlof, Mariëtte, Egberts, Toine C G, van Londen, Liesbeth, de Rotte, Maurits C F J, Souverein, Patrick C, Herings, Ron C M, Heerdink, Eibert R, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Epidemiology and Data Science, APH - Quality of Care, and APH - Methodology

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), Adolescent, Databases, Factual, Laboratory monitoring, Thyrotropin, compliance, guideline compliance, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Medicine, Humans, LITHIUM USE, Medical prescription, Biological Psychiatry, Research Articles, Aged, Netherlands, Retrospective Studies, Creatinine, business.industry, Follow up studies, Guideline, Original Articles, Middle Aged, 030227 psychiatry, Psychiatry and Mental health, monitoring, chemistry, lithium, Emergency medicine, Ambulatory, Practice Guidelines as Topic, Lithium Compounds, Female, Original Article, business, guideline, 030217 neurology & neurosurgery, medicine.drug, Follow-Up Studies
Abstract

OBJECTIVES: Laboratory monitoring of patients using lithium is important to prevent harm and to increase effectiveness. The aim of this study is to determine compliance with the guidelines for laboratory monitoring of patients treated with lithium overall and within subgroups. METHODS: Patients having at least one lithium dispensing for six months or longer between January 2010 and December 2015 were identified retrospectively using data from the Dutch PHARMO Database Network. Laboratory monitoring was defined as being compliant with the Dutch Multidisciplinary Clinical Guideline Bipolar Disorders when lithium serum levels, creatinine and thyroid-stimulating hormone (TSH) had been measured at least every six months during lithium use. RESULTS: Data were analyzed from 1,583 patients with a median duration of seven six-month periods of lithium use. Results indicated that patients had been monitored over six-month periods for lithium serum levels 65% of the time, for creatinine 73% of the time and for TSH 54% of the time. Just over one seventh (16%) of patients had been monitored in compliance with the guidelines for all three parameters during total follow-up. Especially males, patients aged below 65 years, patients receiving prescriptions solely from general practitioners, prevalent users of lithium, patients without interacting co-medication, and patients without other days with laboratory measurements had been monitored less frequently in compliance with the guidelines. CONCLUSION: A considerable proportion of patients had not been monitored in accordance with the guidelines. Further research is needed to understand the reasons for noncompliance and to implement strategies with the ultimate goal of optimizing safety and effectiveness for patients treated with lithium. This article is protected by copyright. All rights reserved.

Published
2019
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13. Complex Machine-Learning Algorithms and Multivariable Logistic Regression on Par in the Prediction of Insufficient Clinical Response to Methotrexate in Rheumatoid Arthritis

Author

Lab Reumatologie/Klinische Immunologie, Unit Opleiding Aios, JC onderzoeksprogramma Methodologie, Gosselt, Helen R, Verhoeven, Maxime, Bulatovic-Calasan, Maja, Welsing, Paco M J, de Rotte, Maurits C. F. J., Hazes, Johanna M. W., Lafeber, Floris, Hoogendoorn, Mark, de Jonge, Robert, Lab Reumatologie/Klinische Immunologie, Unit Opleiding Aios, JC onderzoeksprogramma Methodologie, Gosselt, Helen R, Verhoeven, Maxime, Bulatovic-Calasan, Maja, Welsing, Paco M J, de Rotte, Maurits C. F. J., Hazes, Johanna M. W., Lafeber, Floris, Hoogendoorn, Mark, and de Jonge, Robert

Published
2021

14. Complex Machine-Learning Algorithms and Multivariable Logistic Regression on Par in the Prediction of Insufficient Clinical Response to Methotrexate in Rheumatoid Arthritis

Author

Gosselt, Helen R., primary, Verhoeven, Maxime M. A., additional, Bulatović-Ćalasan, Maja, additional, Welsing, Paco M., additional, de Rotte, Maurits C. F. J., additional, Hazes, Johanna M. W., additional, Lafeber, Floris P. J. G., additional, Hoogendoorn, Mark, additional, and de Jonge, Robert, additional

Published
2021
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15. Compliance with the guidelines for laboratory monitoring of patients treated with lithium: a retrospective follow-up study among ambulatory patients in the Netherlands

Author

Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Nederlof, Mariëtte, Egberts, Toine C G, van Londen, Liesbeth, de Rotte, Maurits C F J, Souverein, Patrick C, Herings, Ron C M, Heerdink, Eibert R, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Nederlof, Mariëtte, Egberts, Toine C G, van Londen, Liesbeth, de Rotte, Maurits C F J, Souverein, Patrick C, Herings, Ron C M, and Heerdink, Eibert R

Published
2019

16. Compliance with the guidelines for laboratory monitoring of patients treated with lithium: A retrospective follow-up study among ambulatory patients in the Netherlands

Author

Apotheek Onderzoek, Nederlof, Mariëtte, Egberts, Toine C G, van Londen, Liesbeth, de Rotte, Maurits C F J, Souverein, Patrick C, Herings, Ron C M, Heerdink, Eibert R, Apotheek Onderzoek, Nederlof, Mariëtte, Egberts, Toine C G, van Londen, Liesbeth, de Rotte, Maurits C F J, Souverein, Patrick C, Herings, Ron C M, and Heerdink, Eibert R

Published
2019

17. Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis

Author

de Rotte, Maurits C. F. J., primary, Pluijm, Saskia M. F., additional, de Jong, Pascal H. P., additional, Bulatović Ćalasan, Maja, additional, Wulffraat, Nico M., additional, Weel, Angelique E. A. M., additional, Lindemans, Jan, additional, Hazes, J. M. W., additional, and de Jonge, Robert, additional

Published
2018
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18. Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis

Author

de Rotte, Maurits C F J, Pluijm, Saskia M F, de Jong, Pascal H P, Bulatović Ćalasan, Maja, Wulffraat, Nico M, Weel, Angelique E A M, Lindemans, Jan, Hazes, J M W, de Jonge, Robert, de Rotte, Maurits C F J, Pluijm, Saskia M F, de Jong, Pascal H P, Bulatović Ćalasan, Maja, Wulffraat, Nico M, Weel, Angelique E A M, Lindemans, Jan, Hazes, J M W, and de Jonge, Robert

Abstract

OBJECTIVE: The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients.METHODS: A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis.RESULTS: The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folate<750 nmol/L. In the derivation cohort, AUC of ROC curve was 0.80 (95%CI: 0.73-0.86), and 0.80 (95%CI: 0.69-0.91) in the validation cohort. Betas of the prediction model were transformed into total risk score (range 0-8). At cutoff of ≥4, probability for insufficient response was 44%. Sensitivity was 71%, specificity 72%, with positive and negative predictive value of 72% and 71%.CONCLUSIONS: A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.

Published
2018

20. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis

Author

de Rotte, Maurits C. F. J., den Boer, Ethan, de Jong, Pascal H. P., Pluijm, Saskia M. F., Bulatovic, Maja, Weel, Angelique E., Huisman, A. Margriet, Gerards, Andreas H., van Schaeybroeck, Barbara, Wulffraat, Nico W., Lindemans, Jan, Hazes, Johanna M. W., de Jonge, Robert, de Rotte, Maurits C. F. J., den Boer, Ethan, de Jong, Pascal H. P., Pluijm, Saskia M. F., Bulatovic, Maja, Weel, Angelique E., Huisman, A. Margriet, Gerards, Andreas H., van Schaeybroeck, Barbara, Wulffraat, Nico W., Lindemans, Jan, Hazes, Johanna M. W., and de Jonge, Robert

Published
2015

22. Prediction of Methotrexate Intolerance in Juvenile Idiopathic Arthritis: a prospective, observational cohort study

Author

Immuno/reuma onderzoek 1 (Vastert), PMC Research, Reumatologie patientenzorg, Infection & Immunity, Child Health, Immuno/reuma patientenzorg, van Dijkhuizen, Evert Hendrik Pieter, Bulatovic, Maja, Pluijm, Saskia M. F., de Rotte, Maurits C. F. J., Vastert, SJ, Kamphuis, Sylvia, de Jonge, Robert, Wulffraat, NM, Immuno/reuma onderzoek 1 (Vastert), PMC Research, Reumatologie patientenzorg, Infection & Immunity, Child Health, Immuno/reuma patientenzorg, van Dijkhuizen, Evert Hendrik Pieter, Bulatovic, Maja, Pluijm, Saskia M. F., de Rotte, Maurits C. F. J., Vastert, SJ, Kamphuis, Sylvia, de Jonge, Robert, and Wulffraat, NM

Published
2015

23. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis

Author

PMC Research, Immuno/reuma onderzoek 1 (Vastert), Cluster B, Infection & Immunity, Child Health, Immuno/reuma patientenzorg, de Rotte, Maurits C. F. J., den Boer, Ethan, de Jong, Pascal H. P., Pluijm, Saskia M. F., Bulatovic, Maja, Weel, Angelique E., Huisman, A. Margriet, Gerards, Andreas H., van Schaeybroeck, Barbara, Wulffraat, Nico W., Lindemans, Jan, Hazes, Johanna M. W., de Jonge, Robert, PMC Research, Immuno/reuma onderzoek 1 (Vastert), Cluster B, Infection & Immunity, Child Health, Immuno/reuma patientenzorg, de Rotte, Maurits C. F. J., den Boer, Ethan, de Jong, Pascal H. P., Pluijm, Saskia M. F., Bulatovic, Maja, Weel, Angelique E., Huisman, A. Margriet, Gerards, Andreas H., van Schaeybroeck, Barbara, Wulffraat, Nico W., Lindemans, Jan, Hazes, Johanna M. W., and de Jonge, Robert

Published
2015

24. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis

Author

de Rotte, Maurits C F J, primary, den Boer, Ethan, additional, de Jong, Pascal H P, additional, Pluijm, Saskia M F, additional, Bulatović Ćalasan, Maja, additional, Weel, Angelique E, additional, Huisman, A Margriet, additional, Gerards, Andreas H, additional, van Schaeybroeck, Barbara, additional, Wulffraat, Nico M, additional, Lindemans, Jan, additional, Hazes, Johanna M W, additional, and de Jonge, Robert, additional

Published
2013
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26. Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study

Author

Heil, Sandra G, primary, de Jonge, Robert, additional, de Rotte, Maurits C F J, additional, van Wijnen, Merel, additional, Heiner-Fokkema, Rebecca M R, additional, Kobold, Anneke C Muller, additional, Pekelharing, J Maurits M, additional, Adriaansen, Henk J, additional, Sanders, Edward, additional, Trienekens, Paul H, additional, Rammeloo, Ton, additional, and Lindemans, Jan, additional

Published
2012
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27. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in juvenile idiopathic arthritis patients.

Author

Bulatović Ćalasan, Maja, den Boer, Ethan, de Rotte, Maurits C. F. J., Vastert, Sebastiaan J., Kamphuis, Sylvia, de Jonge, Robert, and Wulffraat, Nico M.

Abstract

Objective To determine association of erythrocyte methotrexate polyglutamates (MTX-PG) with disease activity and adverse effects in a prospective juvenile idiopathic arthritis (JIA) cohort. Methods One hundred and thirteen JIA patients were followed from MTX start until 12 months. Erythrocyte MTX-PGs with 1-5 glutamate residues were measured at 3 months with tandem mass spectrometry. The outcomes were Juvenile Arthritis Disease Activity Score (JADAS)-27 and adverse effects. To determine associations of MTX-PGs with JADAS-27 at 3 months and during 1 year of MTX treatment, linear regression and linear mixed-model analyses were used. To determine associations of MTX-PGs with adverse effects during 1 year of MTX treatment, logistic regression was used. Analyses were corrected for JADAS-27 at baseline and co-medication. Results Median JADAS-27 decreased from 12.7 (IQR: 7.8-18.2) at baseline to 2.9 (IQR: 0.1-6.5) at 12 months. Higher concentrations of MTX-PG3 (β: -0.006, p=0.005), MTX-PG4 (β: -0.015, p=0.004), MTX-PG5 (β: -0.051, p=0.011) and MTX-PG3-5 (β: -0.004, p=0.003) were associated with lower disease activity at 3 months. Higher concentrations of MTX-PG3 (β: -0.005, p=0.028), MTX-PG4 (β: -0.014, p=0.014), MTX-PG5 (β: -0.049, p=0.023) and MTX-PG3-5 (β: -0.004, p=0.018) were associated with lower disease activity over 1 year. None of the MTX-PGs was associated with adverse effects. Conclusions In the first prospective study in JIA, long-chain MTX-PGs were associated with lower JADAS-27 at 3 months and during 1 year of MTX treatment. Erythrocyte MTX-PG could be a plausible candidate for therapeutic drug monitoring of MTX in JIA. [ABSTRACT FROM AUTHOR]

Published
2015
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29. Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study.

Author

Heil, Sandra G., de Jonge, Robert, de Rotte, Maurits C. F. J., van Wijnen, Merel, Heiner-Fokkema, Rebecca M. R., Muller Kobold, Anneke C., Pekelharing, J. Maurits M., Adriaansen, Henk J., Sanders, Edward, Trienekens, Paul H., Rammeloo, Ton, and Lindemans, Jan

Subjects
VITAMIN B12 deficiency, MEDICAL screening, HEALTH risk assessment, METHYLMALONIC acid, TANDEM mass spectrometry
Abstract

Background: Vitamin B12 deficiency occurs frequently, especially among the elderly. However, screening for vitamin B12 deficiency is hampered by poor sensitivity of the existing total vitamin B12 assay. Methylmalonic acid (MMA) is considered as the most representative indicator of metabolic vitamin B12 deficiency and is used as such in this study. The aim of this study was to validate the clinical usefulness of holotranscobalamin (holoTC) as an initial screening assay for metabolic vitamin B12 deficiency in a mixed patient population. Methods: Three hundred and sixty blood samples were collected by five Dutch hospitals. Vitamin B12 and holoTC in serum were measured (AxSYM; Abbott). MMA in serum was measured by tandem mass spectrometry (LC-MS/MS). Results: Receiver operating curve (ROC) analysis demonstrated a greater area under the curve (AUC) for holoTC than for vitamin B12 in detecting vitamin B12 deficiency characterized by three predefined cut-off levels of MMA. A cut-off value of 32 pmol/L of holoTC resulted in the highest sensitivity (83%) with acceptable specificity (60%) in detecting MMA concentrations above 0.45 μmol/L. The combination of vitamin B12 and holoTC did not improve diagnostic accuracy at this cut-off level. Conclusions: HoloTC has a better diagnostic accuracy than vitamin B12 and can replace the existing vitamin B12 assay as a primary screening test in patients suspected of vitamin B12 deficiency. Critical evaluation of cut-off values of holoTC indicated that a cut-off value of 32 pmol/L can be considered in screening for metabolic vitamin B12 deficiency (defined by MMA . 0.45μmol/L) in a mixed patient population. [ABSTRACT FROM AUTHOR]

Published
2012
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31. Do snapshot statistics fool us in MTX pharmacogenetic studies in arthritis research?

Author

De Rotte, Maurits C. F. J., Luime, Jolanda J., Bulatovic, Maja, Hazes, Johanna M. W., Wulffraat, Nico M., and De Jonge, Robert

Subjects
*LETTERS to the editor, *PHARMACOKINETICS
Abstract

A letter to the editor is presented in response to the article "Do Snapshot Statistics Fool Us in MTX Pharmacogenetic Studies in Arthritis Research?" that was published in a 2010 issue of the journal.

Published
2010
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33. Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

Author

Michels EHA, Appelman B, de Brabander J, van Amstel RBE, Chouchane O, van Linge CCA, Schuurman AR, Reijnders TDY, Sulzer TAL, Klarenbeek AM, Douma RA, Bos LDJ, Wiersinga WJ, Peters-Sengers H, van der Poll T, van Agtmael M, Algera AG, Appelman B, van Baarle F, Beudel M, Bogaard HJ, Bomers M, Bonta P, Bos L, Botta M, de Brabander J, de Bree G, de Bruin S, Bugiani M, Bulle E, Buis DTP, Chouchane O, Cloherty A, Dijkstra M, Dongelmans DA, Dujardin RWG, Elbers P, Fleuren L, Geerlings S, Geijtenbeek T, Girbes A, Goorhuis B, Grobusch MP, Hagens L, Hamann J, Harris V, Hemke R, Hermans SM, Heunks L, Hollmann M, Horn J, Hovius JW, de Jong HK, de Jong MD, Koning R, Lemkes B, Lim EHT, van Mourik N, Nellen J, Nossent EJ, Olie S, Paulus F, Peters E, Pina-Fuentes DAI, van der Poll T, Preckel B, Prins JM, Raasveld J, Reijnders T, de Rotte MCFJ, Schinkel M, Schultz MJ, Schrauwen FAP, Schuurman A, Schuurmans J, Sigaloff K, Slim MA, Smeele P, Smit M, Stijnis CS, Stilma W, Teunissen C, Thoral P, Tsonas AM, Tuinman PR, van der Valk M, Veelo DP, Volleman C, de Vries H, Vught LA, van Vugt M, Wouters D, Zwinderman AHK, Brouwer MC, Wiersinga WJ, Vlaar APJ, and van de Beek D

Subjects
Humans, Aged, Biomarkers, Inflammation, Cytokines, Aging, COVID-19
Abstract

Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19., Methods: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort., Results: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively)., Conclusions: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19., Competing Interests: Conflicts of interest: The authors declare no potential conflicts of interest., (Copyright ©The authors 2023.)

Published
2023
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