Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after COVID-19 hospitalization: an international multicenter prospective observational study
Sung-Min Cho, Lavienraj Premraj, Denise Battaglini, Jonathon Paul Fanning, Jacky Suen, Gianluigi Li Bassi, John Fraser, Chiara Robba, Matthew Griffee, Tom Solomon, Malcolm G Semple, Kenneth Baillie, Louise Sigfrid, Janet T Scott, Barbara Wanjiru Citarella, Laura Merson, Rakesh C Arora, Glenn Whitman, David Thomson, Nicole White, Laurent Abel, Amal Abrous, Kamal Abu Jabal, Hiba Abu Zayyad, Younes Ait Tamlihat, Aliya Mohammed Alameen, Marta Alessi, Beatrice Alex, Kévin Alexandre, Adam Ali, Kazali Enagnon Alidjnou, Clotilde Allavena, Nathalie Allou, Claire Andréjak, Andrea Angheben, François Angoulvant, Séverine Ansart, Jean-Benoît Arlet, Elise Artaud-Macari, Jean Baptiste Assie, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Eyvind W Axelsen, Laurène Azemar, Cecile Azoulay, Benjamin Bach, Delphine Bachelet, Claudine Badr, Roar Bævre-Jensen, John Kenneth Baillie, Firouzé Bani-Sadr, Wendy S Barclay, Marie Bartoli, Joaquín Baruch, Romain Basmaci, Jules Bauer, Alexandra Bedossa, Husna Begum, Sylvie Behilill, Anna Beltrame, Marine Beluze, Nicolas Benech, Delphine Bergeaud, José Luis Bernal Sobrino, Giulia Bertoli, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Krishna Bhavsar, Zeno Bisoffi, Laurent Bitker, Mathieu Blot, Laetitia Bodenes, Debby Bogaert, Anne-Hélène Boivin, Isabela Bolaños, Pierre-Adrien Bolze, François Bompart, Raphaël Borie, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Damien Bouhour, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Anne-Sophie Boureau, Maude Bouscambert, Aurore Bousquet, Marielle Boyer-Besseyre, Axelle Braconnier, Sonja Hjellegjerde Brunvoll, Marielle Buisson, Danilo Buonsenso, Aidan Burrell, Ingrid G Bustos, André Cabie, Eder Caceres, Cyril Cadoz, Jose Andres Calvache, Valentine Campana, Pauline Caraux-Paz, Nicolas Carlier, Thierry Carmoi, Marie-Christine Carret, Gail Carson, Maire-Laure Casanova, Guylaine Castor-Alexandre, François-Xavier Catherine, Paolo Cattaneo, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chakveatze, Meera Chand, Jean-Marc Chapplain, Charlotte Charpentier, Julie Chas, Léo Chenard, Antoine Cheret, Thibault Chiarabini, Catherine Chirouze, Bernard Cholley, Marie-Charlotte Chopin, Yock Ping Chow, Barbara Wanjiru Citarella, Sara Clohisey, Gwenhaël Colin, Marie Connor, Anne Conrad, Graham S Cooke, Hugues Cordel, Andrea Cortegiani, Grégory Corvaisier, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Juan Luis Cruz Bermúdez, Jaime Cruz Rojo, Elodie Curlier, Ana da Silva Filipe, Charlene Da Silveira, Andrew Dagens, John Arne Dahl, Jo Dalton, Etienne De Montmollin, Cristina De Rose, Thushan de Silva, Alexa Debard, Marie-Pierre Debray, Nathalie DeCastro, Romain Decours, Eve Defous, Isabelle Delacroix, Eric Delaveuve, Karen Delavigne, Christelle Delmas, Pierre Delobel, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Diane Descamps, Mathilde Desvallées, Alpha Diallo, Sylvain Diamantis, Fernanda Dias Da Silva, Kévin Didier, Jean-Luc Diehl, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Félix Djossou, Annemarie B Docherty, Christl A Donnelly, Céline Dorival, Eric D'Ortenzio, Nathalie Dournon, Thomas Drake, Amiel A Dror, Vincent Dubee, François Dubos, Alexandre Ducancelle, Susanne Dudman, Paul Dunand, Jake Dunning, Bertrand Dussol, Xavier Duval, Anne Margarita Dyrhol-Riise, Michael Edelstein, Linn Margrete Eggesbø, Mohammed El Sanharawi, Brigitte Elharrar, Merete Ellingjord-Dale, Philippine Eloy, Isabelle Enderle, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Hélène Esperou, Marina Esposito-Farese, Manuel Etienne, Mirjam Evers, Marc Fabre, Isabelle Fabre, Cameron J Fairfield, Karine Faure, Raphaël Favory, François-Xavier Ferrand, Eglantine Ferrand Devouge, Nicolas Ferriere, Céline Ficko, William Finlayson, Thomas Flament, Tom Fletcher, Aline-Marie Florence, Erwan Fourn, Robert A Fowler, Christophe Fraser, Stéphanie Fry, Valérie Gaborieau, Rostane Gaci, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Sérgio Gaião, Linda Gail Skeie, Carrol Gamble, Noelia García Barrio, Esteban Garcia-Gallo, Denis Garot, Valérie Garrait, Anatoliy Gavrylov, Alexandre Gaymard, Eva Geraud, Louis Gerbaud Morlaes, Jade Ghosn, Tristan Gigante, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Daniel Glikman, François Goehringer, Kyle Gomez, Marie Gominet, Yanay Gorelik, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Pascal Granier, Christopher A Green, William Greenhalf, Segolène Greffe, Fiona Griffiths, Jérémie Guedj, Martin Guego, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Thomas Guimard, Ali Hachemi, Nadir Hadri, Matthew Hall, Sophie Halpin, Rebecca Hamidfar, Bato Hammarström, Hayley Hardwick, Ewen M Harrison, Janet Harrison, Lars Heggelund, Ross Hendry, Maxime Hentzien, Diana Hernandez, Liv Hesstvedt, Rupert Higgins, Hikombo Hitoto, Antonia Ho, Alexandre Hoctin, Isabelle Hoffmann, Jan Cato Holter, Peter Horby, Ikram Houas, Jean-Sébastien Hulot, Samreen Ijaz, Patrick Imbert, Mariachiara Ippolito, Margaux Isnard, Mette Stausland Istre, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Clare Jackson, Stéphane Jaureguiberry, Florence Jego, Synne Jenum, Silje Bakken Jørgensen, Cédric Joseph, Mercé Jourdain, Ouifiya Kafif, Florentia Kaguelidou, Sabina Kali, Deepjyoti Kalita, Karl Trygve Kalleberg, Christiana Kartsonaki, Seán Keating, Sadie Kelly, Kalynn Kennon, Younes Kerroumi, Antoine Khalil, Saye Khoo, Beathe Kiland Granerud, Anders Benjamin Kildal, Antoine Kimmoun, Eyrun Floerecke Kjetland Kjetland, Paul Klenerman, Gry Kloumann Bekken, Stephen R Knight, Arsène Kpangon, Oksana Kruglova, Galyna Kutsyna, Marie Lachatre, Marie Lacoste, Nadhem Lafhej, Marie Lagrange, Fabrice Laine, Olivier Lairez, Antonio Lalueza, Marc Lambert, Marie Langelot-Richard, Vincent Langlois, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Jennifer Lee, Gary Leeming, Laurent Lefebvre, Bénédicte Lefebvre, Benjamin Lefèvre, Sylvie LeGac, Jean-Daniel Lelievre, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Marc Leone, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Sophie Letrou, Yves Levy, Bruno Levy, Claire Levy-Marchal, Erwan L'Her, Geoffrey Liegeon, Wei Shen Lim, Bruno Lina, Andreas Lind, Guillaume Lingas, Sylvie Lion-Daolio, Marine Livrozet, Paul Loubet, Bouchra Loufti, Guillame Louis, Jean Christophe Lucet, Carlos Lumbreras Bermejo, Miles Lunn, Liem Luong, Dominique Luton, Moïse Machado, Gabriel Macheda, Guillermo Maestro de la Calle, Rafael Mahieu, Sophie Mahy, Mylène Maillet, Thomas Maitre, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Julie Mankikian, Aldric Manuel, Samuel Markowicz, John Marshall, Guillaume Martin-Blondel, Martin Martinot, Olga Martynenko, Mathieu Mattei, Laurence Maulin, Thierry Mazzoni, Colin McArthur, Sarah E McDonald, Kenneth A McLean, Cécile Mear-Passard, France Mentré, Alexander J Mentzer, Noémie Mercier, Emmanuelle Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Laura Merson, Roberta Meta, Agnès Meybeck, Alison M Meynert, Vanina Meysonnier, Mehdi Mezidi, Céline Michelanglei, Isabelle Michelet, Sarah Moore, Shona C Moore, Lina Morales Cely, Lucia Moro, Hugo Mouquet, Clara Mouton Perrot, Julien Moyet, Jimmy Mullaert, Fredrik Müller, Karl Erik Müller, Marlène Murris, Srinivas Murthy, Nadège Neant, Anthony Nghi, Duc Nguyen, Alistair D Nichol, Mahdad Noursadeghi, Saad Nseir, Elsa Nyamankolly, Anders Benteson Nygaard, Piero L Olliaro, Wilna Oosthuyzen, Peter Openshaw, Claudia Milena Orozco-Chamorro, Paul Otiku, Nadia Ouamara, Rachida Ouissa, Eric Oziol, Maïder Pagadoy, Justine Pages, Massimo Palmarini, Prasan Kumar Panda, Nathalie Pansu, Aurélie Papadopoulos, Rachael Parke, Jérémie Pasquier, Bruno Pastene, Christelle Paul, William A Paxton, Jean-François Payen, Miguel Pedrera Jiménez, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Daniel Perez, Thomas Perpoint, Vincent Pestre, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Walter Picard, Olivier Picone, Lionel Piroth, Chiara Piubelli, Riinu Pius, Laurent Plantier, Julien Poissy, Ryadh Pokeerbux, Georgios Pollakis, Diane Ponscarme, Sébastien Preau, Mark G Pritchard, Víctor Quirós González, Else Quist-Paulsen, Christian Rabaud, Marie Rafiq, Blandine Rammaert, Christophe Rapp, Stanislas Rebaudet, Sarah Redl, Dag Henrik Reikvam, Martine Remy, Anne-Sophie Resseguier, Matthieu Revest, Luis Felipe Reyes, Antonia Ricchiuto, Laurent Richier, Patrick Rispal, Karine Risso, Stephanie Roberts, David L Robertson, Olivier Robineau, Paola Rodari, Pierre-Marie Roger, Amanda Rojek, Roberto Roncon-Albuquerque, Mélanie Roriz, Manuel Rosa-Calatrava, Andrea Rossanese, Patrick Rossignol, Carine Roy, Benoît Roze, Clark D Russell, Aleksander Rygh Holten, Charlotte Salmon Gandonniere, Hélène Salvator, Olivier Sanchez, Vanessa Sancho-Shimizu, Pierre-François Sandrine, Oana Sandulescu, Benjamine Sarton, Egle Saviciute, Arnaud Scherpereel, Marion Schneider, Janet T Scott, James Scott-Brown, Nicholas Sedillot, Malcolm G Semple, Eric Senneville, Pablo Serrano Balazote, Catherine A Shaw, Victoria Shaw, Girish Sindhwani, Nassima Si Mohammed, Jeanne Sibiude, Louise Sigfrid, Dario Sinatti, Vegard Skogen, Sue Smith, Lene Bergendal Solberg, Tom Solomon, Agnès Sommet, Arne Søraas, Albert Sotto, Edouard Soum, Elisabetta Spinuzza, Shiranee Sriskandan, Sarah Stabler, Trude Steinsvik, Birgitte Stiksrud, Adrian Streinu-Cercel, Anca Streinu-Cercel, David Stuart, Richa Su, Charlotte Summers, Lysa Tagherset, Renaud Tamisier, Coralie Tardivon, Pierre Tattevin, Marie-Capucine Tellier, François Téoulé, Olivier Terrier, Nicolas Terzi, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Emma C Thomson, Mathew Thorpe, Ryan S Thwaites, Vadim Tieroshyn, Jean-François Timsit, Noémie Tissot, Kristian Tonby, Cécile Tromeur, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Jean-Marie Turmel, Lance C W Turtle, Anders Tveita, Timothy M Uyeki, Piero Valentini, Sylvie Van Der Werf, Noémie Vanel, Charline Vauchy, Aurélie Veislinger, Benoit Visseaux, Fanny Vuotto, Steve Webb, Jia Wei, Murray Wham, Paul Henri Wicky, Aurélie Wiedemann, Natalie Wright, Yazdan Yazdanpanah, Cécile Yelnik, Hodane Yonis, Marion Zabbe, Maria Zambon, David Zucman,- Neurology
- Cellular and Molecular Neuroscience
- Biological Psychiatry
- Psychiatry and Mental health
Abstract
Although it is known that COVID-19 can present with a range of neurological manifestations and in-hospital complications, sparse data exist if these initial neurological symptoms of COVID-19 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (PANSC) and if female versus male sex impacts the symptom resolution. In this international, multicentre, prospective observational study across 407 sites from 15 countries (January/30th/2020-April/30th/2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time.
PANSC included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia, and muscle aches/joint pain, which were collected at the index hospitalization and during the follow-up assessments. The analysis considered time to resolution of individual and all neurological symptoms. Resulting times were modeled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. Model results were summarized as cumulative probability functions and age- and sex-adjusted median times to resolution.
We included 6,862 hospitalized adults with COVID-19, who had follow-up assessments. The median age of participants was 57 years (39.2% females). Males and females had similar baseline characteristics except that more males (vs. females) were admitted to Intensive Care Unit (30.5% vs. 20.3%) and received mechanical ventilation (17.2% vs. 11.8%).
Approximately 70% of patients had multiple neurological symptoms at the first follow-up (median=102 days). Fatigue (49.9%) and myalgia/arthralgia (45.2%) were the most prevalent symptoms of PANSC at the initial follow-up. Reported prevalence in females was generally higher (vs. males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, though fatigue, altered consciousness, and myalgia remained unresolved in >10% of the cohort. Females had a longer time to resolution (5.2 vs. 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom.
In multivariable analysis, males were associated with a shorter time to resolution of symptoms (Hazard Ratio=1.53; 95% Confidence Interval =1.39–1.69). Intensive Care Unit admission was associated with a longer time to the resolution of symptoms (Hazard Ratio =0.68; 95% Confidence Interval=0.60–0.77). Post-discharge stroke was uncommon (0.3% in females; 0.5% in males).
Despite the methodological challenges of survey data, this international multicentre prospective cohort study demonstrates that PANSC following index hospitalization is high. Symptom prevalence was higher and took longer to resolve in females than in males. This supports that whilst males were sicker during acute illness, females were disproportionately affected by PANSC.