Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after coronavirus disease 2019 hospitalization: an international multi-centre prospective observational study
Authors: Cho Sung-Min , Premraj Lavienraj , Battaglini Denise , Fanning Jonathon Paul , Suen Jacky , Bassi Gianluigi Li , Fraser John , Robba Chiara , Griffee Matthew , Solomon Tom , Semple Malcolm G , Baillie Kenneth , Sigfrid Louise , Scott Janet T , Citarella Barbara Wanjiru , Merson Laura , Arora Rakesh C , Whitman Glenn , Thomson David , White Nicole ,   ISARIC Clinical Characterization Group, Abel Laurent , Abrous Amal , Jabal Kamal Abu , Zayyad Hiba Abu , Tamlihat Younes Ait , Alameen Aliya Mohammed , Alessi Marta , Alex Beatrice , Alexandre Kévin , Ali Adam , Alidjnou Kazali Enagnon , Allavena Clotilde , Allou Nathalie , Andréjak Claire , Angheben Andrea , Angoulvant François , Ansart Séverine , Arlet Jean-Benoît , Artaud-Macari Elise , Assie Jean Baptiste , Auchabie Johann , Aumaitre Hugues , Auvet Adrien , Axelsen Eyvind W , Azemar Laurène , Azoulay Cecile , Bach Benjamin , Bachelet Delphine , Badr Claudine , Bævre-Jensen Roar , Baillie John Kenneth , Bani-Sadr Firouzé , Barclay Wendy S , Bartoli Marie , Baruch Joaquín , Basmaci Romain , Bauer Jules , Bedossa Alexandra , Begum Husna , Behilill Sylvie , Beltrame Anna , Beluze Marine , Benech Nicolas , Bergeaud Delphine , Sobrino José Luis Bernal , Bertoli Giulia , Bessis Simon , Bevilcaqua Sybille , Bezulier Karine , Bhavsar Krishna , Bisoffi Zeno , Bitker Laurent , Blot Mathieu , Bodenes Laetitia , Bogaert Debby , Boivin Anne-Hélène , Bolaños Isabela , Bolze Pierre-Adrien , Bompart François , Borie Raphaël , Botelho-Nevers Elisabeth , Bouadma Lila , Bouchaud Olivier , Bouchez Sabelline , Bouhour Damien , Bouiller Kévin , Bouillet Laurence , Bouisse Camile , Boureau Anne-Sophie , Bouscambert Maude , Bousquet Aurore , Boyer-Besseyre Marielle , Braconnier Axelle , Brunvoll Sonja Hjellegjerde , Buisson Marielle , Buonsenso Danilo , Burrell Aidan , Bustos Ingrid G , Cabie André , Caceres Eder , Cadoz Cyril , Calvache Jose Andres , Campana Valentine , Caraux-Paz Pauline , Carlier Nicolas , Carmoi Thierry , Carret Marie-Christine , Carson Gail , Casanova Maire-Laure , Castor-Alexandre Guylaine , Catherine François-Xavier , Cattaneo Paolo , Cervantes-Gonzalez Minerva , Chair Anissa , Chakveatze Catherine , Chand Meera , Chapplain Jean-Marc , Charpentier Charlotte , Chas Julie , Chenard Léo , Cheret Antoine , Chiarabini Thibault , Chirouze Catherine , Cholley Bernard , Chopin Marie-Charlotte , Chow Yock Ping , Citarella Barbara Wanjiru , Clohisey Sara , Colin Gwenhaël , Connor Marie , Conrad Anne , Cooke Graham S , Cordel Hugues , Cortegiani Andrea , Corvaisier Grégory , Couffignal Camille , Couffin-Cadiergues Sandrine , Courtois Roxane , Cousse Stéphanie , Bermúdez Juan Luis Cruz , Rojo Jaime Cruz , Curlier Elodie , da Silva Filipe Ana , Da Silveira Charlene , Dagens Andrew , Dahl John Arne , Dalton Jo , De Montmollin Etienne , De Rose Cristina , de Silva Thushan , Debard Alexa , Debray Marie-Pierre , DeCastro Nathalie , Decours Romain , Defous Eve , Delacroix Isabelle , Delaveuve Eric , Delavigne Karen , Delmas Christelle , Delobel Pierre , Demonchy Elisa , Denis Emmanuelle , Deplanque Dominique , Descamps Diane , Desvallées Mathilde , Diallo Alpha , Diamantis Sylvain , Da Silva Fernanda Dias , Didier Kévin , Diehl Jean-Luc , Dimet Jérôme , Dinot Vincent , Diop Fara , Diouf Alphonsine , Djossou Félix , Docherty Annemarie B , Donnelly Christl A , Dorival Céline , D'Ortenzio Eric , Dournon Nathalie , Drake Thomas , Dror Amiel A , Dubee Vincent , Dubos François , Ducancelle Alexandre , Dudman Susanne , Dunand Paul , Dunning Jake , Dussol Bertrand , Duval Xavier , Dyrhol-Riise Anne Margarita , Edelstein Michael , Eggesbø Linn Margrete , Sanharawi Mohammed El , Elharrar Brigitte , Ellingjord-Dale Merete , Eloy Philippine , Enderle Isabelle , Engelmann Ilka , Enouf Vincent , Epaulard Olivier , Esperou Hélène , Esposito-Farese Marina , Etienne Manuel , Evers Mirjam , Fabre Marc , Fabre Isabelle , Fairfield Cameron J , Faure Karine , Favory Raphaël , Ferrand François-Xavier , Devouge Eglantine Ferrand , Ferriere Nicolas , Ficko Céline , Finlayson William , Flament Thomas , Fletcher Tom , Florence Aline-Marie , Fourn Erwan , Fowler Robert A , Fraser Christophe , Fry Stéphanie , Gaborieau Valérie , Gaci Rostane , Gagnard Jean-Charles , Gagneux-Brunon Amandine , Gaião Sérgio , Skeie Linda Gail , Gamble Carrol , Barrio Noelia García , Garcia-Gallo Esteban , Garot Denis , Garrait Valérie , Gavrylov Anatoliy , Gaymard Alexandre , Geraud Eva , Morlaes Louis Gerbaud , Ghosn Jade , Gigante Tristan , Giordano Guillermo , Girvan Michelle , Gissot Valérie , Glikman Daniel , Goehringer François , Gomez Kyle , Gominet Marie , Gorelik Yanay , Gorenne Isabelle , Goubert Laure , Goujard Cécile , Goulenok Tiphaine , Granier Pascal , Green Christopher A , Greenhalf William , Greffe Segolène , Griffiths Fiona , Guedj Jérémie , Guego Martin , Guery Romain , Guillaumot Anne , Guilleminault Laurent , Guimard Thomas , Hachemi Ali , Hadri Nadir , Hall Matthew , Halpin Sophie , Hamidfar Rebecca , Hammarström Bato , Hardwick Hayley , Harrison Ewen M , Harrison Janet , Heggelund Lars , Hendry Ross , Hentzien Maxime , Hernandez Diana , Hesstvedt Liv , Higgins Rupert , Hitoto Hikombo , Ho Antonia , Hoctin Alexandre , Hoffmann Isabelle , Holter Jan Cato , Horby Peter , Houas Ikram , Hulot Jean-Sébastien , Ijaz Samreen , Imbert Patrick , Ippolito Mariachiara , Isnard Margaux , Istre Mette Stausland , Jaafar Danielle , Jaafoura Salma , Jabot Julien , Jackson Clare , Jaureguiberry Stéphane , Jego Florence , Jenum Synne , Jørgensen Silje Bakken , Joseph Cédric , Jourdain Mercé , Kafif Ouifiya , Kaguelidou Florentia , Kali Sabina , Kalita Deepjyoti , Kalleberg Karl Trygve , Kartsonaki Christiana , Keating Seán , Kelly Sadie , Kennon Kalynn , Kerroumi Younes , Khalil Antoine , Khoo Saye , Granerud Beathe Kiland , Kildal Anders Benjamin , Kimmoun Antoine , Kjetland Eyrun Floerecke Kjetland , Klenerman Paul , Bekken Gry Kloumann , Knight Stephen R , Kpangon Arsène , Kruglova Oksana , Kutsyna Galyna , Lachatre Marie , Lacoste Marie , Lafhej Nadhem , Lagrange Marie , Laine Fabrice , Lairez Olivier , Lalueza Antonio , Lambert Marc , Langelot-Richard Marie , Langlois Vincent , Laouénan Cédric , Laribi Samira , Lariviere Delphine , Lasry Stéphane , Launay Odile , Laureillard Didier , Lavie-Badie Yoan , Law Andy , Le Minh , Le Bihan Clément , Le Bris Cyril , Le Falher Georges , Le Fevre Lucie , Le Hingrat Quentin , Le Maréchal Marion , Le Mestre Soizic , Le Moal Gwenaël , Le Moing Vincent , Le Nagard Hervé , Lee Jennifer , Leeming Gary , Lefebvre Laurent , Lefebvre Bénédicte , Lefèvre Benjamin , LeGac Sylvie , Lelievre Jean-Daniel , Lemaignen Adrien , Lemee Véronique , Lemeur Anthony , Leone Marc , Lepiller Quentin , Lescure François-Xavier , Lesens Olivier , Lesouhaitier Mathieu , Letrou Sophie , Levy Yves , Levy Bruno , Levy-Marchal Claire , L'Her Erwan , Liegeon Geoffrey , Lim Wei Shen , Lina Bruno , Lind Andreas , Lingas Guillaume , Lion-Daolio Sylvie , Livrozet Marine , Loubet Paul , Loufti Bouchra , Louis Guillame , Lucet Jean Christophe , Bermejo Carlos Lumbreras , Lunn Miles , Luong Liem , Luton Dominique , Machado Moïse , Macheda Gabriel , de la Calle Guillermo Maestro , Mahieu Rafael , Mahy Sophie , Maillet Mylène , Maitre Thomas , Malvy Denis , Manda Victoria , Mandelbrot Laurent , Mankikian Julie , Manuel Aldric , Markowicz Samuel , Marshall John , Martin-Blondel Guillaume , Martinot Martin , Martynenko Olga , Mattei Mathieu , Maulin Laurence , Mazzoni Thierry , McArthur Colin , McDonald Sarah E , McLean Kenneth A , Mear-Passard Cécile , Mentré France , Mentzer Alexander J , Mercier Noémie , Mercier Emmanuelle , Merckx Antoine , Mergeay-Fabre Mayka , Merson Laura , Meta Roberta , Meybeck Agnès , Meynert Alison M , Meysonnier Vanina , Mezidi Mehdi , Michelanglei Céline , Michelet Isabelle , Moore Sarah , Moore Shona C , Cely Lina Morales , Moro Lucia , Mouquet Hugo , Perrot Clara Mouton , Moyet Julien , Mullaert Jimmy , Müller Fredrik , Müller Karl Erik , Murris Marlène , Murthy Srinivas , Neant Nadège , Nghi Anthony , Nguyen Duc , Nichol Alistair D , Noursadeghi Mahdad , Nseir Saad , Nyamankolly Elsa , Nygaard Anders Benteson , Olliaro Piero L , Oosthuyzen Wilna , Openshaw Peter , Orozco-Chamorro Claudia Milena , Otiku Paul , Ouamara Nadia , Ouissa Rachida , Oziol Eric , Pagadoy Maïder , Pages Justine , Palmarini Massimo , Panda Prasan Kumar , Pansu Nathalie , Papadopoulos Aurélie , Parke Rachael , Pasquier Jérémie , Pastene Bruno , Paul Christelle , Paxton William A , Payen Jean-François , Jiménez Miguel Pedrera , Peelman Florent , Peiffer-Smadja Nathan , Peigne Vincent , Perez Daniel , Perpoint Thomas , Pestre Vincent , Petrov-Sanchez Ventzislava , Pettersen Frank Olav , Peytavin Gilles , Picard Walter , Picone Olivier , Piroth Lionel , Piubelli Chiara , Pius Riinu , Plantier Laurent , Poissy Julien , Pokeerbux Ryadh , Pollakis Georgios , Ponscarme Diane , Preau Sébastien , Pritchard Mark G , González Víctor Quirós , Quist-Paulsen Else , Rabaud Christian , Rafiq Marie , Rammaert Blandine , Rapp Christophe , Rebaudet Stanislas , Redl Sarah , Reikvam Dag Henrik , Remy Martine , Resseguier Anne-Sophie , Revest Matthieu , Reyes Luis Felipe , Ricchiuto Antonia , Richier Laurent , Rispal Patrick , Risso Karine , Roberts Stephanie , Robertson David L , Robineau Olivier , Rodari Paola , Roger Pierre-Marie , Rojek Amanda , Roncon-Albuquerque Roberto , Roriz Mélanie , Rosa-Calatrava Manuel , Rossanese Andrea , Rossignol Patrick , Roy Carine , Roze Benoît , Russell Clark D , Holten Aleksander Rygh , Gandonniere Charlotte Salmon , Salvator Hélène , Sanchez Olivier , Sancho-Shimizu Vanessa , Sandrine Pierre-François , Sandulescu Oana , Sarton Benjamine , Saviciute Egle , Scherpereel Arnaud , Schneider Marion , Scott Janet T , Scott-Brown James , Sedillot Nicholas , Semple Malcolm G , Senneville Eric , Balazote Pablo Serrano , Shaw Catherine A , Shaw Victoria , Sindhwani Girish , Mohammed Nassima Si , Sibiude Jeanne , Sigfrid Louise , Sinatti Dario , Skogen Vegard , Smith Sue , Solberg Lene Bergendal , Solomon Tom , Sommet Agnès , Søraas Arne , Sotto Albert , Soum Edouard , Spinuzza Elisabetta , Sriskandan Shiranee , Stabler Sarah , Steinsvik Trude , Stiksrud Birgitte , Streinu-Cercel Adrian , Streinu-Cercel Anca , Stuart David , Su Richa , Summers Charlotte , Tagherset Lysa , Tamisier Renaud , Tardivon Coralie , Tattevin Pierre , Tellier Marie-Capucine , Téoulé François , Terrier Olivier , Terzi Nicolas , Thibault Vincent , Thiberville Simon-Djamel , Thill Benoît , Thomson Emma C , Thorpe Mathew , Thwaites Ryan S , Tieroshyn Vadim , Timsit Jean-François , Tissot Noémie , Tonby Kristian , Tromeur Cécile , Trouillon Tiffany , Truong Jeanne , Tual Christelle , Tubiana Sarah , Turmel Jean-Marie , Turtle Lance C W , Tveita Anders , Uyeki Timothy M , Valentini Piero , Van Der Werf Sylvie , Vanel Noémie , Vauchy Charline , Veislinger Aurélie , Visseaux Benoit , Vuotto Fanny , Webb Steve , Wei Jia , Wham Murray , Wicky Paul Henri , Wiedemann Aurélie , Wright Natalie , Yazdanpanah Yazdan , Yelnik Cécile , Yonis Hodane , Zabbe Marion , Zambon Maria , Zucman David 
Published: February 2024

Abstract
Although it is known that coronavirus disease 2019 can present with a range of neurological manifestations and in-hospital complications, sparse data exist on whether these initial neurological symptoms of coronavirus disease 2019 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; PANSC) and whether female versus male sex impacts symptom resolution. In this international, multi-centre, prospective, observational study across 407 sites from 15 countries (30 January 2020 to 30 April 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 symptoms included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia and muscle ache/joint pain, on which information was collected at index hospitalization and during follow-up assessments. The analysis considered a time to the resolution of individual and all neurological symptoms. The resulting times were modelled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. The model results were summarized as cumulative probability functions and age-adjusted and sex-adjusted median times to resolution. We included 6862 hospitalized adults with coronavirus disease 2019, who had follow-up assessments. The median age of the participants was 57 years (39.2% females). Males and females had similar baseline characteristics, except that more males (versus females) were admitted to the intensive care unit (30.5 versus 20.3%) and received mechanical ventilation (17.2 versus 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. The reported prevalence in females was generally higher (versus males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, although fatigue, altered consciousness and myalgia remained unresolved in &gt;10% of the cohort. Females had a longer time to the resolution (5.2 versus 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom. In the multivariable analysis, males were associated with a shorter time to the 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 and 0.5% in males). Despite the methodological challenges involved in the collection of survey data, this international multi-centre prospective cohort study demonstrated that PANSC following index hospitalization was high. Symptom prevalence was higher and took longer to resolve in females than in males. This supported the fact that while males were sicker during acute illness, females were disproportionately affected by PANSC.