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
Cho S-M., Premraj L., Battaglini D., Fanning JP., Suen J., Bassi GL., Fraser J., Robba C., Griffee M., Solomon T., Semple MG., Baillie K., Sigfrid L., Scott JT., Citarella BW., Merson L., Arora RC., Whitman G., Thomson D., White N., Abel L., Abrous A., Jabal KA., Zayyad HA., Tamlihat YA., Alameen AM., Alessi M., Alex B., Alexandre K., Ali A., Alidjnou KE., Allavena C., Allou N., Andréjak C., Angheben A., Angoulvant F., Ansart S., Arlet J-B., Artaud-Macari E., Assie JB., Auchabie J., Aumaitre H., Auvet A., Axelsen EW., Azemar L., Azoulay C., Bach B., Bachelet D., Badr C., Bævre-Jensen R., Baillie JK., Bani-Sadr F., Barclay WS., Bartoli M., Baruch J., Basmaci R., Bauer J., Bedossa A., Begum H., Behilill S., Beltrame A., Beluze M., Benech N., Bergeaud D., Sobrino JLB., Bertoli G., Bessis S., Bevilcaqua S., Bezulier K., Bhavsar K., Bisoffi Z., Bitker L., Blot M., Bodenes L., Bogaert D., Boivin A-H., Bolaños I., Bolze P-A., Bompart F., Borie R., Botelho-Nevers E., Bouadma L., Bouchaud O., Bouchez S., Bouhour D., Bouiller K., Bouillet L., Bouisse C., Boureau A-S., Bouscambert M., Bousquet A., Boyer-Besseyre M., Braconnier A., Brunvoll SH., Buisson M., Buonsenso D., Burrell A., Bustos IG., Cabie A., Caceres E., Cadoz C., Calvache JA., Campana V., Caraux-Paz P., Carlier N., Carmoi T., Carret M-C., Carson G., Casanova M-L., Castor-Alexandre G., Catherine F-X., Cattaneo P., Cervantes-Gonzalez M., Chair A., Chakveatze C., Chand M., Chapplain J-M., Charpentier C., Chas J., Chenard L., Cheret A., Chiarabini T., Chirouze C., Cholley B., Chopin M-C., Chow YP., Citarella BW., Clohisey S., Colin G., Connor M., Conrad A., Cooke GS., Cordel H., Cortegiani A., Corvaisier G., Couffignal C., Couffin-Cadiergues S., Courtois R., Cousse S., Bermúdez JLC., Rojo JC., Curlier E., da Silva Filipe A., Da Silveira C., Dagens A., Dahl JA., Dalton J., De Montmollin E., De Rose C., de Silva T., Debard A., Debray M-P., DeCastro N., Decours R., Defous E., Delacroix I., Delaveuve E., Delavigne K., Delmas C., Delobel P., Demonchy E., Denis E., Deplanque D., Descamps D., Desvallées M., Diallo A., Diamantis S., Da Silva FD., Didier K., Diehl J-L., Dimet J., Dinot V., Diop F., Diouf A., Djossou F., Docherty AB., Donnelly CA., Dorival C., D'Ortenzio E., Dournon N., Drake T., Dror AA., Dubee V., Dubos F., Ducancelle A., Dudman S., Dunand P., Dunning J., Dussol B., Duval X., Dyrhol-Riise AM., Edelstein M., Eggesbø LM., Sanharawi ME., Elharrar B., Ellingjord-Dale M., Eloy P., Enderle I., Engelmann I., Enouf V., Epaulard O., Esperou H., Esposito-Farese M., Etienne M., Evers M., Fabre M., Fabre I., Fairfield CJ., Faure K., Favory R., Ferrand F-X., Devouge EF., Ferriere N., Ficko C., Finlayson W., Flament T., Fletcher T., Florence A-M., Fourn E., Fowler RA., Fraser C., Fry S., Gaborieau V., Gaci R., Gagnard J-C., Gagneux-Brunon A., Gaião S., Skeie LG., Gamble C., Barrio NG., Garcia-Gallo E., Garot D., Garrait V., Gavrylov A., Gaymard A., Geraud E., Morlaes LG., Ghosn J., Gigante T., Giordano G., Girvan M., Gissot V., Glikman D., Goehringer F., Gomez K., Gominet M., Gorelik Y., Gorenne I., Goubert L., Goujard C., Goulenok T., Granier P., Green CA., Greenhalf W., Greffe S., Griffiths F., Guedj J., Guego M., Guery R., Guillaumot A., Guilleminault L., Guimard T., Hachemi A., Hadri N., Hall M., Halpin S., Hamidfar R., Hammarström B., Hardwick H., Harrison EM., Harrison J., Heggelund L., Hendry R., Hentzien M., Hernandez D., Hesstvedt L., Higgins R., Hitoto H., Ho A., Hoctin A., Hoffmann I., Holter JC., Horby P., Houas I., Hulot J-S., Ijaz S., Imbert P., Ippolito M., Isnard M., Istre MS., Jaafar D., Jaafoura S., Jabot J., Jackson C., Jaureguiberry S., Jego F., Jenum S., Jørgensen SB., Joseph C., Jourdain M., Kafif O., Kaguelidou F., Kali S., Kalita D., Kalleberg KT., Kartsonaki C., Keating S., Kelly S., Kennon K., Kerroumi Y., Khalil A., Khoo S., Granerud BK., Kildal AB., Kimmoun A., Kjetland EFK., Klenerman P., Bekken GK., Knight SR., Kpangon A., Kruglova O., Kutsyna G., Lachatre M., Lacoste M., Lafhej N., Lagrange M., Laine F., Lairez O., Lalueza A., Lambert M., Langelot-Richard M., Langlois V., Laouénan C., Laribi S., Lariviere D., Lasry S., Launay O., Laureillard D., Lavie-Badie Y., Law A., Le M., Le Bihan C., Le Bris C., Le Falher G., Le Fevre L., Le Hingrat Q., Le Maréchal M., Le Mestre S., Le Moal G., Le Moing V., Le Nagard H., Lee J., Leeming G., Lefebvre L., Lefebvre B., Lefèvre B., LeGac S., Lelievre J-D., Lemaignen A., Lemee V., Lemeur A., Leone M., Lepiller Q., Lescure F-X., Lesens O., Lesouhaitier M., Letrou S., Levy Y., Levy B., Levy-Marchal C., L'Her E., Liegeon G., Lim WS., Lina B., Lind A., Lingas G., Lion-Daolio S., Livrozet M., Loubet P., Loufti B., Louis G., Lucet JC., Bermejo CL., Lunn M., Luong L., Luton D., Machado M., Macheda G., de la Calle GM., Mahieu R., Mahy S., Maillet M., Maitre T., Malvy D., Manda V., Mandelbrot L., Mankikian J., Manuel A., Markowicz S., Marshall J., Martin-Blondel G., Martinot M., Martynenko O., Mattei M., Maulin L., Mazzoni T., McArthur C., McDonald SE., McLean KA., Mear-Passard C., Mentré F., Mentzer AJ., Mercier N., Mercier E., Merckx A., Mergeay-Fabre M., Merson L., Meta R., Meybeck A., Meynert AM., Meysonnier V., Mezidi M., Michelanglei C., Michelet I., Moore S., Moore SC., Cely LM., Moro L., Mouquet H., Perrot CM., Moyet J., Mullaert J., Müller F., Müller KE., Murris M., Murthy S., Neant N., Nghi A., Nguyen D., Nichol AD., Noursadeghi M., Nseir S., Nyamankolly E., Nygaard AB., Olliaro PL., Oosthuyzen W., Openshaw P., Orozco-Chamorro CM., Otiku P., Ouamara N., Ouissa R., Oziol E., Pagadoy M., Pages J., Palmarini M., Panda PK., Pansu N., Papadopoulos A., Parke R., Pasquier J., Pastene B., Paul C., Paxton WA., Payen J-F., Jiménez MP., Peelman F., Peiffer-Smadja N., Peigne V., Perez D., Perpoint T., Pestre V., Petrov-Sanchez V., Pettersen FO., Peytavin G., Picard W., Picone O., Piroth L., Piubelli C., Pius R., Plantier L., Poissy J., Pokeerbux R., Pollakis G., Ponscarme D., Preau S., Pritchard MG., González VQ., Quist-Paulsen E., Rabaud C., Rafiq M., Rammaert B., Rapp C., Rebaudet S., Redl S., Reikvam DH., Remy M., Resseguier A-S., Revest M., Reyes LF., Ricchiuto A., Richier L., Rispal P., Risso K., Roberts S., Robertson DL., Robineau O., Rodari P., Roger P-M., Rojek A., Roncon-Albuquerque R., Roriz M., Rosa-Calatrava M., Rossanese A., Rossignol P., Roy C., Roze B., Russell CD., Holten AR., Gandonniere CS., Salvator H., Sanchez O., Sancho-Shimizu V., Sandrine P-F., Sandulescu O., Sarton B., Saviciute E., Scherpereel A., Schneider M., Scott JT., Scott-Brown J., Sedillot N., Semple MG., Senneville E., Balazote PS., Shaw CA., Shaw V., Sindhwani G., Mohammed NS., Sibiude J., Sigfrid L., Sinatti D., Skogen V., Smith S., Solberg LB., Solomon T., Sommet A., Søraas A., Sotto A., Soum E., Spinuzza E., Sriskandan S., Stabler S., Steinsvik T., Stiksrud B., Streinu-Cercel A., Streinu-Cercel A., Stuart D., Su R., Summers C., Tagherset L., Tamisier R., Tardivon C., Tattevin P., Tellier M-C., Téoulé F., Terrier O., Terzi N., Thibault V., Thiberville S-D., Thill B., Thomson EC., Thorpe M., Thwaites RS., Tieroshyn V., Timsit J-F., Tissot N., Tonby K., Tromeur C., Trouillon T., Truong J., Tual C., Tubiana S., Turmel J-M., Turtle LCW., Tveita A., Uyeki TM., Valentini P., Van Der Werf S., Vanel N., Vauchy C., Veislinger A., Visseaux B., Vuotto F., Webb S., Wei J., Wham M., Wicky PH., Wiedemann A., Wright N., Yazdanpanah Y., Yelnik C., Yonis H., Zabbe M., Zambon M., Zucman D.
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 >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.