{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T07:07:36Z","timestamp":1782457656868,"version":"3.54.5"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81572893"],"award-info":[{"award-number":["81572893"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972358"],"award-info":[{"award-number":["81972358"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["91959113"],"award-info":[{"award-number":["91959113"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Foundation of Wuhan Huoshenshan Hospital","award":["2020[18]"],"award-info":[{"award-number":["2020[18]"]}]},{"name":"Key Research& Development Program of Jiangsu Province","award":["BE2018713"],"award-info":[{"award-number":["BE2018713"]}]},{"name":"Key Research& Development Program of Jiangsu Province","award":["BE2017733"],"award-info":[{"award-number":["BE2017733"]}]},{"name":"Medical Innovation Project of Logistics Service","award":["18JS005"],"award-info":[{"award-number":["18JS005"]}]},{"DOI":"10.13039\/501100005145","name":"Basic Research Program of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20180036"],"award-info":[{"award-number":["BK20180036"]}],"id":[{"id":"10.13039\/501100005145","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Infect Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Males and females differ in their immunological responses to foreign pathogens. However, most of the current COVID-19 clinical practices and trials do not take the sex factor into consideration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a sex-based comparative analysis for the clinical outcomes, peripheral immune cells, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) specific antibody levels of 1558 males and 1499 females COVID-19 patients from a single center. The lymphocyte subgroups were measured by Flow cytometry. The total antibody, Spike protein (S)-, receptor binding domain (RBD)-, and nucleoprotein (N)- specific IgM and IgG levels were measured by chemiluminescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that male patients had approximately two-fold rates of ICU admission (4.7% vs. 2.7% in males and females, respectively,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.005) and mortality (3% vs. 1.4%, in males and females, respectively,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.004) than female patients. Survival analysis revealed that the male sex is an independent risk factor for death from COVID-19 (adjusted hazard ratio [HR]\u2009=\u20092.22, 95% confidence interval [CI]: 1.3\u20133.6,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.003). The level of inflammatory cytokines in peripheral blood was higher in males during hospitalization. The renal (102\/1588 [6.5%] vs. 63\/1499 [4.2%], in males and females, respectively,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.002) and hepatic abnormality (650\/1588 [40.9%] vs. 475\/1499 [31.7%],\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.003) were more common in male patients than in female patients. By analyzing dynamic changes of lymphocyte subsets after symptom onset, we found that the percentage of CD19+ B cells and CD4+ T cells was generally higher in female patients during the disease course of COVID-19. Notably, the protective RBD-specific IgG against SARS-CoV-2 sharply increased and reached a peak in the fourth week after symptom onset in female patients, while gradually increased and reached a peak in the seventh week after symptom onset in male patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Males had an unfavorable prognosis, higher inflammation, a lower percentage of lymphocytes, and indolent antibody responses during SARS-CoV-2 infection and recovery. Early medical intervention and close monitoring are important, especially for male COVID-19 patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12879-021-06313-2","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T09:02:45Z","timestamp":1625475765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Sex-based clinical and immunological differences in COVID-19"],"prefix":"10.1186","volume":"21","author":[{"given":"Bin","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kening","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanlin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shukui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongshan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3488-1059","authenticated-orcid":false,"given":"Qianghu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"issue":"13","key":"6313_CR1","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1001\/jama.2020.2648","volume":"323","author":"Z Wu","year":"2020","unstructured":"Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239\u201342. https:\/\/doi.org\/10.1001\/jama.2020.2648.","journal-title":"JAMA"},{"issue":"16","key":"6313_CR2","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1001\/jama.2020.5394","volume":"323","author":"G Grasselli","year":"2020","unstructured":"Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA. 2020;323(16):1574\u201381. https:\/\/doi.org\/10.1001\/jama.2020.5394.","journal-title":"JAMA"},{"key":"6313_CR3","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.cca.2020.03.009","volume":"505","author":"R Liu","year":"2020","unstructured":"Liu R, Han H, Liu F, Lv ZH, Wu KL, Liu YL, et al. Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in Wuhan, China, from Jan to Feb 2020. Clin Chim Acta. 2020;505:172\u20135. https:\/\/doi.org\/10.1016\/j.cca.2020.03.009.","journal-title":"Clin Chim Acta"},{"issue":"18","key":"6313_CR4","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1056\/NEJMoa2002032","volume":"382","author":"G W-j","year":"2020","unstructured":"W-j G, Z-y N, Hu Y, Liang W-h, Ou C-q, He J-x, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708\u201320.","journal-title":"N Engl J Med"},{"issue":"8","key":"6313_CR5","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1056\/NEJMoa2001017","volume":"382","author":"N Zhu","year":"2020","unstructured":"Zhu N, Zhang DY, Wang WL, Li XW, Yang B, Song JD, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727\u201333. https:\/\/doi.org\/10.1056\/NEJMoa2001017.","journal-title":"N Engl J Med"},{"key":"6313_CR6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1365-3156.2008.02147.x","volume":"14","author":"N Jia","year":"2009","unstructured":"Jia N, Feng D, Fang LQ, Richardus JH, Han XN, Cao WC, et al. Case fatality of SARS in mainland China and associated risk factors. Trop Med Int Health. 2009;14:21\u20137. https:\/\/doi.org\/10.1111\/j.1365-3156.2008.02147.x.","journal-title":"Trop Med Int Health"},{"issue":"3","key":"6313_CR7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1093\/aje\/kwh056","volume":"159","author":"J Karlberg","year":"2004","unstructured":"Karlberg J, Chong DSY, Lai WYY. Do men have a higher case fatality rate of severe acute respiratory syndrome than women do? Am J Epidemiol. 2004;159(3):229\u201331. https:\/\/doi.org\/10.1093\/aje\/kwh056.","journal-title":"Am J Epidemiol"},{"key":"6313_CR8","doi-asserted-by":"crossref","unstructured":"Xie J, Tong Z, Guan X, Du B, Qiu H. Clinical characteristics of patients who died of coronavirus disease 2019 in China. Jama Netw Open. 2020;3(4):e205619-e205619.","DOI":"10.1001\/jamanetworkopen.2020.5619"},{"issue":"7","key":"6313_CR9","doi-asserted-by":"publisher","first-page":"3350","DOI":"10.1172\/JCI139306","volume":"130","author":"E Bischof","year":"2020","unstructured":"Bischof E, Wolfe J, Klein SL. Clinical trials for COVID-19 should include sex as a variable. J Clin Invest. 2020;130(7):3350\u20132. https:\/\/doi.org\/10.1172\/JCI139306.","journal-title":"J Clin Invest"},{"issue":"10","key":"6313_CR10","doi-asserted-by":"publisher","first-page":"4046","DOI":"10.4049\/jimmunol.1601896","volume":"198","author":"R Channappanavar","year":"2017","unstructured":"Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol. 2017;198(10):4046\u201353. https:\/\/doi.org\/10.4049\/jimmunol.1601896.","journal-title":"J Immunol"},{"key":"6313_CR11","doi-asserted-by":"crossref","unstructured":"Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, Silva J, Mao T, Oh JE, Tokuyama M. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315-320.","DOI":"10.1038\/s41586-020-2700-3"},{"key":"6313_CR12","doi-asserted-by":"publisher","unstructured":"Jin JM, Bai P, He W, Wu F, Liu XF, Han DM, et al. Gender differences in patients with COVID-19: focus on severity and mortality. Front Public Health. 2020;8. https:\/\/doi.org\/10.3389\/fpubh.2020.00152.","DOI":"10.3389\/fpubh.2020.00152"},{"issue":"15","key":"6313_CR13","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1093\/cid\/ciaa248","volume":"71","author":"C Qin","year":"2020","unstructured":"Qin C, Zhou LQ, Hu ZW, Zhang SQ, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762\u20138. https:\/\/doi.org\/10.1093\/cid\/ciaa248.","journal-title":"Clin Infect Dis"},{"issue":"1","key":"6313_CR14","first-page":"E6","volume":"81","author":"YW Liu","year":"2020","unstructured":"Liu YW, Du XB, Chen J, Jin YL, Peng L, Wang HHX, et al. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Inf Secur. 2020;81(1):E6\u2013E12.","journal-title":"J Inf Secur"},{"issue":"4","key":"6313_CR15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008520","volume":"16","author":"Y Meng","year":"2020","unstructured":"Meng Y, Wu P, Lu W, Liu K, Ma K, Huang L, et al. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: a retrospective study of 168 severe patients. PLoS Pathog. 2020;16(4):e1008520. https:\/\/doi.org\/10.1371\/journal.ppat.1008520.","journal-title":"PLoS Pathog"},{"issue":"10229","key":"6313_CR16","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","volume":"395","author":"P Mehta","year":"2020","unstructured":"Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033\u20134. https:\/\/doi.org\/10.1016\/S0140-6736(20)30628-0.","journal-title":"Lancet"},{"issue":"10","key":"6313_CR17","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","volume":"26","author":"DM Del Valle","year":"2020","unstructured":"Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636.","journal-title":"Nat Med"},{"issue":"6","key":"6313_CR18","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/j.immuni.2020.04.023","volume":"52","author":"L Ni","year":"2020","unstructured":"Ni L, Ye F, Cheng ML, Feng Y, Deng YQ, Zhao H, et al. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity. 2020;52(6):971.","journal-title":"Immunity"},{"issue":"3","key":"6313_CR19","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nri3804","volume":"15","author":"NS De Silva","year":"2015","unstructured":"De Silva NS, Klein U. Dynamics of B cells in germinal centres. Nat Rev Immunol. 2015;15(3):137\u201348. https:\/\/doi.org\/10.1038\/nri3804.","journal-title":"Nat Rev Immunol"},{"issue":"7","key":"6313_CR20","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.4049\/jimmunol.157.7.2947","volume":"157","author":"DJ Topham","year":"1996","unstructured":"Topham DJ, Tripp RA, Hamilton-Easton AM, Sarawar SR, Doherty PC. Quantitative analysis of the influenza virus-specific CD4+ T cell memory in the absence of B cells and Ig. J Immunol. 1996;157(7):2947\u201352.","journal-title":"J Immunol"},{"issue":"1","key":"6313_CR21","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1128\/JVI.72.1.882-885.1998","volume":"72","author":"DJ Topham","year":"1998","unstructured":"Topham DJ, Doherty PC. Clearance of an influenza a virus by CD4+ T cells is inefficient in the absence of B cells. J Virol. 1998;72(1):882\u20135. https:\/\/doi.org\/10.1128\/JVI.72.1.882-885.1998.","journal-title":"J Virol"},{"issue":"10","key":"6313_CR22","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/nri.2016.90","volume":"16","author":"SL Klein","year":"2016","unstructured":"Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626\u201338. https:\/\/doi.org\/10.1038\/nri.2016.90.","journal-title":"Nat Rev Immunol"},{"issue":"11","key":"6313_CR23","doi-asserted-by":"publisher","first-page":"6141","DOI":"10.1172\/JCI142004","volume":"130","author":"S Klein","year":"2020","unstructured":"Klein S, Pekosz A, Park HS, Ursin R, Shapiro J, Benner S, et al. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J Clin Invest. 2020;130(11):6141\u201350. https:\/\/doi.org\/10.1172\/JCI142004.","journal-title":"J Clin Invest"},{"issue":"6","key":"6313_CR24","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1038\/s41423-020-0400-4","volume":"17","author":"WB Tai","year":"2020","unstructured":"Tai WB, He L, Zhang XJ, Pu J, Voronin D, Jiang SB, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020;17(6):613\u201320. https:\/\/doi.org\/10.1038\/s41423-020-0400-4.","journal-title":"Cell Mol Immunol"},{"issue":"6","key":"6313_CR25","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1182\/blood.2020007079","volume":"136","author":"XY Xia","year":"2020","unstructured":"Xia XY, Li KN, Wu LX, Wang ZH, Zhu MY, Huang B, et al. Improved clinical symptoms and mortality among patients with severe or critical COVID-19 after convalescent plasma transfusion. Blood. 2020;136(6):755\u20139. https:\/\/doi.org\/10.1182\/blood.2020007079.","journal-title":"Blood"},{"key":"6313_CR26","doi-asserted-by":"crossref","unstructured":"Li KN, Huang B, Wu M, Zhong AF, Li L, Cai Y, et al. Dynamic changes in anti-SARS-CoV-2 antibodies during SARS-CoV-2 infection and recovery from COVID-19. Nat Commun. 2020;11(1):1-11.","DOI":"10.1038\/s41467-020-19943-y"}],"container-title":["BMC Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12879-021-06313-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12879-021-06313-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12879-021-06313-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T16:38:36Z","timestamp":1672677516000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcinfectdis.biomedcentral.com\/articles\/10.1186\/s12879-021-06313-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["6313"],"URL":"https:\/\/doi.org\/10.1186\/s12879-021-06313-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.08.29.20126201","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.3.rs-78158\/v1","asserted-by":"object"}]},"ISSN":["1471-2334"],"issn-type":[{"value":"1471-2334","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]},"assertion":[{"value":"15 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Medical Ethical Committee of Wuhan Huoshenshan Hospital (HSSLL011), and the Ethical Committee of Nanjing Medical University (2020\u2013511). All the patients were provided with written informed consent before enrollment. In particular, patients under the age of 18 had signed an informed consent form by their guardians.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not Applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"We declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"647"}}