Sex differences in immune responses that underlie COVID-19 disease outcomes
Open accessPublished version of a preprint
Abstract
There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women 1-5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients' age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.
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Proinflammatory cytokines and cardiac biomarkers are elevated in men with COVID-19 compared with women, including ferritin, CRP, IL-6, IL-8, and IL-18.
“Proinflammatory cytokines and cardiac biomarkers have been reported to be elevated in men with COVID-19 compared with women including ferritin, CRP (C-reactive protein), IL-6, IL-8, and IL-18. 13,121-123”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [122]
The ‘Sex differences in cytokines & chemokines’ section reports higher IL-8 and IL-18 in male patients in Cohort A, but those direct sex differences were not significant after age and BMI adjustment or in adjusted Cohort B analyses. It does not establish higher IL-6 in men, and the passages found do not support the attributed claims about ferritin, CRP, or cardiac biomarkers. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMen have more neutrophils and monocytes, whereas women have more T cells, similar to autoimmune myocarditis.
“And men have more neutrophils and monocytes, whereas women have more T cells, 13,121-123 similar to autoimmune myocarditis. 124,125”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [122]
In “Monocyte differences by sex” (page not provided), the paper reports more non-classical monocytes in male COVID-19 patients and fewer T cells in males than females in Cohort B. It does not establish that men have more monocytes overall or report a sex difference in neutrophils. The autoimmune-myocarditis comparison is attached to separate citations in the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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- Authors
- Takahashi, T., Ellingson, M. K., Wong, P., Israelow, B., Lucas, C., Klein, J., Silva, J., Mao, T., Oh, J. E., Tokuyama, M., Lu, P., Venkataraman, A., Park, A., Liu, F., Meir, A., Sun, J., Wang, E. Y., Casanovas-Massana, A., Wyllie, A. L., Vogels, C. B. F., Earnest, R., Lapidus, S., Ott, I. M., Moore, A. J., Yale IMPACT Research Team, Anastasio, K., Askenase, M. H., Batsu, M., Beatty, H., Bermejo, S., Bickerton, S., Brower, K., Bucklin, M. L., Cahill, S., Campbell, M., Cao, Y., Courchaine, E., Datta, R., DeIuliis, G., Geng, B., Glick, L., Handoko, R., Kalinich, C., Khoury-Hanold, W., Kim, D., Knaggs, L., Kuang, M., Kudo, E., Lim, J., Linehan, M., Lu-Culligan, A., Malik, A. A., Martin, A., Matos, I., McDonald, D., Minasyan, M., Mohanty, S., Muenker, M. C., Naushad, N., Nelson, A., Nouws, J., Nunez-Smith, M., Obaid, A., Ott, I., Park, H.-J., Peng, X., Petrone, M., Prophet, S., Rahming, H., Rice, T., Rose, K.-A., Sewanan, L., Sharma, L., Shepard, D., Silva, E., Simonov, M., Smolgovsky, M., Song, E., Sonnert, N., Strong, Y., Todeasa, C., Valdez, J., Velazquez, S., Vijayakumar, P., Wang, H., Watkins, A., White, E. B., Yang, Y., Shaw, A., Fournier, J. B., Odio, C. D., Farhadian, S., Dela Cruz, C., Grubaugh, N. D., Schulz, W. L., Ring, A. M., Ko, A. I., Omer, S. B., & Iwasaki, A.
- Affiliations
- Yale University (US)
- Yale New Haven Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Iwasaki, Akiko
- ORCID
- Takahashi, Takehiro
- Ellingson, Mallory K.
- Wong, Patrick
- Israelow, Benjamin
- Lucas, Carolina
- Klein, Jon
- Mao, Tianyang
- Oh, Ji Eun
- Tokuyama, Maria
- Lu, Peiwen
- Venkataraman, Arvind
- Park, Annsea
- Liu, Feimei
- Meir, Amit
- Wang, Eric Y.
- Casanovas-Massana, Arnau
- Wyllie, Anne L.
- Vogels, Chantal B. F.
- Earnest, Rebecca
- Lapidus, Sarah
- Moore, Adam J.
- Askenase, Michael H.
- Beatty, Hannah
- Bermejo, Santos
- Bickerton, Sean
- Bucklin, Molly L.
- Campbell, Melissa
- Cao, Yiyun
- Datta, Rupak
- DeIuliis, Giuseppe
- Geng, Bertie
- Glick, Laura
- Handoko, Ryan
- Kalinich, Chaney
- Khoury-Hanold, William
- Kim, Daniel
- Kudo, Eriko
- Linehan, Melissa
- Lu-Culligan, Alice
- Malik, Amyn A.
- Martin, Anjelica
- Mohanty, Subhasis
- Muenker, M. Catherine
- Nouws, Jessica
- Obaid, Abeer
- Park, Hong-Jai
- Peng, Xiaohua
- Petrone, Mary
- Prophet, Sarah
- Rice, Tyler
- Rose, Kadi-Ann
- Sewanan, Lorenzo
- Sharma, Lokesh
- Silva, Erin
- Simonov, Michael
- Song, Eric
- Sonnert, Nicole
- Valdez, Jordan
- Velazquez, Sofia
- Vijayakumar, Pavithra
- Wang, Haowei
- White, Elizabeth B.
- Yang, Yexin
- Shaw, Albert
- Fournier, John B.
- Odio, Camila D.
- Farhadian, Shelli
- Grubaugh, Nathan D.
- Schulz, Wade L.
- Ring, Aaron M.
- Ko, Albert I.
- Omer, Saad B.
- Iwasaki, Akiko
- Venue
- Nature
- Published
- 2020-08-26
- Volume
- 588
- Issue
- 7837
- Pages
- 315-320
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7725931
- OpenAlex
- W3080487846
- Cited by
- 1,459
- References
- 20
- Citations by year
- 2026: 87 · 2025: 123 · 2024: 147 · 2023: 231 · 2022: 343 · 2021: 431 · 2020: 96
- FWCI
- 36.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- Yale University
- Ludwig Family Foundation
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Rubicon 019.181EN.004, 019.181EN.004)
- National Institutes of Health (1s10od026996-01, COVID-19, UL1TR001863)
- National Institute on Aging (K24AG042489)
- National Institute of Allergy and Infectious Diseases (R01AI127429, T32AI007210, R37AI041699, R01AI157488, T32AI007517)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- COVID-19 pandemic, sex differences, SARS-CoV-2, immune response, innate immunity, T cell activation, non-classical monocytes, interleukin-8, IL-18, RANTES, plasma cytokines, viral load, antibody titers, disease outcome, age
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