Sex differences in immune responses that underlie COVID-19 disease outcomes
Authors: Carolina Lucas
Eriko Kudo
Nicole Sonnert
Anjelica Martin
Subhasis Mohanty
Nathan D Grubaugh
Ji Eun Oh
Arvind Venkataraman
Abeer Obaid
Elizabeth B White
Michael H Askenase
Melissa Linehan
Maxine Kuang
Marcella Nunez-Smith
Maksym Minasyan
Kadi-Ann Rose
Camila D Odio
Jordan Valdez
Yiyun Cao
Sean Bickerton
William Khoury-Hanold
Isabel M Ott
Ryan Handoko
Charles Dela Cruz
Sarah Lapidus
John B Fournier
Jonathan Sun
Melissa Campbell
Maria Batsu
Mikhail Smolgovsky
Hong-Jai Park
Joseph Lim
Alice Lu-Culligan
Julio Silva
Giuseppe DeIuliis
Sarah Prophet
Feimei Liu
Kristina Brower
Akiko Iwasaki
Albert Shaw
Lorenzo Sewanan
Isabel Ott
Benjamin Israelow
Arnau Casanovas-Massana
Michael Simonov
Lokesh Sharma
Albert I Ko
Eric Y Wang
Amyn A Malik
Rupak Datta
Maria Tokuyama
Chaney Kalinich
Molly L Bucklin
Saad B Omer
Denise Shepard
Nida Naushad
Daniel Kim
Harold Rahming
Jon Klein
Chantal B F Vogels
Codruta Todeasa
Patrick Wong
Amit Meir
Jessica Nouws
Xiaohua Peng
Yale IMPACT Research Team
Hannah Beatty
Mallory K Ellingson
Haowei Wang
Pavithra Vijayakumar
Tianyang Mao
Annie Watkins
Erin Silva
Edward Courchaine
Anne L Wyllie
Allison Nelson
M Catherine Muenker
Yvette Strong
Yexin Yang
Rebecca Earnest
Annsea Park
Shelli Farhadian
Tyler Rice
Staci Cahill
Wade L Schulz
Aaron M Ring
Adam J Moore
Lynda Knaggs
Mary Petrone
Bertie Geng
Takehiro Takahashi
Eric Song
Sofia Velazquez
Santos Bermejo
Irene Matos
Peiwen Lu
David McDonald
Kelly Anastasio
Laura Glick
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: COVID-19; sex differences; immune responses; SARS-CoV-2; viral loads
Affiliations: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA., Boyer Center for Molecular Medicine, Department of Microbial Pathogenesis, Yale University, New Haven, CT, USA., Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA., Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA., Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA., Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA., Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. .

Abstract:  There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1-5. 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. 

Retracted: No

PubPeer comments:
 Regarding this sentence in the article: Intersex and transgender individuals were not represented in this study. Can the authors clarify if  not represented means that there was no determination of those two statuses or that individuals with those statuses were excluded from the study? , 
 #1 Thank you for the question. As you say, there was no determination on this point. Sorry if that description was confusing or unclear. ,