Dear Editor,
Clinical outcomes of coronavirus disease 2019 (COVID-19) differ substantially between women and men, with men facing an increased risk of critical illness and death. Besides differences in age and prevalence of comorbidities, biological (sex) differences in immune responses, expression levels of virus entry receptors, endocrinological mechanisms as well as gender-related factors have been suggested to account for the differential outcomes in women and men [1, 2]. However, recent research has questioned the major impact of biological sex differences on COVID-19 outcomes [3, 4], and it has been hypothesized that non-biological aspects of being male or female (e.g. social roles and personality traits), the so-called “gender” dimension, may provide a better explanation for the observed sex dysbalance in COVID-19 outcomes. Gender, measured by a set of prespecified variables, modifies the outcome in acute coronary syndromes [5], but its role in COVID-19 outcomes has been widely ignored.
We estimated associations between gender (sociocultural factors, Supplementary Materials) and sex (biological factors) with disease severity of acute severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in a prospective, observational cohort study of 3005 (1357 [45.2%] women, mean age 44.8 ± 17.5 years) mildly to critically ill patients in Switzerland (Supplementary Table 1–4/Supplementary Fig. 1) who were recruited for this study at four Swiss study sites. Gender-related characteristics were assessed using the short version of a validated questionnaire (Supplementary Materials) [5], while clinical data were gathered from electronic medical records. Multiple logistic regression models with the backward selection method were applied to assess potential predictors of severe illness (a detailed description of the statistical approach is provided in Supplementary Materials).
In the overall study cohort, male sex (odds ratio (OR) 2.27 [1.39–3.70], p < 0.001) was independently associated with the composite endpoint of intensive care unit (ICU) admission, invasive ventilation, and/or death in logistic regression models. However, once patients were hospitalized, male sex was no longer prognostic for the combined endpoint (OR 1.15 [0.56–2.33], p = 0.707, Fig. 1). Gender did not predict disease severity following multivariable adjustment (OR 0.61 [0.28–1.33], p = 0.211), independent of admission status. Clinical-biological variables including the presence of cardiovascular risk factors (OR 1.42 [1.21–1.67, p < 0.001), dyspnoea (OR 5.76 [4.10–8.09], p < 0.001) or neurological symptoms (OR 2.32 [1.15–4.69], p = 0.02) at presentation, an increased respiratory rate (OR 1.08 [1.021–1.41], p = 0.007) or elevated white blood cells (OR 1.07 [1.02–1.12], p = 0.006) were all independently associated with severe illness, while anosmia (OR 0.48 [0.34–0.67], p < 0.001) or higher testosterone:estradiol ratio (OR 0.88 [0.80–0.98], p = 0.02) were associated with a mild disease course (Fig. 1). Assertiveness (OR 1.25 [1.09–1.42], p = 0.001), having a strong personality (OR 1.22[1.04–1.43, p = 0.016), and lower education (OR 2.88 [1.57–5.26], p = 0.001) were the only gender-related parameters predicting disease severity in our cohort (Fig. 1). Lower education level is a well-known predictor of adverse health outcomes. The fact that hospitalized women had the lowest educational qualification in our cohort (p < 0.001 vs hospitalized men) might point to important health disparities in this group.
Fig. 1.
Incidence of the combined endpoint (composite of death, admission to ICU/IMC, and/or invasive ventilation) in the overall populations (upper panel) and in hospitalized patients (lower panel) stratified by sex (left) or tertiles of gender (right). Data (bar graphs) are presented as incidence rates of the composite outcome and 95% confidence interval (CI). For each population, the prognostic value of biological sex and gender (as competing co-variates) for the combined endpoint are depicted. Models (tables) were adjusted for patient baseline characteristics including symptoms at presentation, pre-existing conditions, medications, anthropometric data, clinical and laboratory data and presented as odds ratio (OR) and 95% confidence interval (CI). Clinical biological predictors (left side) and sociocultural predictors (right side) of the combined endpoint selected by our multivariable models are also depicted. CVRFs cardiovascular risk factors, WBC white blood cells, ASAT aspartate aminotransferase, MAP mean arterial pressure, ICU intensive care unit, IMC intermediate care unit
Taken together, we demonstrate that male sex, but not gender, is independently associated with ICU admission, invasive ventilation, and/or death in COVID-19. Our data suggest that the male propensity towards a more severe disease course of COVID-19 can largely be explained by clinical-biological differences between men and women. However, the biological “advantage” of women disappears once they are hospitalized, indicating that during disease progression, currently unknown factors might adjust survival in both sexes. The risk predictors identified in our study might provide guidance in the current discussion about mask mandates and requirements for booster vaccination in high-risk demographic groups. Our data also emphasize that more research is needed to understand the complex impact of gender on health outcomes. Finally, the question why the survival advantage of women is reduced after hospitalization requires further study.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank the study administration staff including Elvira Krämer, Livia Krüger, Mariano Paredes Heck, Mina Qadirie, Marie-Louise Sieber, Nuria Zellweger, Janna Tontsch, Anna Zaiser, and Anja Zabel as well as the staff of the Department of Nuclear Medicine of the University Hospital Zurich and the Intensive Care Units of the University Hospital Basel and the University Hospital Zurich for their dedication to this study. And last, we thank all the study patients for their valuable time and commitment to the Swiss COGEN Cohort. COGEN (COvid and GENder) study group: Susan Bengs, PhD - Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich; Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland. Bianca Gysi, MD - Intensive Care Unit, Department of Acute Medicine, University Hospital Basel, Basel, Switzerland. Arnaud Dussault-Cloutier - Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Karl Philipp Buehler, MD - Institute of Intensive Care, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Reto A. Schuepbach, MD - Institute of Intensive Care, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Annelies S. Zinkernagel, MD, PhD - Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Silvio D. Brugger, MD, PhD - Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Claudio Acevedo, MD - Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Dimitri Patriki, MD - Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland. Benedikt Wiggli, MD - Infectious Diseases and Hospital Epidemiology, Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland. Jürg H. Beer, MD - Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland; Andrée Friedl, MD - Infectious Diseases and Hospital Epidemiology, Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland. Raphael Twerenbold, MD - Department of Cardiology, University Hospital Basel, Basel, Switzerland; Department of Cardiology and University Center of Cardiovascular Science, University Heart and Vascular Center Hamburg, Hamburg, Germany. Gabriela M. Kuster, MD - Department of Cardiology, University Hospital Basel, Basel; Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. Hans Pargger, MD - Intensive Care Unit, Department of Acute Medicine, University Hospital Basel, University of Basel, Basel, Switzerland. Sarah Tschudin-Sutter, MD, MSc - Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland. Joerg C. Schefold, MD - Department of Intensive Care Medicine, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland. Thibaud Spinetti, PhD - Department of Intensive Care Medicine, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland. Pedro D. Wendel-Garcia, MSc - Institute of Intensive Care, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Daniel A. Hofmaenner, MD - Institute of Intensive Care, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Thomas Scheier, MD - Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Atanas Todorov, MD, PhD - Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich; Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland. Hamid Merdji, MD, PhD - Intensive Care Unit, Department of Acute Medicine, University Hospital Basel, Basel, Switzerland; Université de Strasbourg (UNISTRA), Faculté de Médecine; Hôpitaux universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive-Réanimation, Strasbourg, France. Martin Siegemund, MD - Intensive Care Unit, Department of Acute Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Author contributions
CG, CEG, and VRZ conceptualized and designed the Swiss COGEN study. CEG, NH, and SB coordinated the study. CEG, PG, and SB prepared the study data. PG, CEG, SB, AT, and CG have verified the underlying data, performed the statistical analysis, and prepared tables and figures. CG, BG, CEG, and NH wrote the first manuscript draft. VRZ, KPB, RAS, ASZ, CA, SDB, DP, BW, JHB, AF, RT, GMK, HP, ST, JCS, TS, PDW, DAH, TS, HM, and MS contributed samples or data, participated in the interpretation of the results and critical revision of the manuscript. SB, KPB, CEG, CG, SDB, CA, DP, and BW implemented and coordinated the recruitment of study patients and biobank samples. All authors approved the final manuscript. CG is the guarantor for the study. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding
This work was supported by the Swiss National Science Foundation (Project #196140, to CG, CEG, and VRZ), the LOOP Zurich (CG, VRZ) and an unrestricted research grant from the intensive care unit (ICU) research foundation of the University Hospital of Basel (CEG). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to the anonymized data in the study and share final responsibility for the decision to submit it for publication.
Data availability
Based on the Business Administration System for Ethics Committees (BASEC) ethics approval, the non-anonymized raw data cannot be shared publicly. However, anonymised data that underlie the results reported in this article will become available to interested parties for non-commercial reasons, after the publication upon reasonable requests made to the corresponding author. Data requestors will need to sign a data access agreement.
Declarations
Conflicts of interest
Authors: CG has received research grants or speaker’s fees from from the Novartis Foundation, Sanofi Genzyme, Switzerland, and Bayer Pharmaceuticals outside of the submitted work. The University Hospital Zurich (CG) holds a research contract with GE Healthcare outside of the submitted work. Study group: JCS and TS reports (full departmental disclosure) grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Nycomed, and Phagenesis, outside of the submitted work. The money went into departmental funds, no personal financial gain applies. All other authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.
Footnotes
The members of the COGEN study group are mentioned in the Acknowledgments section.
Publisher's Note
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Caroline E. Gebhard and Nadia Hamouda have contributed equally.
Contributor Information
Caroline E. Gebhard, Email: evacaroline.gebhard@usb.ch
on behalf of the COGEN Investigators:
Susan Bengs, Bianca Gysi, Arnaud Dussault-Cloutier, Karl Philipp Buehler, Reto A. Schuepbach, Annelies S. Zinkernagel, Silvio D. Brugger, Claudio Acevedo, Dimitri Patriki, Benedikt Wiggli, Jürg H. Beer, Andrée Friedl, Raphael Twerenbold, Gabriela M. Kuster, Hans Pargger, Sarah Tschudin-Sutter, Joerg C. Schefold, Thibaud Spinetti, Pedro D. Wendel-Garcia, Daniel A. Hofmaenner, Thomas Scheier, Atanas Todorov, Hamid Merdji, and Martin Siegemund
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Based on the Business Administration System for Ethics Committees (BASEC) ethics approval, the non-anonymized raw data cannot be shared publicly. However, anonymised data that underlie the results reported in this article will become available to interested parties for non-commercial reasons, after the publication upon reasonable requests made to the corresponding author. Data requestors will need to sign a data access agreement.