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Editorial

Towards Precision Medicine: Inclusion of Sex and Gender Aspects in COVID-19 Clinical Studies—Acting Now before It Is Too Late—A Joint Call for Action

1
Department of Advanced Biomedical Sciences, Federico II University of Naples, Via Pansini, 5, 80131 Naples, Italy
2
School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
3
Women’s Brain Project, 8357 Guntershausen, Switzerland
4
Department of Primary and Community Care, Radboud University Medical Center, 6525 Nijmegen, The Netherlands
5
Institute of Legal and Forensic Medicine, Charité—Universitätsmedizin, 10117 Berlin, Germany
6
Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
7
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
8
Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
*
Author to whom correspondence should be addressed.
The Sex and Gender in COVID19 Clinical Trials Working Group members are listed in Appendix A.1.
The Gender and COVID19 Working Group members are listed in Appendix A.2.
Int. J. Environ. Res. Public Health 2020, 17(10), 3715; https://doi.org/10.3390/ijerph17103715
Received: 20 May 2020 / Accepted: 21 May 2020 / Published: 25 May 2020
The COVID-19 global pandemic is accelerating investigations for effective vaccines and repurposable validated therapeutics. Current data analyses strongly suggest that the disease mostly affects the elderly population and patients with pre-existing conditions [1,2]. Considerably less attention has been drawn towards the sex distribution of case fatalities, which is increasingly showing disparities in mortality rates that varies geospatially, and along socioeconomic factors [3,4]. Reported death estimates by sex vary greatly across contexts and population groups and may change over time. In addition, social factors, such as testing and reporting bias in females, or differences in exposure due to behavioral and risk differences, may play a role, e.g., due to comorbidities such as diabetes or differences in societal and gender norms. While the observed male dominance in COVID-19 prevalence and mortality across most countries and cultures may suggest a role for biological differences, the potential long-term impact of gender-related factors on mortality, especially in diverse socioeconomic contextS, cannot be underestimated [5,6].
The role of immunological differences between females and males in the responses to SARS-CoV-2 infection appears to be justified. There is ample evidence that antiviral immunity differs between the sexes [5]. These are caused by e.g., sex steroid hormone signaling (i.e., testosterone, estrogens, and progesterone), genetics (e.g., immune function genes that escape X inactivation), and sex-specific composition of the microbiome. Sex differences in immunosenescence and immune function not only impact immunity to viruses, but to vaccines and immunotherapies, as well [5,6,7]. In the context of SARS-CoV-2, these differences could impact susceptibility and initial response to the virus as well as choice of acute and long-term therapy of the COVID-19 pathology. In current and future trials for COVID-19, sex as a biological variable should be factored in and understood, along with the wider gendered implications of the COVID-19 crises, with the broader concept of how biological factors intersect with gendered differences in exposure, transmission, and socio-economic means. Consequently, the pandemic may not just lead to differences in disease susceptibility and manifestation between men, women, and people with non-binary identities, but also exacerbate unequal access to treatment and long-term vulnerabilities.
Given their non-negligible impact on health, sex and gender dimensions, along with other socio-economic stratifiers, need to inform the design, conduct, analysis, and reporting of current and forthcoming trials. Moving beyond sex-disaggregated data collection and including variables such as disability, age, ethnicity, migration status, socioeconomic status, or geographic location, will contribute to ensure health benefits from clinical trials for all. To better understand and respond to the burden posed by COVID-19, both on health systems and different segments of human populations, gender dimensions must be recognized as an intersecting component of wider structural inequalities [8]. Moreover, the COVID-19 pandemic is exposing, most acutely, the wider social inequalities that are based on gendered social, cultural, and economic faultiness, whether it is leaving a majority of frontline workers (in many contexts mostly women) without PPE, the disproportionate burden of unpaid care on women, or gender-based violence perpetuated within the household, apart from the economic devastations experienced by the poor and women in the poorest quintiles.
Equity in clinical trials starts with the consideration of both sex and gender dimensions in studies on novel and repurposed drugs [9,10]. Biomedical AI-researchers can assist in this effort to reconceptualize the human subgroups included for analysis, emphasizing the rigorous justification of exclusion and avoiding assumptions that may have serious implications in terms of generalizability of outcomes [9,11,12]. Ignoring aspects of sex and gender in data collection and analysis in clinical trials has had detrimental consequences in the past. Eight out of ten drugs withdrawn from the US market in the late 1990s had significantly more side effects in women than men, including fatal torsade-de-pointe after excessive QT interval prolongation. The, yet to be accurately tested, proposed therapeutic regimen of hydroxychloroquine and azithromycin for COVID-19 includes two QT-prolonging agents. Next to potential sex differences in side effects, gender-related aspects have to be considered. For example, despite the disproportionately high mortality of Ebola viral disease (EVD) among pregnant women, the rVSV-ZEBOV vaccine clinical trials excluded pregnant women. This impacted access to critical life-saving interventions during the subsequent Tenth EVD epidemic in DRC, when—due to lack of evidence because of the beforementioned exclusions—pregnant and lactating women did not partake in ring vaccination campaigns, until the decision was reversed 10 months later. This not only led to unnecessary mortality of this vulnerable group, but severely impacted women’s right to decide on research participation and community trust in the intervention, just as did the approval of Truvada solely for cisgender males and transgender women [13,14].
The inclusion of sex and gender aspects in drug development and clinical trials is essential, not just for a thorough understanding of efficacy and safety aspects of drugs, but also to ensure there is equity in the distribution of innovation and discovery benefits of COVID-19 therapeutics and vaccines [3]. A group of clinicians, scientists and gender specialists working on global health, sex and gender research and human rights are thus calling for action towards the inclusion of sex and gender, and other socially relevant variables, into the methodology of COVID-19-related trials. Such an approach should become a universal and manifest part of future clinical studies, to allow more personalized patient care and contribute to universal health coverage.

Author Contributions

Conceptualization and methodology, E.B., S.O.-P., S.L.K. and R.M.; writing—original draft preparation E.B., S.O.-P., S.L.K., writing—review and editing, E.B., S.O.-P., S.L.K. and R.M., project administration, R.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

We would especially like to thank Sulzhan Bali (Women in Global Health), Susan Bell (Drexel University), Chandani Kharel (HERD International), for their tremendous contribution to the manuscript. We would like to thank the entire Gender and COVID-19 Working Group for their thoughts, inputs and ongoing scientific support. We would like to acknowledge Maria Teresa Ferreti and Antonella Santuccione Chadha, as well as the entire Wommen’s Brain Project, for their initial ideas, concepts and significant input in the work.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Appendix A.1. The Sex and Gender in COVID-19 Clinical Trials Working Group

Evelyne BischofShanghai University
Sabine Oertelt-PrigioneRadboud University Medical Center
Rosemary MorganJohns Hopkins Bloomberg School of Public Health
Sabra KleinJohn Hopkins Bloomberg School of Public Health
Clare WenhamLondon School of Economics and Political Science (LSE)
Nazneen DamjiUN Women
Alison ROWEUN Women
Laura MamoSan Francisco State University [email protected]
Sulzhan BaliWomen in Global Health [email protected]
Susan E. BellDrexel University [email protected]
Ann KeelingWomen in Global Health
Chandani KharelHERD International
Ilana LöwyCERMES 3, (INSERM, CNRS, EHESS, Paris V)
Anna CoatesPanamerican Health Organization
Shirin HeidariGENDRO’s Health
Petra VerdonkAmsterdam UMC-VUmc
Arne RuckertUniversity of Ottawa
Luisa EnriaUniversity of Bath
Shelley LeesLondon School of Hygiene and Tropical Medicine (LHTM)
Amber PetermanUniversity of North Carolina
Sean HillierYork University

Appendix A.2. Gender and COVID-19 Working Group

Clare WenhamLondon School of Economics
Rosemary MorganJohn Hopkins University
Julia SmithSimon Fraser University
Evelyne BischofShanghai University of Medicine and Health Sciences, Federico II University, Napoli, Italy, and Women’s Brain Project
Sabra KleinJohn Hopkins University
Madeline JohnsonGlobal Affairs Canada
Chris BerzinsGlobal Affairs Canada
Sulzhan BaliWomen in Global Health
Karen GrepinUniversity of Hong Kong
Susan MackayGAVI
Denise Nacif PimentaOswaldo Cruz Foundation
Niyati ShahUSAID
Kelly Thompsonindependent consultant
Sabine Oertelt-PrigioneRadboud University
Amber PetermanUniversity of North Carolina and UNICEF Innocenti
Ruth KutalekMedizinischen Universität Wien
Sophie HarmanQMUL
Ilana LowyFrench National Centre for Scientific Research
Nazeen DamjiUN Women
Ann KeelingWomen in Global Health
Kate HawkinsPamoja Communications
Myra BetronJhpiego
Susan BellDrexel University
Manasee MishraIIHMR University, India
Sean HillierYork University
Yara M. AsiUniversity of Central Florida
Shelley LeesLondon School of Hygiene and Tropical Medicine
Alan WhiteLeeds Beckett University
Nigel Mxolisi LandaGreat Zimbabwe University
Pavitra Kotini-ShahUniversity of Illinois at Chicago
Megan O’DonnellCenter for Global Development
Jelke BoestenKing’s College London
Goleen SamariColumbia University
Alexa YakubovichUniversity of Toronto
Liana R WoskieHarvard Global Health Institute
Peter BakerGlobal Action on Men’s Health
Camila PimentelOswaldo Cruz Foundation/Aggeu Magalhães Institute
Derek M. GriffithVanderbilt University
Sara DaviesGriffith University
Elena Marbán-CastroBarcelona Institute for Global Health
Claudia Abreu LopesUnited Nations University, International Institute for Global Health

References

  1. Leung, C. Clinical features of deaths in the novel coronavirus epidemic in China. Rev. Med. Virol. 2020. [Google Scholar] [CrossRef] [PubMed]
  2. Zhavoronkov, A. Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections. Aging (Albany NY) 2020. [Google Scholar] [CrossRef] [PubMed]
  3. Bischof, E.; Wolfe, J.; Klein, S.L. Clinical trials for COVID-19 should include sex as a variable. J. Clin. Investig. 2020. [Google Scholar] [CrossRef] [PubMed]
  4. Bali, S.; Dhatt, R.; Lal, A.; Jama, A.; Van Daalen, K.; Sridhar, D.; Gender and COVID-19 Working Group; Women in Global Health, and Gender and COVID-19 Working Group. Off the back burner: Diverse and gender—Inclusive decision—Making for COVID-19 response and recovery. BMJ Glob. Health 2020, 5, e002595. [Google Scholar] [CrossRef] [PubMed]
  5. Klein, S.L.; Flanagan, K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016. [Google Scholar] [CrossRef] [PubMed]
  6. Flanagan, K.L.; Fink, A.L.; Plebanski, M.; Klein, S.L. Sex and Gender Differences in the Outcomes of Vaccination over the Life Course. Annu. Rev. Cell Dev. Biol. 2017, 33, 577–599. [Google Scholar] [CrossRef] [PubMed]
  7. Caruso, C.; Accardi, G.; Virruso, C.; Candore, G. Sex, gender and immunosenescence: A key to understand the different lifespan between men and women? Immun. Ageing 2013, 10, 20. [Google Scholar] [CrossRef] [PubMed]
  8. Lokot, M.; Avakyan, Y. Intersectionality as a lens to the COVID-19 pandemic: Implications for sexual and reproductive health in development and humanitarian contexts. Sex. Reprod. Heal. Matters 2020, 1–5. [Google Scholar] [CrossRef] [PubMed]
  9. Zhavoronkov, A.; Vanhaelen, Q.; Oprea, T.I. Will Artificial Intelligence for Drug Discovery Impact Clinical Pharmacology? Clin. Pharmacol. Ther. 2020, 107, 780–785. [Google Scholar] [CrossRef] [PubMed]
  10. Tannenbaum, C.; Ellis, R.P.; Eyssel, F.; Zou, J.; Schiebinger, L. Sex and gender analysis improves science and engineering. Nature 2019. [Google Scholar] [CrossRef] [PubMed]
  11. Mbuagbaw, L.; Aves, T.; Shea, B.; Jull, J.; Welch, V.; Taljaard, M.; Yoganathan, M.; Greer-Smith, R.; Wells, G.; Tugwell, P. Considerations and guidance in designing equity-relevant clinical trials. Int. J. Equity Health 2017, 16, 1–9. [Google Scholar] [CrossRef] [PubMed]
  12. O’Neill, J.; Tabish, H.; Welch, V.; Petticrew, M.; Pottie, K.; Clarke, M.; Evans, T.; Pardo, J.P.; Waters, E.; White, H.; et al. Applying an equity lens to interventions: Using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health. J. Clin. Epidemiol. 2014. [Google Scholar] [CrossRef] [PubMed]
  13. Gomes, M.F.; De La Fuente-Núñez, V.; Saxena, A.; Kuesel, A.C. Protected to death: Systematic exclusion of pregnant women from Ebola virus disease trials. Reprod. Health 2017. [Google Scholar] [CrossRef] [PubMed]
  14. Voelker, R. PrEP Drug Is Approved for Some Patients but Not for Others. JAMA 2019. [Google Scholar] [CrossRef] [PubMed]
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