On June 16–17, 2022, the National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), convened basic and clinical researchers to review the state of the science in sex/gender differences in COVID-19 outcomes relevant to heart, lung, blood, and sleep (HLBS) disorders. The workshop aimed to identify key knowledge gaps and explore research opportunities to improve our understanding of sex/gender differences in COVID-19 outcomes. The workshop presented a major opportunity to address insufficient overlap between sex differences and COVID-19 research and to promote cross cutting strategies and multidisciplinary partnerships. The ultimate goal of this workshop was to propose strategies to facilitate translation of basic biological discoveries into clinical applications to improve our ability to develop sex/gender-specific prevention, intervention, and implementation strategies for COVID-19-related HLBS disorders. Scientific collaborators from the NIH Office of Research on Women’s Health (ORWH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute on Minority Health and Health Disparities (NIMHD), and the National Institute of Allergy and Infectious Diseases (NIAID) complemented the NHLBI perspective on the research landscape proposed. The workshop also provided an opportunity for community members to share their personal experiences with acute and long COVID-19.
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The coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has changed the world in an unprecedented way. Scientists and clinicians are putting an extraordinary effort into improving insight into underlying mechanisms and clinical presentations, as well as developing relevant preventive and therapeutic approaches. Importantly, emerging epidemiological data reveal significant sex disparities in cardiovascular, pulmonary and blood disorders related to COVID-19 with higher morbidity and mortality in men than women, suggesting that sex-related factors may contribute to worse disease evolution and outcomes in males in the acute COVID-19 setting. It is known that sex differences in genes, chromosomes, and hormones may explain sexual dimorphisms in many diseases. Interestingly, several genes responsible for more efficient immune responses in females as well as angiotensin converting enzyme 2 (ACE2), the protein that SARS-CoV-2 uses as an entry point into the cells, are located on the X chromosome. Furthermore, escape from X-chromosome inactivation may potentially work in concert with sex hormones to offer better protection to females in COVID-19. However, sexual dimorphism in these underlying mechanisms is far from being entirely elucidated in both health and disease.
In contrast to acute illness, so called “long COVID,” or post-acute sequelae of SARS CoV-2 (PASC), is more prevalent in female than male patients. In addition, pregnant women who exhibit COVID-19 symptoms are more likely than nonpregnant women to have severe disease and need care in an intensive care unit, require a ventilator (for breathing support), or die from the illness. Thus, there is an additional need to recognize how altered hormonal milieu related to pregnancy, hormone replacement therapy, disease-related androgen excess in females, gender-affirming hormone therapy, aging, and COVID-19 itself affect these mechanisms and change the acute and chronic course of the disease. It is also necessary to appreciate the potential interaction of sex as a biological variable with other determinants of health such as gender, race, and socio-economic status (SES) in dictating COVID-19 morbidity and mortality.
The NIH planning committee and two chairs identified a diverse group of national and international scientists with expertise in sex/gender aspects of COVID-19. Speakers and moderators covered basic, translational, clinical, and population science of HLBS disorders, exploring the following topics through the lens of sex and gender:
- epidemiology of sex/gender differences in COVID-19;
- mechanisms of sex disparities in COVID-19 outcomes;
- impact of social determinants of health (SDoH) on gender-related COVID-19 HLBS outcomes;
- pregnancy and other conditions that affect susceptibility to SARS-CoV-2;
- sex and gender considerations of cardiovascular and metabolic aspects of COVID-19;
- sex and gender-related mechanisms underlying blood disease in COVID-19; and
- sex and gender differences in COVID-19 related to lung disease and sleep disorders.
In breakout discussions, experts outlined how to facilitate studies of sex/gender in COVID-19 HLBS disorders with the aim of addressing research gaps, barriers, and opportunities in mechanistic, translational, and population/clinical science.
Research Gaps, Barriers and Opportunities
The workshop participants identified important research gaps and barriers and provided their perspectives on research opportunities to close identified knowledge gaps.
Gaps and Barriers
Basic science and translational frontiers
- Experimental models of COVID-19 exist but have limitations. When assessing sex-differences, challenges include mimicking the clinical course of the disease and accounting for variants and dose of SARS-CoV-2 as well as different baseline immune status and/or initial injury. The varying presentations of PASC also present a challenge in creating experimental models of the long-term effects of COVID-19.
- There is insufficient understanding of the mechanisms of sex-differences in COVID-19-related HLBS disorders. For example, challenges related to COVID-19-related myocarditis include the lack of multi-site tissue, blood, & data repositories to obtain sufficient numbers of samples for research, especially after factoring in sex and age. While the mechanisms of PASC-related vascular and cardiac alterations are not yet clearly understood, it is possible that current and subsequent SARS-CoV-2 variants may have less severe vascular and cardiac phenotypes. On the other hand, more effective approaches and systems to link existing biological samples, imaging biomarkers, and clinical data will facilitate better understanding of mechanisms of COVID-19 susceptibility and related sex differences in HLBS outcomes.
- Validated sex- and gender-specific prognostic biomarkers are needed for prediction of severity of SARS-CoV-2 infection and the occurrence of chronic effects.
- Sex-differences in the immune response to COVID-19 infection and vaccination are observed; however, the clinical relevance of immunological differences remains to be determined. There are also insufficient data on the effects of hormone therapy on immune function in patients with COVID-19 as well as on the incidence of long COVID-19. There are no data on the effects of gender affirming hormone therapy on risk of infection and severity of COVID-19.
- There is a lack of mechanistic data on outcomes in COVID-19-related pregnancy regarding either the mother or offspring nor is much known regarding prevention and treatment strategies.
- Women with polycystic ovary syndrome could be at higher risk for COVID-19; however, no data are available on this patient population.
- Long-term follow-up is required to better understand the potential complication of pulmonary hypertension, for which patients with pulmonary thrombotic and respiratory complications may be at higher risk.
- More data are needed on why sleep disturbances triggered by COVID-19 are more prevalent in women than men.
- Imaging findings of COVID-19 often do not match the clinical presentation; the significance of such findings is unknown.
- Development of scores that identify COVID-19-related increased cardiac and vascular risk beyond traditional atherosclerotic cardiovascular disease population risk metrics (e.g., coronary artery calcification and/or inflammatory biomarkers) are needed.
- Autonomic hemodynamic disorders in PASC are frequent; however, little is known regarding the impact of sex/gender on the determinants of these disorders.
- There is a lack of understanding of the impact of sex/gender on thromboembolic events and complications associated with COVID-19 acute infection, or their interaction with other critical variables including Body Mass Index (BMI) and age. These factors need to be considered to develop effective prevention and treatment strategies for thrombotic complications.
Clinical trial and study design frontiers
- There is limited systemic consideration of sex/gender in study design, collection, analysis, and interpretation of COVID-19-related research data. To address COVID-19 disparities and advance our understanding of this condition, investigators need to consider sex/gender as a complex phenomenon that is simultaneously biological and social and investigate their intersectionality in determining COVID-19-relevant HLBS disorders.
- Sex assigned at birth and gender identity are among key components in determining COVID-19 susceptibility, pathophysiology and treatment efficacy and effectiveness. However, data in the literature are not routinely and consistently desegregated by sex and gender.
- Studies are frequently insufficiently powered to determine sex/gender influences on COVID-19 outcomes and treatments. Under-representation of sex and gender minority populations in COVID-19 studies limits the ability for subgroup analyses. This under-representation highlights the need for supporting infrastructure that guarantees diverse recruitment and retention to ensure adequately powered subgroup analyses by sex and gender.
- Limited SES/SDoH information prevents identification of social risk factors contributing to COVID-19 disease severity.
- Lack of longitudinal studies prevents tracking of sex-differences in infection resolution and the time course of symptoms and outcomes. Development of ways to measure the onset of PASC symptoms that do not rely on self-reporting is needed.
- Emphasize the principles of accurately assessing sex differences in SARS-CoV-2 infection and subsequent responses for animal, cell (organoid) and patient studies. Promote partnership of investigators new to sex differences research with experienced investigators.
- Improve the operationalization and capture of sex, gender identity and modality, and sexual orientation variables to better understand how these factors affect immune (and other) responses in SARS-CoV-2 infection. For example, women’s hormonal status and stage of menopause could be captured consistently in clinical trials, which would increase our knowledge of how these factors affect immune and other responses in SARS-CoV-2 infection. Studying sex/gender intersectionality offers many possibilities to advance research and reduce health disparities in COVID-19. Oversampling underrepresented groups – including people of color, sex and gender minorities, and individuals with high social vulnerability – could facilitate these efforts.
- Engage more diverse communities and key stakeholders in longitudinal research, particularly for subpopulations with poor COVID-19-related HLBS outcomes. Collect more SES/SDoH information in biological and other studies to identify more social risk factors. Include remote, decentralized design to make it easier to increase diversity. Collaborate with groups who have collected such data.
- Include pregnant and lactating women in clinical trials for determining short/long term treatment effects, doses/efficacy of intervention.
- Include more patients with chronic kidney disease since they are often excluded in clinical trials.
- Employ intentional alternative statistical study design (e.g., Bayesian design) to promote appropriate representation of women and other subgroups in clinical trials.
- Leverage biological samples, imaging biomarkers, paired clinical data (including information from health records databases), and data science to:
- inform mechanisms of COVID-19 susceptibility and related sex differences in HLBS outcomes;
- determine patterns and occult disease relationships;
- and, identify and validate sex- and gender-specific prognostic biomarkers.
- Develop metrics for identification of COVID-19-related increased cardiovascular disease risk beyond traditional atherosclerotic cardiovascular disease population risk scores.
- Take advantage of populations treated with gender-affirming hormone therapy as a “natural experiment” in which to investigate gender-based differences in disease susceptibility and outcomes mediated through sex steroids.
- Emphasize the following HLBS-relevant priority research areas:
- Development and refinement of animal models that recapitulate COVID-19 and PASC sex-specific phenotypes to elucidate associated mechanisms, potential therapeutic targets, and sex-specific responses to therapies. Models are needed to address the impact of sex, age, hormone status, pregnancy, variants and dose of SARS-CoV-2, baseline immune status and initial sensors in immune cells, COVID-19 phenotypes, and risk factors (e.g., obesity, hypertension, and diabetes), as well as distinguish between acute and long-term effects. In addition to animal models, establishment of human organoid models that retain their sex-basis will promote the understanding of cellular signaling events of viral infection and potential drug treatments.
- Mechanisms and roles of X-chromosome genes and sex hormones in mediating sex differences in immune responses to SARS-CoV-2 to explore immune-specific therapies and address acute COVID-19 related HLBS disorders. Cross-talk between immune-mediated inflammation and vascular inflammatory mediators needs to be explored. Investigation into how the interaction of viruses with mitochondria promotes inflammation, autoantibodies, and heart failure according to sex is needed.
- Clinical and mechanistic investigation into the autoimmune and autoinflammatory basis and sequelae of COVID-19 and PASC. Women are disproportionately represented in these disorders, and investigation providing insight from COVID-19 studies may inform other disorders.
- Clinical studies on COVID-19 in women-specific disorders and conditions such as polycystic ovary syndrome and pregnancy to facilitate the development of relevant prevention and treatment strategies.
- Mechanism(s) of viral infection of the placenta to understand maternal-fetal transmission and the long-term effect on the developing fetus.
- The contribution of sex/gender in longitudinal cohort studies to improve understanding of the time course and outcomes of PASC.
- Pilot pharmacologic trials to explore existing cardiac, vascular, metabolic, and immunologic therapies as potential treatment for PASC-related CVD.
- Sex and gender aspects of COVID-19-relevant HLBS diseases to explore:
- Pathophysiology and potential treatment of PASC-related autonomic hemodynamic disorders.
- Sleep disturbances triggered by COVID-19 and potential conversion to different phenotypes (insomnia/hypersomnia) and discovery of novel sleep interventions.
- Thromboembolic events and complications associated with COVID-19 acute infection.
Discussions of the workshop topics are continuing and a white paper summarizing the key concepts presented at the workshop is considered.
Kathryn Sandberg, Ph.D., Georgetown University Medical Center
Yogen Kanthi, M.D., National Heart, Lung, and Blood Institute, Division of Intramural Research
National Heart, Lung, and Blood Institute, Lead
Jasmina Varagic, M.D., Ph.D., FAHA
NIH Program Planning Committee
National Heart, Lung, and Blood Institute
Division of Cardiovascular Sciences
Jasmina Varagic, M.D., Ph.D., FAHA
W. Patricia Bandettini, M.D.
Patrice Desvigne-Nickens, M.D.
Ilsa I. Rovira, M.S.
Division of Lung Diseases
Marrah Lachowicz-Scroggins, Ph.D.
Division of Blood Diseases
Nahed El Kassar, M.D.
National Institute of Allergy and Infectious Disease
Mercy PrabhuDas, Ph.D., M.B.A.
NIH Office of Research on Women’s Health
Rajeev K. Agarwal, Ph.D.
Shilpa H. Amin, M.D., M.B.Sc., M.J., CAQ, FAAFP
Juliane Caviston, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Monica Longo, M.D., Ph.D.
National Institute on Minority Health and Health Disparities
Larissa Avilés-Santa, M.D., M.P.H.
Speakers and Moderators
Sabine Oertelt-Prigione, M.D., Ph.D., M.Sc.P.H., Radboud University (Netherlands) and Bielefeld
Mark C. Chappell, Ph.D., Wake Forest School of Medicine
Stanley Perlman, M.D., Ph.D., University of Iowa
Daniel Barouch, M.D., Ph.D., Beth Israel Deaconess Medical Center
Eileen Scully, M.D., Ph.D., Johns Hopkins University
John S. Tsang, Ph.D., National Institute of Allergy and Infectious Diseases
Heather Shattuck-Heidorn, Ph.D., University of Southern Maine
Kristen Springer, Ph.D., Rutgers University
Cindy H. Liu, Ph.D., Harvard Medical School
Sadiya S. Khan, M.D., M.Sc., Northwestern University
Gregory Phillips II, Ph.D., Northwestern University
Vesna D. Garovic, M.D., Ph.D., Mayo Clinic
Silvi Shah, M.D., University of Cincinnati
Babette LaMarca, Ph.D., University of Mississippi Medical Center
Licy L. Yanes Cardozo, M.D., University of Mississippi Medical Center
Franck Mauvais-Jarvis, M.D., Ph.D., Tulane University School of Medicine
John F. Randolph, M.D., University of Michigan Medicine
Delisa Fairweather, Ph.D., Mayo Clinic
Noel Bairey-Merz, M.D., Cedars-Sinai Medical Center
Satish Raj, M.D., University of Calgary
James Moon, M.D., Barts Heart Centre | University College London (England)
E. Dale Abel, M.D., Ph.D., University of California at Los Angeles
Zubaid Rafique, M.D., Baylor College of Medicine
Matthew D. Neal, M.D., FACS, University of Pittsburgh Medical Center
Alex Tsoi, Ph.D., University of Michigan
Patricia Silveyra, Ph.D., Indiana University Bloomington, School of Public Health
Charles S. Dela Cruz, M.D., Ph.D., Yale School of Medicine
Elizabeth Oelsner, M.D., M.P.H., Columbia University Irving Medical Center
Kenichi Okuda, M.D., Ph.D., University of North Carolina at Chapel Hill
Janet Mullington, Ph.D., Beth Israel Deaconess Medical Center
Community Perspective Speakers
Michael Sieverts, M.P.P.
Donna McKusick, Ed.D.