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Impact of Sex and Gender on COVID-19 Outcomes in Europe

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Gebhard et al. Biology of Sex Differences (2020) 11:29
https://doi.org/10.1186/s13293-020-00304-9

REVIEW Open Access

Impact of sex and gender on COVID-19

outcomes in Europe
Catherine Gebhard1,2,3*† , Vera Regitz-Zagrosek4,5,6†, Hannelore K. Neuhauser6,7, Rosemary Morgan8 and
Sabra L. Klein9

Abstract
Background: Emerging evidence from China suggests that coronavirus disease 2019 (COVID-19) is deadlier for
infected men than women with a 2.8% fatality rate being reported in Chinese men versus 1.7% in women. Further,
sex-disaggregated data for COVID-19 in several European countries show a similar number of cases between the
sexes, but more severe outcomes in aged men. Case fatality is highest in men with pre-existing cardiovascular
conditions. The mechanisms accounting for the reduced case fatality rate in women are currently unclear but may
offer potential to develop novel risk stratification tools and therapeutic options for women and men.
Content: The present review summarizes latest clinical and epidemiological evidence for gender and sex
differences in COVID-19 from Europe and China. We discuss potential sex-specific mechanisms modulating the
course of disease, such as hormone-regulated expression of genes encoding for the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV2) entry receptors angiotensin converting enzyme (ACE) 2 receptor and TMPRSS2
as well as sex hormone-driven innate and adaptive immune responses and immunoaging. Finally, we elucidate the
impact of gender-specific lifestyle, health behavior, psychological stress, and socioeconomic conditions on COVID-
19 and discuss sex specific aspects of antiviral therapies.
Conclusion: The sex and gender disparities observed in COVID-19 vulnerability emphasize the need to better
understand the impact of sex and gender on incidence and case fatality of the disease and to tailor treatment
according to sex and gender. The ongoing and planned prophylactic and therapeutic treatment studies must
include prospective sex- and gender-sensitive analyses.
Keywords: Gender, Sex, COVID-19, Renin angiotensin aldosterone system, Immune system

Introduction termed coronavirus disease 2019 (COVID-19), which

In December 2019, a novel β-coronavirus, now desig- represents its most frequent lethal complication. Since
nated SARS-CoV2 (severe acute respiratory syndrome its outbreak, SARS-CoV2 has spread to 196 countries
coronavirus 2), was identified as the cause of an out- and has been declared a pandemic by the World Health
break of acute respiratory illness in Wuhan City, China Organization (WHO) on March 11, 2020 [2, 3]. It has
[1]. SARS-CoV2 causes severe respiratory disease, caused over 2 million confirmed infections with over
130,000 deaths worldwide (as of April 15, 2020), of
which two-thirds have occurred in Europe [4]. To date,
* Correspondence: [email protected]
†
Catherine Gebhard and Vera Regitz-Zagrosek contributed equally to this
no specific antiviral treatment for SARS-CoV2 exists,
work. but a number of investigational agents are currently be-
1
Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse ing explored including remdesivir, lopinavir-ritonavir, a
100, 8091 Zurich, Switzerland
2
Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
combined protease inhibitor, chloroquine/hydroxychlor-
Full list of author information is available at the end of the article oquine, colchicine, and tocilizumab, an IL-6 inhibitor
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
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data made available in this article, unless otherwise stated in a credit line to the data.
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 2 of 13

[5]. The worldwide case fatality rate of 3.4% of COVID- worldwide clearly demonstrating similar numbers of
19 now exceeds that from seasonal influenza [2]. Death cases in women and men, but an increased case fatality
results from acute respiratory distress syndrome (ARDS), in men [16] (Fig. 1). Nevertheless, sex-disaggregated data
acute respiratory failure, coagulopathy, septic shock, and are still not provided by all countries, the interaction of
metabolic acidosis [6]. Cardiovascular complications of sex and age is usually not visible in the public databases,
COVID-19 comprise arrhythmias, acute cardiac injury, and number of cases and case fatality vary significantly
and shock, and have been reported in 7–17% of hospital- by region. To obtain a detailed European view and to
ized patients [7]. In Italy, the estimated case fatality rate cover these aspects, we collected latest epidemiological
was 7.2% [8], while it was 0.9% in South Korea [3] and data (as of April 1st) on confirmed COVID-19 cases in
2.3% in China [6]. Case fatality is highest in those aged > Italy, China, Spain, France, Germany, and Switzerland
80 years (14.8% in China, 20.2% in Italy) and in patients [17–22] across multiple disease metrics including re-
with pre-existing conditions including cardiovascular cently published hospitalization and intensive care (ICU)
disease, diabetes mellitus, chronic respiratory disease, admission data. Similar to global statistics, these reports
hypertension, and cancer [6, 9]. Among all comorbidi- show no major sex differences in the absolute number of
ties, cardiovascular disease in the elderly was most con- confirmed COVID-19 cases in those countries where
sistently associated with adverse outcomes, as a case sex-disaggregated data were available (Fig. 2). However,
fatality rate of 10.5% has been reported in this high-risk equal absolute numbers of cases in women and men
population [6]. may point towards a higher incidence in men in the
older age groups (i.e., proportions of COVID-19 diag-
Sex differences in COVID-19 epidemiology and case nosed older men among men in that age group) since
fatality older men are fewer in absolute numbers than older
First reports from China have pointed to a sex imbal- women due to their shorter life expectancy. In fact, re-
ance with regard to detected cases and case fatality rate ports from Switzerland and Germany have recently re-
of COVID-19 [1, 10, 11]. However, to date only few re- ported incidence rates (cases per 100,000 inhabitants by
ports have addressed the sex disproportion in COVID- age and sex), which confirm an increased disease inci-
19 incidence and disease course and a thorough analysis dence in men > 60 years, [21, 22]. In detail, the disease
of underlying causes is currently lacking [12–15]. As the incidence in men per 100,000 Swiss inhabitants in the
disease has spread across multiple continents, the Global age groups of 60–69 years, 70–79 years, and 80+ years
Health 50/50 research initiative presented an impressive was 267, 281, and 477, respectively, as of March 30. The
overview of sex-disaggregated data from countries numbers reported in men exceeded the ones reported in

Fig. 1 Sex-disaggregated data of confirmed COVID-19 cases and deaths provided by Global Health 50%50 data tracker as of April 2, 2020 [16]
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 3 of 13

Fig. 2 Male to female ratios of COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, deaths, and case-fatality rates in European
countries and China as of April 2, 2020. *absolute numbers are provided. Sex-disaggregated data were not available for all indicators

women by 74, 87, and 108 per 100,000 Swiss inhabitants, cases by country as well as national testing strategies, be-
respectively. In Germany, relative differences between sides case fatality. Nevertheless, case fatality rates re-
men and women were similar to Switzerland, but at a ported in China, Italy, Spain, France, Germany, and
lower level, with the incidence in Germany being one- Switzerland are relatively homogenous and range be-
third of that in Switzerland. It is notable, however, that tween 1.7–1.8. This supports the view that a consistent
the number of confirmed cases and therefore also the in- biological phenomenon is operating, accounting for the
cidence depends largely on testing strategy in countries higher case fatality in men, independent of country-
and regions. specific demographics and testing strategies (Fig. 2) [17–
Novel data on disease course and severity show 50% 19, 21, 22]. In addition, pooled data comprising 227,219
more hospitalized men than women (Fig. 2). Notably, al- confirmed cases and 14,364 deaths suggest that the male
though the overall number of confirmed COVID-19 to female case fatality ratio is consistently elevated
cases across all age groups is currently sex balanced in through all age groups and may even be most pro-
Switzerland, the hospitalizations in men exceed the one nounced at middle age (Fig. 3). The latter is a novel ob-
observed in women by 1.5-fold. A similar gender distri- servation which further supports the notion that age as
bution in hospitalization rates is observed in France. well as gender-specific behavior and/or biological vari-
This imbalance supports a higher susceptibility of men ables interact in COVID-19 disease vulnerability. How-
to develop severe respiratory disease following SARS- ever, more data are needed to confirm an interaction
CoV2 infection, leading to more hospital admissions. between age and sex in COVID-19 case fatality.
While the number of ICU admissions of men and
women are currently unknown in Switzerland, in France, Sex differences in ACE2 and TMPRSS2 regulation
and in the Lombardy region (Italy), the number of men To enter cells, SARS-Cov-2 binds to the angiotensin
receiving ICU care is 3-fold and 4-fold higher than the converting enzyme (ACE) 2 receptor and the cellular
number of women [23]. The latter might be indicative of serine protease TMPRSS2 for priming [24] (Fig. 5).
gender differences in COVID-19 disease severity; how- ACE2 is a membrane-bound protein and is expressed in
ever, gender inequity in ICU admission policies may also multiple tissues including the cardiovascular system, adi-
play a role. pose tissue, gut and kidneys, the central nervous system,
Significant differences in the male to female COVID- and in the lungs [25]. The cell-associated form of ACE2
19 case fatality ratio can be observed between European is required for SARS-CoV virus entry into target cells
countries. The latter may also reflect the age-sex mix of [26]. ACE2 is cleared from the cells by the
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 4 of 13

Fig. 3 Male predominance in COVID-19 case fatality (deaths divided by confirmed cases) in Italy, Spain, Germany, and Switzerland by age. A male
to female mortality ratio of 1 would reflect gender balance, the red bars reflect male predominance. Pooled data from Italy as of March 30, 2020,
Spain as of March 31, 2020, Germany as of April 1, 2020, and Switzerland as of March 31, 2020

metalloproteases ADAM10 and ADAM17 [26, 27]. Some along with viral RNA [36]. A loss of ACE2 function
reports indicate that circulating levels of ACE2 are through endocytosis and activation of proteolytic cleav-
higher in healthy and diabetic men as well as in men age following SARS-CoV-2 binding has recently been
with renal disease as compared to women [28]. Others described and could reconcile these apparently contra-
found no sex difference but reported higher ACE2 dictory findings [25].
serum activity in older compared to younger women In the lung, ACE2 is primarily expressed in bronchial
[29]. In patients with type 1 diabetes, circulating ACE2 transient secretory cells or type II alveolar cells [37]. Ex-
activity increases with increasing vascular tone and in perimental evidence derived from murine and rat
the presence of microvascular or macrovascular athero- models suggests a protective role of ACE2 activators in
sclerotic disease [30]. Soluble ACE2 is enzymatically ac- vascular remodeling during pulmonary hypertension, in
tive and has modest inhibitory effects on viral infection allergic airway inflammation associated with asthma, and
efficiency [31]. However, these data are not yet coherent in the reduction of pulmonary fibrosis [38, 39]. Further,
and the link between circulating ACE2 and COVID-19 ACE2 activation improved pulmonary endothelial func-
is not clear. tion in a rat model of pulmonary hypertension via the
ACE2 plays a crucial role in the renin angiotensin al- endothelial nitric oxide synthase (eNOS) pathway and
dosterone system (RAAS) as it opposes the vasocon- seems to play an important role in smoking-induced
strictor actions of angiotensin II by converting lung injury [40]. Indeed, the latter was associated with a
angiotensin II to vasodilatory angiotensin 1–7 in differ- significant reduction of ACE2 expression in lung tissue
ent organs. ACE2 regulates the cellular biology of cardi- which was reversed by Losartan treatment [41]. These
omyocytes, cardiac fibroblasts, and coronary endothelial preclinical studies suggest a protective role and a poten-
cells in both heart failure with reduced ejection fraction tial therapeutic use of ACE2 in a variety of pulmonary
(HFrEF) and heart failure with preserved ejection frac- diseases. It is however currently unclear whether the role
tion (HFpEF) models and after experimental myocardial of ACE2 in pulmonary pathologies differs by sex. In
infarction [32, 33]. Therefore, increasing ACE2 activity addition to the above mentioned studies, ACE inhibitors
was considered a potential therapeutic option for and angiotensin receptor blockers (ARBs) have been re-
COVID-19 [34]. However, a previous report suggests ported to upregulate ACE2 expression in different or-
that high protein expression of ACE2 receptor in specific gans in humans [42, 43] and experimental animals [44],
organs was associated with organ failure in patients in- whereas no effect of ACE inhibitors or ARBs on ACE2
fected by SARS in 2002/2003 [35], while 35% of myocar- activity was found in other reports [33]. The interaction
dial tissue samples of patients who died from SARS between COVID-19 and ACE inhibitors or ARBs in pa-
showed a reduced myocardial ACE2 protein expression tients with heart disease was recently reviewed [45]. This
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 5 of 13

topic is out of the scope of the present review which fo- orchiectomy decreased ACE2 activity. In agreement with
cuses on sex differences. these data, ovariectomy increased ACE2 expression in
There is increasing evidence that sex and sex hor- the female kidney, and adipose tissue, and estradiol re-
mones affect many components of the circulating as well placement reduced ACE2 expression [46]. Thus, testos-
as tissue-based RAAS including ACE2 [46–50] (Fig. 4). terone seems to maintain high ACE2 levels in the heart
Downregulation of angiotensin II receptor type 1 and kidney, whereas estrogen reduces ACE2 expression
(AT1R) by estrogens, and regulation of renin activity by in these organs. Based on these data, we must assume
estrogens have been described and reviewed elsewhere that a significant interaction between sex hormones and
[51, 52]. More recently, it was shown that estrogen mod- ACE2 expression exists.
ulates the local RAAS in human atrial myocardium via In humans, several clinical trials highlight the rele-
downregulation of ACE and simultaneous upregulation vance of sex differences in the RAAS. In fact, a recent
of ACE2, AT2R, and MAS expression levels [53]. The prospective cohort study indicates that women require
ACE2/Ang1-7/Mas receptor axis appears to be of greater lower doses of ACE inhibitors for heart failure treatment
relevance in women than in men [47]. Indeed, genes than men [57]. Also, the neprilysin (NEP) inhibitor sacu-
coding for ACE2 and angiotensin II receptor 2 (AT2R) bitril, which degrades angiotensin peptides, in combin-
are located on the X chromosome suggesting a potential ation with valsartan, has recently been shown to exert
for higher expression in women [54]. Nevertheless, re- beneficial effects in women with HFpEF, but less so in
ports from a number of preclinical studies agree that men [58]. Unfortunately, specific mechanisms account-
ACE2 is frequently higher expressed in males than in fe- ing for this difference have not been reported in these
males, mainly under pathological conditions [47, 50, 55]. studies. A higher tissue expression of ACE2 has been ob-
In addition to sex chromosome complement, sex hor- served in Asian men as compared to women [28, 59],
mones promote opposite effects on ACE and ACE2 ac- while in our own unpublished investigation in tissue
tivity, cardiac hypertrophy, and contractility in samples from patients with aortic valve stenosis, ACE2
spontaneously hypertensive rats [56]. Ovariectomy led to was upregulated 4–5 fold in the myocardium of men as
increased ACE2 activity in females, whereas in males, compared to their female counterparts. In contrast, no

Fig. 4 Estrogen and sex regulate components of the renin angiotensin aldosterone system (RAAS). Estrogen-regulated pathways are depicted in
green. AT2R angiotensin II type 2 receptor, ACE2 angiotensin converting enzyme 2, NEP neutral endopeptidase neprilysin
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 6 of 13

sex difference in ACE2 expression was seen in control currently unclear under which conditions the fusion pro-
hearts [60]. Whether these sex differences in ACE2 regu- tein is generated, whether TMPRSS2 is also regulated by
lation are of clinical relevance remains to be determined. estrogen, and whether it plays a role in COVID-19. The
The second protein, necessary for SARS-CoV2 inva- involvement of TMPRSS2 in viral S protein priming
sion into cells, the cell-surface serine protease TMPRSS2 might explain, at least in part, the higher case fatality
is predominantly expressed in prostate epithelium, in seen in males affected by COVID-19. Accordingly, a
high-grade prostate cancers, and in the majority of hu- TMPRSS2 inhibitor has recently been shown to block
man prostate cancer metastases [61, 62]. Although entry of the virus in vitro and might become a thera-
TMPRSS2 is expressed several fold higher in the pros- peutic strategy for antiviral intervention [24]. Whether
tate relative to any other human tissue, the serine prote- previous prostate cancer and anti-androgenic treatment
ase has also been detected in airway epithelia where its might affect virus entry and the course of disease is cur-
normal physiologic function remains unknown [63]. rently unknown [64].
TMPRSS2 transcription is regulated by androgenic li-
gands and an androgen receptor binding element in the Sex differences in immune responses to viruses
promoter [64] (Fig. 5). Notably, recurrent gene fusions Females and males differ in their susceptibility and re-
of the 5′ untranslated region of TMPRSS2 to the tran- sponse to viral infections, leading to sex differences in
scription factor ERG is the most frequent genomic alter- incidence and disease severity [65]. For infectious dis-
ation in early- and late-stage prostate cancer and results eases caused by viruses, there are numerous and diverse
in overexpression of ERG. The latter is present in both ways in which sex and gender can impact differential
early- and late-stage prostate cancer [64]. However, it is susceptibility between males and females. For example,

Fig. 5 Sexual dimorphism in TMPRSS2-mediated SARS-CoV2 host cell entry. Androgen receptors (ARs) are activated via heat shock proteins (HSPs)
release in response to changes in intracellular testosterone concentration. ARs are then phosphorylated and translocated as homodimers into the
nucleus, prompting transcriptional activation of TMPRSS2 and translation of the TMPRSS2 protein [149]. At the cell membrane, TMPRSS2 facilitates
viral entry and spreads into the host cell by activating the spike proteins [24]
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 7 of 13

human studies reveal that females have over 40% less Sex steroids, particularly testosterone (T), estradiol
human immunodeficiency virus (HIV) RNA in circula- (E2), and progesterone (P4), influence the functioning of
tion than males. Despite having less circulating HIV immune cells. Sex steroids alter the functioning of im-
RNA than males, females who are matched with males mune cells by binding to specific receptors, which are
on their HIV RNA loads have a 1.6-fold higher risk of expressed in various lymphoid tissue cells as well as in
developing AIDS [66]. Although exposure to influenza A circulating lymphocytes, macrophages, and dendritic
viruses is often higher in males, fatality following expos- cells [89]. The binding of sex steroids to their respective
ure to pathogenic influenza A viruses is reportedly steroid receptors directly influences cell signaling path-
higher in females [67]. In contrast, the prevalence of ways, including NF-κB, cJun, and interferon regulatory
serum hepatitis B virus (HBV) surface antigen, HBV factor (IRF) 1, resulting in differential production of cy-
DNA titers, and development of hepatocellular carcin- tokines and chemokines [89]. Although direct effects of
oma is higher in males than females [68–70]. gonadal steroids cause many sex differences in immune
The innate recognition and response to viruses as well function, some sex differences might be caused by the
as downstream adaptive immune responses during viral inherent imbalance in the expression of genes encoded
infections differ between females and males. The num- on the X and Y chromosomes [90]. Polymorphisms or
ber and activity of innate immune cells, including mono- variability in sex chromosomal genes as well as in auto-
cytes, macrophages, and dendritic cells (DCs) as well as somal genes that encode for immunological proteins can
inflammatory immune responses in general are higher in also contribute to sex differences in immune responses
females than in males [71–73]. Toll-like receptor (TLR) [91].
7 is a pattern recognition receptor in the endosomes of Sex differences in immune response in cardiac tissues
several immune cells, including plasmacytoid DCs and B also depend on age. We have recently shown that fe-
cells, and is used to detect single stranded RNA viruses, males develop stronger chronic immune reactions in the
including coronaviruses. The TLR7 gene, encoded on myocardium with old age [92]. Aging is associated with
the X chromosome, may escape X inactivation resulting the development of a chronic low-grade inflammatory
in higher expression levels of TLR7 in females when phenotype (CLIP) [93]. Such CLIP may be induced by
compared to males [74–76]. Exposure of peripheral chronic viral infections, among others. Cellular senes-
blood mononuclear cells (PBMCs) to TLR7 ligands cence may also contribute to CLIP as senescent cells cir-
in vitro causes higher production of interferon-α (IFNα) culate in the tissues through the body. They secrete a
in cells from females than from males [77], and plasma- variety of pro-inflammatory mediators, stimulating CLIP.
cytoid DCs (pDCs) from females and female mice have Furthermore, factors as smoking, decreased production
higher basal levels of IFN regulatory factor 5 (IRF5) and of sex steroids, and accumulation of adipose tissue may
IFNα production following TLR7 ligand stimulation also contribute to CLIP.
[78]. Immune responses to viruses can vary with changes
in sex hormone concentrations naturally observed over Gender-related risk factors and impact
the menstrual cycle, following contraception, after When considering differentials in incidence and case fatal-
menopause and during hormone replacement therapy ity between males and females, we must also consider
(HRT) as well as during pregnancy [79]. how sex intersects with gender to influence vulnerability.
With regard to adaptive immune responses, females Gender is defined as the social and cultural norms, roles,
generally exhibit greater humoral and cell-mediated im- attributes, and behaviors that a society considers appropri-
mune responses to antigenic stimulation, vaccination, ate for men and women or boys and girls [94]. Evidence
and infection than do males [80]. Both basal levels of im- suggests that the current COVID-19 pandemic has both
munoglobulin [81] as well as antibody responses are primary and secondary effects related to sex and gender.
consistently higher in females than in males [82]. In Primary effects include differences between males/men
humans, global analysis of B cell gene expression signa- and females/women in incidence and case fatality, while
tures reveals that the majority of genes differentially secondary effects include differences in social and eco-
expressed between the sexes are significantly upregu- nomic consequences as a result of the pandemic, includ-
lated in B cells from adult females compared with males ing risk of domestic violence [95, 96], economic and job
[83]. Clinical studies reveal that males have lower CD3+ insecurity, and increased domestic workload [15].
and CD4+ cell counts, CD4+:CD8+ cell ratios, and Preliminary data indicate an association between co-
helper T cell type 1 (Th1) responses than females [84– morbidities, such as chronic lung disease, hypertension,
87]. Females also exhibit higher cytotoxic T cell activity and cardiovascular disease, and severity of COVID-19
along with upregulated expression of antiviral and pro- [16]. Worldwide, these morbidities are higher among
inflammatory genes, many of which have estrogen re- men than women [97], except for older age groups. Gen-
sponse elements in their promoters [88]. der differences in risk behaviors, such as smoking and
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 8 of 13

drinking, may be contributing to the gender gaps in Women’s roles as caregivers—both within the health
mortality of such non-communicable diseases [13]. system and at home—may place them at increased risk
Smoking and drinking rates are higher among men than of infection. Approximately 70% of health and social
women worldwide. Such behaviors are associated with care workforce worldwide are women [101], including
the risk of developing comorbidities [16]. These behav- frontline healthcare workers. Women are also more
iors are linked to gender norms related to what is con- likely to care for children or other relatives who are ill
sidered appropriate behaviors and activities for men and [15]. Overall, more research is needed to understand
women [98]. Other gendered norms and behaviors how sex and gender, and the intersection of sex and gen-
which may be contributing to a higher incidence among der, is causing differential outcomes and effects related
men include lower rates of hand washing, which is a rec- to COVID-19 among and between men and women. In
ognized preventative measure, and delayed healthcare particular, there is a need to evaluate the influence of
seeking [16]. Evidence from China suggests that patients such gender variables on disease manifestation and
whose diagnoses were delayed were at greater risk of outcomes.
dying [99]. In this regard, greater system delays between
onset of symptoms and initiation of treatment have been Sex differences in COVID-19 treatment approaches
described in women with cardiovascular disease [100]; Vaccines are the best prophylactic treatment for infec-
however, no data on prehospital delays in COVID-19 are tious diseases as they provide immunity and protection
currently available. Thus, it is currently unknown prior to infection. Sex and gender impact vaccine ac-
whether potential gender differences in prehospital de- ceptance, responses, and outcomes. Females are often
lays impose disadvantages on women. Other gendered less likely to accept vaccines, but once vaccinated, de-
differences which place women and men at differential velop higher antibody responses (i.e., primary correlate
risk of infection and/or mortality include rejection of so- of protection) and report more adverse reactions to vac-
cial isolation, social obligations, psychological stress, low cines than males (Table 1) [80]. For example, after vac-
quality of life, and low socioeconomic status among cination against influenza, yellow fever, rubella, measles,
COVID-19 [13]. A careful analysis of a patient’s history mumps, hepatitis A and B, herpes simplex 2, rabies,
including traditional cardiovascular risk factors, socio- smallpox, and dengue viruses, protective antibody re-
economic status, menopausal status, age at menopause, sponses are twice as high in adult females as compared
number of pregnancies, pregnancy-related complica- with males [80]. Data from inactivated influenza vaccines
tions, fertility treatments, postmenopausal HRT, hormo- indicate that adult (18–45 years of age) females develop
nal contraception, history of breast or prostate cancer, greater IL-6 and antibody responses than males, with di-
and aromatase inhibitors/anti-androgenic treatments will minished differences between the sexes among aged in-
be essential to discover mechanisms accounting for the dividuals (65+ years of age) [128]. Reduced male-female
gender disparities in COVID-19. differences in immune responses to the monovalent
Table 1 Sex differences in adverse reactions, immune responses, and efficacy of vaccines and antiviral drugs in humans
Virus Antiviral drug/vaccine Sex-specific Comments References
features
HIV HAART M<F CD4+ T cell count, adverse reactions, fat accumulation, drug [102–108]
concentration, virus clearance, hepatitis
HAART M>F Fat loss, survival [103, 109]
HSV-2 HSV-2 gD vaccine M<F Humoral immune responses, cell-mediated immune responses, vaccine [110–112]
efficacy
Acyclovir M<F Frequency of prescription, adverse reaction [113, 114]
Acyclovir M>F Reduction of virus shedding [114]
HBV HBV vaccine M<F Humoral immune responses [115–118]
HCV Pegylated interferon M<F Adverse reaction, sustained virologic response1 [119–121]
alpha/ribavirin
Seasonal influenza TIV vaccine M<F Humoral immune responses, adverse reactions [122–125]
viruses
Oseltamivir M<F Drug clearance and metabolism2 [126]
Oseltamivir M>F Alleviation of symptoms, reduction of viral load [127]
Zanamivir M=F Alleviation of symptoms, reduction of viral load [127]
HAART highly active antiretroviral therapy, HBV hepatitis B virus, HCV hepatitis C virus, HIV human immunodeficiency virus, HSV herpes simplex virus, TIV trivalent
inactivated influenza virus. 1premenopausal females only, 2tested in neonates only
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 9 of 13

2009 H1N1 vaccine among aged individuals is partly due The current off-label use of anti-inflammatory drugs,
to reproductive senescence in females, in which higher such as colchicine, for the reduction of excessive inflam-
circulating estradiol concentrations in females are mation caused by SARS-CoV2 is also notable. The COL-
associated with greater antibody responses to the vaccine CORONA trial has just started recruiting patients with
[128]. COVID-19 and will determine whether short-term treat-
For treatment of COVID-19, a number of investiga- ment with colchicine reduces the rate of death and lung
tional agents are currently being explored including complications related to COVID-19 (https://clinical-
remdesivir, lopinavir-ritonavir, a combined protease in- trials.gov/ct2/show/NCT04322682). The drug has re-
hibitor, chloroquine/hydroxychloroquine, colchicine, and cently regained popularity when it was shown that
tocilizumab, an IL-6 inhibitor [5]. Although some of colchicine reduced the risk of ischemic cardiovascular
these compounds have shown promise in inhibiting the events in patients with a recent myocardial infarction
growth of SARS-CoV2 in vitro [5, 129–131, 132], their [143]. However, while the primary efficacy composite
“off-label” use carries the risk of adverse side effects such endpoint was reduced by colchicine in the total cohort
as cardiac arrhythmias and sudden cardiac death [133, and in men, a subgroup analysis pointed to a lower effi-
134]. In particular chloroquine and hydroxychloroquine, cacy in women [143]. Also, previous experimental work
both antimalarial agents inhibiting the cell entry of in rats reports a higher acute oral toxicity of colchicine
SARS-CoV2 by under-glycosylation of ACE2 receptors in females as compared to males with female rats being
[129, 130], are known to trigger life-threatening poly- two times more susceptible to the lethal effects of col-
morphic ventricular tachycardia (torsades de pointes) by chicine than male rats [144]. Thus, a sex-specific analysis
prolonging the heart rate-corrected QT (QTc) interval in the COLCORONA trial will be essential in order to
[134, 135]. Previous reports indicate that women are take these differences into account.
more prone to develop drug-induced torsades de pointes Taken together, these data emphasize the importance
than men, with 65–75% of drug-induced torsades de to consider the effect of age, reproductive status, and ex-
pointes occurring in women [136]. Indeed, there are ogenous hormonal manipulation when antiviral and
substantial sex differences in the electrocardiographic other treatment strategies are applied to COVID-19
pattern of ventricular repolarization with a longer QTc patients.
interval at baseline being observed in women [48, 136,
137]. Protective effects of testosterone have been sug- Conclusion
gested to account for the shorter QTc interval and the The sex and gender disparities observed in COVID-19
reduced incidence of drug-induced torsades de pointes vulnerability emphasize the need to understand the im-
in men. However, mechanisms underlying these differ- pact of sex and gender on incidence and case fatality of
ences are not fully understood. In addition, experimental the disease and to tailor treatment according to sex and
and clinical studies have shown that chloroquine exerts gender. Experiences from past outbreaks and pandemics
different effects on adrenocortical function in female have clearly shown the importance of incorporating a
and male rats [138] and depresses testosterone secretion sex and gender analysis into preparedness and response
and sperm count in men [139]. The latter is of particular efforts of health interventions [67, 145–148]. Policies
interest in the treatment of COVID-19 as the expression and public health efforts, however, have not yet ad-
of TMPRSS2, a protein that primes SARS-CoV-2 entry dressed the gendered impacts of disease epidemics, out-
into cells, is upregulated by androgens [140]. The latter breaks, or pandemics. Some countries have not
has been suggested to account for the higher mortality disaggregated data by sex and age the way other coun-
seen in men affected by COVID-19. However, whether tries have. In conclusion, governments in all countries
anti-androgenic treatment might affect virus entry and should disaggregate and analyze data for sex and age dif-
the course of disease is currently unknown. ferences. Furthermore, as prophylactic and therapeutic
Further, there is evidence that women encounter more treatment studies begin, inclusion of sex and gender
often adverse drug reactions to antiviral treatment than analyses in their protocols must occur.
men (Table 1). In addition, pharmacokinetics and treat-
Abbreviations
ment responses to antiretroviral therapy with ritonavir ARs: Androgen receptors; ARDS: Acute respiratory distress syndrome;
and lopinavir differ between males and females [141]. In ACE: Angiotensin converting enzyme 2; ARBs: Angiotensin receptor blockers;
fact, higher plasma concentrations of ritonavir and a AT2R: Angiotensin II receptor; CLIP: Chronic low-grade inflammatory pheno-
type; COVID-19: Coronavirus disease 2019; DCs: Dendritic cells; HAART: Highly
higher total cholesterol:high-density lipoprotein (HDL) active antiretroviral therapy; HFpEF: Heart failure with preserved ejection
ratio have been reported in girls [141, 142], while an ata- fraction; QTc: Heart rate-corrected QT interval; HSPs: Heat shock proteins;
zanavir plus ritonavir regimen was associated with a Th1: Helper T cell type 1; HBV: Hepatitis B virus; HCV: Hepatitis C virus;
HSV: Herpes simplex virus; HDL: High density lipoprotein; HIV: Human
higher risk of virologic failure in women as compared to immunodeficiency virus; ICU: Intensive care unit; NEP: Neutral endopeptidase;
men [131]. HRT: Postmenopausal hormone replacement therapy; SARS-CoV2: Severe
Gebhard et al. Biology of Sex Differences (2020) 11:29 Page 10 of 13

acute respiratory syndrome coronavirus 2; TIV: Trivalent inactivated influenza 4. Dong E, Du H, Gardner L. An interactive web-based dashboard to track
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