key: cord-0868923-to58xgpd
authors: Wolfe, Jeannette; Safdar, Basmah; Madsen, Tracy E.; Sethuraman, Kinjal N.; Becker, Bruce; Greenberg, Marna Rayl; McGregor, Alyson J.
title: Sex- or gender-specific differences in the clinical presentation, outcome, and treatment of Sars-Cov2
date: 2021-01-16
journal: Clin Ther
DOI: 10.1016/j.clinthera.2021.01.015
sha: e10f9fbfdc7d973ac900140dd352df9a84c9568e
doc_id: 868923
cord_uid: to58xgpd

In this review, we describe the sex and gender differences in COVID-19 presentation, treatment and outcomes. We discuss the differences between genders in susceptibility to infection, the role of sex chromosomes on the body’s immunological response and the influence of hormones on the body’s response to the virus. Additionally the sex differences in clinical and laboratory presentation, complications of infection and outcomes as well as differences in response to treatment and prevention are reviewed.

On March 11th 2020, the World Health Organization (WHO) declared the SARS-Cov-2 (COVID-19) outbreak a pandemic. 1, 2 Since then, clinicians have learned about this single stranded RNA virus, especially that this infection is associated with increased morbidity in older individuals with hypertension (HTN), diabetes, cardiovascular disease and obesity. 3 In addition, even the earliest case reports out of Wuhan China, demonstrated that COVID-19 led to disproportionately greater mortality in men than women. 4 Since these early reports, studies, meta-analyses and global tracking systems confirmed that men are at greater risk for morbidity and mortality from SARS-Cov2. 3, 5 Global Health 50/50 showed higher death rates in men in 68 out of the 84 countries in which sex-disaggregated data was available: death ratios varying from 0.5 to 3.8 (men vs. women). 5 In the United States, the CDC tracking of over 185,000 COVID-19 related deaths revealed that 54% of these deaths occurred in men. 5, 6 Although rates of infection seem to be similar, when infection occurs may be related to sex and age: women aged 20-50 are at increased risk for infection as are men over the age 50. 7 After infected, men have a greater likelihood of ICU admission and death, suggesting that sex and/or gender (S/G) related factors impact disease trajectory. 3 There is increasing evidence that important S/G differences exist in J o u r n a l P r e -p r o o f patients infected with SARS Cov2, yet many researchers aren't evaluating their data for potential S/G influences. A recent review of almost 2500 SARS Cov-2 registered clinical trials demonstrated that less than 5% had planned for sex-disaggregated analysis of their results. 8 The purpose of this article is to review state-of-the-art evidence related to sex-or gender-specific differences in the clinical presentation, physiology and outcome of SARS-Cov2 infection and to highlight the critical necessity of inclusion and analysis of these variables in future research.

The terms biological sex and gender are often misrepresented in scientific research. To ensure clarity, biological sex is based on an individual's sex chromosomes, hormones and anatomy while gender is heavily rooted in sociocultural constructs (see Appendix 1 for additional information of their complex interrelationship).

A summary of these differences can be found in Table 1 .

Although individual differences in habits and behaviors can impact viral exposure rates, to prevent significant illness after infection three things must happen: 1) a rapid innate immune response that alarms the body of viral invasion and attempts to mitigate its impact; 2) the trigger of a secondary adaptive immune response that leads to the production of viral specific antibodies and T cells to neutralize viral particles, kill viral laden cells, and stimulate the production of memory lymphocytes to stand guard for re-exposure; 3) an effective recovery period when innate immune cells and epithelial regenerative pathways repair and/or remove damaged cells. 10-11. Age and sex can influence each of these steps. [10] [11] In COVID-19, women appear to shed the virus for a shorter period of time and may clear it from their body more quickly. 12 Similar to Sars-Cov-2 infection, men are also at greater risk for complications from viral J o u r n a l P r e -p r o o f infection due to Hepatitis B, Sars-Cov-1 MERS-CoV; these BSD in risk are rooted in both sex-based chromosomal and hormonal differences. 13 

There are BSD in immunologic response beginning before puberty and extending into old age. In response to these differences, scientists increasingly are focusing on the role an individual's sex chromosomes play in the immune response. 14 In SARS Cov-2, the gene coding for ACE-2 receptors, the viral binding site on the cell surface membrane, along with many other immune-related genes necessary to combat infection, are found on the X chromosome. 14 As men have only one X chromosome, and, therefore, one copy of any X-linked genes, they may be at a disadvantage if that copy is maladaptive compared to women who have access to a second copy from their other X chromosome. In addition, some of the X-linked immune genes involved with SARS Cov2 avoid "X-inactivation" (the typical cellular process that occurs in females that turn off the expression of one copy of their X chromosome to prevent the over expression of X-linked genes). 15 This creates the possibility that females express a "double dose" of certain immune-related genes which could provide their immune response with an extra boost after exposure to certain infections. The downside is that it could make females more vulnerable to certain types of autoimmune diseases or to pathogens known to trigger exuberant inflammatory responses.

A COVID-19 related gene that appears to avoid typical X inactivation is the gene for Toll-like Receptor 7 (TLR-7). 16 TLR-7 is an important part of the innate immune response relevant to patients' response to COVID-19 as it recognizes single stranded RNA viral invasion and helps stimulate interferon production. 16 Females are noted to have higher amounts of interferon released after TLR-7 activation and case reports suggest a vulnerability for more severe illness in Sars-Cov2 infected males who have a defect in their TLR-7 gene. 17 Besides containing genes that code for specific immunological functions, the X chromosome also contains genes that regulate the expression of genes on other chromosomes, underscoring the importance of sex chromosomes in epigentics and homeostasis. 18 J o u r n a l P r e -p r o o f

Sex based hormones are also likely to influence the severity of disease after Sars-Cov-2 infection (Table 2 ). Both sexes produce estrogen, progesterone and testosterone, but the amount produced varies as a result of biological sex, age, obesity, stage of the menstrual cycle (for women of child-bearing age), and use of exogenous hormones. 19 Many immune cells, including neutophils, macrophages, natural killer cells, T cells and B cells contain receptors for sex hormones. 19, 20 In addition, sex hormones can influence DNA transcription of genes involved in immune cell development and signaling. 10, 21 Testosterone and progesterone are immunosuppressant while estrogen's actions are more variable and complex. 22 Estrogen can be immuno-enhancing or suppressing depending on plasma concentration, site of interaction along immunomodulating pathways, and the type of estrogen receptor binding the estrogen. 23 At low doses, estrogen can promote proinflammatory cytokine release while at high or sustained doses it can help shut off proinflammatory pathways, decrease leukocyte recruitment, and enhance antibody production. 20, 23 The complicated interaction between coronavirus, hormones, and severity of illness is highlighted in research involving SARS Cov-1 infected mice. Male mice experienced higher viral titers and inflammatory changes in their lungs after viral inoculation, but this association was dependent on the age of the mice; in middle aged mice, 90% of infected male mice died compared to only 20% of middle-aged females. 24 This difference disappeared in older mice, or in females who had had their ovaries removed, suggesting that estrogen may help to limit disease severity. 24 Alternatively, during the H1N1 pandemic, researchers reported increased morbidity in women of child-bearing age as H1N1 triggered an exuberant immune response that was amplified by the effects of female ratioed sex hormones. 20 These examples highlight the complex interaction between pathogen and host, morbidity can be influenced by factors surrounding the infection, the immune response, host factors or a combination of both.

There are ongoing clinical trials that examine both the effect of adding and blocking estrogen, particularly estradiol, on the outcome of infected Sar-Cov2 patients. 25 Hormonal augmentation has been studied in other viruses with estrogen therapy showing improved cellular immunity in female HIV patients and decreased progression to liver fibrosis in chronic hepatitis C patients. [26] [27] Testosterone may also contribute to sex-based differences in COVID-19 mortality. 28 It has been postulated that increased TMPRESS 2 levels may enhance infectivity. 28 A small study that explores this theory found that 79% (122/175) of men admitted for COVID-19 symptoms had evidence of male pattern baldness suggesting an excess of androgens. 29 There are trials that are looking at the impact of testosterone suppression on COVID-19 mortality. 25, [30] [31] Conversely, low levels of circulating testosterone have also been linked to increasing male vulnerability for poor outcome. 28 The natural aging process and the secondary effects of hypertension, obesity and diabetes, may cause testosterone levels to fall. Lower testosterone levels can shift the male immune response towards an increased production of proinflammatory cytokines. Obese men may get a double hit as adipose cells convert testosterone to estrogen, predominantly estradiol, leading to the production of more activated inflammatory cytokines.

As the testes contain significant amounts of ACE-2 receptors, it is also theorized that gonadal function and testosterone production may be further impaired in males with Sars Cov-2 infection. 32 A study examining testosterone levels in admitted COVID-19 patients found that more than half of men admitted to hospitals with active infection had evidence of hypogonadism (testosterone levels less than 300ng/dl) and that the chance of ICU admission was inversely correlated with circulating levels. [33] [34] Some have recommended testosterone supplementation in infected, morbid men with low serum testosterone levels. 33, 35 J o u r n a l P r e -p r o o f

There has been speculation over the past few months that seriously ill patients with COVID-19 may be experiencing a 'cytokine storm': a hyperactive immune response associated with the increased expression of inflammatory mediators such as interferons, tumor necrosis factor, and interleukins leading to a hyperinflammatory state and end organ damage. 36 This assumption has been challenged, since some patients with severe COVID-19 have significantly lower levels of multiple inflammatory cytokines in their blood compared to ill non-covid ICU patients. 37 Perhaps it may be more accurate to describe COVID-19 patients as having a 'maladaptive immune response' (MIR).

Those who get severely ill from COVID have different patterns of immune response: severely ill women produce more proinflammatory cytokines while severely ill men, especially if they are older, produce a smaller adaptive T cell response. 38 About 14% of patients with severe COVID-19 may have either a maladaptive genetic variant for interferon or actual autoantibodies against interferon, obstructing its role in communicating with other immune cells. [39] [40] Males reportedly are more likely to have these autoantibodies against interferon. 40 Males with severe disease have a greater Sars-Cov2 antibody response. [41] [42] Importantly, this response may be short-lived as male antibody levels appear to fall more precipitously than females. 42 These considerations become relevant when considering the ideal candidates for convalescent serum donation and the appropriate timing intervals for vaccination redosing.

Patients infected with SARS-CoV-2 have an asymptomatic incubation period of approximately five days and are at greatest risk of viral shedding in the 1-2 days prior to developing symptoms; symptomatic male and female COVID-19 patients commonly complain of cough, fever, shortness of breath, headaches, myalgias, vomiting, diarrhea, and abdominal pain. 43 Women report more initial symptoms of hyposmia, anosmia, and gustatory dysfunction than men. [44] [45] Cutaneous manifestations of COVID-19 include viral exanthem, urticaria and papules; differences by sex have not been well studied. 46 J o u r n a l P r e -p r o o f Women may have a greater incidence of the peculiar chilblain-like rash that has become better known as "covid-toes. [46] [47] Neurological symptoms are common and can range from mild headache and dizziness to encephalopathy, cerebral thrombosis and neuropsychiatric disorders, with one study suggesting that 13% of hospitalized patients have significant new neurological disorders with 2 days of admission. 48 Overall, men are more likely to develop severe symptoms, and are at greater risk for hospitalization, ICU utilization and death. 49 In regards to laboratory testing, investigators in Brazil found that both infected women and men had lower platelets, basophils, eosinophils, and lymphocyte counts, and higher ESR, CRP, GGT, ALT, fibrinogen and ferritin than patients without COVID-19. 50 Men had higher overall levels of CRP, ESR, ALT, AST, GGT, Ferritin, Fibrinogen and LDH, and aPTT versus in women, serum calcium and sodium concentrations were greater and LDH and aPTT remained elevated throughout the hospitalization. 50 Markers of immune mediated responses were more frequently observed to be elevated in COVID-19

patients requiring ICU admission. 50 Furthermore, IL-8 and IL-18 levels were increased in men with COVID-19, while CD8 T cells were increased in women. 51 For the clinician, in addition to hypoxia, biomarkers of vascular injury such as troponin (cardiac), IL-6 and CRP (inflammation), and d-dimer (coagulation) serve as predictors of prognosis in COVID-19 patients. 50

Venous thromboembolic events (VTE) are common with COVID-19 and found to be associated with adverse outcomes. 52 In one study, ICU patients with Sars-Cov2 had a 27% incidence of VTEs and an almost 4% incidence of arterial thrombosis. 53 Besides being vulnerable to the conventional clotting risks of all immobilized, severely ill hospitalized patients, sick COVID-19 patients are at risk for immunothrombosis--this is attributed to microangiopathic dysfunction from endothelial cell activation causing overexpression of pro-thombotic and procoagulant molecules (e.g. von-Willebrand factor), and J o u r n a l P r e -p r o o f reduced anticoagulants (e.g. antithrombin III, protein). 54 This leads to the formation of fibrin clots and subsequently, as the body starts to dissolve that clot, an elevated d-dimer. As a significantly elevated ddimer has been associated with disease severity, the use of a d-dimer may help in prognostication and the early initiation of anticoagulation. 52 This immunothrombosis may not be unique to COVID-19 and can be found associated with other viruses like H1N1 and Dengue fever. 55 and found that the peptide Thymosin β4 (Tβ4), which assists in fibrinolysis, appears to have greater expression in female cells. 61 The gene for Tβ4 is located on the X chromosome and escapes X inactivation; Tβ4 is already being studied for use in cardiovascular disease and as it downregulates proinflammatory cytokines and chemokines there is interest in using it in COVID-19 patients. 61

The above noted 'endothelial disease' and its associated widespread hyperinflammatory and coagulopathic pathology can lead to injury throughout the body. 62 This includes cardiac damage, cerebral thrombosis, and disruption of the endothelial barrier in the lungs. Patients with cardiovascular disease (CVD) are not more prone to getting infected; however, they are at higher risk for hospitalization and adverse outcomes. 54 Men have even worse endothelial pathology when infected with COVID-19 if they have underlying hypertension, obesity and known CVD. 63 Cardiac injury, defined as troponin elevations >99 th percentile, is associated with higher mortality in COVID-19 patients and is more commonly seen in men. 64 Elevated troponin increases the risk of malignant arrhythmias, heart failure. Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) and coagulopathy in COVID-19 patients. 65 SARS-CoV2 binds to ACE2 receptors on the myocardium, causing both overstimulation and dysregulation of the renin-angiotensin-aldosterone system (RAAS) contributing to vasoconstriction and a proinflammatory state. 66 RAAS changes are influenced by sex chromosomes and hormones because the tissue distribution of ACE2 receptors differ between women and men. (Table 3) .

It remains unclear whether sexual dimorphisms in ACE2 directly contribute to the sex-specific severity and mortality seen with COVID-19. 54 Further complicating matters is the complicated J o u r n a l P r e -p r o o f relationship between RAAS and the kinin-kallikrein system, with some suggesting that once RASS gets dysregulated it disrupts the delicate balance of bradykinin production/degradation, leading to excessive bradykinin levels and vascular leakage and inflammation. 61 SARS-CoV2 also leads to an imbalance in T cell activation, increasing IL-6 and other pro-inflammatory markers in the myocardium. Troponin elevations on serial assessments correlated directly with IL-6 elevations in COVID-19 patients. 67 The cause of cardiac injury is uncertain and can occur in the absence of obstructive CAD.

Proposed mechanisms include direct virus invasion leading to extensive inflammation (e.g. myocarditis), or a secondary myocardial stress resulting from extensive lung injury, or a consequence of the MIR. 54 Cardiac complications usually occur 2 weeks after infection lending support for the MIR mechanism, as peak windows of viral invasion have already passed--this window is important to know for the clinician assessing these patients and in seeking evidence of myocardial injury when patients with COVID-19 present with chest pain. 54 A few case reports don't supported a diagnosis of myocarditis on endomyocardial biopsy, thus raising the possibility of additional mechanisms such as microvascular dysfunction, takotsubo, arrhythmias or tamponade with COVID-19. [68] [69] An increased incidence of takotsubo or stress cardiomyopathy has been reported with COVID-19. 70 Although takotsubo is generally much more common in women, there has not been a sex difference in incidence among COVID-19 patients. 70 SARS-CoV2 affects macrophages that are involved with the conducting cells of the AV node which express ACE2, precipitating arrhythmias including atrial fibrillation, sinus tachycardia, complete heart block and cardiac arrest; to this point, no sex difference have been found in the incidence of arrhythmias. 54 However, most antiviral therapies have a QTc prolonging effect that needs to be monitored as women in particular are more susceptible to drug-induced QTc prolongation than men. 54

SARS COV-2 binds to ACE2 receptors on the epithelial cells of the pulmonary vasculature, inducing a vigorous immune response, edema and respiratory failure and obese individuals are at significantly increased risk for lung damage and severe disease because of: chronic inflammation, dysregulated immune response and respiratory compromise (from atelectasis, decreased lung compliance, hypoventilation and reduced chest wall compliance). 71 This leads to abnormal pulmonary perfusion, impaired fibrinolysis and the increased risk of having other comorbid conditions. 71 The proinflammatory effects of obesity can be augmented in men whose testosterone levels are often lower and estrogen levels higher than non-obese males. 71 In addition, ACE2 expression is also increased in adipose tissues which can act as a major reservoir of proinflammatory markers including IL-1 and IL-6. 72 In females, estrogen may provide protection by helping to shift the RAAS pathway towards activation of Angiotensin (1-7) through the MAS receptor that protects the endothelial barrier in acute lung injury and by increasing nitric oxide release and decreasing platelet aggregation. 73 There are known sex-based differences in lung physiology including airway caliber, accessory muscle mechanics, lung volumes, diaphragmatic excursion, and abdominal fat distribution. 74 These differences may impact the management of severe COVID-19 patients. For example, older data suggests that males with Acute Respiratory Distress Syndrome (ARDS) are at greater risk of getting ventilation associated pneumonia after intubation. 75 More recently, research has suggested that testosterone replacement may help men with severe COPD possibly via an anti-catabolic effect on their respiratory muscles. 76 Conversely, a 2019 study found that in patients intubated for ARDS, that 74% of males versus only 50% of females got appropriate lung protective low volume settings. 77 Shorter women appeared to be at particular risk for being placed on unnecessarily high volumes underscoring the importance of using height to estimate ideal body weight when setting ventilator parameters. 78

During the initial stages of the pandemic it was common practice to intubate mildly hypoxic patients even if they clinically appeared otherwise well, as this practice did not appear to benefit many patients, strategies to help avert early intubation have become increasingly popular. 79 From previous ARDS research, it has been shown that proning intubated patients can significantly decrease mortality. [80] [81] A meta-analysis of proning spontaneous breathing COVID-19 patients suggests an improvement in oxygenation and likely a decreased need for subsequent intubation. 79 The physiological advantage of proning appears to be an overall improvement of ventilation/perfusion matching that can enhance oxygenation. 82 Data is scarce as to whether proning equally benefits males and females. The 2017 metaanalysis on more than 2100 proned mechanically ventilated ARDS patients did not sex-disaggregate their outcome data and published data is thus far limited in the evaluation of COVID-19 proned patients. 79, 81, 83 Although there are S/G differences of who needs to be admitted to an ICU, once in a unit there are no S/G differences in mortality as shown by a recent global COVID-19 meta-analysis involving greater than 16,000 patients. 84 Sixty-nine percent of ICU admissions were male, there were no S/G differences in ICU mortality and overall, about 68% of patients required intubation and 28% died. 84 Long haulers: COVID-19 patients with persistent symptoms 'Long haulers' are individuals who have had SARS CoV-2 and experience lingering symptoms beyond what is typical for most viral illnesses. 85 The prevalence of long haulers are variable. A report in the British Medical Journal estimates that about 10% of infected patients go on to have residual symptoms while a CDC phone survey involving almost 274 SARS Cov2 symptomatic non-hospitalized patients found that 35% still reported symptoms 2-3 three weeks after their positive test. . [86] [87] The pathophysiology leading to symptoms in long haulers is poorly understood. Different theories include a hidden persistent reservoir of virus that intermittently sheds, immune reactions to residual viral particles, a hyperactive inflammatory response involving bradykinin with increased J o u r n a l P r e -p r o o f endothelial permeability, and an autoimmune response. 61, [88] [89] Long haulers can have a myriad of different symptoms including dysautonomia, myalgic encephalomyelitis, severe fatigue, difficulty sleeping, headache, anxiety and shortness of breath, despite normal oxygen levels. 88 Unfortunately, there are several factors that complicate the study of long haul patients, most importantly the challenges of confirming actual previous Sars-Cov2 infection. Many long haulers were not tested during their initial illness due to test scarcity or because they were not sick enough to require hospitalization. In addition, many patients may lack evidence of residual elevated antibody titers. 90 This can make it challenging to distinguish those with previous exposure/falling titers or false negative tests from those who suffer from unrelated conditions.

Although the current identification and understanding of potential S/G differences in long haulers is still in its infancy, women appear to be at much greater risk for persistent symptoms. 88, 91 As many of the long haul syndromes overlap with those associated with myalgic encephalomyelitis (ME)/chronic fatigue syndrome or fibromyalgia syndromes, there has been growing research interest in studying this potential connection. 88 Historically, ME has also impacted a greater number of women (3:1 ratio), frequently develops after an infectious exposure, and has defied straight forward objective diagnoses. 92 BSD in ME/long haul symptomatology may likely be amplified by sex differences in pain physiology and nociception. 93 Due to increasing prevalence of "long haulers", more hospital systems are developing postcovid clinics. 88 Hopefully, this will help drive research to better define prevalence, physiology and treatment options for these patients.

Known sex differences in the immune response to new antigens such as SARS-CoV-2 along with documented sex differences in pharmacokinetics and adverse drug reactions have the potential to lead to sex differences in the efficacy and side effects of medications used for COVID-19. [94] [95] The paucity or J o u r n a l P r e -p r o o f complete absence of sex-disaggregated data to compare benefits or adverse effects of novel COVID-19

treatments creates major knowledge gaps which will continue to widen and impact the lives of both women and men as the pandemic continues.

Socially constructed roles and expectations may influence the Covid-19 pandemic in many important ways. Specifically, gendered behaviors, occupations, and habits are likely to impact disease vulnerabilities and outcomes. For instance, men use tobacco more frequently 96 women are more likely to

seek out medical care, and older women are more likely to live alone and experience social isolation. 97 There also appear to be gender differences in risk tolerance: a study of US men found that they are more likely to downplay the severity of the virus's potential to harm them and are less likely than women to report avoiding large public gatherings or close physical contact with those outside their home. 98 Similar patterns of gender based public health choices appear when hand washing and mask-wearing are examined; one study demonstrated that women were 50% more likely to wear a mask than men. 99 Age can be an additional modifier, for example, older men may perceive their risk of COVID-19 to be higher than younger men, yet be less willing to commit to behavioral changes and to engage in preventive measures such as handwashing. 100 Messaging targeted to improve compliance with public health measures must consider that the values and motivators of different groups may be deeply impacted by gender identities and other sociocultural characteristics. 101 Worldwide, gender influences occupational trends and can greatly impact susceptibility of COVID-19 infection; for instance in the United States, over 75% of healthcare workers are women, and women are more likely to be defined as "essential workers. 102 Men are more likely to be employed in jobs J o u r n a l P r e -p r o o f that are associated with a greater risk of death from COVID-19, like working in food processing, transportation, delivery, warehousing, construction, and manufacturing. 103 Gender relations and positive and negative externalities must be considered when governments formulate policies. For example, 'stay at home' orders may put individuals at increased risk for domestic violence and early research has demonstrated that the incidence and severity of physical intimate partner violence has significantly escalated during the pandemic in the U.S and worldwide. 104

The evidence presented here underscores the critical importance of including S/G variables in future COVID-19 related research to ensure that care is optimized for all patients infected with Sars

CoV2 .Mitigating the sex and gender based outcomes that result from health disparities requires a multiprong approach. There must be gender equity in leadership positions, ensuring that sex and gender are considered de facto as variables for inclusion and analysis in scientific research, policy and task force initiatives. 105 J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Estrogen -Its effect on immune response is complex and appears to be dependent upon circulating levels and site of action along different immune pathways.

-Low physiological levels appear to enhance production of certain proinflammatory cytokines (IL-6, IL12, IL-Iβ)

-Higher levels suppress many inflammatory cytokines, triggers regulatory cytokine (IL-10) and decreases migration of neutrophils and monocytes to -The RAAS and kininkallikrein systems are closely interwoven and decreases in ACE or ACE-2 levels can lead to excessive amounts of bradykinin and increased vascular permeability -ACE-2 expression is enhanced in smokers -children may have decreased ACE-2 expression in nasal mucosa -Testosterone tips the balance of RAAS towards its vasoconstricting and hyperinflammatory arm by increasing renin and activating the ACE/AngII/ATR1 axis which can lead to cardiotoxicity --testosterone enhances TMPRSS2, a transmembrane protease, that aids viral bound ACE-2 into cells -serum (unbound) ACE-2 levels are greater in males than females with congestive heart failure --significant amounts of ACE-2 in testes -ADAM-17 (which cleaves ACE-2 from cell membranes leading to increased ACE-2 plasma levels) is increased in testis Estrogen tips RAAS balance towards the cardioprotective vasodilatory arm by decreasing renin, increasing angiotensinogen, ACE, ANG1, aldosterone and ANG (1-7) and enhancing binding at AT2R, MasR (which are both vasodilatory).

-gene for ACE-2 is encoded on X chromosome, allowing a second copy of gene in females -Progesterone competes with aldosterone for the mineralocorticoid receptor.

J o u r n a l P r e -p r o o f

World Health Organization. WHO Interactive Timeline. Geneva: World Health Organization

Timeline of WHO's response to COVID-19. Geneva: World Health Organization

Novel coronavirus infection (Covid-19) in humans: a scoping review and meta-analysis

Global Health 50/50. The COVID-19 Sex-Disaggregated Data Tracker

Demographic trends of covid-19 cases and deaths in the US reported to CDC

Gender and age effects on the rates of infection and deaths in individuals with confirmed sars-cov-2 infection in six European countries

Lack of consideration of sex and gender in clinical trials for COVID-19

Sex-and Gender-Based Medicine: The Need for Precise Terminology 1 2. Gender and the Genome

Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection

Implications of Sex Differences in Immunity for SARS-CoV-2 Pathogenesis and Design of Therapeutic Interventions

Factors Associated With Prolonged Viral RNA Shedding in Patients with Coronavirus Disease 2019 (COVID-19)

SeXX Matters in Infectious Disease Pathogenesis

Sex-based differences in immune function and responses to vaccination

The X chromosome and sex-specific effects in infectious disease susceptibility

TLR7 escapes X chromosome inactivation in immune cells

Presence of Genetic Variants Among Young Men With Severe COVID-19

The X chromosome and immune associated genes

Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes

Mechanisms of sex disparities in influenza pathogenesis

Sex differences in infectious diseases-common but neglected

Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19)

The Complex Role of Estrogens in Inflammation

Sex-based differences in susceptibility to SARS-CoV infection

Are sex discordant outcomes in COVID-19 related to sex hormones?

Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection

Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure

Commentary: Testosterone, a key hormone in the context of COVID-19 pandemic

Androgenetic alopecia present in the majority of hospitalized COVID-19 patients -the "Gabrin sign

VA degarelix (blocks gonadotropin-releasing hormone) trial using for COVID-19 patients

Promote Recovery Form COVID-19 with Endocrine Therapy Trial

Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. medRxiv2020

Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: a cohort study

The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive Care in

Screening for low testosterone is needed for early identification and treatment of men at high risk of mortality from Covid-19

SARS-CoV-2: A storm is raging

Is a "Cytokine Storm" relevant to Covid-19?

Sex differences in immune responses that underlie COVID-19 disease outcomes

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Men make more corona virus antibodies than women, making them better plasma donors. NHS Blood and Transplant

Sex differences in the decline of neutralizing antibodies

Symptom Profiles of a Convenience Sample of Patients with COVID-19 -United States

Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection

Classification of the cutaneous manifestations of COVID19: a rapid prospective nationwide consensus study in Spain with 375 cases

Cutaneous signs in COVID-19 patients: A review

Going viral: A brief history of Chilblain-like skin lesions

A Prospective Study of Neurologic Disorders in Hospitalized COVID-19 Patients

Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China

In-depth Analysis of Laboratory Parameters Reveals the Interplay Between Sex, Age and Systemic Inflammation in Individuals with COVID-19

Sex differences in immune responses that underlie COVID-19 disease outcomes

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19

Dengue and influenza associated acute pulmonary embolism: An overview

Association Between Pulmonary Embolism and COVID-19 in Emergency Department Patients Undergoing Computed Tomography Pulmonary Angiogram: The PEPCOV International Retrospective Study

Elevated D-Dimer Levels are Associated with Increased Risk of Mortality in COVID-19: A Systematic Review and Meta-Analysis

Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis

Increased Incidence of Acute Pulmonary Embolism in Emergency Department Patients During the COVID-19 Pandemic

Association of testosterone therapy with risk of venous thromboembolism among men with and without hypogonadism

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

COVID-19 is, in the end, an endothelial disease

The European Society for Cardiology. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic

Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19)

Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System

Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome

Incidence of Stress Cardiomyopathy During the Coronavirus Disease

Obesity: A critical risk factor in the COVID-19 pandemic

Is Adipose Tissue a Reservoir for Viral Spread, Immune Activation, and Cytokine Amplification in CoronavirusDisease

Estrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation

Increased understanding of basic biological, pathophysiological, and behavioral mechanisms leading to better health for female patients with lung disease

Risk factors for ICU-acquired pneumonia

Testosterone replacement therapy and hospitalization rates in men with COPD

Demographics, management and outcome of females and males with acute respiratory distress syndrome in the LUNG SAFE prospective cohort study

Protective Lung Volume Reference

Effect of awake prone positioning in COVID-19 patients-A systematic review. Trends in Anaesthesia and Critical Care

Prone positioning in severe acute respiratory distress syndrome

Prone position for acute respiratory distress syndrome. A systematic review and meta-analysis

Prone position in ARDS patients: why, when, how and for whom

Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study

Global impact of COVID-19 infection requiring admission to the intensive care unit: a systematic review and meta-analysis

Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19

Management of post-acute covid-19 in primary care

Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network -United States

As Their Numbers Grow, COVID-19 "Long Haulers" Stump Experts

Covid immune responses explained. Medicine and the MachinePodcastAugust2020

The tragedy of post-Covid "long haulers". Harvard Health Blog

Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review

Sex differences and estradiol involvement in hyperalgesia and allodynia in an experimental model of fibromyalgia

National Institutes of Health Office of Research on Women's Health

Sex differences in pharmacokinetics predict adverse drug reactions in women

Women and Health. Ten facts on gender and tobacco

Aubrey-Bassler K The influence of gender and other patient characteristics on health care-seeking behavior: a QUALICOPC study

Gender, masculinity, and COVID-19. The Gender Policy Report

Who is wearing a mask? Gender, age-,and location-related differences during the COVID-19 pandemic

COVID-19 worries and behavior changes in older and younger men and women

Why Sex and Gender Matter in Implementation Research

WHO: Gender equity in the health workforce: Analysis of 104 countries. Healthcare Workforce working Paper 1

How millions of women became the most essential workers in America

Exacerbation of Physical Intimate Partner Violence during COVID-19 Lockdown

Where the Women Aren't: On Coronavirus Task Forces. NPR

Abbreviations RAAS-Renin-Angiotensin-Aldosterone system, ACE-Angiotensin converting enzyme, ACE-2-Angiotensin converting enzyme

ATR1-Angiotensin II Receptor type 1, ATR2-Angiotensin II Receptor type 2. TMPRSS2-Transmembrane Serine Protease

Biological sex refers to an individual's innate combination of sex chromosomes and hormones and is usually binary-male versus female whereas Gender refers to a social construct that is heavily influenced by societal roles and expectations and occurs along a spectrum bracketed by "man" and "woman". 9 When a clinically important medical outcome is noted to differ between men, women, and non-binary individuals (MWN), it is helpful to determine if that difference is rooted in biological sex or gender identity. In reality, this can often be quite difficult. Gender influences start before birth (i.e. gender reveal parties or sex-selective abortions) and gendered experiences can affect exposure rates to different toxins and pathogens. In addition, even if MWN are exposed to the same infection or carcinogen, their physiological response may be quite different due to biological sex-based differences (BSD) in epigenetics that influence which genes are expressed in response to the trigger. Rather than thinking of sex and gender as two distinct entities separated by a vertical line, it is more helpful to consider them as being part of a circle that is continuously looping.