I’m coming to you from the front lines of the battle against the novel coronavirus, aka SARS-CoV-2.
As an associate professor of emergency medicine at the Warren Alpert Medical School of Brown University, I spend dozens of hours a week in the emergency department. It’s my job to direct and oversee our residents, as well as care for patients.
You’ve heard at length about the ongoing equipment shortages, lack of personal protective equipment (PPE) and other challenges health care providers are facing, so I won’t belabor them here. However, while the worries at ground level are overwhelming, my greatest concerns are larger and more systemic; in particular, I’m concerned that our male-centric medical system is missing the opportunity to gather crucial information about COVID-19 patients that could potentially save lives and reduce pandemic severity in the future.
As the co-founder and director for the Division of -Sex and Gender in Emergency Medicine (SGEM) at the Brown University Emergency Medicine Department and the co-founder for the national organization Sex and Gender Women’s Health Collaborative, I study sex differences in medicine—particularly in emergency medicine. This means that I research and teach about the ways in which women are biologically different than men, and how these differences impact everything from diagnoses to treatment protocols to pharmaceutical bioavailability (to name a few areas).
My concerns around COVID-19 are many, but among them is our lack of understanding about how the virus may affect women and men differently, and how this lack may prevent us from delivering the most appropriate and personalized care for all patients with COVID-19.
Women are biologically different than men from the level of our DNA on up. We are not simply men with breasts and ovaries; we are unique in every cell of our bodies. But because our modern medical system is male-centric—meaning that it is foundationally based on knowledge of, research on and observation of male bodies and male patterns of illness—women often don’t fit the textbook models by which we as physicians learn to diagnose and treat our patients.
Across every facet of our medical system, women have poorer outcomes than men. They have delays in diagnosis for the most common and deadly conditions, and a greater likelihood of receiving a psychiatric diagnosis for physical symptoms. Many pharmaceuticals are also metabolized differently by women, and therefore produce different outcomes and side effects than they do for men. Women even experience pain through different biological mechanisms than men.
Why does any of this matter? It matters because we know next to nothing about how the methods we’re using to treat COVID-19 patients affect women’s unique biology. Neither do we know how and why the virus is affecting men and women differently on a biological level. That lack of knowledge may result in poorer outcomes for everyone—not only in this pandemic, but in future outbreaks.
There have been many news stories about how COVID-19 seems to hit men harder than women. At last update, it appears that men account for over 61 percent of coronavirus deaths. But it seems that, except for some references to men’s poor handwashing practices and higher rates of smoking, little is being done to investigate this.
Epidemiological data from the SARS and MERS outbreaks of recent decades suggest that there may be sex differences in coronavirus disease outcomes beyond what one would expect from gendered social and lifestyle habits. A paper published in the American Journal of Epidemiology found that “males had a significantly (p < 0.0001) higher case fatality rate than females did,” 21.9 percent versus 13.2 percent. The authors cited no specific causes for this disparity, but their findings were correlated by an animal study conducted in 2017, wherein researchers injected age-matched male and female mice with SARS-CoV, the virus that caused the SARS outbreak. The male mice were found to have elevated virus titers, alveolar edema and other markers compared to the females.
However, when the ovaries of the female mice were removed, their susceptibility to the virus increased to a level on par with the males. Estrogen receptor antagonists (drugs which prevent estrogen from binding to cells) produced the same effect, leading researchers to believe that women may have an “estrogen-protective effect” when it comes to respiratory coronaviruses.
Women also have different immune response pathways than men. Their bodies treat “attackers” differently. However, we don’t understand enough about these mechanisms to apply them to COVID-19.
Incredible amounts of data are being gathered daily from all parts of the world, and that information is becoming available online almost immediately. However, even with all of our technologies, there are little to no sex-specific data with regard to current patients in the U.S. or elsewhere. This needs to change immediately.
If we have the ability to track COVID-19 cases and provide daily updates on new cases, we have the ability to gather sex-specific information on those infected as well. Making these data available would allow researchers like me to start evaluating susceptibility trends and outcomes with greater focus and specificity, potentially allowing us to reduce the spread of the virus and suggest more effective preventive measures for future pandemics. If in fact women do have some natural protection against these viruses, we can put it to work to create better outcomes for men and women alike.
The primary drug being used to treat COVID-19 patients is hydroxychloroquine—an older drug sold under the brand name Plaquenil and used to treat (among other things) lupus, rheumatoid arthritis and malaria.
While weight-based dosing is recommended, there is no sex-specific dosing for this drug—even though we know that this drug works by suppressing immunity, and that men and women have different immune responses. We don’t know how sex differences influence its efficacy, or whether sex-specific dosing might produce fewer side effects and more positive outcomes.
This is just one of many areas where our lack of sex-specific knowledge may be crippling our ability to effectively fight this virus. My colleagues in the research field are working at a breakneck pace to try to find a drug—or a cocktail of drugs—that works reliably to cripple the virus. But if they are following established standards for research protocols, their models and projections are likely based on past male-centric research, the behaviors of male cells in petri dishes, and test results in male animal subjects.
In the eyes of the medical community, this isn’t a failure or an oversight. It’s simply the way things have always been done.
Researching on male cells, animals and study participants saves time and expenses, because we don’t have to test for pregnancy, or account for the hormonal differences at each phase of menstruation. However, because women and men are biologically different, what works for men may not always work reliably (or safely) for women.
FDA regulations set up in 1998 require that new drug applications include reporting and analysis by gender, race and age. However, the agency cannot mandate specific demographics for clinical trials, or that data gathered in drug trials be analyzed specifically for sex differences.
The Office for Research on Women’s Health (ORWH), part of the NIH, has required the inclusion of sex as a biological variable (SABV) since 2016, and has mandated “inclusion of women and minority groups in all NIH-funded clinical research in a manner that is appropriate to the scientific question under study.” However, these recommendations only apply to NIH-funded research, and cannot be enforced with regard to research by other groups.
My concern isn’t that we lack the capacity to gather the information we need to understand sex differences in viral diseases. Rather, I fear that in situations like the one we are now facing—where time is of the essence, and everyone is racing to find a cure—researchers will turn to the most understood and straightforward testing pathways: male-dominant, with the results of all test subjects lumped together in the final analysis, and that the new guidelines for SABV will be set aside as a matter of “practicality.”
While this may not sound like a big deal given what we’re facing, it is.
Because women more often experience adverse reactions to prescription drugs, it’s necessary to analyze the data from female test subjects separately to ensure that an accurate picture is attained. For example, let’s say that 40 women and 60 men participated in a new drug trial. If 30 percent of women but only 5 percent of men displayed adverse reactions in a drug trial, a lack of sex-specific analysis might lead researchers to conclude that the drug only carried a 15 percent risk of complications, because a total of 15 out of 100 subjects displayed these effects. In turn, this number might be deemed acceptable to the FDA when clearing the drug for market. However, a sex-specific analysis would clearly show that the drug carried unacceptably high risks for women.
In hospitals treating patients with COVID-19, protocols are changing daily based on incoming information. There is little precedent to draw upon, so we are evolving our approach in real time. We are combining information shared by doctors in China and Italy with our knowledge of antivirals and the behavior of related coronaviruses (like SARS and MERS). However, we don’t even have height/weight–based prescribing guidelines for many of the potent antivirals being given to critical patients, let alone sex-based dosing!
I know that many will say that our need to get COVID-19 drugs and vaccines to market supersedes the need to adhere to the new, more complex research methods. However, I would argue that now is the time to gather as much data as possible, so we can create personalized treatments for each patient’s unique biology. Not only will this help individual patients to recover faster, with fewer complications, it will set a precedent for better reporting, analysis and treatment pathways than we have ever had before.
It’s my belief that sex differences can and should be integrated into our understanding of susceptibility, illness severity, treatments, pharmaceuticals, and vaccine formulations. We have more sophisticated surveillance and reporting at our disposal than ever before in history; let’s use this volume of data to gain a better understanding of not only how the coronavirus affects individuals based on biological sex, but how we can improve our capacities for response and treatment of all future health threats.
Lives are on the line. We need to do this right.
