Many aspects of the novel coronavirus known as COVID-19 still puzzle scientists and clinicians, especially as the data continue to evolve. But one fact has remained the same: COVID-19 affects men more severely than women.

Reports from China published by the World Health Organization in February 2020 indicated that the death rate among those confirmed with the virus was 4.7 percent for men and 2.8 percent for women. Italian researchers found that men in their fifties died at four times the rate of women in their fifties. In New York City, as of mid-April, men accounted for approximately two-thirds of deaths from COVID-19, according to the city's health department.

The GenderSci Lab at Harvard University, which advances the study of gender and biomedical sciences, operates a data tracker on COVID-19 cases in the United States, including charts of cases and deaths by sex (at least for states that provide those breakdowns; several do not). In many states, women account for a higher percentage of cases of COVID-19 than men, but more men are dying from the disease.

Researchers are pondering the questions: Is this phenomenon related to immune system differences? Do women have a stronger immune system that enables them to fight off a severe viral infection better yet is also more prone to attack the body's tissues? Is this a double-edged sword that may account for higher rates of many autoimmune disorders among women, including neurologic conditions such as multiple sclerosis (MS) and myasthenia gravis?

Many experts think it's largely environmental and social considerations—such as higher rates of smoking, obesity, diabetes, and cardiovascular disease—that put men at higher risk for serious illness. In an opinion piece published in the New York Times on June 24, the directors of the GenderSci Lab acknowledged that sex-linked biology is a factor but said several analyses have shown that in places where more men are dying than women, men also are far more likely on average to smoke and have co-occurring conditions related to smoking, such as heart disease.

"Innate immune differences could play a role," says Nikolaos Patsopoulos, MD, PhD, assistant professor of neurology at Brigham and Women's Hospital in Boston and Harvard Medical School. "But the most overwhelming evidence has to do with conditions that also contribute to sex-based differences in other diseases, such as stroke and hypertension."

Men also may be less likely to wear masks, says Kenneth L. Tyler, MD, FAAN, chair of neurology at the University of Colorado School of Medicine in Aurora. "If men are exposed they may be more likely to experience more severe illness." Men also may be less likely to receive preventive care, says neurologist Aimee Borazanci, MD, an MS specialist at the Barrow Neurological Institute in Phoenix. "That said, sex-based differences in the immune system may play a role too. At this point we are collecting data on trends."

Immune differences between men and women are partly attributable to hormones, Dr. Borazanci says. "We know that women are more susceptible to some autoimmune diseases, such as MS, lupus, and rheumatoid arthritis," she says. "We think hormones in women, such as estrogen, may play a stimulating role in some of these diseases, and that may explain why they are more prevalent in women, while perhaps androgens found in men are protective."

But the hormonal factor in the immune response and autoimmune disease is complicated. Even though MS is three times more common in women than men, according to a 2019 report in Neurology, men often have more severe cases—faster development of disability and worse recovery from relapses.

"In general, the immune system of the average woman is a lot more sophisticated than that of the average man because it has to adapt to the most amazing thing—creating life," says Dr. Patsopoulos. "It has to be able to maintain a foreign body inside the womb without rejecting it throughout pregnancy. It is not surprising that most immune cells have different receptors for hormones such as estrogen. And different studies of these immune cells point to the same thing: that there is some kind of priming or local environmental influence in the immune system of women that contributes to the way they are poised to react. Sometimes hormones from your own body, sometimes environmental influences, and sometimes something like a virus may change this balance to activate an immune response."

What all this means for COVID-19 is still unclear. "We have a modest understanding given the evidence, but every week there is another study, and it is difficult to evaluate evidence within a time frame of such urgency," Dr. Patsopoulos says. "I will not be surprised if, at the end of the day, with large-scale studies, our understanding of the sex differences in this disease will be different than it is right now."

It is certain, however, that the current health crisis underscores the importance of studying sex differences in the immune response. "Women being more likely to get some of these autoimmune diseases would be more consistent with a more robust immune response, which is also consistent with women doing better with COVID-19," says Rhonda Voskuhl, MD, professor of neurology at UCLA Health and president of the Organization for the Study of Sex Differences. "There are all kinds of sex differences in the immune response within different organs—the lungs, the skin, the kidneys, the brain. But even though the immune response may be quantitatively higher overall, it may be qualitatively different between these target organs."

Beginning in 2016, the National Institutes of Health (NIH) required all funded research to factor sex as a biological variable into its design, analyses, and reporting. "While the NIH insists that both males and females be represented in trials, almost no trials are designed to see differences based on sex," says Dr. Voskuhl. To detect if efficacy of a new drug varies between men and women, a study would need to be designed differently from the outset.

Sex has a significant impact on many diseases in both humans and animals, though in animal models of disease, the factor is not confounded by differences in behaviors or co-existing conditions, Dr. Voskuhl says. "If we understood how sex hormones or sex chromosomal factors affect disease in the peripheral immune system or in target organs, we could develop treatments focused on that to help both men and women. If we had studied these sex differences previously, we might be closer to effective treatments for COVID-19 today. While behaviors or co-occuring diseases can play a role in COVID-19, this is not mutually exclusive of a role for sex hormones or chromosomes."

Surviving COVID-19 with Multiple Sclerosis

Musician Sue Goldberg, 64, had been living with relapsing-remitting multiple sclerosis (MS) for 30 years when she tested positive for COVID-19 in April. She spent two weeks in the hospital—three days of it on a ventilator. "For a while it didn't look good for my survival, but then it started to reverse itself somehow," she says. Today, she's recovering in the home she shares with her partner in Provincetown, MA, slowly working her way back to the level of function she'd had prior to COVID. But she would like to know if ocrelizumab (Ocrevus), the disease-modifying drug she was taking for MS, put her at higher risk for contracting COVID-19 or developing more severe complications.

"I do wonder if it hit me so hard because I was on this immunosuppressant," says Goldberg, whose neurologist switched her from glatiramer acetate (Copaxone) to ocrelizumab when her MS worsened two years ago. "Two different doctors have commented to me about that. One said the medication was probably part of it, while the other said it probably had nothing to do with it." Since she'd started taking ocrelizumab, Goldberg had had three infusions (they are administered twice a year)—the most recent in January—before getting COVID-19.

As an immunosuppressant, ocrelizumab depletes the body's disease-fighting B cells, which could leave patients more vulnerable to infection. The medication was approved by the US Food and Drug Administration in 2017 after trials showed it reduced MS relapse rates by nearly 50 percent compared with older interferon-based therapies.

"The fact that she had severe COVID may be unrelated to the use of Ocrevus. Certainly many individuals not on immune medications also have had severe disease," says neuroimmunologist Erin Longbrake, MD, PhD, assistant professor of neurology at the Yale School of Medicine. "The outcome might have been the same if she were still on Copaxone or on no treatment at all. We don't know."

At the start of the pandemic, many neurologists expected that patients on immunosuppressants would fare worse if they developed the disease. "Overall, however, we haven't seen that trend," says neurologist Aimee Borazanci, MD, an MS specialist at the Barrow Neurological Institute in Phoenix. "In virtual meetings with other MS centers, we have access to a database of patients who have COVID-19 and what disease-modifying therapies they have been on, and for the most part these patients have been recovering well."

That database is COViMS (COVID-19 Infections in MS & Related Diseases), a joint effort of the Consortium of Multiple Sclerosis Centers, the National Multiple Sclerosis Society, and the Multiple Sclerosis Society of Canada, led by researchers at Washington University School of Medicine in St. Louis. As of July 1, the majority (90.9 percent) of the 351 cases in COViMS had either recovered, were recovering, or had never developed symptoms despite testing positive. Twenty-one patients (6 percent) had died, while the remaining 2.8 percent had unknown outcomes.

"Right now, we have no concrete factors that would predict outcomes for COVID-19 patients," Dr. Borazanci says. "We have seen various outcomes of different MS patients on the same immune therapy who have contracted COVID-19—some have done well, and some have not. At this time, we do not have any evidence that their recovery is related to their immune treatment."

Disease-modifying therapies for MS are not all alike, says Rhonda Voskuhl, MD, professor of neurology and director of the MS program at UCLA Health. "You can't lump them together and say there's no difference in outcomes. And we know that responses to vaccines like those for tetanus and pneumococcal disease are suppressed while on Ocrevus, so it makes sense that immune response to COVID could be impaired as well," she notes. "On the other hand, in some people COVID-19 induces a severe hyperinflammatory reaction called cytokine storm, and it's theoretically possible that immune-modulating therapies could control some of that inflammation."

The data are relatively sparse, cautions Kenneth L. Tyler, MD, FAAN, chair of neurology at the University of Colorado School of Medicine in Aurora. "And even smaller when parsed out for individual drugs."

One drug used to treat MS, fingolimod (Gilenya), is now being studied in an open-label trial in China as a possible preventive treatment for acute respiratory distress syndrome (ARDS) among COVID-19 patients.

Guidelines for neuromyelitis optica spectrum disorder during the COVID-19 pandemic" href="https://n.neurology.org/content/94/22/949.long" target="_blank" rel="noopener">treating MS during the pandemic are published online by the American Academy of Neurology. "In most people with MS, the benefits of continuing treatment will outweigh the risks of stopping because of concerns over COVID-19," a June 2 article says.

In general, the guidelines consider it safe during the pandemic for patients to start or continue the interferons (Betaseron and Avonex) and glatiramer acetate, as well as dimethyl fumarate (Tecfidera), teriflunomide (Aubagio), and natalizumab (Tysabri). They recommend more caution for drugs with a moderate risk of immune suppression—including ocrelizumab, rituximab (Rituxan), fingolimod, siponimod (Mayzent), and ozanimod (Zeposia)—and suggest delaying these treatments if they are new for the patient. For those already on these therapies, the guidelines advise doctors to monitor lymphocyte counts and consider extended interval dosing for agents like ocrelizumab and rituximab. They recommend against taking highly immune-suppressive treatments, such as cladribine (Mavenclad), alemtuzumab (Lemtrada), and stem cell transplantation.

Dr. Longbrake notes that "such guidelines do not have a high level of evidence to support them" but rather are based largely on expert opinion. "So I would take any published recommendations on this subject with a grain of salt," she says. "I tell patients that we consider use of immunotherapies to be at least a theoretical risk for infections, including COVID-19.

"Nevertheless, any increase in risk associated with these medications appears to be small," says Dr. Longbrake. "We must recognize that this pandemic is not going away quickly, and therefore we must weigh the risk of using an immunomodulator during the pandemic against the risk of permanent disability caused by uncontrolled MS if the patient is untreated or undertreated."

"These are important questions to talk about with your neurologist," says Dr. Borazanci. "No one should change their dosage or stop taking a medication without discussing it with their doctor."