Harvard Paper Trashes Yale Study on Sex Disparity in COVID Response

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Do men and women have different immune responses to COVID?
Do men and women have different immune responses to COVID?Credit: Valery Sidelnykov / Shutterstock

Men and women have similar immune responses to COVID-19, a Harvard University study has concluded, trashing a study done at Yale University that claimed to find sex-based differences. Yale trashed back and insisted there are sex differences in the human response to the coronavirus. Unmoved, the Harvard researchers are insistent that the paper by their Yale colleagues is substandard and argue that it doesn’t provide grounds to consider sex-based medical treatment or vaccine regimens.

It has become a conventional wisdom that COVID hits men worse than women. Is that true? If so, why? Do men and women really evince different immune responses, as the Yale researchers say?

In mid-2020, a paper published by Yale’s Takehiro Takahashi and colleagues in the prestigious journal Nature claimed that men and women had different immune responses to SARS-CoV-2, the virus causing COVID. The paper, “Sex differences in immune responses that underlie COVID-19 disease outcomes,” had been driven by “increasing evidence” that men suffered a higher mortality rate from COVID, the team explained.

The Yale team set out to examine whether the higher male mortality rate might be due to differences in immune system responses to the coronavirus (among the unvaccinated, mark you). They concluded that there ARE gender differences in the immune responses to the coronavirus and suggested consideration of different therapeutic and vaccine regimes for men and women.

The paper is badly designed, overreached and over-interpreted the data, claimed a rebuttal from Harvard researchers, also published in Nature: “A finding of sex similarities rather than differences in COVID-19 outcomes.”

“It’s a stunning example of sex-different analysis poorly done. It’s unsophisticated in the analyses it does,” the Harvard team’s co-lead author Sarah Richardson tells Haaretz.

In the journal Nature, of all places? “Unfortunately, hyped claims and unsophisticated models of gender/sex differences are a pattern in biomedicine,” Harvard’s Joseph Bruch says.

Of mice and males

It isn’t that Yale muffed the math per se, clarifies Harvard’s co-lead author Heather Shattuck-Heidorn. They had the right statistics but  the question is what those stats meant. The work is based on small sample groups: just 98 participants in total, and certain analyses were based on as few as five people, the Harvard team argues.

That isn’t enough to reach conclusions about deep immune system differences between men and women, or to suggest differing regimes, say the Harvard researchers.

Yale’s Takahashi is standing firm. “Sex difference in immune responses is proven across species, humans to fruit flies, and there are numerous studies on it,” he says in rebutting the rebuttal. “They are criticizing us [for] not being in the context of gender disparities and respiratory disease outcome differences, but our study is in the context of those numerous sex difference studies. After our study, even a mouse study, which doesn’t have any social/gender disparity factors, confirmed that male mice are more susceptible to severe disease from SARS-CoV-2 than female mice,” he explained to Haaretz.

“That is sort of irrelevant,” Harvard’s Richardson says. “They need to defend this study.” The immune system is vastly complicated and other studies may find sex differences in immune responses but this one didn’t do it. She says this study was “absolutely flawed from design to interpretation.”

In any case, extrapolating from mouse to man is problematic; it is true that murine models are convenient, but that doesn’t mean what works for Mickey works for you.

‘Stunning similarities’

Dr. Elisabetta Teti explains to 67-year-old patient Roberto Tortosa how his new respirator works atTor Vergata Polyclinic Hospital, in Rome, Nov. 7, 2020. Credit: Alessandra Tarantino/AP

Takahashi also stresses that the Harvard team says immune responses are “similar” between sexes but doesn’t define the term. “We are examining the immune responses of men and women – both Homo sapiens, and immune responses against the same virus, SARS-CoV-2. It is pointless to stress that responses are ‘similar’,” he says. “The important point is if, among lots of immune factors, there are even just several factors that are different, and we indeed found the difference in some critical factors that are known to determine clinical trajectories. By using the term ‘similarity,’ they seem to admit that there are indeed differences.”

Richardson explains that they were actually grounding their work in a theoretical framework regarding sex differences, originating with the psychologist Janet Shibley Hyde’s “gender similarities hypothesis.”

Of course, even if just one is the mother of all differences – it matters. But the Yale group looked at over 500 comparisons, possibly more – and found three differences of statistical significance, Richardson says. If the differences were robust, they would appear across different cohorts and analyses, but they don’t. “If there was a strong signal here, one would expect to find it more widely across analyses,” she says. If anything, the Harvard team thinks it’s the similarities that are stunning, she says.

As for sample size, Takahashi replies that the Yale study was exploratory – to provide the basis for further investigations – and adds that following the study’s publication, studies from other groups supported the differences.

Tales of the testicles

COVID is a very new disease. Lord knows when it first arose, but it was first reported in November 2019, and we are all still learning about it. As of this writing, according to the Worldometer website, there have been roughly 234 million cases worldwide, involving 4.8 million deaths and 211 million recoveries. Surely we should have some sort of picture by now. Yet in truth, the statistics are all over the place.

Why might men get it worse, if they do? It bears adding that the coronavirus isn’t just a pulmonary disease, as had been thought at first. It affects pretty much all organs, including the brain. The virus also hides out in odd corners of the body, including the testicles, and sometimes testicular pain and infertility may ensue, and even dysfunction. (See the paper “’Mask up to keep it up’: Preliminary evidence of the association between erectile dysfunction and COVID-19” published in the Journal of Andrology.

“There is evidence in many places of greater male mortality from COVID,” says Shattuck-Heidorn. This applied as well to SARS and MERS, which are also coronaviruses. But in other places, male and female mortality seems to be almost equal.

With SARS and MERS, female cases were driven by young healthcare workers catching the diseases, and they did relatively well. Among men, many had multiple comorbidities – other medical conditions – and they had a harder time. Once the statistics were controlled for comorbidities, men and women had equal mortality rates, Shattuck-Heidorn explains. Therefore, the seeming gender difference was an artifact of the conditions.

In some places, COVID seems to hit men harder, for example in Italy, but in the United States, there is no evidence that the male death rate from the coronavirus is higher than from mortality of all causes. American men die at higher rates than women of chronic disease, but one doesn’t see an increase from coronavirus in the mix. That indicates that the male death rate from the coronavirus is being driven by comorbidity and other linked factors, she says.

Even if that’s so, might men and women have different immune responses to COVID, as Yale claims? Maybe, but it isn’t proven, says Harvard. Among other things, the Yale study fails to account for other influences, such as age and body mass index, which affect … well everything. Finally, the Yale paper refers to unadjusted data, they say; once corrected for Body Mass Index, age and other features, the Harvard researchers claim the statistical difference disappears. That indicates the finding wasn’t due to sex differences, but to other characteristics such as BMI and age.

Takahashi agrees that disparities and comorbidities play important roles but believes that sex should be included as a key variable for studying infectious diseases. The one thing all agree on is that we don’ t know enough about this coronavirus.

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