In June last year, as the first reports of long COVID-19 began to filter through the medical community, doctors attempting to grapple with this mysterious malaise began to notice an unusual trend.
While acute cases of the virus — particularly those hospitalized with the disease — tended to be mostly men aged 50 or older, long COVID-19 sufferers were, by contrast, relatively young and overwhelmingly women.
Early reports of long COVID-19 at a Paris hospital between May and July last year suggested that the average age was about 40, and women afflicted by the longer-term effects of COVID-19 outnumbered men by four to one.
Illustration: Mountain People
Over the past year, a similar gender skew has become apparent around the world. From long- COVID-19 patients monitored by hospitals in Bangladesh and Russia to the COVID Symptom Study app, and from a UK-wide post-hospitalization COVID-19 study assessing the longer-term effects of the virus to the medical notes of specialized post-COVID-19 care clinics across the US and the UK, a picture has steadily emerged of young to middle-aged women being disproportionately vulnerable.
Sarah Jolley, who runs a post-COVID-19 care clinic in Aurora, Colorado, told the Observer that about 60 percent of her patients have been women.
In Sweden, Petter Brodin, a researcher at the Karolinska Institute who leads the long-COVID-19 arm of the COVID Human Genetic Effort global consortium, suspects that the overall proportion of women among people with long COVID-19 might even be higher, potentially 70 to 80 percent.
“This pattern has been seen in other post-infectious syndromes,” said Melissa Heightman, who runs a post-COVID-19 care clinic in north London. “Around 66 percent of our patients have been women. A lot of them were in full-time jobs, have young children, and now more than one-quarter of them are completely unable to work because they’re so unwell. Economically, it’s a bit of a catastrophe.”
As Heightman points out, this is not a new trend when it comes to infectious diseases, rather one that has historically been neglected. Women are known to be up to four times more likely to get myalgic encephalomyelitis, also known as chronic fatigue syndrome (CFS), a condition believed to have infectious origins in the majority of cases, while studies have also shown that patients with chronic Lyme disease are significantly more likely to be female.
There are anecdotal reports that female patients’ persistent symptoms are being dismissed or attributed to anxiety, but despite this, there have been relatively few attempts to drill down into why this is the case. Instead, because these conditions predominantly affect women, they have more often been dismissed as being psychological in origin.
Over the years, CFS and chronic Lyme disease have been ridiculed by sectors of the medical community as forms of hypochondria.
“In general, there’s not as much research money and attention on conditions that primarily affect women,” said Julie Nusbaum, an assistant professor at New York University Long Island School of Medicine. “That’s just a general disparity in medical research. I think certain biases persist that when women present with a lot of body aches or pains, there’s more often an emotional or personality component to it than medical origin.”
Worryingly, signs of these biases have over the past year crept in with long COVID-19. There are anecdotal reports of female patients complaining that their persistent symptoms have been dismissed or attributed to anxiety.
Janet Scott, an infectious diseases specialist at the University of Glasgow, said that there remains a school of thought within the academic community that the long COVID-19 gender skew might simply be an artifact of women being more likely to report symptoms than men.
“I don’t buy it myself,” Scott said. “I think it plays into the narrative of ‘don’t worry about long COVID, it’s just a bunch of hysterical, middle-aged women.’”
However, Scott and other scientists around the world are trying to delve into the different factors that make women more prone to developing long COVID-19. Understanding them could be crucial to shedding a light on this mysterious condition in general, as well as other illnesses which can be triggered by an infection.
At Yale University’s School of Medicine, immunologist Akiko Iwasaki has spent much of the past year trying to tease apart the differences between how men and women respond to the virus.
One of her early findings was that T cells — a group of cells important to the immune system that seek out and destroy virus-infected cells — are much more active in women than men in the early stages of infection. One component of this is thought to be due to genetics.
“Women have two copies of the X chromosome,” Iwasaki said. “Many of the genes that code for various parts of the immune system are located on that chromosome, which means different immune responses are expressed more strongly in women.”
However, it is also linked to a theory called “pregnancy compensation hypothesis,” which suggests that women of reproductive age have more reactive immune responses to the presence of a pathogen because their immune systems have evolved to support the heightened need for protection during pregnancy.
This robust immune response is thought to be one of the reasons that women are much less likely to die from COVID-19 during the acute phase of the infection — but it comes with a catch. One of the major theories for long COVID-19 is that fragments of the virus manage to linger for many months in remote pockets of the body, known as reservoirs.
Iwasaki said that remnants of virus have been discovered in almost every tissue from the brain to the kidneys.
As women react so strongly to the presence of a virus, some scientists think that these viral reservoirs are more likely to trigger waves of chronic inflammation throughout the body, leading to the symptoms of pain, fatigue and brain fog experienced by many with long COVID-19.
Evidence to support this idea has been found in studies of chronic Lyme disease. The bacterium Borrelia burgdorferi, which causes Lyme disease, is also capable of burrowing into tissue and nerves, and hiding out in the body, leading to chronic symptoms.
Research has shown that women have a more intense response to the presence of B burgdorferi, producing much higher levels of inflammatory cytokines — small proteins — than men.
“There’s increasing evidence that women respond more to this kind of persistent, low-grade infection than men,” said Raphael Stricker, a Lyme disease researcher based in San Francisco. “They’re much more likely to have chronic inflammation.”
However, it is unlikely that this is the sole explanation. Many scientists studying long COVID-19 believe that, in a proportion of cases, the virus might have triggered an autoimmune disease, causing elements of the immune system to produce self-directed antibodies known as autoantibodies, which attack the body’s own organs.
Since December last year, Iwasaki and others have published studies that have identified elevated levels of more than 100 different autoantibodies in the blood of people with COVID-19, directed against a range of tissues from the lining of blood vessels to the brain. While the level of some of these autoantibodies subsided naturally over time, others lingered.
Iwasaki believes that if these self-directed antibodies remain in the blood of people with long COVID-19 for many months, it could explain many of the common symptoms, from cognitive dysfunction to clots, as well as dysautonomia — a condition where people experience an uncomfortable and rapid increase in heartbeat when attempting any kind of activity.
There have previously been indications of this in studies of CFS.
Women with the condition have been found to be far more likely to experience autoimmune-related ailments, from new allergies to muscle stiffness and joint pain, a similar symptom profile to many of those with long COVID-19.
Iwasaki is conducting another study looking to examine whether certain autoantibodies are present in particularly high levels in women with long COVID-19. If this proves to be the case, it would not come as a complete surprise. Viruses have long been linked to the onset of autoimmune diseases, ranging from type 1 diabetes to rheumatoid arthritis — and all of these conditions are far more prevalent in women, with surveys finding that women comprise 78 percent of autoimmune disease cases in the US.
“Viral infections prompt the immune system to respond,” Nusbaum said. “And for many women, particularly if they’re genetically predisposed, that immune response can be so robust that you enter into this kind of dysregulated immunity, which doesn’t get turned off even after the virus is cleared.”
Women are more prone to autoimmune problems for a number of reasons, ranging from a molecular switch called VGLL3, which women have in far higher levels than men and which can tip the immune system into overdrive, to the sex hormone oestrogen, which can increase inflammation.
On the other hand, men are more protected against developing autoimmune-related problems due to their higher levels of testosterone, which suppress the number of autoantibody-producing cells called B cells.
Iwasaki believes that this tendency might well be the major factor that explains the long COVID-19 gender skew.
“In the case of long COVID, the virus may tip the balance towards autoimmunity in people who already have that tendency to begin with,” she said.
Some scientists have begun describing long COVID-19 as an oestrogen-associated autoimmune disease, calling for more research dedicated to identifying personalized and gender-specific long-COVID-19 treatments.
If autoantibodies are consistently found in particularly high levels in women with long COVID-19, one approach could be to treat them with immunosuppressive medications, such as steroids.
“We need to try and identify the underlying causes in each case,” Iwasaki said. “That could be one approach, while in other cases, where the problem is a persistent COVID-19 infection, you might want to treat those patients with antivirals. We’ll continue to get more information on this over the next few months.”
Many hope that the answers gleaned from understanding the long-COVID-19 gender skew could also help provide more insights into treating other conditions that are particularly prevalent in women, such as CFS, and even certain autoimmune illnesses.
“A lot of the symptoms being experienced by the COVID-19 long haulers are very similar to chronic fatigue syndrome, fibromyalgia and some of these other chronic conditions that we don’t fully understand,” Nusbaum said. “I do think it’s possible that the attention now being placed on long COVID could help provide an insight into that, which would be a very welcome benefit.”
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