By Helen Collins
On Friday 11th March 2020, the World Health Organisation (WHO) officially declared the SARS-CoV-2 outbreak a pandemic. Since then, more than 482 million people have been infected with the virus and suffered from COVID-19, resulting in over 6 million deaths.
Even in the first few weeks of the pandemic, scientists realised that men are more likely to be critically ill and die from COVID-19, with evidence of other risk factors including cardiovascular disease, diabetes and old age soon emerging. Initial resources were therefore focused on reducing the risk of hospitalisation and death in the most critically ill patients, as well as developing vaccines to prevent people catching and passing on the virus.
Two years later, fears of dying from COVID-19 are waning. Despite its greater transmissibility, the risk of death from the most recent variant, Omicron, is 67% lower than the earlier Delta variant [1]. Weekly deaths have now fallen below 1,000 a week in the UK, 10-fold lower than in April 2020.
Yet this good news is soured by the soaring rates of ‘post COVID-19 condition’, known colloquially as long COVID. Long COVID is characterised by persistent COVID-like symptoms, commonly fatigue, psychological symptoms such as depression, and cognitive dysfunction or ‘brain fog’, that last for at least two months after a COVID-19 diagnosis. In the UK, an estimated 1.3 million people are currently living with long COVID, with sufferers reporting that ‘their ability to undertake their day-to-day activities had been “limited a lot”’ [2]. Moreover, up to two thirds of patients that are hospitalised with COVID-19 are not back to normal health within 6 months of the infection [3]. Hence, the challenge doctors and scientists now face is not how to stop people dying from COVID-19, but how to limit its negative impact on the lives of its survivors.
More women experience long COVID
Just like COVID-19 itself, the burden of long COVID isn’t being shared equally across the population. Numerous studies, as well as anecdotal evidence, suggest that women are more likely to get long COVID than men. Nonetheless, variation in how studies are conducted, and the limited numbers of patients included, makes it difficult to draw broad conclusions about the sex and gender risk factors for long COVID.
Nonetheless, a review published this month in the Italian Journal of Gender Specific Medicine has confirmed these individual reports [4]. The international team of researchers, led by Professor Maria Carmela Tartaglia at the University of Toronto, scoured the literature for reports of sex and gender differences in rates of long COVID. Of the 32 papers they found that looked at this issue, 26 reported sex differences in long COVID symptoms.
Long COVID is characterised by persistent COVID-like symptoms, commonly fatigue, psychological symptoms such as depression, and cognitive dysfunction or ‘brain fog’, that last for at least two months after a COVID-19 diagnosis.
Overall, women are twice as likely to experience long COVID symptoms than men, although the rates are similar in older men and women (>60-70 years old). Women also report more, and more severe, long COVID symptoms and are less likely than men to have recovered from illness 6-8 months after their initial diagnosis [5]. This was even true of mild COVID-19 cases, with one study reporting that 72% of people still experiencing symptoms after 12 months were women [6].
Women are also getting different symptoms to men; for example, women are more likely to experience neuropsychiatric symptoms such as anxiety and depression. One study even found that 90% of patients suffering from post-traumatic stress disorder (PTSD) after COVID-19 were women [7]. The review also found differences in the physical symptoms of long COVID, in particular fatigue, suggesting that three to four times more women are experiencing persistent fatigue six months after COVID-19 infection.
Why are women more susceptible to long COVID?
Despite these clear sex differences, there are currently no studies directly addressing their biological or social causes. Nonetheless, the authors of the review speculate about potential mechanisms. Firstly, there are thought to be sex differences in the expression and regulation of ACE2 (the receptor to which the SARS-CoV-2 virus binds to enter human cells), which could lead to variation in how cells respond to infection. Additionally, women are more likely to experience mental health conditions such as anxiety and depression. It may be that COVID-19 is simply exposing or exaggerating a pre-existing psychiatric illness or a vulnerability to developing these conditions.
Sociocultural factors may also be at play. For example, a 2021 study reported that greater feminine gender identity (measured by the Bem Sex-Role Inventory) was associated with higher rates of long COVID in women [8]. Interestingly, women caring for family members when they got ill with COVID-19 were at lower risk of developing long COVID, further suggesting there may be gender risk factors. Women are also more likely to report symptoms and seek treatment for any illness than men [9], which may also be contributing to the perceived sex and gender differences.
‘We are witnessing a historical change and we have to seize this opportunity. Wouldn’t it be wonderful if we could take advantage of the lesson of long COVID and out of a tragedy find novel solutions for medicine?’
Maria Teresa Ferretti, TEDx Talk ‘Listen to one patient to help a million’ [10]
Yet the strongest hypothesis for why more women experience long COVID is differences in the female immune system. Women, particularly young women, tend to have stronger immune responses than men. This can lead to faster clearance of viruses, potentially explaining why women are less likely to be critically ill with COVID-19. Yet this enhanced immune response may also be why women are more prone to developing autoimmune disorders, diseases where an overactive immune system wrongly attacks the body’s own cells. In fact, scientists have likened long COVID to autoimmune disorders such as multiple sclerosis, fibromyalgia, and chronic fatigue syndrome (CFS), all of which include neurological symptoms such as fatigue and brain fog.
‘A turning point in medicine’
Understanding long COVID could not only reveal new mechanisms of action of COVID-19, but it could also help to treat other autoimmune disorders. Speaking at a TEDx event in July 2021 [10], Maria Teresa Ferretti, a co-author of the paper and the co-founder of the Women’s Brain Project, said she believes ‘long COVID represents a turning point in medicine’. She thinks that researching long COVID may produce insight into other autoimmune disorders that have so far been under-researched due to historically entrenched gender stereotypes and the dismissal of women’s symptoms. ‘We are witnessing a historical change and we have to seize this opportunity. Wouldn’t it be wonderful if we could take advantage of the lesson of long COVID and out of a tragedy find novel solutions for medicine?’
As the SARS-CoV-2 virus continues to evolve and new variants appear, the spectrum of long-term impacts of COVID-19 will continue to grow. Moreover, we need to pay special attention to the sex and gender factors that determine how someone recovers from the illness. But long COVID is also a chance to learn. Writing in the review, the authors state: ‘we must take advantage of this opportunity to provide professionals with the adequate tools to address [sex and gender] discrepancies and effectively tailor assessments and treatments towards individual needs, thus advancing precision medicine’.
References
- ONS (February 2022) Comparing the risk of death involving coronavirus (COVID-19) by variant, England: December 2021. Available online: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/causesofdeath/articles/comparingtheriskofdeathinvolvingcoronaviruscovid19byvariantengland/december2021
- ONS (January 2022) Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 6 January 2022. Available online: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/6january2022
- Logue JK, Franko NM, McCulloch DJ, McDonald D, Magedson A, Wolf CR, et al. Sequelae in adult 6 months after COVID-19 infection. JAMA Netw Open. 2021;4(2):e210830
- Jensen A, Castro AW, Ferretti MT, Martinkova J, Vasilevskaya A, Santuccione Chadha A, Tartaglia MC. Sex and gender differences in the neurological and neuropsychiatric symptoms of long COVID: a narrative review. Ital J Gender-Specific Med, 8(1). Available online: https://www.gendermedjournal.it/archivio/3768/articoli/37554/
- Menges D, Ballouz T, Anagnostopoulos A, Aschmann HE, Domenghino A, Fehr JS et al. Burden of post-COVID-19 syndrome and implications for healthcare service planning: a population-based cohort study. PLoS ONE. 2021;16(7):e0254523
- Boscolo-Rizzo P, Guida F, Polesel J, Marcuzzo AV, Antonucci P, Capriotti V, et al. Self-reported smell and taste recovery in coronavirus disease 2019 patients: a one-year prospective study. Eur Arch Otorhinolaryngol. 2021;279(1):515-520.
- Beck K, Vincent A, Becker C, Keller A, Cam H, Schaefert R et al. Prevalence and factors associated with psychological burden in COVID-19 patients and their relatives: a prospective observational cohort study. PLoS ONE. 2021;16(5):e0250590
- Gebhard CE, Sütsch C, Bengs S, Deforth M, Buehler KP, Hamouda N et al. Sex- and gender-specific risk factors of post-COVID-19 syndrome: a population-based cohort study in Switzerland. medRxiv. 2021.06.30.21259757
- Barsky AJ, Peekna HM, Borus JF. Somatic symptom reporting in women and men. J Gen Intern Med. 2001;16(4):266-75.
- Tedx Talks (2021, June 30). Listen to one patient to help a million [Video]. YouTube, URL: https://www.youtube.com/watch?v=-RNtmkYIQkU
