Intended for healthcare professionals

Feature Christmas 2017: All Creatures Great and Small

The science behind “man flu”

BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j5560 (Published 11 December 2017) Cite this as: BMJ 2017;359:j5560
  1. Kyle Sue, clinical assistant professor in family medicine
  1. Health Sciences Centre, Memorial University of Newfoundland, St John’s, NL, Canada
  1. ksue{at}ualberta.ca

Kyle Sue explores whether men are wimps or just immunologically inferior

“Man flu” is a term so ubiquitous that it has been included in the Oxford and Cambridge dictionaries. Oxford defines it as “a cold or similar minor ailment as experienced by a man who is regarded as exaggerating the severity of the symptoms.”1 Since about half of the world’s population is male, deeming male viral respiratory symptoms as “exaggerated” without rigorous scientific evidence, could have important implications for men, including insufficient provision of care.

Despite the universally high incidence and prevalence of viral respiratory illnesses,2 no scientific review has examined whether the term “man flu” is appropriately defined or just an ingrained pejorative term with no scientific basis. Tired of being accused of over-reacting, I searched the available evidence (box) to determine whether men really experience worse symptoms and whether this could have any evolutionary basis.

Methods

I searched PubMed/MedLine, EMBASE, Cochrane, CINAHL, Web of Science, Scopus, and Google Scholar using combinations and variants of terms “man”/“male”, “woman”/”female”, “gender”/“sex”, “influenza”/“flu”, “viral”, “respiratory”, “common cold”, “difference”, “comparison”, “intensive care.” I read the abstracts of all articles found and narrowed articles down by relevance. References in each article were then hand searched to ensure comprehensiveness.

Of mice and men

Mice have long been accepted as good models of human physiology for medical research,3 with records dating back to William Harvey in 17th century England.4 Several studies show that female mice have higher immune responses than males.56 This led to the hypothesis that sex dependent hormones have an important role in outcomes of influenza. Further studies suggest that oestradiol is implicated in this response in mice,7 with one study concluding that the hormone reduces “responses associated with immunopathology” and enhances “responses associated with recruitment of innate immune cells…into the lungs.” 8

However, another mouse study suggests that stress and corticosterone levels have a role, concluding that “the increase in infection-induced corticosterone levels demonstrated in females may have suppressed the behavioural symptoms of infection.”9

Lending further weight to the oestradiol theory, an in-vitro study sniffs at an underlying reason for man flu. Using human nasal epithelial cell cultures infected with seasonal influenza A, researchers showed that exposure to oestradiol or select oestrogen receptor modulators (SERMs) decreased influenza A titres in tissue from female, but not male, donors. Oestradiol also significantly downregulated cell metabolic processes. Adding oestrogen receptor antagonists reversed this antiviral effect.10

Another study isolated mononuclear cells from 63 healthy people grouped according to age and sex and cultured the cells with rhinovirus. Cells cultured from premenopausal women had a stronger immune response to rhinovirus than those from men of the same age. This difference was not observed when post-menopausal women were compared with men of the same age, suggesting a hormonal link.1112

Patterns in humans

Although animal and in-vitro studies are weak sources of evidence, human research also points to different responses to influenza in men and women. Even the World Health Organization stresses that “sex should be considered when evaluating influenza exposure and outcomes.”13 Epidemiological data from 2004-10 for seasonal influenza in Hong Kong showed that adult men had a higher risk of hospital admission,14 and in a US observational study of influenza mortality from 1997 to 2007, men had higher rates of influenza associated deaths compared with women in the same age groups. This was true regardless of underlying heart disease, cancer, chronic respiratory system disease, and renal disease.15

Studies of influenza vaccination suggest that women are more responsive to vaccination than men.1617 This is supported by the finding that women report more local and systemic reactions to influenza vaccine than men in questionnaires.18 One study noted that men with higher testosterone levels had more down regulation of antibody response to vaccination, suggesting an immunosuppressive role for testosterone.16 This is consistent with animal and in-vitro studies showing testosterone has an immunosuppressive effect1920 and a finding of higher levels of inflammatory cytokines in men with androgen deficiencies than in healthy controls.21

The sex differences extend to other respiratory infections beyond influenza. In many acute respiratory diseases, males are more susceptible to complications and exhibit a higher mortality.22 Wyke and colleagues surveyed men and women consulting general practitioners for common symptoms of minor infectious respiratory illness, finding that “women were significantly more likely to report cutting down activities in response to only one symptom in each cohort.”23 This contradicts the common myth that men cut down activities more than women by exaggerating the severity of symptoms.

Furthermore, in an analysis of retrospective data from a common cold unit on 1700 volunteers inoculated with virus (rhinovirus, coronavirus, influenza, etc) during 1984-89, MacIntyre postulated that “clinical observers are more ready to attribute symptoms and illness to women than to men, and…they under-rate men’s symptoms.” 24

Finally, in an unscientific survey completed by 2131 readers of a popular magazine, men reported taking an average of three days to recover from viral respiratory illness compared with 1.5 days for women. The male authors of this study conclude that caregivers should “go that extra mile to care for us when we are stricken with it, so that future shelves can be erected, cars can be maintained and football stadia throughout the land can be well attended”25—listing only a few of the many ways male viral respiratory illnesses can affect society.

Immunity gap

Some evidence clearly supports men having higher morbidity and mortality from viral respiratory illness than women because they have a less robust immune system. However, conclusions may be limited by author bias, inclusion of some low level evidence, and not reporting a critical appraisal of the studies cited. Additionally, the differences observed in these studies may not be representative of all respiratory viruses, and differences may be hidden within studies that did not stratify the various viruses or other differences between the sexes.

The sex difference in immunity has been suggested to be modulated by hormonal differences, with oestradiol being immunoprotective and testosterone being immunosuppressive. However, the reviewed studies did not consider other differences between the sexes—for example, men have higher rates of smoking worldwide26 and are less likely to take preventive care or seek care when ill.27 Hormonal influence on immune response is supported by evidence that pregnant women have more severe influenza symptoms and reduced symptoms from autoimmune diseases than non-pregnant women.2829 However, it is unclear how this is mediated or might apply to a difference between the sexes, given the changes in oestrogen, progesterone, and other hormones along with other stressors that occur during pregnancy.

If the differences found in the above studies are real, the evolutionary purpose of men’s higher symptoms from viral respiratory infections remains unclear. Zuk postulates that “if males require, for example, testosterone for aggressive behaviour and the development of male secondary sexual characteristics, selection for winning at the high-stakes game males play may override the cost of any immunosuppressive effects of the hormone.”30 Likewise, the authors of another study speculate that reduced immunity is less important for men because males of many species are more likely to die from trauma before an infection kills them.16 Other academics agree that across species, the male strategy of “live hard, die young” arising from stronger intra-sexual competition than among females has led to less investment in immunity31 and that “mounting immune responses to clear viruses requires metabolic resources that might otherwise be used for other biological processes, such as growth, maintenance of secondary sex characteristics, and reproduction.”32

Avitsur and colleagues suggest that the increase in male sickness may be a strategy important for survival since “it promotes energy conservation and reduces the risk of encountering predators.”9 Classic modes of energy conservation may include lying on the couch, not getting out of bed, or receiving assistance with basic activities of daily living, which could all be effective for avoiding predators.

Further higher quality research is needed to clarify other aspects of man flu. It remains uncertain whether viral titres, immune response, symptoms, and recovery time can be affected by environmental conditions. An example of future research may include a controlled trial in which men are infected with a respiratory virus, then subjected to rigorous research conditions in which all their requests are met by a healthy designated caregiver or they are left to fend for themselves. Another potential study may examine whether men with robust immune systems are less successful at mating compared with those with weaker immune systems and correspondingly higher testosterone. In other words, can the blame for man flu be shifted to the people who select these men as sexual partners rather than the men themselves?

Time to rest

The concept of man flu, as commonly defined, is potentially unjust. Men may not be exaggerating symptoms but have weaker immune responses to viral respiratory viruses, leading to greater morbidity and mortality than seen in women. There are benefits to energy conservation when ill. Lying on the couch, not getting out of bed, or receiving assistance with activities of daily living could also be evolutionarily behaviours that protect against predators. Perhaps now is the time for male friendly spaces, equipped with enormous televisions and reclining chairs, to be set up where men can recover from the debilitating effects of man flu in safety and comfort.

Footnotes

  • Competing interests: I have read and understood BMJ policy on declaration of interests and declare that I have no competing interests.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

References

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