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Abstract

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 overreacting , I searched the available evidence (box) to determine whether men really experience worse symptoms and whether this could have any evolutionary basis. 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. 5 6 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. 11 12 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. 16 17 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 effect 19 20 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 ksue@ualberta.ca For personal use only: See rights and reprints
CHRISTMAS 2017: ALL CREATURES GREAT AND SMALL
The science behind man flu
Kyle Sue explores whether men are wimps or just immunologically inferior
Kyle Sue clinical assistant professor in family medicine
Health Sciences Centre, Memorial University of Newfoundland, St Johns, NL, Canada
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 worlds 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.
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.5 6
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 cellsinto 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.11 12
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.16 17 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 effect19 20 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
ksue@ualberta.ca
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BMJ 2017;359:j5560 doi: 10.1136/bmj.j5560 Page 1 of 3
Feature
FEATURE
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.
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, andthey
under-rate mens 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 attended25listing 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 sexesfor 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.28 29 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 mens 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 the 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.
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.
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2 Tang JW, Lam TT, Zaraket H, et al. INSPIRE Investigators. Global epidemiology of
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BMJ 2017;359:j5560 doi: 10.1136/bmj.j5560 Page 2 of 3
FEATURE
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FEATURE
... A second possible explanation concerns differences in reporting patterns in men and women, rather than 'real' differences in symptom levels. Considering the evidence related to influenza, Sue [43] provocatively asked whether "men are wimps or just immunologically inferior". Much evidence supports a notion of men having higher morbidity and mortality in response to influenza compared to women [44,45]. ...
... Much evidence supports a notion of men having higher morbidity and mortality in response to influenza compared to women [44,45]. While the reasons for this are not fully understood, there may be different immune responses, including different responses to vaccines, between men and women [8,9,43]. Hormonal constitution may be partly responsible for this gender difference, as an immunorepressive effect of testosterone has been suggested [46]. ...
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... The above data may be correlated with the more efficient immune response promoted by estrogens compared to the immunosuppressive role of androgens. Females have a greater humoral response than males, as evidenced by higher titers of serum immunoglobulin, and a greater antibody response to various antigens after immunization [36,37]. In addition, the observation that women have a lower incidence of tumors and faster skin allograft rejection has led to the hypothesis that they also have a stronger cell-mediated immune response [38]. ...
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... Sex-differences related to the immune system are well-established (57,58) with recent evidence of sex-divergent monocyte aging (38). Some sex-differences seem constitutive, such as the higher TLR4 expression observed here in female HCs. ...
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