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The science behind "man flu"

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Kyle Sue at University of Alberta
Kyle Sue
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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
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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 John’s, 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 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.
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 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, 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.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 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 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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BMJ 2017;359:j5560 doi: 10.1136/bmj.j5560 Page 2 of 3
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6Hoffmann J, Otte A, Thiele S, Lotter H, Shu Y, Gabriel G. Sex differences in H7N9 influenza
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8 Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL. 17β-estradiol protects females
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doi:10.1093/aje/kwv068 pmid:26219977.
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Epidemiol 2014;179:156-67. doi:10.1093/aje/kwt235 pmid:24190951.
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17 Engler RJ, Nelson MR, Klote MM, et al. Walter Reed Health Care System Influenza
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BMJ 2017;359:j5560 doi: 10.1136/bmj.j5560 Page 3 of 3
FEATURE
... Males were predominant among patients aged < 20 years, and females were predominant among patients aged � 25 years. Among both sexes, most patients were aged 5-9, followed by those aged 10-14 and 0-4, with a second peak seen in those aged [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. Patients aged < 20 accounted for 37.6% of the total, while patients aged � 65 accounted for 12.2%. ...
... Boys were more likely to be prescribed anti-influenza drugs and their in-hospital prescription rate was higher than that for girls. It has been reported that males are more vulnerable to influenza in terms of risk of hospitalization and mortality compared with females [47]. In Hong Kong, male patients, especially those aged < 18 years, tended to have a higher excess hospitalization rate compared with female patients [48]. ...
Prescription of anti-influenza drugs in Japan, 2014–2020: A retrospective study using open data from the national claims database
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Background Both physicians and patients are proactive towards managing seasonal influenza in Japan and six drugs are approved. Although many countries have national influenza surveillance systems, data on nationwide prescription practices of anti-influenza drugs are lacking. Therefore, we aimed to clarify the status of anti-influenza drug use in Japan by analyzing real-world data. Methods This retrospective study analyzed open data from the National Database of Health Insurance Claims and Specific Health Checkups, which covers most claims data from national health insurance. We estimated the annual number of patients prescribed anti-influenza drugs, which drugs they were prescribed, the patients’ age and sex distribution, drug costs, and regional disparities for the period 2014–2020. Results For 2014–2019, an estimated 6.7–13.4 million patients per year were prescribed anti-influenza drugs, with an annual cost of 22.3–48.0 billion JPY (Japanese Yen). In addition, 21.1–32.0 million rapid antigen tests were performed at a cost of 30.1–47.1 billion JPY. In 2017, laninamivir was the most frequently prescribed anti-influenza drug (48%), followed by oseltamivir (36%), while in 2018, the newly introduced baloxavir accounted for 40.8% of prescriptions. After the emergence of COVID-19, the estimated number of patients prescribed anti-influenza drugs in 2020 dropped to just 14,000. In 2018, 37.6% of prescriptions were for patients aged < 20 years compared with 12.2% for those aged ≥ 65 years. Prescriptions for inpatients accounted for 1.1%, and the proportion of prescriptions for inpatients increased with age, with men were more likely than women to be prescribed anti-influenza drugs while hospitalized. Conclusions Based on our clarification of how influenza is clinically managed in Japan, future work should evaluate the clinical and economic aspects of proactively prescribing anti-influenza drugs.
View
... Ankita Sharma indicated that many cases are tested through RT-PCR and RDT (Antibody), so it is possible to perceive the exact numbers and classification of the infected cases of COVID-19 (23 Our study indicated that males outstripping females were susceptible to SARS-CoV-2, and the gender ratio was 1.9:1. According to Dr. Kyle Sue, sex hormones, including estrogen and testosterone, have a more vital role in severely affecting males than females in viral respiratory diseases (34). According to Schurz et al., the X-chromosome possesses the highest proportion of antibodies in the human genomes, which has a prominent influence in severely impacting males than females in viral respiratory problems (35). ...
SARS-COV-2 PREVALENCE IN INDIA COMPARED TO THE REST OF THE GLOBE AND ASCERTAINS EPIDEMIOLOGICAL CHARACTERISTICS ASSOCIATED WITH THE COVID-19 PANDEMIC DURING 2020 IN INDIA
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  • Oct 2023
Objectives: SARS-CoV-2 triggers a pandemic of COVID-19. We ascertain the pandemic burden of COVID-19 disease between India and the rest of the world; monitor the burden of COVID-19 disease in Indian states and union territories compared to other countries with nearly equivalent population sizes, and study the epidemiological characteristics. Material and Methods: A population-based comparative optimization algorithms study was conducted on all COVID positive cases reported by 31st December 2020. Results: Confirmed cases resulted in India with a ratio of 1:7.2 to the rest of the world, with a lower mortality rate with a ratio of 1:12 (CMR per 100,000 people) than other countries. Many Indian administrative regions have lower morbidity rates (Z-values range from -2653.7369 to -11.6403)and mortality (Z-values range from -439.446 to -4.86) than the countries selected. In India, 184,728,001 tests were done, with 5.6% cases confirmed, 96.1% recovered, and 1.4% dying due to COVID-19. COVID-19 was more prevalent in males and patients aged 25–44, whereas SARSCoV-2 killed the most people over the age of 60. Bihar had the most cases of infection, while Punjab had the most deaths. Conclusion: SARS-CoV-2 disease led India to have a lower morbidity and mortality burden than the rest of the world. The pandemic curves of COVID-19 resulted in daily peaks most significantly, and the cumulative number of cases increased tremendously with an upward trend. Analytical, spatial, and temporal research studies will be carried out to understand the effect of climate change and indicators that correlate with the epidemiological characteristics of the emerging coronavirus.
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... There are theories that indicate that men have an increased perception of "sickness" that could be related to the immunosuppressive role of testosterone (19,20). If the predominance of men in septoplasty studies reflects men suffering more from their respiratory problems, including nasal breathing, they might be more likely than women to seek healthcare and have their septal deviation diagnosed and treated. ...
A comparison of men and women undergoing septoplasty—the Swedish national septoplasty register
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  • Jul 2023
Objective Men represent more than two-thirds of septoplasty patients in many studies, but differences between men and women in terms of patient selection or outcome are seldom reported. This study aims to investigate whether women undergoing septoplasty differ from men in critical variables before and after surgery, in a large national sample of septoplasties. Design Cross-sectional register study. Participants The study includes 2,532 patients from the National Swedish Septoplasty Register undergoing septoplasty with or without additional turbinoplasty on the indication of nasal obstruction in 2014–2019. Patients in the register have not been preselected. Main outcome measures Preoperative variables and postoperative outcome were compared between men and women. Results Men accounted for 1,829 (72%) of the patients. There was no significant difference between men and women in severity of self-reported nasal obstruction or type of surgery performed (septoplasty with or without turbinoplasty). Mean postoperative nasal obstruction 12 months after surgery and overall satisfaction with the result were similar. Women, however, reported more complications 12 months postoperatively, while men reported more problems with snoring and obstructive sleep apnea preoperatively. Conclusion In this large national patient cohort undergoing septoplasty, we found no differences in preoperative nasal obstruction or postoperative patient-rated outcome in men and women undergoing septoplasty, despite the fact that 72% of the patients were men. It thus remains unclear why women are under-represented in septoplasty surgery in this and many other cohorts.
View
... [13] In addition to these recent findings on COVID-19 earlier studies on infectious disease also reveal similar experiences in relation to mortality and morbidity amongst men. The prevalence of influenza among men has rendered a different name as "man flu." [14] Considering the significance of this World Health Organizations has emphasized that "sex should be considered while evaluating Influenza exposure and outcome." [15] One of the studies that evaluated the epidemiological data of seasonal influenza from 2004 to 2010 in Hongkong revealed that men had a higher risk of hospital admission than that of the female. ...
Gender perspectives of COVID-19
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Corona virus disease (COVID)-19 is a global threat. This pandemic has created a whole lot of problems in the entire globe. In addition to the typical bio-medical problems for which the entire scientific community is searching for solutions the pandemic has also created a plethora of social problems that the social scientists are grappling with to find out redressal measures. This pandemic has created problems in the realm of “gender” as a separate entity. Pandemics of such nature affects the men and women differently creating different biological, social, occupational and behavioral problems. Pandemics make the existing gender inequalities worse and strongly affects the care and support that the women and girls receive. Research evidences reveal that men are more strongly affected by COVOD-19 compared to women. Thus, it becomes utmost important that the gender perspectives of COVID-19 should be understood properly and proper institutional mechanisms should be in place to address gender equality while finding mitigating measures to curb the pandemic of COVID-19.
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... The higher expression of IgG2b among females in mice and IgG2 in humans may help explain why females often fare better than males when vaccinated or when exposed to viruses such as influenza and SARS-CoV-2 [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. In the context of COVID-19, IgG2 assists the reduction of antibody dependent enhancement (ADE) and the modulation of immune pathologies [79]. ...
How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans
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Full-text available
  • Feb 2023
Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.
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... It typically describes a suspected hypersensitivity associated with histrionic or hypochondriac tendencies that men supposedly show when suffering from ARS symptoms. Due to its widespread reception, the term 'man flu' was included in the Oxford English Dictionary [2] and was subject of a BMJ Christmas article [3]. However, conformity to masculine norms of the image of tough men who show no weakness [4] can have severe consequences for the physical and mental health [5,6]. ...
Man flu is not a thing – Gender-specific secondary analysis of a prospective randomized-controlled trial for acute rhinosinusitis
Article
Full-text available
  • Sep 2022
  • J PSYCHOSOM RES
Background ‘Man-flu’ is a popular term to describe hypersensitivity to acute rhinosinusitis (ARS) in men. While this pop-cultural description may influence the social perspective of ARS, so far, no prospective observational data on the gender-specific natural development of ARS is available. Methods Secondary data analyses were performed from the placebo arm of a prospective, interventional phase IV clinical trial. Objective measurement of ARS symptoms were assessed with the Major Symptom Score (MSS), a clinician-rated assessment tool. The Sino-Nasal Outcome Test-22 (SNOT-22) was used for symptom self-report. Repeated measures analysis of variance (ANOVA) with gender as a group variable were used to investigate changes in MMS and SNOT-22 total score and subscales over time. Results While MMS scores did not differ at baseline, women showed a significantly greater reduction than men with a medium effect size (p = .040) over time. In the patient-reported symptom score, women showed a significantly higher symptom load at baseline (p = .038), but also a significantly faster subjective improvement of symptoms than men during the course of time with a medium effect size (p = .020). However, when separately assessing the SNOT-22 subscales, a significant time*gender effect was only found for emotional symptoms (p = .047). No gender effect was found for neither nasal, otological, or sleep symptoms (all p > .05). Discussion Although a certain gender difference was found both in the clinician- as well as patient-rated ARS symptoms, the hypothesis of a ‘man-flu’ should be disregarded. Gender differences in ARS symptomatology should be carefully evaluated without stigmatizing symptom distress based on gender perceptions.
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Sex differences in COVID‐19 symptom severity and trajectories among ambulatory adults
Article
  • Dec 2023
Background The ongoing COVID‐19 pandemic has led to hundreds of millions of infections worldwide. Although differences in COVID‐19 hospitalization rates between males and females have been described, many infections in the general population have been mild, and the severity of symptoms during the course of COVID‐19 in non‐hospitalized males and females is not well understood. Methods We conducted a case‐ascertained study to examine household transmission of SARS‐CoV‐2 infections in Nashville, Tennessee, between April 2020 and April 2021. Among enrolled ambulatory adult participants with laboratory‐confirmed SARS‐CoV‐2 infections, we assessed the presence and severity of symptoms (total, systemic, and respiratory) daily using a symptoms severity questionnaire, from illness onset and throughout the 2‐week follow‐up period. We compared the mean daily symptom severity scores (0–3: none, mild, moderate, and severe) and change in symptoms between males and females using a multivariable linear mixed effects regression model. Results The analysis included 223 enrolled adults with SARS‐CoV‐2 infection (58% females, mostly white, non‐Hispanic) from 146 households with 2917 total daily symptom reports. The overall mean severity of total symptoms reported over the illness period was 1.04 and 0.90 for females and males, respectively. Mean systemic and respiratory scores were higher for females than for males ( p < 0.001). In multivariable analyses, females reported more severe total and systemic symptoms during the illness period compared with males. However, no significant differences in reported respiratory symptoms were observed. Conclusions Our findings indicate that among ambulatory adults with SARS‐CoV‐2 infections, females reported slightly higher symptom severity during their illness compared with males.
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MEN’S HEALTH AND THE INFLUENCE OF TESTOSTERONE AND ITS ANALOGS IN THE IMMUNE RESPONSE: A REVIEW
Article
Full-text available
  • Jul 2023
Introduction: Testosterone and its analogues are described in the literature as immunomodulators. The use of androgen anabolic steroids transcends age, which requires research that points to the specific care needed for these patients, usually male. In addition, the use of this hormone can have deleterious consequences for immunity, with the risk of triggering greater problems. Thanks to ingrained sexism in society, men tend to seek health services less. Objective: To report the interactions of testosterone with the male immune system, addressing its lower search for health services, and from that, to suggest a physiological cause that complements the sociological one. Methods: Bibliographic review of works from the English and Portuguese medical literature, published from 2004 to 2022 and found on Google Scholar, PubMed and Scielo. Literature Review: Due to the high titers of the hormone, men tend to generate a weaker immune response to diseases, compared to women. Testosterone and its analogues are also described as inhibitors of antioxidant activity, helpers in the gain of secondary sexual characteristics, and recovery agents in physical exercises. The immunosuppression generated by this hormone is one of the possible undesirable effects of its use. Because of this, elderly men on hormone replacement are susceptible to the same immunosuppression, which requires greater monitoring. Final Considerations: Testosterone usually has immunosuppressive activity, masking symptoms. Such severity increases when talking about the male public, since there is already a tendency to abstain from health services, thanks to the sexist factor present in society.
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Global epidemiology of non-influenza RNA respiratory viruses: Data gaps and a growing need for surveillance
Article
Full-text available
  • Apr 2017
Together with influenza, the non-influenza RNA respiratory viruses (NIRVs), which include respiratory syncytial virus, parainfluenza viruses, coronavirus, rhinovirus, and human metapneumovirus, represent a considerable global health burden, as recognised by WHO's Battle against Respiratory Viruses initiative. By contrast with influenza viruses, little is known about the contemporaneous global diversity of these viruses, and the relevance of such for development of pharmaceutical interventions. Although far less advanced than for influenza, antiviral drugs and vaccines are in different stages of development for several of these viruses, but no interventions have been licensed. This scarcity of global genetic data represents a substantial knowledge gap and impediment to the eventual licensing of new antiviral drugs and vaccines for NIRVs. Enhanced genetic surveillance will assist and boost research and development into new antiviral drugs and vaccines for these viruses. Additionally, understanding the global diversity of respiratory viruses is also part of emerging disease preparedness, because non-human coronaviruses and paramyxoviruses have been listed as priority concerns in a recent WHO research and development blueprint initiative for emerging infectious diseases. In this Personal View, we explain further the rationale for expanding the genetic database of NIRVs and emphasise the need for greater investment in this area of research.
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Mouse Models of Human Disease: An Evolutionary Perspective
Article
Full-text available
  • Apr 2016
The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans.
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How sex and age affect immune responses, susceptibility to infections, and response to vaccination
Article
Full-text available
Do men die young and sick, or do women live long and healthy? By trying to explain the sexual dimorphism in life expectancy, both biological and environmental aspects are presently being addressed. Besides age-related changes, both the immune and the endocrine system exhibit significant sex-specific differences. This review deals with the aging immune system and its interplay with sex steroid hormones. Together, they impact on the etiopathology of many infectious diseases, which are still the major causes of morbidity and mortality in people at old age. Among men, susceptibilities toward many infectious diseases and the corresponding mortality rates are higher. Responses to various types of vaccination are often higher among women thereby also mounting stronger humoral responses. Women appear immune-privileged. The major sex steroid hormones exhibit opposing effects on cells of both the adaptive and the innate immune system: estradiol being mainly enhancing, testosterone by and large suppressive. However, levels of sex hormones change with age. At menopause transition, dropping estradiol potentially enhances immunosenescence effects posing postmenopausal women at additional, yet specific risks. Conclusively during aging, interventions, which distinctively consider the changing level of individual hormones, shall provide potent options in maintaining optimal immune functions. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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Risk management of seasonal influenza during pregnancy: current perspectives
Article
Full-text available
  • Jul 2014
Influenza poses unique risks to pregnant women, who are particularly susceptible to morbidity and mortality. Historically, pregnant women have been overrepresented among patients with severe illness and complications from influenza, and have been more likely to require hospitalization and intensive care unit admission. An increased risk of adverse outcomes is also present for fetuses/neonates born to women affected by influenza during pregnancy. These risks to mothers and babies have been observed during both nonpandemic and pandemic influenza seasons. During the H1N1 influenza pandemic of 2009–2010, pregnant women were more likely to be hospitalized or admitted to intensive care units, and were at higher risk of death compared to nonpregnant adults. Vaccination remains the most effective intervention to prevent severe illness, and antiviral medications are an important adjunct to ameliorate disease when it occurs. Unfortunately, despite national guidelines recommending universal vaccination for women who are pregnant during influenza season, actual vaccination rates do not achieve desired targets among pregnant women. Pregnant women are also sometimes reluctant to use antiviral medications during pregnancy. Some of the barriers to use of vaccines and medications during pregnancy are a lack of knowledge of recommendations and of safety data. By improving knowledge and understanding of influenza and vaccination recommendations, vaccine acceptance rates among pregnant women can be improved. Currently, the appropriate use of vaccination and antiviral medications is the best line of defense against influenza and its sequelae among pregnant women, and strategies to increase acceptance are crucial. This article will review the importance of influenza in pregnancy, and discuss vaccination and antiviral medications for pregnant women.
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17 -Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs
Article
Full-text available
Unlabelled: 17β-Estradiol (E2) treatment limits the pathology associated with pulmonary diseases caused by pathogens, allergens, and asthma, partly by reducing the production of proinflammatory cytokines and chemokines. To test the hypothesis that E2 protects against influenza A virus (IAV) infection by altering the recruitment and activity of innate immune cells and T cells, chemokine concentrations were measured and innate and adaptive immune cells were enumerated from the lungs of E2- and placebo-treated ovariectomized female C57BL/6 mice following infection. Females treated with E2 experienced less morbidity but had similar lung virus titers to placebo-treated females. Females treated with E2 had lower induction of CCL2 but higher CCL3 and CXCL1 responses in their lungs than placebo-treated females. Pulmonary recruitment of neutrophils, NK cells, macrophages, and dendritic cells was increased following infection, but only neutrophil numbers were greater in E2-treated than placebo-treated females. Neutrophils enhance the responses of influenza virus-specific CD8 T cells to promote virus clearance and improve the outcome of infection. Total numbers of virus-specific CD8 T cells were not altered by treatment with E2, but the proportion of gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing, virus-specific CD8 T cells was increased. Neutrophil depletion in E2-treated females increased morbidity, reduced pulmonary production of chemoattractants for neutrophils, and reduced IFN-γ production by virus-specific CD8 T cells. Neutrophils mediate both inflammation and tissue repair during IAV infection and are regulated by E2 to improve the outcome of influenza in females. Importance: Severe influenza is associated with excessive inflammation that leads to tissue damage. We demonstrate that estradiol (E2) is a potent anti-inflammatory hormone that reduces the severity of influenza A virus infection in females. Treatment of female C57BL/6 mice with E2 does not affect virus replication but rather alters the production of chemokines, pulmonary recruitment of neutrophils, and the cytokine responses of virus-specific CD8 T cells to protect females against severe influenza.
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Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination
Article
Full-text available
  • Dec 2013
  • P NATL ACAD SCI USA
Significance There are marked differences between the sexes in their immune response to infections and vaccination, with females often having significantly higher responses. However, the mechanisms underlying these differences are largely not understood. Using a systems immunology approach, we have identified a cluster of genes involved in lipid metabolism and likely modulated by testosterone that correlates with the higher antibody-neutralizing response to influenza vaccination observed in females. Moreover, males with the highest testosterone levels and expression of related gene signatures exhibited the lowest antibody responses to influenza vaccination. This study generates a number of hypotheses on the sex differences observed in the human immune system and their relationship to mechanisms involved in the antibody response to vaccination.
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Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors
Article
  • Dec 2015
Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17β-estradiol (E2) or select estrogen receptor modulators (SERMs), then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects where sex-dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor- 2 (ESR2) as neither genomic ESR1 nor non-genomic GPR30 were expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion, but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans.
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Sex differences in H7N9 influenza A virus pathogenesis
Article
  • Aug 2015
Sex, gender and age have an impact on incidence and severity of several infectious diseases. Here, we analyzed reported human cases of avian H7N9 influenza A virus infections for potential sex-dependent incidence and mortality. We report that females in their reproductive years display an increased tendency to die of H7N9 influenza than males (female-to-male ratio=1.2). Next, we challenged this potential sex-dependent difference in influenza disease outcome using a mouse infection model. In general, female mice underwent more severe disease than male mice upon infection with various influenza A virus subtypes, such as H7N9, 2009 pH1N1 and H3N2. However, morbidity and mortality were most significantly affected in H7N9 influenza virus infected female mice associated with an increased inflammatory host response. Thus, our mouse infection model described here might assist future investigations on the underlying mechanisms of sex-dependent disease outcome upon zoonotic H7N9 influenza virus infection. Moreover, our findings might help to guide patient management strategies and current vaccine recommendations. Copyright © 2015. Published by Elsevier Ltd.
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Age and Sex Differences in Rates of Influenza-Associated Hospitalizations in Hong Kong
Article
  • Jul 2015
Few studies have explored age and sex differences in the disease burden of influenza, although men and women probably differ in their susceptibility to influenza infections. In this study, quasi-Poisson regression models were applied to weekly age- and sex-specific hospitalization numbers of pneumonia and influenza cases in the Hong Kong SAR, People's Republic of China, from 2004 to 2010. Age and sex differences were assessed by age- and sex-specific rates of excess hospitalization for influenza A subtypes A(H1N1), A(H3N2), and A(H1N1)pdm09 and influenza B, respectively. We found that, in children younger than 18 years, boys had a higher excess hospitalization rate than girls, with the male-to-female ratio of excess rate (MFR) ranging from 1.1 to 2.4. MFRs of hospitalization associated with different types/subtypes were less than 1.0 for adults younger than 40 years except for A(H3N2) (MFR = 1.6), while all the MFRs were equal to or higher than 1.0 in adults aged 40 years or more except for A(H1N1)pdm09 in elderly persons aged 65 years or more (MFR = 0.9). No MFR was found to be statistically significant (P < 0.05) for hospitalizations associated with influenza type/subtype. There is some limited evidence on age and sex differences in hospitalization associated with influenza in the subtropical city of Hong Kong. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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