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Feature Christmas 2017: All Creatures Great and Small

The science behind “man flu”

BMJ 2017; 359 doi: (Published 11 December 2017) Cite this as: BMJ 2017;359:j5560

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Re: The science behind “man flu”: less inflammation, but more suffering in men than women

It is with great interest that we read the paper of Dr. Sue regarding the phenomenon called “man flu”.(1) In the paper extensive evidence from animal and human studies is put forward, illustrating that men might indeed suffer more in response to the same microbial challenge, that this may be related to sex hormones, and that it might have an evolutionary benefit. Following the reproductive phase, not only for viral infections, but also for bacterial sepsis, outcome in men is worse compared to women.(2) However, as Dr. Sue points out, data from RCT’s in humans are scarce. We would like to provide relevant additional human in vivo data we obtained by subjecting male and female volunteers to the highly-controlled and reproducible model of experimental human endotoxemia, a model of systemic inflammation typically resulting in flu-like symptoms in the subjects.

Being men ourselves, and having had several near death experiences enduring the flu, we were intrigued by the same question as Dr. Sue. We therefore challenged 30 young healthy subjects (15 males, 15 females) with an intravenous dose of 2 ng/kg of purified E. Coli endotoxin and measured their inflammatory response (circulating cytokine levels), perceived symptoms (grading of headache, backache, shivering, nausea and vomiting on a 0-5 Likert scale) and vascular reactivity (changes in forearm blood flow in response to the intra-arterial administration of vasoactive medication). We too found a significantly enhanced pro-inflammatory immune response in females compared to males. Peak levels of the pro-inflammatory cytokine Tumor Necrosis Factor-[alpha] were more than twice as high in females compared with males (965 ± 193 pg/mL vs. 411 ± 34.6 pg/mL, p < .0001) and IL-1[beta] was slightly elevated in females, whereas is was not significantly elevated in males (12 ± 1.6 pg/mL vs. 8 ± 0.1 pg/mL, p = .005). Interferon-[gamma] increased to 136 ± 31.7 pg/mL in females versus 60 ± 10.4 pg/mL in males (p = .001). In contrast to the proinflammatory cytokines, the increase in the anti-inflammatory cytokine IL-10 was not significantly different between females and males (95 ± 15.3 pg/mL vs. 129 ± 14.6 pg/mL respectively, p = .23). While proinflammation was less, vascular reactivity was attenuated to a greater extent in males, as the sensitivity to norepinephrine was decreased after the administration of endotoxin in male subjects (p = .002), but did not change significantly in females (p = .55).

This illustrates that the innate immune response may be less pronounced in men, but at the same time the clinical consequences may be more severe. Surprisingly, the amount of perceived symptoms was identical.(3) In a post-hoc analysis we now performed, we indeed found that the male subjects did not erect shelves, maintain cars or attend a football match (or engaged in reproductive activities for that matter) directly following the endotoxemia study, illustrating how inflammation may affect social life. It was previously hypothesized that a blunted innate immune response may lead to impaired pathogen killing and may ultimately account for the observed worse clinical outcome in men compared to women.(4)

So yes, we men complain when feeling sick, just like women do. However, in our controlled human in vivo setting, men did not complain more, while end-organ dysfunction was more pronounced. The observed attenuated innate immune response may account for the observed impaired prognosis from infectious diseases in man. Clearly, we do not nag about it, we just take it like a man.

Lucas van Eijk, Peter Pickkers

1. Sue K. The science behind "man flu". BMJ 2017;359:j5560. doi: 10.1136/bmj.j5560
2. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):1303-10.
3. van Eijk LT, Dorresteijn MJ, Smits P, et al. Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers. Crit Care Med 2007;35(6):1464-69.
4. Netea MG, van der Meer JW, van Deuren M, et al. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends in immunology 2003;24(5):254-8.

Competing interests: No competing interests

14 December 2017
Lucas T van Eijk
Resident Anaesthesiology
Peter Pickkers
Dept of Intensive Care Medicine and Dept of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center Nijmegen, The Netherlands
Radboud University Medical Center Nijmegen, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands