key: cord-0895073-k6r2n6up
authors: Scully, Eileen P.; Gupta, Amita; Klein, Sabra L.
title: Sex-biased clinical presentation and outcomes from COVID-19
date: 2021-04-01
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.03.027
sha: c8bad5649a6000eb5956d94bee44fec692a06ea7
doc_id: 895073
cord_uid: k6r2n6up

Males are disproportionately affected by severe disease and death from SARS-CoV-2 infection. In their recent article, Mussini et al. found that among people admitted with severe COVID-19, males had higher biomarkers of peripheral inflammation and were more likely to require invasive mechanical ventilation and die from COVID-19 than females. These findings provide evidence that the clinical progression of COVID-19, including development of respiratory failure, is worse for males than females. Greater consideration of sex a biological variable is needed in studies of COVID-19 outcomes and even vaccination.

Authors: Eileen P. Scully 1 , Amita Gupta 1 , and Sabra L. Klein Abstract: Males are disproportionately affected by severe disease and death from SARS-CoV-2 infection. In their recent article, Mussini et al. found that among people admitted with severe COVID-19, males had higher biomarkers of peripheral inflammation and were more likely to require invasive mechanical ventilation and die from COVID-19 than females. These findings provide evidence that the clinical progression of COVID-19, including development of respiratory failure, is worse for males than females. Greater consideration of sex a biological variable is needed in studies of COVID-19 outcomes and even vaccination.

Around the world, while males and females are equally likely to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), males are significantly more likely to be hospitalized, admitted into intensive care units, and die from the 2019 coronavirus disease (COVID-19) [1, 2] . Although globally there are similar proportions of males and females testing positive for SARS-CoV-2, there are a number of genderassociated differences with behavior (e.g., acceptance of public health measures that limit virus spread) [3] , occupations [4] , and access to healthcare for testing [5] that contribute to notable regional differences in SARS-CoV-2 exposure between the sexes [6] .

Gender differences (i.e., social construct that defines norms for men and women) are separate from but complementary to biological sex differences that are mediated by sex J o u r n a l P r e -p r o o f chrom osom e com plem ent, differential rep ro ductive tissues, an d differential concentrations of sex steroid horm o nes. Th e en richm ent of the X ch rom osom e for im m une res p onse g en es [7] , com bine d w ith the prese nce of sex steroid h orm o ne receptors o n diverse innate a nd ad aptive im m une cells and the pres enc e of horm o ne response elem ents in the prom otors of num erous im m une resp onse genes c an give rise to sex differenc es in im m unity to viruses [8] . C onsequ ently, th ere are sex differences in im m unity to S A R S -C oV -2, control of virus replication, develo pm ent of im m unopathologies, a nd lon g-term protectio n [9] . For ex am ple, d eleterious m utations in X -linked ge nes (e.g., TLR 7) have bee n linked to w orse outcom es fro m C O V ID -19 in m ales [10] . M ales co ns istently have g reate r proinflam m atory c ytokin e pro duction (e.g., IL-6) than fem ales in the co ntext of C O V ID -19 , although it is unclear w hethe r this difference is a m arker of sex differenc es in disease sev erity [11, 1 2] . O lder m ales w ith C O V ID -19 hav e low er C D 8+ T cell activity (e.g., IF N -prod uction an d proliferation) [13] , but have greater antibody responses [14] th an fem ales. The durability of neutralizing antibo dies, h ow ever, is low e r for m ales than fem ales over tim e [15] . C onsiste nt w ith obs ervations of sex differences in inflam m ation, the pa pe r b y M ussini et al. [16] re ported that b aseline as w ell as follow -up conce ntrations of C -re active protein and ferritin w ere g reater in m ales tha n fem ales. This w as d espite th e fact that fem ales w ere significantly m ore likely to be ob es e, a c on dition w hich is gen erally ass ociated w ith increase d inflam m ation. Th ese m ale C O V ID -19 patie nts also had m ore res piratory im pairm ent at pres enta tion (i.e., baseline P a O 2 /FiO 2 ) and w ere m ore likely th an fem ales to re quire m ec hanical ventilation and die from C O V ID -19. In linear m ixed m odels, it w as J o u r n a l P r e -p r o o f CRP that was the greatest mediator of the risk of invasive mechanical ventilation and death from COVID-19 pneumonia.

The population under study in this paper [16] included only those patients already meeting a definition of severe disease on presentation; the persistence of sex differences even in this group points to biological mechanisms that underlie differential outcomes in males and females. These data highlight the need to disaggregate and analyze data for sex differences to better understand the pathogenesis of COVID-19 disease. It remains unknown what role CRP has in prospectively predicting sex-specific risk or whether it should be analyzed using different sex-specific cutoffs. Larger datasets are needed to help answer these questions. It will be necessary for future studies to evaluate whether sex differences in inflammatory mediators exist in patients with less severe COVID-19 from other centers. It will also be equally important for studies of the COVID-19 vaccine to disaggregate data by sex. While vaccine efficacy appears to be similar between the sexes [17] , adverse reactions are more frequently reported by female than male vaccinees , which could provide insight into sex-specific dosing and monitoring of vaccinees. In summary, the study by Mussini et al. [16] provides evidence that respiratory failure caused by COVID-19 is worse for males than females and inflammatory proteins, including CRP, may serve as biomarkers for severe disease in males. 

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Gender differences in COVID-19 attitudes and behavior: Panel evidence from eight countries

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Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: A retrospective study of 168 severe patients

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