Abstract
Biological sex affects the outcome of diverse respiratory viral infections. The pathogenesis of respiratory infections caused by viruses ranging from respiratory syncytial virus to influenza viruses and severe acute respiratory syndrome coronavirus 2 differs between the sexes across the life course. Generally, males are more susceptible to severe outcomes from respiratory viral infections at younger and older ages. During reproductive years (i.e., after puberty and prior to menopause), females are often at greater risk than males for severe outcomes. Pregnancy and biological sex affect the pathogenesis of respiratory viral infections. In addition to sex differences in the pathogenesis of disease, there are consistent sex differences in responses to treatments, with females often developing greater immune responses but experiencing more adverse reactions than males. Animal models provide mechanistic insights into the causes of sex differences in respiratory virus pathogenesis and treatment outcomes, where available.
Highlights
Viruses cause the vast majority of respiratory infections [1]
The pathogenesis of respiratory viral infections is heterogenous with biological sex intersecting with age and reproductive status to explain the significant variability in the outcomes of respiratory infectious diseases and their associated treatments (Table 1)
Reduced sex differences in immune responses to the monovalent 2009 H1N1 vaccine among aged individuals are partly due to reproductive senescence in females, in which higher circulating E2 concentrations are associated with greater antibody responses to the vaccine [114]
Summary
The pathogenesis of respiratory viral infections is heterogenous with biological sex intersecting with age and reproductive status to explain the significant variability in the outcomes of respiratory infectious diseases and their associated treatments (Table 1). Important are the host factors, including age, body mass index, diet, microbiome, reproductive status, gender, and biological sex, which all contribute to variability in immune responses and outcomes of respiratory viral infection. Gender can intersect with sex to affect outcomes of many diseases [5], but for this review our focus is on sex as a biological variable and its role in explaining heterogeneity in the pathogenesis and treatments of respiratory viral infections. Among children (i.e., individuals less than 18 years of age) (Table 1), males are more vulnerable to severe outcomes from respiratory viral infections, such as RSV, than females [9] (Figure 1). Through analyses of some of the more ubiquitous respiratory viruses (Table 1), the epidemiological observations of sex differences in respiratory viral pathogenesis are presented, clinical studies of antivirals and vaccines that disaggregate and analyze data by sex are reviewed, and mechanistic insights are provided from both human and animal studies
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