Exploring the critical differences that shape disease outcomes and transform public health responses
Imagine two patients arriving at a hospital with the same infectious disease, displaying similar symptoms, and receiving identical treatment. One recovers swiftly while the other develops severe complications. What if their differing outcomes could be explained not just by age or pre-existing conditions, but by something more fundamental—their sex and gender?
This isn't a hypothetical scenario; throughout the COVID-19 pandemic, we witnessed consistent disparities where men often experienced more severe outcomes while women generally mounted stronger immune responses 2 5 .
For decades, medical research has largely treated sex and gender as afterthoughts rather than essential variables. The historical exclusion of female subjects from clinical trials, based on concerns about hormonal fluctuations complicating results, has created critical knowledge gaps in our understanding of how diseases work and how treatments affect different populations 1 4 .
Women experience approximately 50-70% more adverse drug reactions than men, partly because dosage recommendations were primarily based on male physiology 1 .
When scientists talk about "sex" in research contexts, they're referring to the biological characteristics that typically define males and females. These include chromosomal differences (XX vs. XY), reproductive organs, and concentrations of sex hormones like estrogen, progesterone, and testosterone.
Females generally mount more robust innate and adaptive immune responses, which can translate to faster pathogen clearance but may also contribute to increased development of immunopathology and inflammatory conditions 1 .
The X chromosome contains a significantly higher number of immune-related genes than the Y chromosome—nearly 50 genes involved in immune function are located on the X chromosome 6 .
"Gender" refers to the socially constructed roles, behaviors, expressions, and identities of girls, women, boys, men, and gender-diverse people. Unlike sex, which is biological, gender influences disease risk through different mechanisms:
Gender norms can influence whether and when individuals seek medical care or comply with treatment regimens 2 .
Gender-based barriers to healthcare can delay diagnosis and treatment for some groups.
"Differences observed between cisgender men and women must be interpreted as a combination of both biological and psychosocial differences—and not solely sex differences" 8 .
One of the most comprehensive approaches to understanding sex and gender differences in infectious diseases comes from a 2025 study that developed a conceptual framework based on the Susceptible-Exposed-Infectious-Recovered/Deceased (SEIR/D) compartmental model 2 3 5 .
The research team adapted this classic model to map how both biological sex and sociocultural gender might influence each stage of disease progression:
The analysis revealed consistent patterns across multiple studies:
| Outcome Measure | Pattern Observed | Probable Contributing Factors |
|---|---|---|
| Infection rates | Women often showed higher reported rates in certain contexts | Greater testing uptake, occupational exposure in healthcare roles |
| Hospitalization | Men were more frequently hospitalized | Biological susceptibility to severe disease, delayed care-seeking |
| Mortality | Men had consistently higher case-fatality ratios | Combination of biological susceptibility and behavioral factors |
| Long COVID | Women appeared more susceptible | Sex-based differences in immune response and autoimmune mechanisms |
This modeling approach provides a theoretical foundation for integrating sex and gender into infectious disease models more broadly. By identifying specific points where these factors influence disease progression, the framework helps researchers develop more accurate predictions and targeted interventions.
The COVID-19 pandemic served as a crucial case study, but the principles apply to many infectious diseases. For respiratory infections specifically, a multi-year analysis of hospital data revealed consistent patterns of male vulnerability across multiple pathogens.
Data from 9
Research into sex and gender differences requires specialized approaches and tools.
| Research Tool | Function | Examples/Applications |
|---|---|---|
| Sex-disaggregated data | Separating data by biological sex | Revealing differential disease outcomes and treatment effects |
| Gender-sensitive measures | Assessing gender-related variables | Evaluating how social roles, norms, and identities influence health |
| Animal models (both sexes) | Preclinical testing in male and female animals | Identifying sex differences in drug metabolism and efficacy |
| Hormone manipulation tools | Testing hormonal influences on immunity | Gonadectomy, hormone supplementation, hormone receptor blockers |
| X chromosome analysis tools | Studying X inactivation and escape | Identifying dosage effects of immune genes on X chromosome |
| Y chromosome analysis tools | Studying loss of Y chromosome (LOY) | Investigating LOY as biomarker of immune aging in men |
| Cell lines from both sexes | In vitro studies using male and female cells | Revealing cell-intrinsic sex differences in immune responses |
Despite growing recognition of their importance, sex and gender considerations still face significant barriers to full integration into biomedical research. These include 8 :
Confusion between "sex" and "gender" and how to properly measure gender-related variables.
Limited availability of sex-disaggregated data and even less data on transgender and non-binary populations.
Inappropriate analytical approaches that fail to properly account for sex and gender variables.
Integrating sex and gender into infectious disease research isn't just about being inclusive—it's about developing more effective, precise public health interventions that account for real-world diversity.
To different populations' needs and circumstances
Based on sex-specific pharmacology
That account for sex differences in immune response
By targeting interventions to those at highest risk
The journey to fully integrate sex and gender into infectious disease research is just beginning, but the potential benefits are enormous. As we've seen from COVID-19 and other infectious diseases, ignoring these critical dimensions leaves blind spots in our understanding and creates gaps in our public health response.
The future of sex and gender-based studies will likely involve more sophisticated modeling approaches that dynamically integrate both biological and social factors, larger clinical trials that deliberately include underrepresented groups, and more nuanced public health messaging that recognizes different populations have different needs and constraints.
"Following guidelines to address sex and gender bottlenecks will support the development of more efficient and equitable care strategies for all" 8 . In a world increasingly confronted by emerging infectious threats, this isn't just scientific progress—it's a public health imperative.