Session:
A breath of diversity: impact of biological sex on cellular and molecular mechanisms in respiratory disease
Speakers:
Dr. Dawn Newcomb (USA) and dr Maarten van den Berge (Netherlands)
Prevalence patterns differ
Both asthma and COPD are multifaceted diseases with many factors in play, including environmental, genetic and epigenetic factors. They may present differently in men and women, however this is not reflected in current guidelines.1 Prevalence of asthma is higher in boys, but the pattern changes past puberty and in adulthood, more women suffer from asthma, including severe asthma. In COPD, the prevalence is increasing in women, and smoking is more harmful for women than men.2
Biological mechanisms behind sex differences in asthma
The role that sex hormones are playing in immune response in asthma was in focus for a presentation by dr Dawn Newcomb. As an example, females are more prone to develop autoimmune diseases and have higher response to vaccines, whereas men are more likely to develop Heptitis B, C and non-reproductive cancer.3 In addition, and highly importantly for asthma, women have a higher CD4+ T-cell activation and proliferation. 3 CD4+ T cells are important drivers of inflammation in asthma, but the direct influence of sex hormones on CD4+ T-cell is not fully understood.
Sex hormones as modulators of immune response
Dr Newcomb presented research conducted with her colleagues, showing that both oestrogen and androgen receptors are involved. Oestrogen signaling through ER-a increases eosinophil and neutrophil infiltration, while signaling through ER-b decreases eosinophil infiltration. Androgens on the other hand, such as testosterone, signaling through AR, decrease eosinophil and infiltration.4
In addition, in a series of elaborate in vivo and in vitro experiments, it was shown that females have a higher metabolic protein expression in Th17cells, and that androgens, signaling via AR, decreased Th17 cell differentiation and restricted airway inflammation.5
Clinical phenotyping and potential sex differences for treatment of asthma and COPD
The ATLANTIS study, a large multinational observational study on asthma, attempted to also answer questions around the importance of sex differences and clinical phenotyping.6 Maarten van den Berge presented findings from this study, including 773 patients from 9 countries. Based on the findings, women experienced more exacerbations, and reported more symptoms than men with similar lung function. In addition, a higher airway resistance, as measured by impulse oscillometry, was seen in women, which according to the speaker could be explained by the airway size, i.e. because the resistance is higher in smaller lungs. Therefore, his suggestion account and adjusted for sex when performing oscillometry. Male patients, on the other hand, were found to have a more severe airflow obstruction, and a higher prevalence of PAL.
Inflammatory biomarkers
Regarding immune response, the ATLANTIS study did not find any significant sex differences in the majority of the inflammatory markers, i.e. FeNO, and blood and sputum eosenophils. However, significantly higher blood neutrophils counts were found in women with asthma. Finally, there were no significant sex differences on treatment patterns.
Clinical phenotyping and treatable traits
To summarize, sex differences are present in respiratory diseases, particularly in asthma, and should potentially be taken into account in the clinical setting. Nevertheless, the picture is complicated, with many factors involved (environmental, genetic, epigenetic) and decision making should be guided by clinical phenotyping and identifying treatable traits and not by sex alone.
Eleni Kopsida
Value & Access Lead, Nordics
References
- Rogliani P, Cavalli F, Ritondo BL, Cazzola M, Calzetta L. Sex differences in adult asthma and COPD therapy: a systematic review. Respir Res. 2022 Aug 29;23(1):222. doi: 10.1186/s12931-022-02140-4. PMID: 36038873; PMCID: PMC9426004.
- Downs SH, Brändli O, Zellweger JP, Schindler C, Künzli N, Gerbase MW, Burdet L, Bettschart R, Zemp E, Frey M, Keller R, Tschopp JM, Leuenberger P, Ackermann-Liebrich U; SAPALDIA team. Accelerated decline in lung function in smoking women with airway obstruction: SAPALDIA 2 cohort study. Respir Res. 2005 May 26;6(1):45. doi: 10.1186/1465-9921-6-45. PMID: 15918902; PMCID: PMC1177989.
- Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016 Oct;16(10):626-38. doi: 10.1038/nri.2016.90. Epub 2016 Aug 22. PMID: 27546235.
- Chowdhury NU, Guntur VP, Newcomb DC, Wechsler ME. Sex and gender in asthma. Eur Respir Rev. 2021 Nov 17;30(162):210067. doi: 10.1183/16000617.0067-2021. PMID: 34789462; PMCID: PMC8783601.
- Chowdhury NU, Cephus JY, Henriquez Pilier E, Wolf MM, Madden MZ, Kuehnle SN, McKernan KE, Jennings EQ, Arner EN, Heintzman DR, Chi C, Sugiura A, Stier MT, Voss K, Ye X, Scales K, Krystofiak ES, Gandhi VD, Guzy RD, Cahill KN, Sperling AI, Peebles RS Jr, Rathmell JC, Newcomb DC. Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation. J Clin Invest. 2024 Oct 15;134(23):e177242. doi: 10.1172/JCI177242. PMID: 39404231; PMCID: PMC11601904.
- Kole TM, Muiser S, Kraft M, Siddiqui S, Fabbri LM, Rabe KF, Papi A, Brightling C, Singh D, van der Molen T, Nawijn MC, Kerstjens HAM, van den Berge M. Sex differences in asthma control, lung function and exacerbations: the ATLANTIS study. BMJ Open Respir Res. 2024 Jun 19;11(1):e002316. doi: 10.1136/bmjresp-2024-002316. PMID: 38901877; PMCID: PMC11191767.
ID 17077-03.10.2025