Understanding the role of biological sex can optimize care and drug development in asthma

KEYWORDS:

• Asthma
• airways
• biological sex
• inflammation
• lungs
• therapy

1. Introduction

Biological sex has a profound impact on health and disease, across different organ systems, immunity, and response to therapy [1,2]. The terms ‘sex’ and ‘gender’ are often conflated in scientific literature. Sex (male, female, and intersex) refers to biological attributes such as chromosomal complement, reproductive tissues, and sex steroids (hormones) [1,2]. Whereas, gender denotes social construct representing identities such as men, women, and gender diverse people, along with intersectional concepts related to behavior and interactions of peoples [1]. Although both sex and gender influence respiratory diseases, here we focus on biological sex.

In asthma, there is a clear sex bias in disease prevalence and severity [3,4]. In children (<15 years) the prevalence of asthma is higher in males, while adult females exhibit higher prevalence with higher rate of asthma exacerbations and hospitalization [4,5]. Recent studies illustrate distinct sex-related differences in biological processes associated with airway inflammation and remodeling in the pathophysiology of asthma [5–8]. Moreover, sex disparities are also associated with response to asthma treatments [9–11]. Despite these differences, sex-related differences have been mostly ignored in drug development research and clinical trials for asthma. In this editorial, we discuss various factors that influence sex-related differences in asthma immunobiology, clinical presentation, response to therapy and care. We also explore the importance and challenges of sex-specific therapeutics strategies for asthma management and drug development.

2. Effect of sex on airway immunobiology

Sex dimorphisms in immune responses in the lungs such as leukocyte composition, immune cell proliferation, and cytokine profile are well established in airway inflammation and asthma [4,6–8]. Emerging studies suggest that both sex steroids and chromosomes can influence various immunophenotypes in asthma. Notwithstanding the heterogeneity in immunophenotypes, broadly asthma can be differentiated as Th2-high and Th2-low. Th2-high asthma is typically characterized with eosinophilic airway inflammation, elevated IL-4, IL-5 and IL-13, and type 2 innate lymphoid cells (ILC2) and CD4+Th2 cells in the lungs [4,12]. Whereas, Th2-low asthma elicits more neutrophilic airway inflammation, increased Th1-driven IFNγ and Th17-driven IL-17 cytokines in the lungs, with propensity of steroid-unresponsive severe asthma [4,12].

Airway inflammation is differentially modulated by sex steroids such as estrogen and androgen. In general, androgens (including testosterone) signals via the androgen receptor to dampen airway inflammation with decrease in ILC2 proliferation, IL-33 and TSLP abundance, IL-17 production and neutrophil infiltration in the lungs [4]. In contrast, estrogen signaling via the ERα receptor enhances mediators of both Th2-high (e.g. Th2 signature cytokines and IL-33) and Th2-low (e.g. IL-17) airway inflammation [4]. ERα signaling also enhances Th17 cell proliferation and T cell metabolism, and IL-17 production [4,13]. This is aligned with animal studies demonstrating that females have a higher Th17-skewed cytokine profile in the lungs [6], and clinical observations that females have higher severe steroid-unresponsive asthma [3,4]. However, signaling via ERα and ERβ differentially regulate airway remodeling. For example, ERα exacerbates airway inflammation and remodeling, whereas ERβ activation regulates airway smooth muscle migration and blunts airway remodeling [14,15]. Differential expression of ER isoforms in the lungs, and how that influences estrogen-driven pathophysiology in asthma, remains unresolved.

Nevertheless, recent studies provide some insight into the interplay of sex steroids in airway inflammation and remodeling, and how this impacts asthma pathophysiology [5]. Changes in the levels of sex steroids and its impact on airway inflammation is associated with the temporal shift of sex-related differences in asthma over lifespan [5]. Interestingly, the protective effect of testosterone is corroborated by clinical studies demonstrating an inverse association of serum testosterone with the prevalence of asthma and lung function, independent of sex [16]. In general, enhanced levels of estrogen are correlated with exacerbation of airway inflammation and asthma in adult females [5,8]. This is also aligned with observations that post-menopausal females demonstrate a reduced risk of developing asthma, albeit the relationship between the immunobiology of airway inflammation and menopause is inconclusive [5]. However, a recent study using ovariectomized female mice showed that higher innate and adaptive immune responses to allergen challenge in females is not dependent on physiological concentrations of 17β-estradiol/estrogen [17]. In addition, sex bias pre-puberty in asthma indicates involvement of factors that may be independent of sex steroids.

Transcriptomics studies reveal the contributions of sex chromosomes, and epigenetic regulations mediated by miRNA, in allergen-induced airway inflammation [18,19]. Critical inflammatory proteins in the TLR-to-NF-κB pathways are encoded in the X chromosome, and some of these escape X inactivation, thus making females predisposed to inflammatory responses [20]. However, chromosomal contributions to airway inflammation in asthma seem to be intertwined with that of sex steroids. Two recent studies using the Four Core Genotype transgenic mouse model have attempted to tease out the role of sex steroids and chromosomes. These studies showed that female gonadal hormones may be the predominant contributing factor to inflammatory gene and miRNA networks related to airway inflammation and higher susceptibility of females in asthma [18,19]. Overall, how the combinatorial effect of sex steroids and genes influence sex-related differences in asthma immunobiology, and its intersectionality with age, is complex and remains unresolved.

3. Effect of sex on asthma epidemiology and clinical presentation

3.1. Sex disparities in asthma onset, care, and response to treatment

As discussed above, in early life males with asthma are more common than females, but this tendency reverses (more females than males) with age, with the transition occurring somewhere in the early teens [4]. This shift in prevalence is presumably underpinned by rates of incidence (initial asthma diagnosis) that appear to be tied significantly to puberty [21]. There are likely multiple factors driving this phenomenon, which presumably vary somewhat by regional, socioeconomic, and cultural aspects. Asthma as a diagnosis requires both consistent symptoms and objective measures (testing), so it is worth considering the role of sex in each of these separately.

In terms of typical asthma symptoms, wheeze seems to generally track the trend for decreased male predominance once into the teenage years. Airway hyperresponsiveness is the prototypical physiologic reflection of asthma, and by age 14 is more common in females [22]. However, at that age atopy is more common in males, while a particular condition, exercise-induced asthma, presents near equally in adult males and females [23]. Another notable phenotypic difference is that type 2 inflammatory markers among severe asthmatics appear to be higher in males [24]. Also, the specific phenotype of exercise-induced bronchoconstriction in atopics is predominantly male, suggesting a complex interplay of underlying physiologic drivers [23].

In some studies, rates of asthma hospitalization also seem to transition in the mid-teens, from male-predominant to female-predominant, suggesting that the need for inpatient care tracks similarly to incidence and prevalence [25]. This transition appeared to have persistent implications into later life, as a study of severe asthma in the United States showed that the adult peak (approximately 50 years of age) in hospitalization for asthma was female-predominant [26]. However, a different consortium in the United States showed similarity in asthma control, and no difference in treatment failures between females and males, where age rather than sex was the key predictor on failed response to therapy [27]. Although the response to asthma pharmacologic treatment seems similar between the sexes, there is evidence indicating that adult males respond better to inhaled corticosteroids [28] and adult females to antileukotrienes [29]. However, a high intensity of treatment in males is also associated, at least within one health insurance system, with higher exacerbation rates [30]. An important intertwined factor in all clinical aspects of sex-based differences in asthma, including diagnosis and treatment, is provider bias. Care professionals’ interpretation of symptoms and need for testing, for example, may be distorted by erroneous implicit or explicit assumptions based on sex [11].

3.2. Sex as an effect modifier in asthma driven by the workplace and environment

Historically, occupational asthma has been more prevalent in males [31], as it was assumed that men subjected themselves to more occupational asthmagens, as demonstrated in some regions [32]. However, it is unclear to what extent this may be accurate due to reporting bias. Whether due to temporal or social variability, this is not necessarily true and occupational asthma has proven more prevalent in women than men in some contexts [32]. Nevertheless, it remains unclear whether sex-related differences in occupational asthma is due to only vulnerability (related to the likelihood of adverse exposure) or some degree of susceptibility (sex-based factors that alter the physiologic response to a given exposure). In some cases, disentangling the contribution of vulnerability from that of susceptibility is difficult. For example, a Scandinavian study demonstrated that although occupational exposures such as dust and fume were several fold more common among males than females, being female along with occupational exposure was associated with increased asthma risk [33]. While this is presumed due to the exposure differential alone, one cannot exclude there being an element of susceptibility. There is evidence for susceptibility based on sex, for example, changes in body composition and testosterone increasing airway resistance in males [34], but how these factors intersect with exposure remains uncertain. To confidently elicit the relative contributions of vulnerability versus susceptibility ultimately would require a very careful study controlling for relevant factors such as not only occupational exposure but also other behavioral factors that may be sex-differentiated. One study that provides a model for this, albeit for a very specific exposure (woodsmoke particles in the context of viral infection), found that the sex-specific effects varied at baseline and then further depended on the exact type of exposure [35]. Beyond occupation, sex-altered differences in asthmagenic exposures (e.g. vulnerability to asthma) become even more complex given that nutrition, exposure to viruses, home cooking and cleaning, and childcare patterns, etc., all of which may vary by sex. Given the potential that better understanding therein may lead to helpful preventive strategies, this is a complex but rich area for research.

4. Expert opinion

In this era of personalized medicine, it is imperative to consider sex as a biological variable (SABV) in drug development, clinical trial, and healthcare. Unfortunately, SABV is largely ignored in asthma drug development, even though in some clinical trials females are enrolled at a higher percentage than males [36]. Typically, data is pooled and analysis is performed adjusting for sex, which can lead to misinterpretation and loss of sex-specific information [1]. Thus, it is critical to efficiently integrate SABV in studies related to asthma pathophysiology, immunobiology, and pharmacotherapy [9,11,37]. Sex disaggregated data analysis, i.e. reporting outcomes in females and males separately can identify small but important sex-specific differences. In intervention studies, one may consider examining the interaction effect of sex and intervention, i.e. sex as an effect modifier of response. A challenge for the integration of SABV in asthma research is that the varied intersectional factors such as age and environmental exposures can all influence sex-related differences. Nevertheless, failure to include SABV can lead to forsaking data and missed opportunities for beneficial sex-specific outcomes.

Considering SABV in clinical care seems of unquestionable benefit, given the implications. The challenge, perhaps, is understanding the degree to which we can rely on historical data to inform our current decisions. Such data are likely biased by outdated and problematic assumptions that detract from the quality of the data collection and, likely, its analysis and interpretation. Accordingly, more research is needed to deepen the strength of evidence by which we diagnose and care for our patients. Similarly, a better understanding of exposures and the extent to which preventive paradigms need attend to SABV is a critical newer frontier.

Declarations of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.