Sex and gender in rhinosinusitis: a review

ABSTRACT

Rhinosinusitis is a highly prevalent, inflammatory condition affecting the nose and paranasal sinuses, impacting an individual’s quality of life with significant health care burden. Sinusitis is more frequent in females, and they typically present with more severe symptoms and worse quality of life scores. Males are more likely to present with nasal polyps and have higher objective scores on imaging studies. Differences in sinus microbiota by sex may play a role in understanding differences in clinical presentations between them, but additional research is required. An improved understanding of sex and gender-based differences in pathophysiology and clinical presentations will help to decrease inequities in accessing healthcare and optimizing long-term personalized patient outcomes.

1. Introduction

Rhinosinusitis is a common disease that is characterized by inflammation of the nasal cavities and sinuses. The management of rhinosinusitis costs billions per year and has a significant negative impact on a person’s quality of life [1]. Rhinosinusitis may exacerbate asthma and chronic lung diseases and impact other outcomes such as fatigue and mental health [2–4].

Rhinosinusitis symptoms manifest when mucosal inflammation impairs the mucociliary function of the nose and paranasal sinuses [5]. Rhinosinusitis can be classified as chronic rhinosinusitis (CRS) when sinonasal symptoms persist for greater than 12 weeks [6]. CRS is a heterogenous inflammatory disorder [7] that is commonly categorized into two main phenotypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) [7]. The health status of people with CRS is comparable to individuals with arthritis and cancer, and CRS significantly impacts quality of life by inhibiting social function and causing persistent facial pain [4,8]. Although certain conditions like cystic fibrosis and immunodeficiencies predispose an individual to CRS, the pathophysiological mechanisms of the disease are incompletely understood, largely due to endotype heterogeneity [9,10]. Understanding the various endotypes that contribute to CRS will facilitate the development of therapies to target underlying disease mechanisms [11,12].

Acute rhinosinusitis (ARS) lasts fewer than 4 weeks and is typically caused by a viral infection [7]. ARS is usually a self-resolving condition, and the incidence of severe complications is very low [13,14]. Some individuals with ARS may experience complications due to decreased mucociliary activity and sinus obstruction which create a favorable environment for bacterial growth [11,15]. Less than 2% of viral rhinosinusitis episodes are affected by secondary bacterial infections but physicians prescribe antibiotics for over 85% of rhinosinusitis presentations [16]. Evidence also suggests that antibiotic therapy does not necessarily shorten symptom duration or reduce ARS complication rates in adults [17].

Studying the sex and gender differences in disease is key to appropriately deliver personalized care and a step toward reducing health related inequities [18,19]. Sex-based differences have been observed in rhinosinusitis and vary between sub-types of both CRS and ARS [20,21]. There are few studies that have directly examined the relationship between gender identity and rhinosinusitis, although gender is likely a key determinant (including its intersectionality with other health determinants) in rhinosinusitis outcomes [22]. As an example, gender identity can influence risk factor exposure and decision-making in accessing health care, leading to differences in rhinosinusitis susceptibility and severity [22,23].

2. Sex and gender in health

Sex is determined by the physiological characteristics that differentiate males and females; these differences include primary and secondary sex characteristics, sex chromosome complement, and sex steroid hormones [24,25]. Sex is an important determinant of health, as disease rates, responses to therapies, and clinical presentations often vary by sex [24]. Gender refers to the socially constructed norms that shape our behaviors, roles, and relationships within society. The roles and responsibilities that are reinforced by gender identity influence our exposure to disease risk factors, interactions with the healthcare system, and personal health decision making [25]. While it is important to consider the influences of sex and gender on health independently, examining the intersection of sex and gender (and other socio-demographic factors) is necessary for a comprehensive understanding of how an individual’s identity impacts health experience [26]. Female subjects have historically been excluded from scientific research, such that our traditional understanding of disease is representative of the male population [18,27]. Elucidating the unique impacts that sex and gender have on health will facilitate the delivery and accessibility of personalized care [18].

3. Sinus infection microbiology and pathogenesis

Traditional dogma suggested the sinuses were effectively sterile; however, emerging evidence has disputed this notion (Figure 1) [28]. The upper respiratory tract (URT) microbiota mainly consists of Proteobacteria, Firmicutes, Actinobacteria, Fusobacteria, and Bacteroidetes phyla, with genera like Neisseria, Gemella, Corynebacterium, Streptococcus, and Haemophilus [29–32]. The connection through the ostia allows bacteria from the nasopharynx to enter the sinuses, serving as a potential reservoir for pathogens. If the ostium closes, these bacteria can translocate and cause inflammation, as both aerobic (e.g., S. aureus, H. influenza) and anaerobic (e.g., Prevotella, Fusobacterium) bacteria have been identified in non-inflamed sinuses [33–35]. In CRS, microbial dysbiosis occurs with reduced diversity and community restructuring, leading to chronic inflammation – with studies demonstrating increased Proteobacteria (Pseudomonas) and Bacteroidetes (Prevotella) [36]. Choi et al. found this shift is mainly driven by increased Proteobacteria and decreased Bacteroidetes abundance [37] Aurora et al found those with CRS had a sinus microbiome signature dominated by Pseudomonadaceae, Corynebacteriaceae, Streptococcaceae and Staphylococcaceae [38]. Lal and colleagues conducted a comparative analysis of the microbiota in the middle and inferior meatus between CRS patients and healthy individuals [39]. CRS patients with nasal polyps exhibited a higher presence of Haemophilus, Streptococcus, and Fusobacterium species. Wei et al. conducted a comparative analysis of the bacterial composition in the middle meatus and found across 136 CRS with nasal polyps cases, presence of Corynebacterium (20%), S. epidermidis (19%), Streptococcus (15%), and S. aureus (11%) as the most common isolates were observed by culture-based techniques [40]. Beyond bacteria, our understanding of the roles of fungi and viruses in the nasal microbiota is evolving but out of the scope for this review. Moreover, the literature has clearly described microbiologic dysbiosis associated with CRS; however, it is important to acknowledge other factors associated with CRS development and progression including the immune system and response to therapeutics – for which many studies have reported sex-based differences, but relatively absent on gender. These are summarized below (Table 1).

Figure 1.

Overview of the microbiologic pathophysiology of chronic rhinosinusitis. As disease progresses, relative dysbiosis through proliferation of microbes (i.e., anaerobes) occurs with reduction in microbial diversity. These factors may be attenuated through intervening factors (i.e., prebiotics) but require further study.

Table 1.

Sex-based differences in microbiology, immune response, symptom severity, and treatment outcomes.

Category	Male	Female	Comments
Microbiome Composition	Higher levels of specific pathogens (e.g., Staphylococcus aureus) [41]	Higher microbial diversity overall [41–44]	Sex differences in microbial communities could affect inflammation and CRS symptoms.
Immune Response	Greater neutrophilic response, leading to more inflammatory reactions [45]	Enhanced mucosal immunity and lower neutrophilic response [45]	Females may show lower inflammation markers in CRS studies.
Symptom Severity	Increased nasal congestion and mucous production [46,47]	Higher reported levels of pain and fatigue [46,48]	Symptom perception may vary due to hormonal influences and immune system variability
Hormonal Influences	Less fluctuation in symptom severity [49]	Fluctuation in symptoms with menstrual cycle and menopause [47,49]	Estrogen and progesterone can modulate mucosal immunity in CRS
Treatment Outcomes	Higher success rates with antibiotics targeting specific pathogens [50]	Greater responsiveness to anti-inflammatory and hormone-targeted therapies [49]	Female CRS patients may require more customized, less pathogen-focused treatment
Recurrence Rates	Slightly higher recurrence, may be linked to smoking and environmental factors [51]	Lower recurrence, but higher association with allergies and hormonal shifts [41,49]	Lifestyle and environmental factors may exacerbate recurrence in males

4. Sex and gender considerations in sinus disease

Epidemiological studies and health survey-based reports have typically reported a higher prevalence of chronic rhinosinusitis in females compared with males [52], although differences in disease definitions (patient-reported symptoms, radiographic and/or endoscopic findings) makes generalization about the true sex-based prevalence estimates challenging. Additionally, research to date has typically included sex (male/female) classification rather than gender classification. Table 2 summarizes current literature comparing the sex-based variations in CRS.

Table 2.

Sex based differences in CRS presentation and outcomes.

Prevalence of CRS	Unclear. Several studies showed higher prevalence rates for females vs. males, but others found no statistically significant differences[53–55]
Phenotype of CRS	Higher rates of CRSwP in males and in females with lower estradiol levels compared to females with higher estradiol levels [53,54]
Patient reported symptoms	Higher SNOT-22 scores in females overall [55,56] Higher scores in subdomain of ear/facial, sleep, and psychological domains in females
Radiographic scores	Higher radiographic disease burden consistently seen in males vs. females [57]
Surgical outcomes	No difference in rates of surgery Lower overall symptom scores post-surgery in males, but similar change score in both sexes comparing pre- and post-surgery outcomes [55,58]
Depression	Unclear. Potentially higher rates of depression among females with CRS as compared to males [59]

CRS phenotypes also vary by sex, with more males presenting with CRSwNP, while females have higher rates of CRSsNP [60–62]. Several human and animal studies have examined the impact of sex-hormones on nasal symptoms with males and females with lower estradiol levels having higher rates of nasal polyps as compared to females with higher estradiol levels [61,63]. Animal studies have seen higher density of muscarinic receptors in those with higher estrogen levels and lower density of alpha-adrenergic receptors in those with higher progesterone, both of which are hypothesized to relate to increased nasal secretion and swelling of the nasal mucosa [64]. Those presenting with CRSwP were more likely to be offered endoscopic sinus surgery as compared to those without polyps, another factor which may contribute to sex-based differences in long-term outcomes for people living with CRS.

The experience of CRS symptoms and their subsequent impact on quality of life (QoL) may also be influenced by sex and gendered factors. A Brazilian study of healthy controls confirmed higher rates of Sinonasal Outcomes Test-22 (SNOT-22) scores among females as compared to healthy males in middle aged participants [65]. Males are more likely to experience congestion and nasal obstruction while females are more likely to present with symptoms of facial pain and headache [61]. Across several studies females scored worse on QoL assessments such as the SNOT-22 and The Rhinosinusitis Disability Index, even though they often demonstrate equal or less severe disease according to objective computed tomography findings and endoscopic assessments [55,66–68]. This higher symptom burden impacting QoL tends to be driven by face and ear symptoms, psychological and sleep related difficulties, worse nasal drainage and reduced functional capacity. In patients with cystic fibrosis, more frequent exacerbations of their CRS were seen in female patients [69]. Higher rates of aspirin exacerbated respiratory disease (AERD), a recalcitrant and severe form of CRSwP has also been consistently seen in more females compared to males [53].

Sex and gender-based factors may also play a significant role in presentation to care, compliance with medical therapy and surgical decision-making. Despite higher rates of patient reported symptoms in females, there have been no significant differences seen in number of patients who elect to undergo sinus surgery [67]. Females have also been shown to have higher pre- and post-operative SNOT-22 scores, compared to their male counterparts [68,70], although both groups appear to benefit symptomatically following surgery with similar change scores. These findings are congruent with previous reports of sex and gender-based differences in symptomatic experiences across various disorders, including instances of acute sinusitis [71].

A meta-analysis in 2023, examined prevalence of anxiety and depression among patients with CRS and found pooled prevalence rates of 25.2% and 28.9% for depression and anxiety, respectively [59]; both of which were significantly higher than that of the general population (5–10%). The authors hypothesized systemic factors such as sleep disturbances and pain, along with social isolation secondary to sinus symptoms may explain the high rates of mental health impairments in people with CRS. Studies examining the intersect of sex and depression in CRS have been inconsistent with some suggesting higher rather of depression in females with CRS. Gender-based differences related to care-giver burden, lower socioeconomic status and higher rates of childcare responsibilities among women may also be factors in understanding how people present to care as well as adherence to treatment which is essential for long-term maintenance of this chronic condition.

Sex-specific differences have also been identified in nasal microbiome composition and bacterial density [41]. Liu and colleagues enrolled monozygotic (n = 46 pairs) and dizygotic (n = 43 pairs) twins from the Danish Twin Registry and identified host genetics and nasal bacterial density were significantly linked [72]. Nasal bacterial densities, as measured by absolute abundance of 16S rRNA copies per swab, of monozygotic twins were significantly more correlated than that of dizygotic twins. Bacterial density was greater in males compared to females and Staphylococcus species and polymicrobial growth were more frequent in males compared to females [41].

5. Conclusion

Rhinosinusitis is a very frequent disease with a significant health care impact. A number of sex-based differences in prevalence, presentation, symptomatology and health behaviors and outcomes have been reported. There is limited data on gendered factors and their impacts on sinus disease. Future studies should incorporate sex and gender to work toward reducing inequities and improving outcomes in people living with this disease.

6. Future perspectives

People with CRS with lower socioeconomic status have been identified to have lower rates of follow up after undergoing endoscopic sinus surgery (ESS). Higher household income was found to be an independent predictor of symptomatic improvement in people with CRS following ESS [73]. Given the important of adherence to treatment post operatively for long-term sinonasal outcomes, the impact of socio-economic status may be an essential factor to explore with a sex and gender lens [74].

Higher rates of depression are seen in females and the impact of gender-based factors such as social isolation, caregiver burden and differences in socioeconomic status may play a major role in identifying barriers to access to care and establishment of treatment protocols and warrant additional investigations beyond biologic sex-based differences to optimize long-term patient outcomes. Disparities among different races and SES have been reported relating to presentation to care for acute and chronic sinus symptoms [75], and no research to date has examined the impact of transgendered care and sinusitis. Various gender-related factors may play a significant role in presentation and long-term management of CRS and remain to be understood.

Although studies have discussed gender-based differences, the inherent comparisons are entirely sex-based with no incorporation of gender-based variables. The use of men/women and males/female interchangeably is seen frequently in the sinusitis literature and highlights the need for more gender-based considerations rather than details based on biologic sex alone to more comprehensively understand health impacts as they relate to sinus disease.

Funding Statement

This paper was not funded.

Article highlights

Introduction:

• Rhinosinusitis is a very common condition characterized by inflammation of the nasal cavities and sinuses and costs billions annually in its management.

• Phenotypes include acute and chronic rhinosinusitis with the latter including or not including nasal polyps.

• Studying sex and gender differences in rhinosinusitis can help to develop more tailored and effective diagnoses and management strategies for rhinosinusitis.

Sinus Infection Microbiology and Pathogenesis:

• The upper respiratory tract consists of diverse microbial communities and alteration of these can result in the inflammation seen particularly in chronic rhinosinusitis.

• There are differences in bacterial communities between those with and without chronic rhinosinusitis as well as between males and females with rhinosinusitis.

Sex and gender considerations in sinus disease:

• There is a greater prevalence of chronic rhinosinusitis in females compared with males and most studies only track biologic sex.

• Sex and gender factors can influence the presentation, health behaviors and quality of life for chronic rhinosinusitis.

Future perspectives:

• Socio-economic and demographic factors can significantly influence health behaviors and outcomes from chronic rhinosinusitis and must be more carefully considered in studies in this area.

• Little exists in the literature to explore gendered factors in their association and impact on chronic rhinosinusitis.

Disclosure statement

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.

No writing assistance was utilized in the production of this manuscript.