Chronic rhinosinusitis and the central role of the nasal epithelium

What is CRS?  

Chronic rhinosinusitis (CRS) is divided into two main phenotypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP).² There are other phenotypes of CRS, including aspirin-exacerbated respiratory disease (AERD), infectious rhinosinusitis and fungal rhinosinusitis, a subtype of which is allergic fungal rhinosinusitis (AFRS).⁷

Estimates of CRS prevalence vary: over 10% of the population has been estimated to have CRS based on the presence of either symptoms or objective evidence alone, while the presence of both has produced estimates of less than 5%.³ Reported prevalence also varies between countries.⁸

CRSsNP accounts for approximately 80% of cases, while patients with CRSwNP, although constituting a smaller proportion of CRS cases, tend to have more severe clinical disease.⁹

The burden of disease

CRS has a substantial negative impact on health-related quality of life.^4,10 Patients report that symptoms have a major impact on daily activities, including reducing food enjoyment, reducing sleep quality and causing feelings of embarrassment; thus, the disease represents a significant psychological and social burden.⁴ 

In fact, the symptoms of CRS are perceived to result in a comparable health state to those of Parkinson’s disease or congestive heart failure, as defined by mean Short-Form Six-Dimension (SF-6D) impairment scores.¹⁰ Furthermore, compared with non-AERD CRSwNP or CRSsNP, data suggest that patients with AERD suffer the most burdensome symptoms.¹¹

Additionally, several studies have shown an association between CRS and increased rates of depression and anxiety.^12,13

Despite the significant impact of CRS, patients perceive an underestimation of disease burden by healthcare professionals (HCPs).⁴ Timely diagnosis and management is critical for patient outcomes and effective healthcare utilisation; delayed surgical intervention for CRS is associated with greater postoperative healthcare needs.^14,15 Yet, patients’ feelings of being dismissed can act as a barrier to effective communication with HCPs, which contributes to delays in diagnosis and, therefore, treatment.¹⁶

The unmet need in CRS

Current treatment algorithms for CRS recommend intranasal corticosteroids and/or saline rinses as the first-line treatment and as maintenance therapy.¹⁷ Subsequent treatment is advanced stepwise, through short courses of oral corticosteroids (OCS), endoscopic sinus surgery (ESS), and then revision surgery or, more recently, approved biologics.^8,17

However, there are limitations to these approaches: OCS often provide only temporary alleviation of symptoms such as anosmia,¹⁸ and recurrent use of systemic corticosteroids (SCS) is associated with an increased risk of several adverse events, including pneumonia, osteoporosis, cardiovascular disease, cataracts, sleep apnoea, depression/anxiety and diabetes.¹⁹

Even appropriate medical therapy and surgery often do not achieve disease control in the long term:²⁰ at least 40% of patients with CRS may have uncontrolled disease 3–5 years after functional ESS,²¹ and 35% of patients with CRSwNP who underwent ESS were found to have nasal polyp recurrence at 6-month follow up.²² 

Pathophysiology: the central role of the epithelium

Advances in understanding have enabled a paradigm shift from viewing CRS pathophysiology through the lens of airflow obstruction to a model in which the airway epithelium plays a crucial role.²³

The airway and nasal epithelia orchestrate the complex interactions between the body’s external and internal environments.^24,25 The nasal passage is the first point of entry for environmental triggers (such as pathogens, allergens and pollutants) and odorants entering the respiratory tract that interact with the highly specialised nasal and olfactory epithelia, respectively.^25–27

The healthy nasal epithelium maintains homeostasis through a variety of immune and non-immune functions including acting as a physical barrier to environmental agents, driving mucociliary clearance, orchestrating innate immune responses through pattern-recognition receptors and regulating adaptive immune cells via the release of cytokines.²⁵

However, dysregulation of the epithelium is an important characteristic of CRS whereby the ability of the epithelium to act as a robust physical and immune barrier against the external environment becomes impeded:¹ 

• There is excess secretion and altered composition of mucus, mainly associated with glandular hyperplasia in CRSsNP and goblet cell hyperplasia in CRSwNP²⁸ 
• Reduced ciliary beating, in conjunction with excess mucus, impairs mucociliary clearance, contributing to chronic infection and inflammation^25,29 
• The olfactory epithelium also appears to be altered in CRS.³⁰ Olfactory dysfunction is a key predictor of reduced quality of life in patients with CRSwNP.³¹ In part, anosmia/hyposmia may be caused by reduced airflow due to physical obstruction by nasal polyps.³⁰ However, there is also evidence that inflammation within the olfactory epithelium leads to the impairment or death of sensory neurons, and hence the loss of sense of smell³⁰
• Recent evidence indicates that damage to the epithelium may initiate nasal polyp formation through the process of epithelial-mesenchymal transition (EMT).³² In response to damage, epithelial cells can proliferate and undergo EMT, transforming into fibroblasts that promote tissue remodelling and, ultimately, polyp formation³² 

Epithelial barrier dysfunction and impaired mucociliary clearance can lead to accumulation of pathogens and allergens, amplifying the inflammatory immune responses.²⁶ Inflammation and remodelling at the epithelium promote one another in a positive feedback loop, exacerbating CRS pathology.³³ Restoration of epithelial homeostasis may play a role in achieving disease remission in CRSwNP.³⁴

Pathophysiology: the endotypes of CRS 

Understanding the mechanisms of pathogenesis is critical to providing optimised patient care, but this is challenging because of the highly heterogeneous nature of CRS.^25,35

It was previously thought that CRSsNP and CRSwNP were characterised by distinct inflammatory endotypes, the former by Type (T)1 inflammation and the latter by T2 inflammation.²⁵ However, recent studies show that both phenotypes can manifest in three main endotypes: T1, T2 or T3 inflammation.^25,35 These endotypes are characterised by their profile of elevated cytokines and immune cells.³⁵

Adding additional layers of complexity, a number of patients present with a mixed endotype or no clear endotype,³⁶ and endotype prevalence appears to vary geographically:

• T2 is the predominant endotype of CRSwNP and CRSsNP in Western countries.³⁶ This predominance is weaker in the CRSsNP population, and a higher proportion of this patient population have no clear endotype³⁶ 
• Asian countries show higher proportions of T1 and T3 endotypes of CRSwNP.^37,38 However, there has been an increasing prevalence of T2 inflammation in the past two decades, possibly owing to shifting environmental factors^37,38

Pathophysiology: the central role of epithelial cytokines

The epithelium can regulate various mediators associated with the endotypes of CRS, such as T2 cytokines, through the release of the epithelial cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33.^39,40 These cytokines play key roles in the initiation of inflammatory pathways and structural changes underlying respiratory diseases such as asthma.^41,42

Elevated expression of TSLP, IL-33 and IL-25 has also been demonstrated in the nasal epithelium of patients with CRSwNP.⁵ Levels of TSLP, the TSLP receptor (TSLPR) and the IL-33 receptor (ST2L) have been shown to correlate not only with markers of T2 inflammation in CRSwNP, but also with markers of disease severity in eosinophilic CRSwNP.⁶

Further investigation of IL-25 expression in CRSwNP is required.²⁵ There are conflicting results about cytokine levels in CRSsNP, and further research with larger sample sizes is required.⁴³

Comorbidities and ‘united airways disease’ 

CRS and asthma are both associated with epithelial barrier dysfunction and shared profiles of inflammatory cytokines.⁴⁴

This shared pathogenesis is evidence towards the ‘united airways disease’ concept, which describes how inflammatory diseases of the upper and lower airways frequently co-occur and share similar pathophysiology.⁴⁴

In regard to frequent comorbidity, estimates suggest that 40–67% of patients with CRSwNP have comorbid asthma⁴⁰ and asthma severity is positively correlated with CRS severity (as measured by Lund-Mackay scores).⁴⁵ Similarly, in asthmatics, CRS is associated with increased asthma exacerbation frequency⁴⁶ and is an independent negative predictor of quality of life.⁴⁷

A number of other comorbidities, such as allergy and chronic obstructive pulmonary disease (COPD), are more frequent in patients with CRS than in controls.⁴⁸