The airway is a continuous structure that extends from the nasal vestibule to the alveolar units of the lung. Its mucosal surface is constantly exposed to the outside world. It is thus highly adapted in its role as first defence against diverse environmental insults, whether from irritants, allergens or microorganisms. The airway must mount a rapid and effective mucosal response against such harmful agents when needed, whilst at the same time regulating the extent of such mucosal activation, terminating such reactions appropriately. This defence response is instigated using the highly effective innate and adaptive arms of the immune system, dysregulation of which is implicated in the pathogenesis and sustenance of allergic rhinitis, chronic rhinosinusitis (CRS) and asthma. The strong coexistence of allergic rhinitis and CRS with asthma and the common overlap in immunopathology suggests these diseases are related. They may therefore benefit from similar immunomodulatory therapeutic approaches. Recent findings that highlight common factors in the upper and lower airway in relation to allergic rhinitis, CRS and asthma are evaluated.
Epidemiological studies provide insight into the factors that may predispose to disease and highlight significant associations. Despite the close association of rhinitis and CRS with asthma, along with the greater prevalence of more symptomatic asthma in individuals with associated upper airway disease, how different sinonasal phenotypes relate to exact asthma phenotypes remains unknown. In a postal-based survey with over 18 000 responses, the findings were that greater the prevalence of rhinitis and CRS symptoms singly or together, the higher was the association of more symptomatic asthma . Also, separate environmental influences such as mould or mould risk (home water damage), pollutants and dust exposure predisposed to a higher odds ratio (OR) for asthma with CRS rather than allergic rhinitis alone. Symptom expression in asthma was different in relation to the coexistent sinonasal clinical type, with CRS associated with more difficult asthma symptoms, prompting the authors to speculate how different upper airway phenoendo types may relate to asthma subtypes. More work is needed to take forward such ideas, but this observation would appear to support previous findings that asthmatics with associated CRS rather than allergic rhinitis declare more asthma-related poor quality of life (QOL) . The recent demonstration of the parallel existence of severe asthma with difficult more-extensive CRS, albeit associated with potential disease-modifying factors of nasal polyps and allergic sensitization , may further support the concept of bidirectional upper and lower airway inflammation demonstrated previously in allergic rhinitis [4,5].
No real data on early life predisposing factors for allergic rhinitis in relation to disease incidence have previously been available. Using a questionnaire-based survey in 8486 individuals at baseline and 9 years apart, useful information on the natural history of rhinitis in Europe and independent predictors of disease has been obtained [6▪]. Early childhood risk of allergic rhinitis decreases in children with exposure to siblings or day school, whilst farm upbringing was associated with less rhinitis in adolescence. Individuals with a maternal history of smoking in pregnancy and early childhood demonstrated consistently increased risk of rhinitis as did individuals with a family history of allergic disease [6▪]. A separate study, using a Swedish birth cohort from 1973 to 2009, showed that a low gestational age at birth rather than the degree of foetal growth led to less allergic rhinitis later on [7▪]. The authors here hypothesize this may be as a result of earlier exposure to microbes that confers immunological protection. Such studies bring us closer to perhaps initiating preventive measures for high-risk individuals in the future and allow further hypotheses on mechanistic and therapeutic approaches to be developed. These studies provide growing support for the ‘hygiene hypothesis’ for allergic rhinitis as established in asthma. Interestingly, a recent prospectively performed study showed that being born and raised on a farm significantly reduced the odds risk ratio for asthma, whereas atopic status had no association . Also, a detailed study demonstrates that diversity of microbial exposure is inversely related to the risk of asthma [9▪▪]. Thus, early microbial exposure may be an early life determinant for both allergic rhinitis and asthma development and airway immune intolerance as such is very much influenced by environmental factors.
CRS is subdivided into with (CRSwNP) and without nasal polyps (CRSsNP) subtypes. Epidemiological CRS data is sparse. It is only recently that the overall European prevalence of CRS using the EP3OS diagnostic criteria  has been determined at 10.9% of the population, with an excess of smokers in this group . The first population-based survey to definitely show the strong association of CRS with asthma, particularly when allergic rhinitis coexists, was recently published [12▪]. Also, nonallergic CRS is associated with late-onset nonallergic asthma, both being airway phenotypes that are more difficult to treat.
CRSwNP and asthma are commonly seen together. In fact, lower airway dysfunction suggesting an underlying asthma phenotype has been shown to be present in CRSwNP even when overt clinical asthma has not been declared . It would be helpful to undertake longitudinal studies in such ‘asymptomatic’ individuals to determine the time course to active asthma development if ever and see whether upper airway intervention modulates such progression. Overall, these recent studies confirm the strong coexistence of CRS in asthma and would suggest overlapping disease mechanisms.
CLASSIFICATION OF DISEASE
Current thinking considers rhinitis, CRS and asthma as syndromes rather than exact disease entities, with distinct clinical phenotypes and biological endotypes. Both rhinitis and asthma are broadly divided into allergic and nonallergic rhinitis (NAR) subtypes based on demonstration of IgE to an aeroallergen compatible with a history of symptoms on exposure. Recent findings demonstrate that this classification is not strictly correct, being far too simplistic. In individuals with no demonstration of skin or blood IgE to allergen, excess nasal and bronchial mucosal IgE has been demonstrated previously, although the exact antigenic specificity of such IgE has so far been speculative . It has now been shown that a proportion of individuals with NAR have local mucosal IgE production to an array of allergens that can provoke symptoms on allergen challenge [15▪▪]. Such rhinitis is being classified now with the new term local allergic rhinitis (LAR). The prevalence of these new LAR phenotypes needs to be determined and whether they will respond to immunotherapy as a therapeutic intervention remains unknown. Nonallergic asthmatics have also been shown to demonstrate increased bronchial house dust mite (HDM) specific IgE recently, although allergen challenge failed to provoke asthma . The emerging role for local mucosal IgE in CRS and the implications for CRS classification are discussed later.
In allergic rhinitis, CRS and asthma, antigen-specific IgE production, mast cell activation with degranulation and eosinophilia are the key findings . Previous studies have failed to analyse upper and lower airway biopsies from the same volunteer together. The analysis of nasal and bronchial biopsies in the same individual with allergic rhinitis and asthma demonstrated similar numbers of mast cells, eosinophils, neutrophils and CD3+ T cells, confirming parallel upper and lower inflammation in the same airway .
So far, the focus has been in relation to understanding the airway adaptive immune system (Fig. 1). Allergen sensitization to aeroallergens such as HDM begins in childhood with the production of allergen-specific IgE. The most simplistic concept is that such IgE on mast cells recognizes allergen and leads to mast cell degranulation which initiates a series of inflammatory cascades. This then rapidly manifests as disease symptoms with repetitive allergen exposure leading to a chronic disease state (Fig. 1). Allergen sensitization occurs via antigen-presenting cells called dendritic cells. These cells are found in association with the airway epithelium and submucosa, but will have migrated from the bone marrow in response to signals from the airway in relation to injury and activation of the epithelium by microbes, irritants and after antigen sensitization. Allergen is actively taken up by dendritic cells and presented to naïve T cells that undergo polarization to immune subtypes based on coexistent immune signals. The selective expansion of naïve T cells into predominantly Th2 cells that secrete an important group of cytokines which include interleukin (IL)-4 (for IgE isotype class switching on B cells and Th2 cell survival), IL-5 (eosinophil development, recruitment and survival), IL-9 (mast cell maturation) and IL-13 (promotion of allergic inflammation and mucus production) is considered fundamental to disease pathogenesis in allergic rhinitis and asthma, and important roles in CRS are now apparent.
Specific roles for other T-cell subtypes such as Th1 (associated with more bacterial or viral infection related immunity), Th9 (Th2 cell differentiation) and Th17 (neutrophilic inflammation) are emerging in airway disease. Although early reports indicate increased numbers of Th17 cells in both serum and nasal tissue in allergic rhinitis, the relationship to pathogenesis of allergic rhinitis is not understood . In the CRSsNP subgroup, Th1 dominance with a more significant neutrophilic inflammation is common along with a cytokine profile of excess IFN-γ, IL-1, IL-3, IL-6 and IL-8 (neutrophil chemoattractant) that reflect a more Th1 T-cell immune response . Late-onset nonallergic neutrophilic asthma with excess IL-8 expression can be associated with this CRS phenotype, and both diseases are often poorly responsive to corticosteroids but may respond to macrolide antibiotics [10,21]. The exact role for Th17 cells in asthma is still unknown, but may contribute to neutrophil-driven, steroid-resistant severe asthma.
CRSwNP is a more distinct immunological disease. Th2 dominance with excess IL-5 (tissue eosinophilia) and increased IL-4 and IL-13 expression is observed, and aspirin-sensitive asthma is a distinct association with this CRS phenotype . Studies so far have not shown any increase of Th17 cells in either CRSsNP or CRSwNP in nasal tissue from a European population . This is surprising as CRSwNP has a high bacterial burden and IL-17 is important in immune defence to extracellular bacteria and augments inflammation. In contrast, Chinese polyp tissue expresses IL-17 in excess, regardless of coexistent or dominant eosinophilic inflammation [23,24]. The reasons for such differences are unclear, but important to understand to allow functional understanding of CRS endotypes. Bronchial biopsies from such patients with coexistent asthma looking for Th17 cells in particular will be important as it may allow us to understand the role these important cells play in asthma.
Several innate immunological signalling pathways and cytokines have been identified that augment airway adaptive immunity and thus inflammation (Fig. 1). Epithelial toll-like receptors (TLRs) are now increasingly relevant and recognize structurally conserved molecules derived from microbes called pathogen-associated molecular patterns (PAMPs). Recognition by TLRs can directly activate immune cell responses. Thymic stromal lymphopoietin (TSLP) is predominantly derived from epithelium and augments Th2 inflammation by selectively upregulating the costimulatory molecule OX40L ligand on dendritic cells leading to potent Th2 stimulation. Other recently discovered important Th2-augmenting cytokines are IL-33 and IL-25. Epithelium generates TSLP, IL-25 and IL-33 in response to epithelial injury or activation by the TLR system. IL-25 enhances Th2 responses alongside TSLP. TSLP, IL-25 and IL-33 are produced as a first line of defence against infection, thus leading to potent enhancement of allergic inflammation, acting as a ‘bridge’ between innate and adaptive airway mucosal immunity.
Out of an analysis of 98 candidate genes, TSLP gene polymorphisms demonstrate the greatest statistical significance with asthma  and similar associations are emerging in allergic rhinitis . TSLP is linked to severity of allergic disease and in recent meta-analysis has been associated with asthma along with IL-33 . TSLP expression distinguishes severe asthma cohorts . Interestingly, TSLP receptor is highly expressed in both CRS subtypes, indicating that the two main forms of CRS are not Th2-immunologically distinct as previously thought [29▪] and highlights the overall immaturity of our understanding in this disease.
IL-33 and its receptor ST2 expression is increased in allergic rhinitis epithelial cells . T cells and mast cells also have a high density of ST2 expression. Thus, individuals with high IL-33 expression have the potential to rapidly induce Th2 cell expansion and release cytokines. IL-33 knockout mice fail to demonstrate allergic rhinitis in a murine model of allergen-induced allergic rhinitis [31▪▪] and CRSwNP patients with recalcitrant disease express high levels of epithelial IL-33 .
An exciting finding in CRSwNP is the presence of a relatively large population of novel innate lymphoid cells (ILCs) responsive to IL-25 and IL-33 leading to production of excess amounts of the key Th2 cytokine IL-13 [33▪▪]. These cells are of great interest as they can potentially link innate immunity to cell-mediated, Th2-driven inflammation. Furthermore, they may allow the airway mucosa to completely bypass the adaptive immune system. A mouse model of asthma highlights the critical role such cells and cytokines may play in an asthmatic airway in that these cells have been shown to induce disease independent of the traditional Th2 pathway [34▪,35▪]. The race to find such ILC populations in the allergic rhinitis and asthmatic airway is intense, as they may provide the link pathway by which innate immunity to allergen or infection drives airway disease. Targeting molecules that are upstream of adaptive immunity may be more effective than current approaches.
As well as proinflammatory Th cell subset suppression, self-antigen tolerance and nonresponse to environmental antigens is maintained by active immune regulation by T cells termed T regulatory cells (Tregs). Tregs expressing the transcription factor forkhead box protein 3 (FoxP3) represent a particular subtype. Suppression of Th2 responses to allergen by Tregs may be defective in seasonal allergic rhinitis  and CRSwNP tissue demonstrates minimal FoxP3+ cells . Bronchial lavage  and blood  from asthmatics show reduced numbers and impaired function of such cells. Thus, these diseases all demonstrate a common theme of impaired immune regulation. Allergen provocation increases Foxp3+ Treg cells in a highly proliferative state in the nose, probably as part of inflammatory resolution events . It will be important to know if such cells have impaired regulatory function. Strategies by which induction of immune regulation can be achieved are still unknown, but helpful to understand as this may offer novel therapeutic intervention possibilities.
Vitamin D is a potent immunomodulatory hormone and may promote Treg cell function as well as improving steroid responsiveness in inflammatory disease . Observational studies in allergic rhinitis and asthma demonstrate Vitamin D deficiency in disease cohorts . A causal role is not yet demonstrated and overall the results are conflicting. For example in children, serum 25-hydroxyvitamin D3 deficiency was associated with sensitization to ragweed and oak on serum IgE analysis to 17 allergens, but serum vitamin D levels did not predict the prevalence of actual rhinitis symptoms . The adults failed to show any relationship of Vitamin D levels to either IgE sensitization or rhinitis symptoms. Similar conflicting findings are shown in asthma . It is likely that there are other confounding factors restricting such studies from defining a clear disease association with Vitamin D. Studies in CRS also suggest Vitamin D levels are deficient in CRSwNP rather than CRSsNP  and may be relevant to disease pathogenesis, but these are early findings. Vitamin D replacement cannot be recommended with confidence until the results of clinical trials demonstrating safety and clinical efficacy are available.
Nonallergic asthma is found in excess in CRS, particularly with CRSwNP, and the extent of sinonasal disease correlates with asthma severity. An emerging explanation for such association of disease is the airway superantigen hypothesis . Superantigens direct nonspecific activation of T cells, resulting in polyclonal T-cell expansion with massive cytokine release and directly stimulate B-cell proliferation. In addition, superantigens can induce immunoglobulin class-switching to IgE and the production of allergen-specific IgE in mucosal B cells. Intense mucosal inflammation independent of traditional allergen-driven pathways can be established. Bacteria are an important source of superantigen. A role for superantigens in allergic rhinitis in relation to local IgE and mucosal events was recognized some years ago . Such local IgE production, in relation to Staphylococcus aureus enterotoxin (SAE) superantigens in particular, along with a functional role in disease pathogenesis has also been established for CRSwNP  and this IgE was recently shown to be functional [48▪]. As with local IgE in LAR, asthma and CRSwNP, phenotypes of CRS with negative skin and blood allergen IgE also demonstrate excess sinonasal mucosal IgE-encoding transcripts . It may be that local IgE has a functional role in CRSsNP also, that so far has not been considered. Recent meta-analysis of nine clinical studies confirms an increased prevalence of S. aureus exposure or SAE IgE positivity in allergic rhinitis and asthma, with an OR of 2.4 and 3.3, respectively . In fact, serum IgE SAE rather than inhalant allergen IgE is a predictor of asthma severity with a very high OR of 11.09 [51▪▪]. This is important as it points to a common disease overlap mechanism in relation to superantigen drive of airway inflammation relevant to both CRS and asthma [51▪▪]. Overall what these studies demonstrate is that in allergic rhinitis, CRS and asthma phenotypes without an obvious IgE-mediated mechanism, local mucosal IgE-mediated pathways are present and probably functionally more important than previously considered. A common role for bacterial superantigen-driven, local IgE-mediated disease may be relevant, particularly in relation to more severe airway inflammatory disease. Thus, strict definition of allergic or nonallergic disease based on skin or serum IgE positivity can no longer be applied and a future change in classification terminology will be needed. Given the emerging role for bacterial superantigens, antimicrobial treatments which so far have had limited success in CRS and asthma may re-emerge as an effective disease intervention.
EPITHELIAL BARRIER FUNCTION
Loss of epithelial barrier function can lead to both mucosal vulnerability and greater penetration by allergens, microbes and pollutants, predisposing to an activated epithelial state and sustained submucosal inflammation. Restoration of tissue integrity offers a novel therapeutic approach. Defective barrier function is demonstrated in allergic rhinitis, CRS and asthma.
Intercellular tight junctions are the principal components of the epithelial paracellular permeability barrier. Epithelial cells in both asthma and CRSwNP demonstrate inadequate tight junction structure and function [52,53]. IL-4 (a Th2 cytokine) and IFN-γ (innate cytokine) can further disrupt such integrity . Such intrinsic airway vulnerability is exacerbated by environmental factors that further compromise barrier integrity. For example, the cysteine proteinase allergen Der p 1 from faecal pellets of the HDM Dermatophagoides pteronyssinus disrupts tight junctions. Recent data on nasal lavage biomarkers indicative of epithelial permeability correlated with HDM IgE sensitization in allergic rhinitis , suggesting that defects in epithelial barrier related to IgE are indeed relevant to allergic rhinitis and allergic asthma, and most probably CRS where local IgE mechanisms are implicated.
Although clinical observations show viral infection can exacerbate both allergic rhinitis and CRS, definite mechanistic studies are not available. Viral double-stranded RNA (dsRNA) is a potent trigger for antiviral immune responses via sensors such as the TLR system. Interestingly, synthetic dsRNA (polyinosinic: polycytidylic acid) induces marked disruption of airway epithelial barrier structure and function in vivo via a TLR-3 pathway . Such defective barrier induction mechanism may be relevant to the association of airway viral infection with allergic airway sensitization.
GENE ASSOCIATION STUDIES
Genomewide association studies (GWAS) are limited in rhinitis, but data so far implicate genes associated with immune regulation, Th2 inflammation and innate immunity. In nearly 4000 individuals with seasonal allergic rhinitis, disease significantly associated with polymorphisms in LLRC32 (leucine-rich repeat containing 32) which is critical for tethering transforming growth factor (TGF)-β to the T regulatory cell surface [57▪,58]. TGF-β isoforms are potent regulators of inflammation and tissue repair. LLRC32 is also associated with increased allergic asthma risk reaching genomewide significance . Polymorphisms near the genes for TMEM232 (transmembrane protein 232) and SLC25A46 (solute carrier family 25 member 46) also significantly associated with allergic rhinitis and are relevant given the proximity of this region to regulation of TSLP expression on chromosome 5. Using a candidate-gene approach, TSLP, TLR-6 and NOD1 (nucleotide-binding oligomerization domain containing 1) had an association P value less than 10−4. TLR and NOD both have potent roles in innate immunity in defence against infection at the epithelial level. Infections are associated with exacerbation of allergic disease and thus understanding the innate response to microbes may allow development of disease intervention. A recent murine model suggests that TLR-6 may be protective against asthma pathogenesis  and one can speculate TLR-6 will confer similar function in the nose. NOD receptor expression is modulated in both SAR  and CRSwNP  during allergen season or steroid treatment, respectively, suggesting a functional role in disease. Further work to understand the important roles of such innate epithelial signalling pathways is underway.
GWAS studies are lacking in CRS and a candidate-gene approach in several CRS phenotypes (with a focus on refractory CRS) has failed so far to identify any single causative gene. Studies have mainly looked at genes related to innate immunity and downstream immune regulation. Given the limitations inherent to such methods, the data so far are interesting but limited. Studies implicate multiple defects in innate immune recognition mechanisms such as the TLR system and regulatory pathways. The genes evaluated are summarized in the review by Mfuna-Endam et al.. It is relevant that previous GWAS in asthma also highlight disease susceptibility genes that have function in innate immunity and local tissue integrity .
Trials of potential disease intervention with novel biologics, previously considered in asthma, have now been extended to allergic rhinitis and CRS. Whilst anti-IL-13 therapy failed to attenuate disease symptoms in an allergen challenge model of allergic rhinitis, subanalysis suggests that individuals with excess IL-13 have a trend towards attenuation of symptoms . An anti-IL-5 pilot study directed at attenuating eosinophilic inflammation in CRSwNP demonstrates significant improvement in disease [66▪▪]. As with the above allergic rhinitis study, whether anti-IL-13 therapy is effective in clinical asthma remains unanswered , but it may be that disease subtypes with excess IL-13 are those that respond. Future planned studies must phenoendotype volunteers more rigorously. One very successful therapeutic approach in asthma has been anti-IgE therapy and given the established or emerging role of IgE-driven pathways in allergic rhinitis and CRS, one would speculate significant therapeutic impact with such intervention. Anti-IgE studies are eagerly awaited.
Recent work highlights common disease associations and overlapping mechanisms in allergic rhinitis, CRS and asthma. Further studies are needed to take forward these early findings. Information from carefully selected clinical phenotypes with sampling from both the upper and lower airway together with functional studies is needed. ENT surgeons must work alongside allergists and pulmonologists at both the bench and the bedside in the future.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 90).
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