Current Opinion in Otolaryngology & Head & Neck Surgery:
NOSE AND PARANASAL SINUSES: Edited by Samuel S. Becker
Allergic rhinitis, chronic rhinosinusitis and asthma: unravelling a complex relationship
Kariyawasam, Harsha H.; Rotiroti, Giuseppina
Allergy and Medical Rhinology Section, Royal National Throat Nose Ear Hospital, UCLH NHS Foundation Trust, University College London, London, UK
Correspondence to Harsha H. Kariyawasam, PhD, MBBS, Allergy and Medical Rhinology Section, Royal National Throat Nose and Ear Hospital, 330 Gray's Inn Road, London WC1X 8DA, UK. Tel: +44 207 915 1674; fax: +44 207 915 1674; e-mail: firstname.lastname@example.org
Purpose of review: Allergic rhinitis, chronic rhinosinusitis (CRS) and asthma have a high worldwide prevalence and confer a significant socioeconomic burden. This article reviews the recent advances in allergic rhinitis, CRS and asthma with view to understanding the upper and lower airway as one system.
Recent findings: Allergic rhinitis, CRS and asthma demonstrate strong epidemiological coassociation, and early life risk factors for upper airway disease are now apparent. The absence of demonstrable peripheral IgE does not strictly classify airway disease as nonallergic. Excess mucosal inflammation with immune dysregulation is a common feature to all. An important role for innate immunity is now apparent and offers prospects of novel therapeutic approaches in the future. A role for bacterial superantigens is also emerging in all three diseases. Genetic studies highlight common associations between allergic rhinitis, CRS and asthma.
Summary: Whether such overlapping pathological findings reflect a manifestation of the same disease but in relation to the different airway locations in individuals with genetic predisposition remains unknown, although likely. This continues under investigation and debate. The current research priorities are to understand what key events predispose to both upper and lower airway disease together and the critical immunological factors that establish and sustain airway inflammation.
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).
1. Eriksson J, Bjerg A, Lotvall J, et al. Rhinitis phenotypes correlate with different symptom presentation and risk factor patterns of asthma. Respir Med 2011; 105:1611–1621.
2. Dixon AE, Kaminsky DA, Holbrook JT, et al. Allergic rhinitis and sinusitis in asthma: differential effects on symptoms and pulmonary function. Chest 2006; 130:429–435.
3. Lin DC, Chandra RK, Tan BK, et al. Association between severity of asthma and degree of chronic rhinosinusitis. Am J Rhinol Allergy 2011; 25:205–208.
4. Braunstahl GJ, Kleinjan A, Overbeek SE, et al. Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care Med 2000; 161:2051–2057.
5. Braunstahl GJ, Overbeek SE, Kleinjan A, et al. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 2001; 107:469–476.
6▪. Matheson MC, Dharmage SC, Abramson MJ, et al. Early-life risk factors and incidence of rhinitis: results from the European Community Respiratory Health Study – an international population-based cohort study. J Allergy Clin Immunol 2011; 128:816–823.
This study provides important insight into the risk factors associated with allergic rhinitis development via a prospective approach and validates the ‘hygiene hypothesis’ in allergic rhinitis.
7▪. Crump C, Sundquist K, Sundquist J, Winkleby MA. Gestational age at birth and risk of allergic rhinitis in young adulthood. J Allergy Clin Immunol 2011; 127:1173–1179.
Increased duration of early life microbial exposure can decrease the risk of allergic rhinitis development, further supporting an important role for early microbial contact in preventing allergic airway disease such as allergic rhinitis.
8. Omland O, Hjort C, Pedersen OF, et al. New-onset asthma and the effect of environment and occupation among farming and nonfarming rural subjects. J Allergy Clin Immunol 2011; 128:761–765.
9▪▪. Ege MJ, Mayer M, Normand AC, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364:701–709.
This study firmly supports the ‘hygiene hypothesis’ in asthma, highlighting that the diversity of early microbial exposure decreases asthma risk.
10. Fokkens WJ, Lund VJ, Mullol J, et al.
European Position Paper on rhinosinusitis and nasal polyps. Rhinol Suppl 2012; 1–298.
11. Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe – an underestimated disease. A GA(2)LEN study. Allergy 2011; 66:1216–1223.
12▪. Jarvis D, Newson R, Lotvall J, et al. Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe. Allergy 2012; 67:91–98.
This study confirms the strong coexistence of CRS and asthma together using strict CRS diagnostic criteria that improve the accuracy of reporting CRS.
13. Williamson PA, Vaidyanathan S, Clearie K, et al. Airway dysfunction in nasal polyposis: a spectrum of asthmatic disease? Clin Exp Allergy 2011; 41:1379–1385.
14. James LK, Durham SR. Rhinitis with negative skin tests and absent serum allergen-specific IgE: more evidence for local IgE? J Allergy Clin Immunol 2009; 124:1012–1013.
15▪▪. Rondon C, Campo P, Herrera R, et al. Nasal allergen provocation test with multiple aeroallergens detects polysensitization in local allergic rhinitis. J Allergy Clin Immunol 2011; 128:1192–1197.
This study confirms that patients with no obvious peripheral IgE to allergen still react in an allergic rhinitis manner upon nasal allergen challenge, confirming local mucosal IgE is functional. New disease classification as ‘local allergic rhinitis’ may be needed in the future.
16. Mouthuy J, Detry B, Sohy C, et al. Presence in sputum of functional dust mite specific IgE antibodies in intrinsic asthma. Am J Respir Crit Care Med 2011; 184:206–214.
17. Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev 2011; 242:31–50.
18. Bhimrao SK, Wilson SJ, Howarth PH. Airway inflammation in atopic patients: a comparison of the upper and lower airways. Otolaryngol Head Neck Surg 2011; 145:396–400.
19. Ciprandi G, Filaci G, Battaglia F, Fenoglio D. Peripheral Th-17 cells in allergic rhinitis: new evidence. Int Immunopharmacol 2010; 10:226–229.
20. Van Zele T, Claeys S, Gevaert P, et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy 2006; 61:1280–1289.
21. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012; 18:716–725.
22. Van Bruaene N, Perez-Novo CA, Basinski TM, et al. T-cell regulation in chronic paranasal sinus disease. J Allergy Clin Immunol 2008; 121:1435–1441.1441.
23. Zhang N, Van Zele T, Perez-Novo C, et al. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J Allergy Clin Immunol 2008; 122:961–968.
24. Jiang XD, Li GY, Li L, et al. The characterization of IL-17A expression in patients with chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy 2011; 25:e171–e175.
25. He JQ, Hallstrand TS, Knight D, et al. A thymic stromal lymphopoietin gene variant is associated with asthma and airway hyperresponsiveness. J Allergy Clin Immunol 2009; 124:222–229.
26. Bunyavanich S, Melen E, Wilk JB, et al. Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma. Clin Mol Allergy 2011; 9:1–10.
27. Torgerson DG, Ampleford EJ, Chiu GY, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet 2011; 43:887–892.
28. Shikotra A, Choy DF, Ohri CM, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol 2012; 129:104–111.
29▪. Boita M, Garzaro M, Raimondo L, et al. The expression of TSLP receptor in chronic rhinosinusitis with and without nasal polyps. Int J Immunopathol Pharmacol 2011; 24:761–768.
CRSsNP and CRSwNP may not be immunologically distinct as previously thought, and Th2 inflammation may be relevant to both subtypes.
30. Kamekura R, Kojima T, Takano K, et al. The role of IL-33 and its receptor ST2 in human nasal epithelium with allergic rhinitis. Clin Exp Allergy 2012; 42:218–228.
31▪▪. Haenuki Y, Matsushita K, Futatsugi-Yumikura S, et al. A critical role of IL-33 in experimental allergic rhinitis. J Allergy Clin Immunol 2012; 130:184–194.
The critical role of the innate immune system (via IL-33) in a model of allergic rhinitis is highlighted here.
32. Reh DD, Wang Y, Ramanathan M Jr, Lane AP. Treatment-recalcitrant chronic rhinosinusitis with polyps is associated with altered epithelial cell expression of interleukin-33. Am J Rhinol Allergy 2010; 24:105–109.
33▪▪. Mjosberg JM, Trifari S, Crellin NK, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 2011; 12:1055–1062.
Nasal polyp tissue has excesss innate lymphoid cells that can drive inflammation in a potent manner.
34▪. Kim HY, Chang YJ, Subramanian S, et al. Innate lymphoid cells responding to IL-33 mediate airway hyepractivity independently of adaptive immunity. J Allergy Clin Immunol 2012; 129:216–227.
A mechanistic insight into how innate lymphoid cells can drive airway inflammation is provided.
35▪. Barlow JL, Bellosi A, Hardman CS, et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol 2012; 129:191–198.
This study shows how innate lymphoid cells can independently produce asthma in an animal model with intranasal IL-25 and IL-33.
36. Ling EM, Smith T, Nguyen XD, et al. Relation of CD4+
regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 2004; 363:608–615.
37. Hartl D, Koller B, Mehlhorn AT, et al. Quantitative and functional impairment of pulmonary CD4+
regulatory T cells in pediatric asthma. J Allergy Clin Immunol 2007; 119:1258–1266.
38. Provoost S, Maes T, van Durme YM, et al. Decreased FOXP3 protein expression in patients with asthma. Allergy 2009; 64:1539–1546.
39. Skrindo I, Scheel C, Johansen FE, Jahnsen FL. Experimentally induced accumulation of Foxp3(+) T cells in upper airway allergy. Clin Exp Allergy 2011; 41:954–962.
40. Chambers ES, Hawrylowicz CM. The impact of vitamin D on regulatory T cells. Curr Allergy Asthma Rep 2011; 11:29–36.
41. Litonjua AA. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma. Curr Opin Allergy Clin Immunol 2012; 12:179–185.
42. Sharief S, Jariwala S, Kumar J, et al. Vitamin D levels and food and environmental allergies in the United States: results from the National Health and Nutrition Examination Survey. J Allergy Clin Immunol 2011; 127:1195–1202.
43. Paul G, Brehm JM, Alcorn JF, et al. Vitamin D and asthma. Am J Respir Crit Care Med 2012; 185:124–132.
44. Mulligan JK, Bleier BS, O’Connell B, et al. Vitamin D3 correlates inversely with systemic dendritic cell numbers and bone erosion in chronic rhinosinusitis with nasal polyps and allergic fungal rhinosinusitis. Clin Exp Immunol 2011; 164:312–320.
45. Stow NW, Douglas R, Tantilipikorn P, Lacroix JS. Superantigens. Otolaryngol Clin North Am 2010; 43:489–502.vii..
46. Coker HA, Harries HE, Banfield GK, et al. Biased use of VH5 IgE-positive B cells in the nasal mucosa in allergic rhinitis. J Allergy Clin Immunol 2005; 116:445–452.
47. Van Zele T, Gevaert P, Holtappels G, et al. Local immunoglobulin production in nasal polyposis is modulated by superantigens. Clin Exp Allergy 2007; 37:1840–1847.
48▪. Zhang N, Holtappels G, Gevaert P, et al. Mucosal tissue polyclonal IgE is functional in response to allergen and SEB. Allergy 2011; 66:141–148.
Tissue IgE in sinus tissue demonstrates immunological activity in response to common allergens and bacterial superantigen. Further supports that classification of airway disease needs to be reconsidered.
49. Levin M, Tan LW, Baker L, et al. Diversity of immunoglobulin E-encoding transcripts in sinus mucosa of subjects diagnosed with nonallergic fungal eosinophilic sinusitis. Clin Exp Allergy 2011; 41:811–820.
50. Pastacaldi C, Lewis P, Howarth P. Staphylococci and staphylococcal superantigens in asthma and rhinitis: a systematic review and meta-analysis. Allergy 2011; 66:549–555.
51▪▪. Bachert C, van Steen K, Zhang N, et al.
Specific IgE against Staphylococcus aureus
enterotoxins: an independent risk factor for asthma. J Allergy Clin Immunol 2012; 130:376–381.
This study strongly supports the superantigen hypothesis that can unite upper and lower airway inflammation in allergic rhinitis, CRS with asthma.
52. Xiao C, Puddicombe SM, Field S, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011; 128:549–556.
53. Rogers GA, Den BK, Parkos CA, et al. Epithelial tight junction alterations in nasal polyposis. Int Forum Allergy Rhinol 2011; 1:50–54.
54. Soyka MB, Wawrzyniak P, Eiwegger T, et al.
Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-gamma and IL-4. J. Allergy Clin Immunol 2012; 130:1087–1096.
55. Sardella A, Voisin C, Nickmilder M, et al. Nasal epithelium integrity, environmental stressors, and allergic sensitization: a biomarker study in adolescents. Biomarkers 2012; 17:309–318.
56. Rezaee F, Meednu N, Emo JA, et al. Polyinosinic:polycytidylic acid induces protein kinase D dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells. J Allergy Clin Immunol 2011; 128:1216–1224.
57▪. Ramasamy A, Curjuric I, Coin LJ, et al. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J Allergy Clin Immunol 2011; 128:996–1005.
This study identifies genes linked to immune regulation and innate immunity as important in allergic rhinitis.
58. Tran DQ, Andersson J, Wang R, et al. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+
regulatory T cells. Proc Natl Acad Sci USA 2009; 106:13445–13450.
59. Ferreira MA, Matheson MC, Duffy DL, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 2011; 378:1006–1014.
60. Moreira AP, Cavassani KA, Ismailoglu UB, et al. The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A. J Clin Invest 2011; 121:4420–4432.
61. Bogefors J, Rydberg C, Uddman R, et al. Nod1, Nod2 and Nalp3 receptors, new potential targets in treatment of allergic rhinitis? Allergy 2010; 65:1222–1226.
62. Mansson A, Bogefors J, Cervin A, et al. NOD-like receptors in the human upper airways: a potential role in nasal polyposis. Allergy 2011; 66:621–628.
63. Mfuna-Endam L, Zhang Y, Desrosiers MY. Genetics of rhinosinusitis. Curr Allergy Asthma Rep 2011; 11:236–246.
64. Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010; 363:1211–1221.
65. Nicholson GC, Kariyawasam HH, Tan AJ, et al. The effects of an anti-IL-13 mAb on cytokine levels and nasal symptoms following nasal allergen challenge. J Allergy Clin Immunol 2011; 128:800–807.
66▪▪. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, a treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011; 128:989–995.
Treatment with anti-IL-5 in CRSwNP shows therapeutic efficacy, confirming that treatments designed to treat asthma may have clinical impact in associated upper airway disease. It is a proof-of-principle study.
67. Gauvreau GM, Boulet LP, Cockcroft DW, et al. Effects of interleukin-13 blockade on allergen induced airway responses in mild atopic asthma. Am J Respir Crit Care Med 2011; 183:1007–1014.
This article has been cited 1 time(s).
Revue Francaise D AllergologieAllergic rhinitis in children: A phenotype at risk for persistence into adulthoodRevue Francaise D Allergologie
allergic rhinitis; asthma; chronic rhinosinusitis; disease overlap; immunopathogenesis
© 2013 Lippincott Williams & Wilkins, Inc.
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