REVIEW URRENT C OPINION
An update on the pathogenesis of the upper airways in aspirin-exacerbated respiratory disease Jeong-Hee Choi a, Mi-Ae Kim b, and Hae-Sim Park b
Purpose of review The key features of aspirin-exacerbated respiratory diseases (AERDs) include chronic, severe asthma and a high prevalence (60–80%) of chronic rhinosinusitis with nasal polyps, all of which are exacerbated by exposure to aspirin and other NSAIDs. Although the pathogenic mechanisms of AERD are not completely understood, repeated instances have shown intense eosinophilic infiltrations of upper and lower airway mucosa, and dysregulation of arachidonate metabolisms. Here, recent updates on the pathogenic mechanisms of chronic rhinosinusitis with nasal polyps in aspirin-exacerbated respiratory diseases are summarized. Recent findings Intense eosinophilic infiltration is closely related to the elevated production of cytokines and chemokines such as IL-5 and eotaxin. The response of local immunoglobulin E to staphylococcal enterotoxins contributes to eosinophilic inflammation in nasal polyp tissue. Other characteristics include the overproduction of cysteinyl leukotrienes and increased expression of cysteinyl leukotriene receptor-1, reduced production of prostaglandin E2, and the down-regulation of cyclooxygenase-2 and E-prostanoid receptor subtype-2. A recent gene expression profiling study has also suggested that periostin is the most up-regulated gene in the nasal polyp tissue of AERD patients. Summary Chronic rhinosinusitis with nasal polyps is a major comorbid condition of AERD patients that is closely associated with severe asthmatic symptoms. Significant pathologic findings in nasal polyp tissues include intense eosinophilic inflammation, which is caused by elevated production of eosinophil-related cytokines and chemokines, specific immunoglobulin E responses to staphylococcal enterotoxins, and altered arachidonic acid metabolism. This could affect the current treatments and methodologies that are used to control asthma, leading to a more severe and intractable AERD phenotype. Keywords aspirin hypersensitivity, asthma, chronic rhinosinusitis, nasal polyp
INTRODUCTION Aspirin-exacerbated respiratory disease (AERD) is characterized by hypersensitivity to aspirin and NSAIDs, asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) [1,2]. Together, these symptoms have come to be known as Samter’s triad [3]. Investigation into the natural progression of AERD has revealed that viral infection-related rhinitis was the first symptom observed in half of patients [4]. This persistent rhinitis appeared around the age of 30 years and was difficult to treat, leading to a loss of smell in 55% of those suffering. Two years after the development of rhinitis, the first symptoms of asthma began to appear. Intolerance to aspirin became evident 4 years later. Nasal polyps were also diagnosed around that time in 60% of individuals [4]. Thus, upper airway involvement manifested as
CRSwNP is an establishing condition for the diagnosis of AERD. Aspirin-exacerbated respiratory disease affects 10–20% of asthmatic patients and 8–26% of those diagnosed with CRSwNP [5 ,6 ]. The presence of aspirin and/or other NSAID-induced hypersensitivity in patients with CRSwNP is associated with a &
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a Department Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Hwaseong and bDepartment of Allergy and Clinical Immunology, Ajou University Hospital, Suwon, Korea
Correspondence to Professor Hae-Sim Park, MD, PhD, Department of Allergy and Clinical Immunology, Ajou University School of Medicine, San 5, Wonchondong, Youngtonggu, Suwon, Korea. Tel: +82 31 219 5196; e-mail: [email protected] Curr Opin Allergy Clin Immunol 2014, 14:1–6 DOI:10.1097/ACI.0000000000000021
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KEY POINTS CRSwNP is the most common comorbid condition of AERD. It is characterized by intense eosinophilic infiltration, leading to a need for more aggressive courses of medical treatments and surgical therapies. The pathogenesis of CRSwNP in AERD patients can be attributed to the overproduction of CysLTs with a downregulation of COX-2 and a consequential reduction of PGE2 production, and down-regulation of the EP2 receptor. Staphylococcal enterotoxins functioning as superantigens induce local and systemic IgE responses, leading to the intense eosinophilic inflammation seen in CRSwNP in AERD patients.
particularly severe, persistent, and treatment-resistant form of the disease [4]. In addition, the upper and lower airways of those diagnosed with AERD share similar pathogenic mechanisms to those seen in severe asthma, such as dense eosinophilic infiltration and dysregulation of arachidonic acid metabolism [5 ,6 ]. Recent advances in the study of the pathogenic mechanisms of CRSwNP that are associated with AERD will be summarized herein. &
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ALTERED ARACHIDONIC ACID METABOLISM Although the pathogenesis of AERD is not completely understood, the dysregulation of arachidonic acid metabolism has been demonstrated extensively. Aspirin and NSAIDs inhibit cyclooxygenase (COX) enzymes and divert arachidonic acid from membrane phospholipids to the lipoxygenase (LOX) pathway. This results in the overproduction of cysteinyl leukotrienes (CysLTs) and the reduction of prostaglandin E2 (PGE2) [7].
Lipoxygenase pathway Cysteinyl leukotrienes are potent proinflammatory mediators that can cause bronchoconstriction, eosinophilic airway inflammation, mucus hypersecretion, and increased vascular permeability [7]. The urinary leukotriene E4 (LTE4), the end metabolite of CysLTs, is reported to have a significantly higher baseline level in AERD patients when compared with those with aspirin-tolerant asthma (ATA) [8,9 ]. The levels of CysLTs increased even further when AERD patients were challenged with oral, intravenous, and intranasal aspirin treatments [9 ,10,11,12 ]. Moreover, it has been demonstrated &
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that CRSwNP patients with AERD show a significant increase in sinonasal tissue CysLTs levels when compared with ATA patients [13]. A large decrease in urinary LTE4 has also been reported after endoscopic sinus surgery in CRSwNP in AERD patients when compared with CRSwNP in ATA patients [8,9 ]. This is likely a consequence of the debulking of CysLTproducing cells in the sinus. Recent findings are in line with these results, in that CysLTs levels increase significantly in nasal lavage fluid (NLF) after aspirin nasal provocation tests in AERD patients compared with those with ATA. An increase in eosinophil cationic protein (ECP) was also seen at higher levels in AERD patients with CRSwNP than in those without it. This confirms that eosinophil activation and overproduction of CysLTs are key symptoms of exacerbation after aspirin exposure in AERD patients with CRSwNP [12 ]. The increased production of CysLTs in CRSwNP is associated with the increased expression of LTC4 synthase (LTC4S), the rate-limiting enzyme in CysLTs biosynthesis. Both CysLT production and LTC4S expression are significantly correlated with the level of the eosinophilic inflammation markers IL-5 and ECP in sinonasal tissues [13]. Two major CysLT receptors, CysLT receptor-1 (CysLTR1) and CysLT receptor-2 (CysLTR2), have been identified [14]. Nasal and bronchial mucosal biopsies from patients with allergic rhinitis and asthma show strong expression of CysLTR1 by neutrophils, eosinophils, macrophages, and mast cells [15,16]. In addition, higher expression of both CysLTR1 and CysLTR2 was noted in the mucosal tissue of CRSwNP in patients with AERD than in those without [17,18,19 ]. Three single-nucleotide polymorphisms in the promoter region of CYSLTR1 have been reported in AERD patients. They are believed to increase gene promoter activity, suggesting that these polymorphisms could modulate CYSLTR1 expression and contribute to the development of AERD [20]. These results imply that the intense eosinophilic infiltration that results from CysLT overproduction, and the increased expression of corresponding enzymes and their receptors, is a key factor in the pathogenic mechanisms of CRSwNP in AERD. Levels of lipoxin A4 (LXA4), an endogenous antiinflammatory eicosanoid generated by cell-to-cell interaction, have been reported to be lower in the tissue of CRSwNP in AERD patients compared with those from ATA patients [13]. A recent study has also reported that urinary levels of the epimer of LXA4 (15-epi-LXA4) were significantly lower in AERD patients compared with those with ATA and healthy controls. Urinary LTE4 levels were higher in AERD &
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Upper airways in aspirin-exacerbated respiratory disease Choi et al.
patients than those in ATA patients and control groups [21], indicating that the deficient regulation of anti-inflammatory arachidonic acid metabolites may contribute to the development and progression of CRSwNP in AERD, although additional supporting data are required.
Cyclooxygenase pathway Cyclooxygenase is an important enzyme for the biosynthesis of several PGEs and thromboxanes [22]. Two important COX isoenzymes in humans are COX-1 and COX-2. COX-1 is expressed constitutively in most tissues and produces the eicosanoids that are involved primarily in physiological regulation of homeostatic functions. COX-2, on the contrary, exists as an inducible form that can be up-regulated under inflammatory conditions [22]. Considering that CRSwNP is a chronic inflammatory disease of the nasal mucosa, whether associated with aspirin intolerance or not, alterations of the COX-2 pathway may be more relevant in determining disease causation. In fact, studies [13,19 ,23–26] have shown that COX-2 expression is down-regulated in the nasal polyps of patients with and without aspirin hypersensitivity. Reductions in the production of PGE2, expression of COX-2, and down-regulation of the E-prostanoid receptor subtype 2 (EP2) receptor have also been documented in the nasal polyp tissue of CRSwNP in AERD patients compared with CRSwNP in ATA patients [13,23]. The EP2 receptor is one of four PGE2 receptors, designated EP1 through EP4. Most of the anti-inflammatory effects of PGE2 are induced by stimulation of the EP2 receptor [27]. Therefore, lower expression of the COX-2 enzyme with consequent reduction of PGE2 production and lower expression of the EP2 receptor could intensify the inflammatory process seen in the nasal mucosa of CRSwNP, especially in AERD patients. &
Expressed and Secreted, which are able to induce their own differentiation and activation in an autocrine fashion [31–34]. In AERD patients, a significant correlation was found between higher IL-5 levels and the levels of CysLTs and ECP in nasal polyps and NLF [12 ,13]. Meanwhile, IL-5 levels seem to be inversely correlated with anti-inflammatory PGE2 levels [13]. Treatment with the anti-IL-5 monoclonal antibody, mepolizumab, could reduce nasal polyp size in patients with severe eosinophilic nasal polyposis [35]. These findings indicate that mediators, especially IL-5, can contribute to the development and intensity of eosinophilic inflammation in the CRSwNP tissue of AERD patients. Several studies [12 ,34] have reported increased expression of eotaxin in the CRSwNP tissue of AERD patients. Significantly higher levels of serum eotaxin-2 were reported in AERD patients compared with those in ATA patients [36]. The baseline levels of eotaxin-2 also tend to be higher in the NLF of AERD patients compared with ATA patients [12 ]. Thus, eotaxin-2 may be involved in the basal activation status of eosinophils in the upper airway mucosa of AERD patients. A recent proteomic analysis of NLF of AERD patients after aspirin nasal provocation tests showed significant up-regulation of apolipoprotein A1 (ApoA1), a2-macroglobulin (a2M), and ceruloplasmin [12 ]. This up-regulation was further increased in AERD patients with CRSwNP and significantly correlated with levels of CysLTs and ECP [12 ]. However, further study will be needed to elucidate exactly how these newly defined inflammatory mediators affect the eosinophilic inflammation seen in CRSwNP in AERD patients. The number of activated mast cells and T cells, especially Th2 cells, is higher in CRSwNP of AERD compared with those from ATA [32]. These mast cells are suggested to be a major source of CysLT production in NLF after exposure to aspirin [12 ]. Although the mechanisms underlying activation of mast cells after aspirin exposure are not known, these inflammatory cells contribute to the elevated levels of cytokines, including IL-5 and eicosanoids, which lead to intense and persistent eosinophilic inflammation in the CRSwNP tissue of AERD patients. &
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INFLAMMATORY CELLS AND CYTOKINES Chronic rhinosinusitis with nasal polyps is a chronic inflammatory disease of the mucous membranes in the nose and paranasal sinuses, characterized by an infiltration of eosinophils. The intensity of eosinophilic infiltration is regarded as a key histologic feature of CRSwNP found in AERD, compared with other types of nasal polyps [28,29]. The chronic intense eosinophilic inflammation seen in AERD patients can be explained by the increased level of ECP in their nasal polyp tissue [13,30] and the reduced apoptosis of eosinophils through the production of various cytokines and chemokines, including IL-5, granulocyte-macrophage colony- stimulating factor, eotaxin, and Regulated on Activation, Normal T
Staphylococcal enterotoxins in chronic rhinosinusitis with nasal polyps Recently, local or systemic immunological responses to staphylococcal enterotoxins have been suggested as having a role in the pathogenesis of CRSwNP [37 ]. In fact, staphylococcal colonization was identified in 64% of CRSwNP, a level twice that
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seen in CRS without nasal polyps. This frequency rises to 87% in patients also exhibiting AERD [37 ]. The incidence of specific IgE to staphylococcal enterotoxins in nasal polyp tissue is significantly higher than that in normal mucosa [38]. Moreover, specific IgE levels to staphylococcal enterotoxins in the nasal polyp tissue of AERD patients are significantly higher than those from ATA patients [30,39]. The levels of specific IgE to staphylococcal enterotoxins in nasal polyp tissue homogenate from AERD patients correlate with those of ECP and IL-5, indicating that the local IgE response to staphylococcal enterotoxins could drive eosinophilic activation in the nasal polyp tissues of AERD patients [30,39]. Although the underlying mechanism of activation of eosinophils in nasal polyps by staphylococcal enterotoxins is not clearly understood, staphylococcal enterotoxins acting as superantigens have been shown to induce the activation of Th2 cells and the release of Th2 cytokines, such as IL-4, IL-5, and IL-13, resulting in the development of eosinophilic inflammation which is characteristic of CRSwNP [40,41]. Recent reports have stated that the presence of serum-specific IgE to staphylococcal enterotoxins represents a high risk for the development of bronchial asthma and an even higher risk in patients with severe asthma. These results are independent of the presence of specific IgE to common inhalant allergens, implying that polyclonal IgE production to staphylococcal enterotoxins may play a role in the development of asthma, especially severe cases [42 ]. It has also been demonstrated that AERD patients with high levels of serum-specific IgE to staphylococcal enterotoxins had higher peripheral eosinophil counts and total serum IgE levels [43 ]. Furthermore, treatment with omalizumab could potentially reduce total nasal endoscopic polyp scores and symptoms in CRSwNP with asthma patients, regardless of any allergy, suggesting that anti-IgE therapy could functionally inhibit local IgE response in nasal polyp tissues and have a beneficial effect on the treatment of CRSwNP [44 ]. Taken together, staphylococcal superantigens may contribute substantially to eosinophil activation in the pathogenesis of CRSwNP in AERD via polyclonal T and B-cell activation. This induces skewing in the release of Th2 cytokines and polyclonal IgE production to staphylococcal enterotoxins. &
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THE RESULTS OF GENE EXPRESSION PROFILING IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS WITH ASPIRINEXACERBATED RESPIRATORY DISEASE Using genome-wide expression profiling, Stankovic et al. [45] reported recently that mesenchymal– 4
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epithelial transition (MET) factor, periostin (POSTN), and protein phosphatase1 regulatory subunit 9B (PP1R9B) were up-regulated, whereas prolactininduced protein (PIP) and zinc alpha2-glycoprotein (AZGP1) were down-regulated in nasal polyp tissue taken from CRS patients. Among these genes, only POSTN was up-regulated specifically in the CRSwNP tissue of AERD patients. Considering that eosinophils are the major inflammatory cells within the CRSwNP tissue of AERD patients, these results are comparable with a previous report that serum periostin levels are a significant biomarker of bronchial asthma, of which the concentration is positively correlated with the severity of eosinophilic airway inflammation [46]. Liu et al. [47] found increased expression of PIP and lactoferrin, and a deletion in malignant brain tumor protein 1 (DMBTP1) in CRSwNP in AERD patients, whereas Stankovic et al. [45] found decreased expression of these genes in a larger cohort of CRSwNP in AERD patients. These discrepant results may be attributed to use of different testing methodologies and ethnicities of test participants. Although the role of these genes has yet to be determined, it is speculated that they may play a role in immune function and eosinophil activation. On the contrary, some studies [48,49] of gene expression profiling of nasal polyp tissues in patients with CRSwNP showed the presence of genes encoding cytokines such as IL-5 and IL-17, which contribute to proinflammatory activity in asthma. Up-regulation of the IL-5 gene corresponds to the pathologic features of eosinophilic activation in CRSwNP tissue. Therefore, altered gene expression and the consequential increase in cytokine levels may cause intense eosinophilic infiltration, contributing to the pathogenesis of CRSwNP in AERD. A genome-wide association study [50 ] of the Korean population was recently performed in a relatively large cohort of AERD patients (117 AERD patients, 685 asthmatic patients without AERD). The HLA-DPB1 gene (rs1042151, Met105Val) showed the most significant association with susceptibility to AERD (P ¼ 5.11 10 – 7 ). This result supports previous findings that HLA-DPB10301 was significantly associated with the AERD phenotype in Korean and Polish populations [51,52]. In addition, the AERD patients with the HLA-DPB10301 gene had a higher prevalence of CRSwNP and lower pulmonary functions than those without this gene [53]. Thus, HLA-DPB1 gene polymorphisms may be a highly important genetic factor associated with the phenotype of CRSwNP and the more severe clinical features in AERD patients. &&
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Upper airways in aspirin-exacerbated respiratory disease Choi et al.
• Overproduction of CysLTs with increased expression of LTC4S and CysLTR1 • Reduced production of PGE2 with downexpression of COX-2 and EP2 receptor
ECP EDN ü Eosinophil ü Mast cell
HLA DPB1 polymorphism
Th2 cells
CRS W NP
Eosinophil
IL-5 Eotaxin
ü Th2 cells CysLTs
Staphylococcal superantigens
FIGURE 1. The pathogenic mechanisms of chronic rhinosinusitis with nasal polyps in aspirin exacerbated respiratory disease. COX-2, cyclooxygenase-2; CysLTs, cysteinyl leukotrienes; CysLTR1, cysteinyl leukotriene receptor-1; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EP2 receptor, E-prostanoid receptor subtype-2; LTC4S, leukotriene C4 synthase; PGE2, prostaglandin E2.
CONCLUSION Chronic rhinosinusitis with nasal polyps is a major comorbid condition of AERD. It has a great impact on asthma control and the frequency of symptom exacerbation. Intense eosinophilic inflammation exhibiting higher expression of related cytokines and chemokines, and the overproduction of CysLTs with increased expression of CysLT receptors, are both key features of CRSwNP that are present to greater degrees in AERD patients compared with those with ATA. Several mechanisms have been suggested in the pathogenesis of CRSwNP in AERD. Dysregulation of arachidonic acid metabolisms with reduction of anti-inflammatory mediators such as LXA4 and PGE2, and down-regulation of COX-2 and EP2 receptors were well noted. Specific IgE responses to staphylococcal enterotoxins are suggested to be involved in the eosinophil activation seen in CRSwNP in AERD patients. Genetic mechanisms have also been suggested to be causative of the pathogenesis of CRSwNP in AERD. The HLA DPB10301 allele has consistently demonstrated to be associated with a higher prevalence of CRSwNP in AERD (Fig. 1). Up-regulation of the POSTN and IL-5 genes in the nasal polyp tissues of CRSwNP in AERD patients has also been identified recently. Further investigations of the pathogenic mechanisms of CRSwNP are needed to improve the management of this condition. Acknowledgements None. Conflicts of interest The study was supported by a grant from the Korean Health Ministry and Welfare (A111218–11-PG01) and
the Basic Science Research Program through the National Research Foundation of Korea (NRF), as funded by the Ministry of Education, Science and Technology (2012R1A1A1012349). There are no conflicts of interest.
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35. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized antiIL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011; 128:989–995. 36. Palikhe NS, Kim SH, Cho BY, et al. Genetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease. Allergy 2010; 65:338–346. 37. Bachert C, Zhang N. Chronic rhinosinusitis and asthma: novel understanding & of the role of IgE ’above atopy’. J Intern Med 2012; 272:133–143. This article reviews an up-to-date knowledge of the role of specific IgE to staphylococcal enterotoxins in CRS and asthma. 38. Seiberling KA, Conley DB, Tripathi A, et al. Superantigens and chronic rhinosinusitis: detection of staphylococcal exotoxins in nasal polyps. Laryngoscope 2005; 115:1580–1585. 39. Pe´rez-Novo CA, Kowalski ML, Kuna P, et al. Aspirin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship. Int Arch Allergy Immunol 2004; 133:255–260. 40. Conley DB, Tripathi A, Seiberling KA, et al. Superantigens and chronic rhinosinusitis: skewing of T-cell receptor Vb-distributions in polyp-derived CD4 þ and CD8 þ T cells. Am J Rhinol 2006; 20:534–539. 41. Patou J, Gevaert P, Van Zele T, et al. Staphylococcus aureusenterotoxin B, protein A, and lipoteichoic acid stimulations in nasal polyps. J Allergy Clin Immunol 2008; 121:110–115. 42. 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 shows that enterotoxin IgE positivity was significantly greater in severe asthma than in normal controls irrespective of their atopic status, suggesting a new mechanism of superantigen-derived polyclonal IgE production in the pathogenesis of severe asthma, especially nonatopic asthma. 43. Yoo HS, Shin YS, Liu JN, et al. The role of staphylococcal superantigens in & aspirin-exacerbated respiratory disease. Int Arch Allergy Appl Immunol 2013; 162:340–345. This study further supports the role of sraphylococcal superantigens in activation of eosinophils in AERD patients showing that serum levels of specific IgE to staphylococcal enterotoxins were positively correlated with peripheral eosinophil counts in AERD. 44. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and & nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 2013; 131:110–116. Omalizumab is a treatment option in patients with NP and comorbid asthma, suggesting a possibility of the role of local tissue IgE including specific IgE to staphylococcal enterotoxins in NPs and asthma. 45. Stankovic KM, Goldsztein H, Reh DD, et al. Gene Expression profiling of nasal polypsassociated with chronic sinusitis and aspirin-sensitive asthma. Laryngoscope 2008; 118:881–889. 46. Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 2012; 130:647–654. 47. Liu Z, Kim J, Sypek JP, et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783–790. 48. Wang X, Dong Z, Zhu D-D, Guan B. Expression profile of immune-associated genes in nasal polyps. Ann Otol Rhinol Laryngol 2006; 115:450–456. 49. Figueiredo CR, Santos RP, Silva ID, Weckx LL. Microarray cDNA to identify inflammatory genes in nasal polyposis. Am J Rhinol 2007; 21: 231–235. 50. Park BL, Kim TH, Kim JH, et al. Genome-wide association study of aspirin&& exacerbated respiratory disease in a Korean population. Hum Genet 2013; 132:313–321. This GWAS study using a high-density BeadChip demonstrated HLA-DPB1 gene polymorphism as the most susceptible genetic factor in AERD in a Korean population, which confirmed the previous results that HLA DPB10301 was significantly associated with AERD in a Korean and a Polish population. 51. Choi JH, Lee KW, Oh HB, et al. HLA association in aspirin-intolerant asthma: DPB10301 as a strong marker in a Korean population. J Allergy Clin Immunol 2004; 113:562–564. 52. Dekker J, Nizankowska E, Schmitz-Schumann M, et al. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin Exp Allergy 1997; 27:574–577. 53. Lee HY, Lee JW, Lee KW, et al. The HLA allele marker for differentiating ASA hypersensitivity phenotypes. Allergy 2009; 64:1385–1387.
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An update on the pathogenesis of the upper airways in aspirin-exacerbated respiratory disease Jeong-Hee Choi a, Mi-Ae Kim b, and Hae-Sim Park b
Purpose of review The key features of aspirin-exacerbated respiratory diseases (AERDs) include chronic, severe asthma and a high prevalence (60–80%) of chronic rhinosinusitis with nasal polyps, all of which are exacerbated by exposure to aspirin and other NSAIDs. Although the pathogenic mechanisms of AERD are not completely understood, repeated instances have shown intense eosinophilic infiltrations of upper and lower airway mucosa, and dysregulation of arachidonate metabolisms. Here, recent updates on the pathogenic mechanisms of chronic rhinosinusitis with nasal polyps in aspirin-exacerbated respiratory diseases are summarized. Recent findings Intense eosinophilic infiltration is closely related to the elevated production of cytokines and chemokines such as IL-5 and eotaxin. The response of local immunoglobulin E to staphylococcal enterotoxins contributes to eosinophilic inflammation in nasal polyp tissue. Other characteristics include the overproduction of cysteinyl leukotrienes and increased expression of cysteinyl leukotriene receptor-1, reduced production of prostaglandin E2, and the down-regulation of cyclooxygenase-2 and E-prostanoid receptor subtype-2. A recent gene expression profiling study has also suggested that periostin is the most up-regulated gene in the nasal polyp tissue of AERD patients. Summary Chronic rhinosinusitis with nasal polyps is a major comorbid condition of AERD patients that is closely associated with severe asthmatic symptoms. Significant pathologic findings in nasal polyp tissues include intense eosinophilic inflammation, which is caused by elevated production of eosinophil-related cytokines and chemokines, specific immunoglobulin E responses to staphylococcal enterotoxins, and altered arachidonic acid metabolism. This could affect the current treatments and methodologies that are used to control asthma, leading to a more severe and intractable AERD phenotype. Keywords aspirin hypersensitivity, asthma, chronic rhinosinusitis, nasal polyp
INTRODUCTION Aspirin-exacerbated respiratory disease (AERD) is characterized by hypersensitivity to aspirin and NSAIDs, asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) [1,2]. Together, these symptoms have come to be known as Samter’s triad [3]. Investigation into the natural progression of AERD has revealed that viral infection-related rhinitis was the first symptom observed in half of patients [4]. This persistent rhinitis appeared around the age of 30 years and was difficult to treat, leading to a loss of smell in 55% of those suffering. Two years after the development of rhinitis, the first symptoms of asthma began to appear. Intolerance to aspirin became evident 4 years later. Nasal polyps were also diagnosed around that time in 60% of individuals [4]. Thus, upper airway involvement manifested as
CRSwNP is an establishing condition for the diagnosis of AERD. Aspirin-exacerbated respiratory disease affects 10–20% of asthmatic patients and 8–26% of those diagnosed with CRSwNP [5 ,6 ]. The presence of aspirin and/or other NSAID-induced hypersensitivity in patients with CRSwNP is associated with a &
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a Department Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Hwaseong and bDepartment of Allergy and Clinical Immunology, Ajou University Hospital, Suwon, Korea
Correspondence to Professor Hae-Sim Park, MD, PhD, Department of Allergy and Clinical Immunology, Ajou University School of Medicine, San 5, Wonchondong, Youngtonggu, Suwon, Korea. Tel: +82 31 219 5196; e-mail: [email protected] Curr Opin Allergy Clin Immunol 2014, 14:1–6 DOI:10.1097/ACI.0000000000000021
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KEY POINTS CRSwNP is the most common comorbid condition of AERD. It is characterized by intense eosinophilic infiltration, leading to a need for more aggressive courses of medical treatments and surgical therapies. The pathogenesis of CRSwNP in AERD patients can be attributed to the overproduction of CysLTs with a downregulation of COX-2 and a consequential reduction of PGE2 production, and down-regulation of the EP2 receptor. Staphylococcal enterotoxins functioning as superantigens induce local and systemic IgE responses, leading to the intense eosinophilic inflammation seen in CRSwNP in AERD patients.
particularly severe, persistent, and treatment-resistant form of the disease [4]. In addition, the upper and lower airways of those diagnosed with AERD share similar pathogenic mechanisms to those seen in severe asthma, such as dense eosinophilic infiltration and dysregulation of arachidonic acid metabolism [5 ,6 ]. Recent advances in the study of the pathogenic mechanisms of CRSwNP that are associated with AERD will be summarized herein. &
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ALTERED ARACHIDONIC ACID METABOLISM Although the pathogenesis of AERD is not completely understood, the dysregulation of arachidonic acid metabolism has been demonstrated extensively. Aspirin and NSAIDs inhibit cyclooxygenase (COX) enzymes and divert arachidonic acid from membrane phospholipids to the lipoxygenase (LOX) pathway. This results in the overproduction of cysteinyl leukotrienes (CysLTs) and the reduction of prostaglandin E2 (PGE2) [7].
Lipoxygenase pathway Cysteinyl leukotrienes are potent proinflammatory mediators that can cause bronchoconstriction, eosinophilic airway inflammation, mucus hypersecretion, and increased vascular permeability [7]. The urinary leukotriene E4 (LTE4), the end metabolite of CysLTs, is reported to have a significantly higher baseline level in AERD patients when compared with those with aspirin-tolerant asthma (ATA) [8,9 ]. The levels of CysLTs increased even further when AERD patients were challenged with oral, intravenous, and intranasal aspirin treatments [9 ,10,11,12 ]. Moreover, it has been demonstrated &
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that CRSwNP patients with AERD show a significant increase in sinonasal tissue CysLTs levels when compared with ATA patients [13]. A large decrease in urinary LTE4 has also been reported after endoscopic sinus surgery in CRSwNP in AERD patients when compared with CRSwNP in ATA patients [8,9 ]. This is likely a consequence of the debulking of CysLTproducing cells in the sinus. Recent findings are in line with these results, in that CysLTs levels increase significantly in nasal lavage fluid (NLF) after aspirin nasal provocation tests in AERD patients compared with those with ATA. An increase in eosinophil cationic protein (ECP) was also seen at higher levels in AERD patients with CRSwNP than in those without it. This confirms that eosinophil activation and overproduction of CysLTs are key symptoms of exacerbation after aspirin exposure in AERD patients with CRSwNP [12 ]. The increased production of CysLTs in CRSwNP is associated with the increased expression of LTC4 synthase (LTC4S), the rate-limiting enzyme in CysLTs biosynthesis. Both CysLT production and LTC4S expression are significantly correlated with the level of the eosinophilic inflammation markers IL-5 and ECP in sinonasal tissues [13]. Two major CysLT receptors, CysLT receptor-1 (CysLTR1) and CysLT receptor-2 (CysLTR2), have been identified [14]. Nasal and bronchial mucosal biopsies from patients with allergic rhinitis and asthma show strong expression of CysLTR1 by neutrophils, eosinophils, macrophages, and mast cells [15,16]. In addition, higher expression of both CysLTR1 and CysLTR2 was noted in the mucosal tissue of CRSwNP in patients with AERD than in those without [17,18,19 ]. Three single-nucleotide polymorphisms in the promoter region of CYSLTR1 have been reported in AERD patients. They are believed to increase gene promoter activity, suggesting that these polymorphisms could modulate CYSLTR1 expression and contribute to the development of AERD [20]. These results imply that the intense eosinophilic infiltration that results from CysLT overproduction, and the increased expression of corresponding enzymes and their receptors, is a key factor in the pathogenic mechanisms of CRSwNP in AERD. Levels of lipoxin A4 (LXA4), an endogenous antiinflammatory eicosanoid generated by cell-to-cell interaction, have been reported to be lower in the tissue of CRSwNP in AERD patients compared with those from ATA patients [13]. A recent study has also reported that urinary levels of the epimer of LXA4 (15-epi-LXA4) were significantly lower in AERD patients compared with those with ATA and healthy controls. Urinary LTE4 levels were higher in AERD &
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Upper airways in aspirin-exacerbated respiratory disease Choi et al.
patients than those in ATA patients and control groups [21], indicating that the deficient regulation of anti-inflammatory arachidonic acid metabolites may contribute to the development and progression of CRSwNP in AERD, although additional supporting data are required.
Cyclooxygenase pathway Cyclooxygenase is an important enzyme for the biosynthesis of several PGEs and thromboxanes [22]. Two important COX isoenzymes in humans are COX-1 and COX-2. COX-1 is expressed constitutively in most tissues and produces the eicosanoids that are involved primarily in physiological regulation of homeostatic functions. COX-2, on the contrary, exists as an inducible form that can be up-regulated under inflammatory conditions [22]. Considering that CRSwNP is a chronic inflammatory disease of the nasal mucosa, whether associated with aspirin intolerance or not, alterations of the COX-2 pathway may be more relevant in determining disease causation. In fact, studies [13,19 ,23–26] have shown that COX-2 expression is down-regulated in the nasal polyps of patients with and without aspirin hypersensitivity. Reductions in the production of PGE2, expression of COX-2, and down-regulation of the E-prostanoid receptor subtype 2 (EP2) receptor have also been documented in the nasal polyp tissue of CRSwNP in AERD patients compared with CRSwNP in ATA patients [13,23]. The EP2 receptor is one of four PGE2 receptors, designated EP1 through EP4. Most of the anti-inflammatory effects of PGE2 are induced by stimulation of the EP2 receptor [27]. Therefore, lower expression of the COX-2 enzyme with consequent reduction of PGE2 production and lower expression of the EP2 receptor could intensify the inflammatory process seen in the nasal mucosa of CRSwNP, especially in AERD patients. &
Expressed and Secreted, which are able to induce their own differentiation and activation in an autocrine fashion [31–34]. In AERD patients, a significant correlation was found between higher IL-5 levels and the levels of CysLTs and ECP in nasal polyps and NLF [12 ,13]. Meanwhile, IL-5 levels seem to be inversely correlated with anti-inflammatory PGE2 levels [13]. Treatment with the anti-IL-5 monoclonal antibody, mepolizumab, could reduce nasal polyp size in patients with severe eosinophilic nasal polyposis [35]. These findings indicate that mediators, especially IL-5, can contribute to the development and intensity of eosinophilic inflammation in the CRSwNP tissue of AERD patients. Several studies [12 ,34] have reported increased expression of eotaxin in the CRSwNP tissue of AERD patients. Significantly higher levels of serum eotaxin-2 were reported in AERD patients compared with those in ATA patients [36]. The baseline levels of eotaxin-2 also tend to be higher in the NLF of AERD patients compared with ATA patients [12 ]. Thus, eotaxin-2 may be involved in the basal activation status of eosinophils in the upper airway mucosa of AERD patients. A recent proteomic analysis of NLF of AERD patients after aspirin nasal provocation tests showed significant up-regulation of apolipoprotein A1 (ApoA1), a2-macroglobulin (a2M), and ceruloplasmin [12 ]. This up-regulation was further increased in AERD patients with CRSwNP and significantly correlated with levels of CysLTs and ECP [12 ]. However, further study will be needed to elucidate exactly how these newly defined inflammatory mediators affect the eosinophilic inflammation seen in CRSwNP in AERD patients. The number of activated mast cells and T cells, especially Th2 cells, is higher in CRSwNP of AERD compared with those from ATA [32]. These mast cells are suggested to be a major source of CysLT production in NLF after exposure to aspirin [12 ]. Although the mechanisms underlying activation of mast cells after aspirin exposure are not known, these inflammatory cells contribute to the elevated levels of cytokines, including IL-5 and eicosanoids, which lead to intense and persistent eosinophilic inflammation in the CRSwNP tissue of AERD patients. &
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INFLAMMATORY CELLS AND CYTOKINES Chronic rhinosinusitis with nasal polyps is a chronic inflammatory disease of the mucous membranes in the nose and paranasal sinuses, characterized by an infiltration of eosinophils. The intensity of eosinophilic infiltration is regarded as a key histologic feature of CRSwNP found in AERD, compared with other types of nasal polyps [28,29]. The chronic intense eosinophilic inflammation seen in AERD patients can be explained by the increased level of ECP in their nasal polyp tissue [13,30] and the reduced apoptosis of eosinophils through the production of various cytokines and chemokines, including IL-5, granulocyte-macrophage colony- stimulating factor, eotaxin, and Regulated on Activation, Normal T
Staphylococcal enterotoxins in chronic rhinosinusitis with nasal polyps Recently, local or systemic immunological responses to staphylococcal enterotoxins have been suggested as having a role in the pathogenesis of CRSwNP [37 ]. In fact, staphylococcal colonization was identified in 64% of CRSwNP, a level twice that
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seen in CRS without nasal polyps. This frequency rises to 87% in patients also exhibiting AERD [37 ]. The incidence of specific IgE to staphylococcal enterotoxins in nasal polyp tissue is significantly higher than that in normal mucosa [38]. Moreover, specific IgE levels to staphylococcal enterotoxins in the nasal polyp tissue of AERD patients are significantly higher than those from ATA patients [30,39]. The levels of specific IgE to staphylococcal enterotoxins in nasal polyp tissue homogenate from AERD patients correlate with those of ECP and IL-5, indicating that the local IgE response to staphylococcal enterotoxins could drive eosinophilic activation in the nasal polyp tissues of AERD patients [30,39]. Although the underlying mechanism of activation of eosinophils in nasal polyps by staphylococcal enterotoxins is not clearly understood, staphylococcal enterotoxins acting as superantigens have been shown to induce the activation of Th2 cells and the release of Th2 cytokines, such as IL-4, IL-5, and IL-13, resulting in the development of eosinophilic inflammation which is characteristic of CRSwNP [40,41]. Recent reports have stated that the presence of serum-specific IgE to staphylococcal enterotoxins represents a high risk for the development of bronchial asthma and an even higher risk in patients with severe asthma. These results are independent of the presence of specific IgE to common inhalant allergens, implying that polyclonal IgE production to staphylococcal enterotoxins may play a role in the development of asthma, especially severe cases [42 ]. It has also been demonstrated that AERD patients with high levels of serum-specific IgE to staphylococcal enterotoxins had higher peripheral eosinophil counts and total serum IgE levels [43 ]. Furthermore, treatment with omalizumab could potentially reduce total nasal endoscopic polyp scores and symptoms in CRSwNP with asthma patients, regardless of any allergy, suggesting that anti-IgE therapy could functionally inhibit local IgE response in nasal polyp tissues and have a beneficial effect on the treatment of CRSwNP [44 ]. Taken together, staphylococcal superantigens may contribute substantially to eosinophil activation in the pathogenesis of CRSwNP in AERD via polyclonal T and B-cell activation. This induces skewing in the release of Th2 cytokines and polyclonal IgE production to staphylococcal enterotoxins. &
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THE RESULTS OF GENE EXPRESSION PROFILING IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS WITH ASPIRINEXACERBATED RESPIRATORY DISEASE Using genome-wide expression profiling, Stankovic et al. [45] reported recently that mesenchymal– 4
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epithelial transition (MET) factor, periostin (POSTN), and protein phosphatase1 regulatory subunit 9B (PP1R9B) were up-regulated, whereas prolactininduced protein (PIP) and zinc alpha2-glycoprotein (AZGP1) were down-regulated in nasal polyp tissue taken from CRS patients. Among these genes, only POSTN was up-regulated specifically in the CRSwNP tissue of AERD patients. Considering that eosinophils are the major inflammatory cells within the CRSwNP tissue of AERD patients, these results are comparable with a previous report that serum periostin levels are a significant biomarker of bronchial asthma, of which the concentration is positively correlated with the severity of eosinophilic airway inflammation [46]. Liu et al. [47] found increased expression of PIP and lactoferrin, and a deletion in malignant brain tumor protein 1 (DMBTP1) in CRSwNP in AERD patients, whereas Stankovic et al. [45] found decreased expression of these genes in a larger cohort of CRSwNP in AERD patients. These discrepant results may be attributed to use of different testing methodologies and ethnicities of test participants. Although the role of these genes has yet to be determined, it is speculated that they may play a role in immune function and eosinophil activation. On the contrary, some studies [48,49] of gene expression profiling of nasal polyp tissues in patients with CRSwNP showed the presence of genes encoding cytokines such as IL-5 and IL-17, which contribute to proinflammatory activity in asthma. Up-regulation of the IL-5 gene corresponds to the pathologic features of eosinophilic activation in CRSwNP tissue. Therefore, altered gene expression and the consequential increase in cytokine levels may cause intense eosinophilic infiltration, contributing to the pathogenesis of CRSwNP in AERD. A genome-wide association study [50 ] of the Korean population was recently performed in a relatively large cohort of AERD patients (117 AERD patients, 685 asthmatic patients without AERD). The HLA-DPB1 gene (rs1042151, Met105Val) showed the most significant association with susceptibility to AERD (P ¼ 5.11 10 – 7 ). This result supports previous findings that HLA-DPB10301 was significantly associated with the AERD phenotype in Korean and Polish populations [51,52]. In addition, the AERD patients with the HLA-DPB10301 gene had a higher prevalence of CRSwNP and lower pulmonary functions than those without this gene [53]. Thus, HLA-DPB1 gene polymorphisms may be a highly important genetic factor associated with the phenotype of CRSwNP and the more severe clinical features in AERD patients. &&
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Upper airways in aspirin-exacerbated respiratory disease Choi et al.
• Overproduction of CysLTs with increased expression of LTC4S and CysLTR1 • Reduced production of PGE2 with downexpression of COX-2 and EP2 receptor
ECP EDN ü Eosinophil ü Mast cell
HLA DPB1 polymorphism
Th2 cells
CRS W NP
Eosinophil
IL-5 Eotaxin
ü Th2 cells CysLTs
Staphylococcal superantigens
FIGURE 1. The pathogenic mechanisms of chronic rhinosinusitis with nasal polyps in aspirin exacerbated respiratory disease. COX-2, cyclooxygenase-2; CysLTs, cysteinyl leukotrienes; CysLTR1, cysteinyl leukotriene receptor-1; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EP2 receptor, E-prostanoid receptor subtype-2; LTC4S, leukotriene C4 synthase; PGE2, prostaglandin E2.
CONCLUSION Chronic rhinosinusitis with nasal polyps is a major comorbid condition of AERD. It has a great impact on asthma control and the frequency of symptom exacerbation. Intense eosinophilic inflammation exhibiting higher expression of related cytokines and chemokines, and the overproduction of CysLTs with increased expression of CysLT receptors, are both key features of CRSwNP that are present to greater degrees in AERD patients compared with those with ATA. Several mechanisms have been suggested in the pathogenesis of CRSwNP in AERD. Dysregulation of arachidonic acid metabolisms with reduction of anti-inflammatory mediators such as LXA4 and PGE2, and down-regulation of COX-2 and EP2 receptors were well noted. Specific IgE responses to staphylococcal enterotoxins are suggested to be involved in the eosinophil activation seen in CRSwNP in AERD patients. Genetic mechanisms have also been suggested to be causative of the pathogenesis of CRSwNP in AERD. The HLA DPB10301 allele has consistently demonstrated to be associated with a higher prevalence of CRSwNP in AERD (Fig. 1). Up-regulation of the POSTN and IL-5 genes in the nasal polyp tissues of CRSwNP in AERD patients has also been identified recently. Further investigations of the pathogenic mechanisms of CRSwNP are needed to improve the management of this condition. Acknowledgements None. Conflicts of interest The study was supported by a grant from the Korean Health Ministry and Welfare (A111218–11-PG01) and
the Basic Science Research Program through the National Research Foundation of Korea (NRF), as funded by the Ministry of Education, Science and Technology (2012R1A1A1012349). There are no conflicts of interest.
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35. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized antiIL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011; 128:989–995. 36. Palikhe NS, Kim SH, Cho BY, et al. Genetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease. Allergy 2010; 65:338–346. 37. Bachert C, Zhang N. Chronic rhinosinusitis and asthma: novel understanding & of the role of IgE ’above atopy’. J Intern Med 2012; 272:133–143. This article reviews an up-to-date knowledge of the role of specific IgE to staphylococcal enterotoxins in CRS and asthma. 38. Seiberling KA, Conley DB, Tripathi A, et al. Superantigens and chronic rhinosinusitis: detection of staphylococcal exotoxins in nasal polyps. Laryngoscope 2005; 115:1580–1585. 39. Pe´rez-Novo CA, Kowalski ML, Kuna P, et al. Aspirin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship. Int Arch Allergy Immunol 2004; 133:255–260. 40. Conley DB, Tripathi A, Seiberling KA, et al. Superantigens and chronic rhinosinusitis: skewing of T-cell receptor Vb-distributions in polyp-derived CD4 þ and CD8 þ T cells. Am J Rhinol 2006; 20:534–539. 41. Patou J, Gevaert P, Van Zele T, et al. Staphylococcus aureusenterotoxin B, protein A, and lipoteichoic acid stimulations in nasal polyps. J Allergy Clin Immunol 2008; 121:110–115. 42. 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 shows that enterotoxin IgE positivity was significantly greater in severe asthma than in normal controls irrespective of their atopic status, suggesting a new mechanism of superantigen-derived polyclonal IgE production in the pathogenesis of severe asthma, especially nonatopic asthma. 43. Yoo HS, Shin YS, Liu JN, et al. The role of staphylococcal superantigens in & aspirin-exacerbated respiratory disease. Int Arch Allergy Appl Immunol 2013; 162:340–345. This study further supports the role of sraphylococcal superantigens in activation of eosinophils in AERD patients showing that serum levels of specific IgE to staphylococcal enterotoxins were positively correlated with peripheral eosinophil counts in AERD. 44. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and & nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 2013; 131:110–116. Omalizumab is a treatment option in patients with NP and comorbid asthma, suggesting a possibility of the role of local tissue IgE including specific IgE to staphylococcal enterotoxins in NPs and asthma. 45. Stankovic KM, Goldsztein H, Reh DD, et al. Gene Expression profiling of nasal polypsassociated with chronic sinusitis and aspirin-sensitive asthma. Laryngoscope 2008; 118:881–889. 46. Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 2012; 130:647–654. 47. Liu Z, Kim J, Sypek JP, et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783–790. 48. Wang X, Dong Z, Zhu D-D, Guan B. Expression profile of immune-associated genes in nasal polyps. Ann Otol Rhinol Laryngol 2006; 115:450–456. 49. Figueiredo CR, Santos RP, Silva ID, Weckx LL. Microarray cDNA to identify inflammatory genes in nasal polyposis. Am J Rhinol 2007; 21: 231–235. 50. Park BL, Kim TH, Kim JH, et al. Genome-wide association study of aspirin&& exacerbated respiratory disease in a Korean population. Hum Genet 2013; 132:313–321. This GWAS study using a high-density BeadChip demonstrated HLA-DPB1 gene polymorphism as the most susceptible genetic factor in AERD in a Korean population, which confirmed the previous results that HLA DPB10301 was significantly associated with AERD in a Korean and a Polish population. 51. Choi JH, Lee KW, Oh HB, et al. HLA association in aspirin-intolerant asthma: DPB10301 as a strong marker in a Korean population. J Allergy Clin Immunol 2004; 113:562–564. 52. Dekker J, Nizankowska E, Schmitz-Schumann M, et al. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin Exp Allergy 1997; 27:574–577. 53. Lee HY, Lee JW, Lee KW, et al. The HLA allele marker for differentiating ASA hypersensitivity phenotypes. Allergy 2009; 64:1385–1387.
Volume 14 Number 1 February 2014
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