Pathophysiology of Chronic Rhinosinusitis Peter Tomassen 1 , Thibaut Van Zele 1 , Nan Zhang 1 , Claudina Perez-Novo 1 , Nicholas Van Bruaene 1 , Philippe Gevaert 1 , and Claus Bachert 1 1 Upper Airways Research Laboratory, Department of Otorhinolaryngology and Logopaedic-Audiological Science, Ghent University, Ghent, Belgium Chronic rhinosinusitis (CRS), a disease presenting with chronic symptoms such as nasal obstruction, rhinorrhea, hyposmia and facial pain, is highly prevalent and has a considerable impact on quality of life and health care expenditures. The disease is characterized by chronic inflammation of the sinonasal mucosa and can present with nasal polyps. Current consensus classifies CRS into CRS with nasal polyps and CRS without nasal polyps. This review illustrates the diversity of pathophysiological observations in CRS and highlights selected etiological hypotheses. A wide spectrum of alterations is described regarding histopathology, pattern of T cells and inflam- matory effector cells, remodeling, immunoglobulin production, chemokine and eicosanoid production, and the role of microorgan- isms. The pathophysiological diversity observed in CRS seems to stand in contrast to its nonspecific clinical presentation, but is of the utmost importance in the development and application of highly individualized treatments. Identification of specific disease sub- groups and their etiologies is an important and challenging task for future research. Keywords: nasal polyps; sinusitis; superantigens; airway remodeling; enterotoxins The first contact of the respiratory system with the external environment happens in the nose, where air filtering, humidi- fication, and temperature regulation take place. Because of this intimate contact of the respiratory mucosa with a great range of pathogens and allergens, upper respiratory illnesses are among the most frequent diseases in humans. Chronic rhinosinusitis (CRS) is often described as a chronic inflammatory condition of the sinonasal mucosa, but the syndrome is actually defined by its clinical presentation rather than by markers of inflammation. The disease has a considerable impact on quality of life and health care expenses (1–3), and high prevalences of up to 19.7% have been reported in Europe (4). Despite great advances in the elucidation of its pathophysiology, the exact etiology of chronic inflammatory conditions of the nose and sinuses is still largely unknown. It is of the utmost importance to have an etiopatho- physiological understanding of the disease, as this has already proven to provide new therapeutic insights (5). This review illustrates the diversity of pathological observations in chronic rhinosinusitis, and highlights some etiological hypotheses. DEFINITION OF CHRONIC SINUS DISEASE Clinicians and researchers need to adequately define the concept of rhinosinusitis, mainly to improve the comparability between studies and to facilitate evidence-based clinical prac- tice. A number of guidelines and consensus documents have been published to define diagnostic criteria (6–8). Although the terms rhinitis, sinusitis, and rhinosinusitis semantically implicate an inflammation of an anatomically well-defined type of tissue, in practice these terms are now used in a syndromal context, to describe constellations of sinonasal symptoms, and no assump- tions about etiology are thus made. Rhinosinusitis (formerly sinusitis) is defined on the basis of symptoms such as nasal obstruction or stuffiness, facial pain or pressure, anterior or posterior mucopurulent rhinorrhea, and hyposmia. This defini- tion stands in contrast to rhinitis, which is defined mainly as nasal obstruction, sneezing, nasal itching, and watery rhinor- rhea. ‘‘Sinusitis’’ is in current guidelines replaced by the term ‘‘rhinosinusitis,’’ given the observation that the nasal mucosa is a continuum with the sinus mucosa and that nasal symptoms are prevalent in patients with sinus inflammation. This concept has been supported by findings indicating that the inflammatory changes in ethmoidal mucosa of patients with CRS are reflected in the inferior turbinate mucosa (9). Chronic rhinosinusitis is defined as the presence of the previously described symptoms during more than 12 weeks/year. Chronic rhinosinusitis is often taken as an umbrella term for a heterogeneous group of sinus diseases, as they all share a common pattern of symptoms. However, nasal polyps can easily be discerned on nasal endoscopy, and these patients report less facial pain and more olfactory dysfunction and nasal obstruction, and have higher total symptom scores (10–13). There have been numerous attempts to classify chronic sinus disease regarding pathophysiological and clinical properties. Current consensus differentiates CRS with nasal polyps (CRSwNP) from CRS without nasal polyps (CRS sine NP, CRSsNP) as subgroups of CRS. Although this concept is sup- ported by differences in the inflammatory profile (10), it is not clear whether these types represent etiopathogenetically different entities. Whereas some features indistinguishably hallmark nasal polyposis, other properties of CRSwNP are also found in CRSsNP to a lesser extent. Furthermore, evidence indicates considerable variation within the CRSwNP subgroup (14). REMARKABLE DIVERSITY IN IMMUNOLOGICAL CHANGES CRSsNP is characterized by fibrosis, basement membrane thickening, goblet cell hyperplasia, subepithelial edema, and mononuclear cell infiltration, whereas CRSwNP is character- ized by an intense edematous stroma with albumin deposition, formation of pseudocysts, and subepithelial and perivascular inflammatory cell infiltration (15). A long-standing misconcep- tion is that CRS is a disease uniformly dominated by eosino- phils, as evidence supporting a wide diversity of inflammatory phenotypes is accumulating. Eosinophilic inflammation is a key feature of white patients with CRSwNP, as demonstrated by marked infiltration of EG2-positive (ECP secreting) eosinophils and high concentrations of eosinophilic cationic protein (ECP) (10, 15, 16). Furthermore, cytokines regulating eosinophils such as IL-5, eotaxin, and RANTES (regulated on activation, nor- mal T-cell expressed and secreted) are involved in the tissue (Received in original form May 19, 2010; accepted in final form July 13, 2010) Supported by grants to Claus Bachert from the Flemish Scientific Research Board FWO (nos. A12/5-HB-KH3 and G.0436.04), the Global Allergy and Asthma European Network (GA 2 LEN, Sixth EU Framework program for research no. FOOD-CT-2004–506378), and the Interuniversity Attraction Poles Program- Belgian State Science Policy (no. IAP P6/35). Correspondence and requests for reprints should be addressed to Claus Bachert, M.D., Ph.D., De Pintelaan 185, 9000 Ghent, Belgium. E-mail: claus.bachert@ ugent.be Proc Am Thorac Soc Vol 8. pp 115–120, 2011 DOI: 10.1513/pats.201005-036RN Internet address: www.atsjournals.org
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pats201005036rn 115..120Peter Tomassen1, Thibaut Van Zele1, Nan Zhang1, Claudina Perez-Novo1, Nicholas Van Bruaene1, Philippe Gevaert1, and Claus Bachert1
1Upper Airways Research Laboratory, Department of Otorhinolaryngology and Logopaedic-Audiological Science, Ghent University, Ghent, Belgium
Chronic rhinosinusitis (CRS), a disease presenting with chronic symptomssuch asnasal obstruction, rhinorrhea,hyposmiaand facial pain, is highly prevalent and has a considerable impact on quality of life and health care expenditures. The disease is characterized by chronic inflammation of the sinonasal mucosa and can present with nasal polyps. Current consensus classifies CRS into CRS with nasal polyps and CRS without nasal polyps. This review illustrates the diversity of pathophysiological observations in CRS and highlights selected etiological hypotheses. A wide spectrum of alterations is described regarding histopathology, pattern of T cells and inflam- matory effector cells, remodeling, immunoglobulin production, chemokine and eicosanoid production, and the role of microorgan- isms. The pathophysiological diversity observed in CRS seems to stand in contrast to its nonspecific clinical presentation, but is of the utmost importance in the development and application of highly individualized treatments. Identification of specific disease sub- groups and their etiologies is an important and challenging task for future research.
Keywords: nasal polyps; sinusitis; superantigens; airway remodeling; enterotoxins
The first contact of the respiratory system with the external environment happens in the nose, where air filtering, humidi- fication, and temperature regulation take place. Because of this intimate contact of the respiratory mucosa with a great range of pathogens and allergens, upper respiratory illnesses are among the most frequent diseases in humans. Chronic rhinosinusitis (CRS) is often described as a chronic inflammatory condition of the sinonasal mucosa, but the syndrome is actually defined by its clinical presentation rather than by markers of inflammation. The disease has a considerable impact on quality of life and health care expenses (1–3), and high prevalences of up to 19.7% have been reported in Europe (4). Despite great advances in the elucidation of its pathophysiology, the exact etiology of chronic inflammatory conditions of the nose and sinuses is still largely unknown. It is of the utmost importance to have an etiopatho- physiological understanding of the disease, as this has already proven to provide new therapeutic insights (5). This review illustrates the diversity of pathological observations in chronic rhinosinusitis, and highlights some etiological hypotheses.
DEFINITION OF CHRONIC SINUS DISEASE
Clinicians and researchers need to adequately define the concept of rhinosinusitis, mainly to improve the comparability
between studies and to facilitate evidence-based clinical prac- tice. A number of guidelines and consensus documents have been published to define diagnostic criteria (6–8). Although the terms rhinitis, sinusitis, and rhinosinusitis semantically implicate an inflammation of an anatomically well-defined type of tissue, in practice these terms are now used in a syndromal context, to describe constellations of sinonasal symptoms, and no assump- tions about etiology are thus made. Rhinosinusitis (formerly sinusitis) is defined on the basis of symptoms such as nasal obstruction or stuffiness, facial pain or pressure, anterior or posterior mucopurulent rhinorrhea, and hyposmia. This defini- tion stands in contrast to rhinitis, which is defined mainly as nasal obstruction, sneezing, nasal itching, and watery rhinor- rhea. ‘‘Sinusitis’’ is in current guidelines replaced by the term ‘‘rhinosinusitis,’’ given the observation that the nasal mucosa is a continuum with the sinus mucosa and that nasal symptoms are prevalent in patients with sinus inflammation. This concept has been supported by findings indicating that the inflammatory changes in ethmoidal mucosa of patients with CRS are reflected in the inferior turbinate mucosa (9). Chronic rhinosinusitis is defined as the presence of the previously described symptoms during more than 12 weeks/year.
Chronic rhinosinusitis is often taken as an umbrella term for a heterogeneous group of sinus diseases, as they all share a common pattern of symptoms. However, nasal polyps can easily be discerned on nasal endoscopy, and these patients report less facial pain and more olfactory dysfunction and nasal obstruction, and have higher total symptom scores (10–13). There have been numerous attempts to classify chronic sinus disease regarding pathophysiological and clinical properties. Current consensus differentiates CRS with nasal polyps (CRSwNP) from CRS without nasal polyps (CRS sine NP, CRSsNP) as subgroups of CRS. Although this concept is sup- ported by differences in the inflammatory profile (10), it is not clear whether these types represent etiopathogenetically different entities. Whereas some features indistinguishably hallmark nasal polyposis, other properties of CRSwNP are also found in CRSsNP to a lesser extent. Furthermore, evidence indicates considerable variation within the CRSwNP subgroup (14).
REMARKABLE DIVERSITY IN IMMUNOLOGICAL CHANGES
CRSsNP is characterized by fibrosis, basement membrane thickening, goblet cell hyperplasia, subepithelial edema, and mononuclear cell infiltration, whereas CRSwNP is character- ized by an intense edematous stroma with albumin deposition, formation of pseudocysts, and subepithelial and perivascular inflammatory cell infiltration (15). A long-standing misconcep- tion is that CRS is a disease uniformly dominated by eosino- phils, as evidence supporting a wide diversity of inflammatory phenotypes is accumulating. Eosinophilic inflammation is a key feature of white patients with CRSwNP, as demonstrated by marked infiltration of EG2-positive (ECP secreting) eosinophils and high concentrations of eosinophilic cationic protein (ECP) (10, 15, 16). Furthermore, cytokines regulating eosinophils such as IL-5, eotaxin, and RANTES (regulated on activation, nor- mal T-cell expressed and secreted) are involved in the tissue
(Received in original form May 19, 2010; accepted in final form July 13, 2010)
Supported by grants to Claus Bachert from the Flemish Scientific Research Board
FWO (nos. A12/5-HB-KH3 and G.0436.04), the Global Allergy and Asthma
European Network (GA2LEN, Sixth EU Framework program for research no.
FOOD-CT-2004–506378), and the Interuniversity Attraction Poles Program-
Belgian State Science Policy (no. IAP P6/35).
Correspondence and requests for reprints should be addressed to Claus Bachert,
M.D., Ph.D., De Pintelaan 185, 9000 Ghent, Belgium. E-mail: claus.bachert@
ugent.be
Proc Am Thorac Soc Vol 8. pp 115–120, 2011 DOI: 10.1513/pats.201005-036RN Internet address: www.atsjournals.org
eosinophilia of nasal polyps. Although eosinophilic infiltration and activation is also present in CRSsNP, this is significantly less pronounced than in CRSwNP. However, myeloperoxidase- staining cells, and myeloperoxidase and IL-8 concentrations, are increased in CRSsNP and nasal polyps, indicating that neutrophils are also involved in nasal polyp pathogenesis.
Of interest, it has been demonstrated that nasal polyps from southern Chinese patients do not share the inflammatory pat- tern of polyps in white patients, as they were characterized by neutrophil infiltration but lacked increases in ECP, eotaxin, immunoglobulin E (IgE), and IL-5 as well as GATA-3 (14, 17). As these neutrophilic polyps are clinically and morphologically indistinguishable from other polyps, this indicates that eosino- philic inflammation is not essential for polyp formation. Further evidence is found in nasal polyps from patients with cystic fibrosis, which show marked neutrophilic inflammation greatly surpassing any eosinophilic marker (10, 18).
Activated T lymphocyte infiltration occurs in all subtypes of chronic sinus disease, especially in nasal polyposis; however, different T-lymphocyte subsets contribute to it. As indicated by different cytokine signals, namely IFN-g (helper T type 1 [Th1] related) and IL-5 (a helper T type 2 [Th2] cytokine), the Th1/ Th2 ratio characterizes CRSsNP as a Th1-polarized disease, whereas CRSwNP reveals a Th2 polarization (10). IL-5 plays a central role in the activation and increased survival of eosinophils in the nasal polyps of white individuals(19). Low transforming growth factor (TGF)-b1 levels in nasal polyps have been related to decreased T-regulatory cell function, as CRSwNP shows decreased levels of forkhead box protein P3 (FOXP3) expression (20). Together with increased expression of T-bet (Th1-specific) and GATA-3 (Th2-specific), this in- dicates deficient T-regulatory function in CRSwNP, which is not observed in CRSsNP. Chinese, predominantly neutrophilic polyps share the down-regulation of FOXP3 and TGF-b1 with those of white individuals; however, a mixed Th1 and Th17 pattern was observed in this group, with significantly lower GATA-3 expression and higher IL-17 concentrations compared with the polyps of white individuals. Increased levels of IL-17 expression have previously been described in nasal polyposis (21) and orchestrate a neutrophilic inflammation.
EXTRACELLULAR MATRIX REMODELING: A CONSERVED MECHANISM OF DISEASE
Striking differences exist in the histological appearance of chronic sinus disease: nasal polyps typically consist of albumin accumu- lation and edema formation, whereas CRSsNP is marked by fibrosis. This has been demonstrated by picrosirius red staining, which indicated loose connective tissue and a low collagen con- tent in CRSwNP, but excessive production of thick collagen fibers in CRSsNP (22).
TGF-b plays a crucial role in remodeling processes in the airway by the attraction and induction of proliferation of fibroblasts, and the up-regulation of extracellular matrix (ECM) synthesis. Increases in TGF-b1 protein and mRNA have been measured repeatedly in CRSsNP, in contrast to decreases or lack of increases in CRSwNP (10, 20, 22, 23). In contrast, TGF-b2 is increased in both CRSsNP and CRSwNP. Furthermore, TGF-b receptor I and III (TGF-bRI and TGF- bRIII) mRNA expression and the number of pSmad 2– positive cells were increased in CRSsNP, in contrast with decreased TGF-bRII mRNA, TGF-bRIII and pSmad 2 cells in CRSwNP. These results confirm the up-regulation of the TGF-b signaling pathway in CRSsNP in contrast with its down-regulation in CRSwNP. Of interest, these results were confirmed in a Chinese population (24), indicating that TGF-
b1 and its signaling may be a well-conserved key marker for CRS differentiation.
Remodeling is a dynamic process in both health and disease, balancing ECM production and degradation. ECM breakdown is regulated mainly by a family of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloprotei- nases (TIMPs). In sinus disease, differing results and a multitude of MMP subtypes make it difficult to interpret data. In CRSsNP, levels of MMP-9 (gelatinase B) and its inhibitor, TIMP-1, are increased. Findings of increased concentrations of MMP-9 in nasal polyps, but not of TIMP-1, suggest that the MMP-9/TIMP-1 balance is associated with ECM degradation in CRSwNP (24– 27). Again, as for TGF-b1, results in a Chinese population were analogous to those in a white population. Moreover, MMP-9 was found to be involved in wound healing and predicts poor healing after sinus surgery (28). This is illustrated by the observation that doxycycline-releasing stents, placed in the frontal recess, signif- icantly lowered MMP-9 concentrations and were associated with improved postoperative healing (29). In contrast, the roles of MMP-2 and MMP-7 are less clear. MMP-2 may be up-regulated in nasal polyp tissue (30, 31), whereas other studies could not detect changes in MMP-2 concentrations (24, 32). MMP-7 can be found up-regulated mainly in nasal polyps (26) but also in CRSsNP (30); however, in CRSsNP, the metalloproteinase is counteracted again by TIMPs. More systematic well-designed studies are underway, relating different MMPs to the phenotype of disease (33).
SUPERANTIGEN HYPOTHESIS IN THE PATHOGENESIS OF NASAL POLYPOSIS
The discovery of IgE antibodies to Staphylococcus aureus enterotoxins A and B in nasal polyp tissue homogenates (34) indicated that these bacterial superantigens could be involved in the pathogenesis of nasal polyposis. Staphylococcus aureus is a frequent colonizer of the nose, with an average persistent colonization rate in 20–30% of individuals (35). Although S. aureus can be isolated frequently in acute and chronic rhinosi- nusitis, a disease-modifying role for its presence has never been proven previously. S. aureus has been isolated at comparable rates in control subjects and patients with CRSsNP (36, 37). In nasal swab cultures from patients with CRSwNP, higher S. aureus colonization rates have been observed compared with control patients and patients with CRSsNP, with even higher rates in asthmatic and aspirin-intolerant patients (38–40), although other studies could not demonstrate increased colonization rates (41).
Although S. aureus has traditionally been regarded as an extracellular pathogen, there is increasing evidence that it has the ability to invade and survive in nonphagocytic eukaryotic cells such as keratinocytes and respiratory epithelial cells (42). An intracellular reservoir of S. aureus in patients with CRS has been shown by confocal immunofluorescence microscopy in nasal epithelial cells, mucous gland cells, myofibroblasts, and CD45-positive phagocytes (42, 43). An increased presence of intracellular S. aureus has also been detected by peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) in the nasal polyps of an aspirin-sensitive subgroup (44) and later also in the CRSwNP group in general, but not in the CRSsNP group (45).
S. aureus secretes enterotoxins (SAEs), small proteins able to mount a massive inflammatory reaction resulting from a polyclonal activation of T and B lymphocytes, independent of a specific adaptive immune response, a unique interaction for which they are known as superantigens, as first described by Marrack and Kappler in 1990 (46). SAEs directly activate T cells by bridging the major histocompatibility (MHC) class II molecule with the T-cell receptor in a nonspecific way, without
116 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 8 2011
being processed by antigen-presenting cells (47). Indirect evi- dence for the involvement of these superantigens came from reports showing the presence of immunoglobulin E specific to staphylococcal enterotoxins (SAE-IgE) in subgroups of up to 50% of patients with polyps (34, 38, 39). The colonization rates always exceeded the SAE-IgE rates, indicating that coloniza- tion may not necessarily lead to the generation of an IgE response. Nasal polyps positive for SAE-IgE have increased concentrations of eosinophils, IgE, ECP, eotaxin, and IL-5, and these patients have more asthma and aspirin-exacerbated re- spiratory disease. These results suggest that a superantigen action is related to the hallmark eosinophilic pathology of nasal polyps. SAE-IgE was previously also detected in a small fraction of control subjects and patients with CRSsNP (38, 48); however, these findings are inconsistent with a Global Allergy and Asthma European Network (Ga2len) case–control study (our unpublished data).
Although the presence of IgE directed to SAE is indirect proof of superantigen involvement, direct demonstration of superantigen presence by ELISA has been demonstrated by Seiberling and colleagues (49), who detected common staphy- lococcal toxins (staphylococcal enterotoxin A [SEA], SEB, SEC1–SEC3, SED, toxic shock syndrome toxin [TSST]-1) in 48% of patients with polyps and in 7.7% of patients with CRSsNP. In a study of Chinese patients with sinus disease, the same superantigens were detected by ELISA in 12 of 22 polyps, compared with none in patients with CRSsNP or control subjects (50). On interaction with the T-cell receptor, staphylo- coccal superantigens show specificity for one or more Vb
subdomains of the T cell receptor, expanding specific T-cell populations and creating a superantigen-specific Vb signature (51). In several studies, ‘‘skewing’’ of the T cell receptor rep- ertoire with a signature characteristic for SAE has been shown in nasal polyps by flow cytometry (52–55), supporting the hypothesis that staphylococcal enterotoxins exert their effect in nasal polyps via the superantigen mechanism.
In an ex vivo study (56), nasal polyp and inferior turbinate fragments were suspended in culture medium and stimulated with SEB and staphylococcal protein A (SpA) for 30 minutes and 24 hours. Spontaneous release of IL-5, IL-13, tumor necrosis factor- a, and IL-10 was significantly and substantially greater in polyps than in control tissue. Twenty-four–hour stimulation with SEB caused a significant increase in Th1 and Th2 cytokines (IFN-g, IL- 2, IL-4, IL-5, IL-10, IL-13) in inferior turbinates and to a greater extent in polyp tissue. By calculating the ratio of the increase in polyps to the increase in control tissue it became apparent that the increase in cytokine production was due predominantly to Th2 cytokines (IL-4, IL-5) but that T-regulatory cytokine pro- duction (IL-10 and TGF-b) was disfavored by SEB stimulation. This study clearly confirmed that SEB can polarize mucosal inflammation to a Th2 pattern.
IMMUNOGLOBULIN PRODUCTION IN NASAL POLYPOSIS
The presence of IgE in tissue is another hallmark of CRSwNP. By detailed analysis of the pattern of increased IgE in nasal polyps and in serum, three groups of nasal polyps can be discerned (34, 39): (1) a group with no detectable specific IgE and low total IgE, (2) a group with increased concentrations of total IgE and the presence of selected specific IgE antibodies to aeroallergens, corresponding to those found in serum and to skin prick test positivity, and (3) a group with a polyclonal pat- tern of IgE expression with specific IgE to a majority of allergens and increased total IgE, reflecting only partially the serum IgE response and independent of skin prick test positiv-
ity. SAE-IgE is almost exclusively found in the polyclonal group.
Although extravasation of serum proteins has been shown in nasal polyps (15), there is indirect evidence of local production of IgE rather than local reflection of systemic production. Total IgE and SAE-IgE concentrations were in all cases higher in polyp tissue compared with serum (39); SAE-IgE may be de- tected in the serum of patients with polyps, unrelated to atopic status, especially when asthma coexists (57, 58). Moreover, the IgE/albumin ratios in polyp tissue and serum were dissociated, and specific IgE antibodies in polyp tissue showed only a partial relation to serum IgE antibodies, indicating that tissue IgE is, rather, the result of local IgE production than of extravasation (39). Lymphoid aggregations and lymphoid follicular structures could be shown in nasal polyps by immunohistochemistry, supporting the hypothesis of local production of polyclonal IgE. Further evidence is pending, showing the presence of a germinal center reaction, receptor revision, and immunoglobu- lin class switching in nasal polyp tissue (59). Furthermore, the immunoglobulin production is not limited to IgE: increased local concentrations of IgA and IgG but not of IgM have been reported in nasal polyps, and the IgG4 subclass is specifically linked to SAE-IgE–positive polyps (60).
It has been shown that nasal symptoms and markers of inflammation did not increase in relation to seasonal allergen exposure even in ragweed-sensitive patients with nasal polyps, and nasal provocation was largely unsuccessful in patients with nasal polyps (61). A polyclonal IgE pattern in nasal polyps may, however, cause a permanent degranulation of mast cells by conventional aeroallergens and superantigens, maintaining polyp growth, but not giving rise to acute allergic symptoms. This hypothesis needs further study, but may be of the utmost im- portance in also explaining similar mechanisms in nonatopic but IgE-positive asthma.
CHEMOKINES AND ADHESION MOLECULES
Recruitment of inflammatory cells is a paramount property of the immune reaction and is regulated by vascular adhesion molecules and chemokines. CC chemokines eotaxin-1, -2, and -3 preferentially attract and activate eosinophils via the CCR-3 receptor. Nasal polyp fibroblasts are able to produce eotaxins after stimulation with LPS, IL-1b, and tumor necrosis factor-a (62). Increased production of eotaxins and RANTES has repeatedly been observed in CRSwNP (63–65), and may be important in promoting the local chemotaxis of eosinophils. Moreover, increased staining for vascular cell adhesion mole- cule (VCAM)-1 has been described in nasal polyps (63, 66, 67), and correlates with tissue eosinophilia, suggesting a role for VCAM-1 in eosinophil extravasation in nasal polyps.
Increased concentrations of the neutrophil attractant and activator IL-8 have been detected in tissue and nasal lavage fluid of patients with CRSsNP and to a greater extent in CRSwNP tissue (10, 68). Production of CXC chemokines IL-8 and growth- related oncogene-a (GRO-a) has been shown to be induced by Staphylococcus epidermidis supernatants in cultured epithelial cells from nasal polyps and healthy control inferior turbinates (69); however, SEB was not able to stimulate IL-8 production in nasal polyp and inferior turbinate tissue fragments (56). Macro- lide therapy has the ability to reduce IL-8 levels and neutrophil recruitment, providing therapeutic opportunities in selected patients (70). Stimulation of cultured human nasal epithelial cells with staphylococcal superantigen SEB leads to the pro- duction of interferon-inducible protein (IP)-10, monokine in- duced by IFN-g (MIG), granulocyte colony-stimulating factor (G-CSF), RANTES, and monocyte chemoattractant protein-1
Tomassen, Van Zele, Zhang, et al.: Pathophysiology of CRS 117
(MCP-1), but not of IL-8 (71). As the supernatants increased neutrophil chemotaxis and increased eosinophil survival, these results point to the importance of the epithelium in the orches- tration of granulocyte-dominated inflammation.
EICOSANOID METABOLISM AND ASPIRIN SENSITIVITY
Nasal polyposis is frequently associated with asthma and…
1Upper Airways Research Laboratory, Department of Otorhinolaryngology and Logopaedic-Audiological Science, Ghent University, Ghent, Belgium
Chronic rhinosinusitis (CRS), a disease presenting with chronic symptomssuch asnasal obstruction, rhinorrhea,hyposmiaand facial pain, is highly prevalent and has a considerable impact on quality of life and health care expenditures. The disease is characterized by chronic inflammation of the sinonasal mucosa and can present with nasal polyps. Current consensus classifies CRS into CRS with nasal polyps and CRS without nasal polyps. This review illustrates the diversity of pathophysiological observations in CRS and highlights selected etiological hypotheses. A wide spectrum of alterations is described regarding histopathology, pattern of T cells and inflam- matory effector cells, remodeling, immunoglobulin production, chemokine and eicosanoid production, and the role of microorgan- isms. The pathophysiological diversity observed in CRS seems to stand in contrast to its nonspecific clinical presentation, but is of the utmost importance in the development and application of highly individualized treatments. Identification of specific disease sub- groups and their etiologies is an important and challenging task for future research.
Keywords: nasal polyps; sinusitis; superantigens; airway remodeling; enterotoxins
The first contact of the respiratory system with the external environment happens in the nose, where air filtering, humidi- fication, and temperature regulation take place. Because of this intimate contact of the respiratory mucosa with a great range of pathogens and allergens, upper respiratory illnesses are among the most frequent diseases in humans. Chronic rhinosinusitis (CRS) is often described as a chronic inflammatory condition of the sinonasal mucosa, but the syndrome is actually defined by its clinical presentation rather than by markers of inflammation. The disease has a considerable impact on quality of life and health care expenses (1–3), and high prevalences of up to 19.7% have been reported in Europe (4). Despite great advances in the elucidation of its pathophysiology, the exact etiology of chronic inflammatory conditions of the nose and sinuses is still largely unknown. It is of the utmost importance to have an etiopatho- physiological understanding of the disease, as this has already proven to provide new therapeutic insights (5). This review illustrates the diversity of pathological observations in chronic rhinosinusitis, and highlights some etiological hypotheses.
DEFINITION OF CHRONIC SINUS DISEASE
Clinicians and researchers need to adequately define the concept of rhinosinusitis, mainly to improve the comparability
between studies and to facilitate evidence-based clinical prac- tice. A number of guidelines and consensus documents have been published to define diagnostic criteria (6–8). Although the terms rhinitis, sinusitis, and rhinosinusitis semantically implicate an inflammation of an anatomically well-defined type of tissue, in practice these terms are now used in a syndromal context, to describe constellations of sinonasal symptoms, and no assump- tions about etiology are thus made. Rhinosinusitis (formerly sinusitis) is defined on the basis of symptoms such as nasal obstruction or stuffiness, facial pain or pressure, anterior or posterior mucopurulent rhinorrhea, and hyposmia. This defini- tion stands in contrast to rhinitis, which is defined mainly as nasal obstruction, sneezing, nasal itching, and watery rhinor- rhea. ‘‘Sinusitis’’ is in current guidelines replaced by the term ‘‘rhinosinusitis,’’ given the observation that the nasal mucosa is a continuum with the sinus mucosa and that nasal symptoms are prevalent in patients with sinus inflammation. This concept has been supported by findings indicating that the inflammatory changes in ethmoidal mucosa of patients with CRS are reflected in the inferior turbinate mucosa (9). Chronic rhinosinusitis is defined as the presence of the previously described symptoms during more than 12 weeks/year.
Chronic rhinosinusitis is often taken as an umbrella term for a heterogeneous group of sinus diseases, as they all share a common pattern of symptoms. However, nasal polyps can easily be discerned on nasal endoscopy, and these patients report less facial pain and more olfactory dysfunction and nasal obstruction, and have higher total symptom scores (10–13). There have been numerous attempts to classify chronic sinus disease regarding pathophysiological and clinical properties. Current consensus differentiates CRS with nasal polyps (CRSwNP) from CRS without nasal polyps (CRS sine NP, CRSsNP) as subgroups of CRS. Although this concept is sup- ported by differences in the inflammatory profile (10), it is not clear whether these types represent etiopathogenetically different entities. Whereas some features indistinguishably hallmark nasal polyposis, other properties of CRSwNP are also found in CRSsNP to a lesser extent. Furthermore, evidence indicates considerable variation within the CRSwNP subgroup (14).
REMARKABLE DIVERSITY IN IMMUNOLOGICAL CHANGES
CRSsNP is characterized by fibrosis, basement membrane thickening, goblet cell hyperplasia, subepithelial edema, and mononuclear cell infiltration, whereas CRSwNP is character- ized by an intense edematous stroma with albumin deposition, formation of pseudocysts, and subepithelial and perivascular inflammatory cell infiltration (15). A long-standing misconcep- tion is that CRS is a disease uniformly dominated by eosino- phils, as evidence supporting a wide diversity of inflammatory phenotypes is accumulating. Eosinophilic inflammation is a key feature of white patients with CRSwNP, as demonstrated by marked infiltration of EG2-positive (ECP secreting) eosinophils and high concentrations of eosinophilic cationic protein (ECP) (10, 15, 16). Furthermore, cytokines regulating eosinophils such as IL-5, eotaxin, and RANTES (regulated on activation, nor- mal T-cell expressed and secreted) are involved in the tissue
(Received in original form May 19, 2010; accepted in final form July 13, 2010)
Supported by grants to Claus Bachert from the Flemish Scientific Research Board
FWO (nos. A12/5-HB-KH3 and G.0436.04), the Global Allergy and Asthma
European Network (GA2LEN, Sixth EU Framework program for research no.
FOOD-CT-2004–506378), and the Interuniversity Attraction Poles Program-
Belgian State Science Policy (no. IAP P6/35).
Correspondence and requests for reprints should be addressed to Claus Bachert,
M.D., Ph.D., De Pintelaan 185, 9000 Ghent, Belgium. E-mail: claus.bachert@
ugent.be
Proc Am Thorac Soc Vol 8. pp 115–120, 2011 DOI: 10.1513/pats.201005-036RN Internet address: www.atsjournals.org
eosinophilia of nasal polyps. Although eosinophilic infiltration and activation is also present in CRSsNP, this is significantly less pronounced than in CRSwNP. However, myeloperoxidase- staining cells, and myeloperoxidase and IL-8 concentrations, are increased in CRSsNP and nasal polyps, indicating that neutrophils are also involved in nasal polyp pathogenesis.
Of interest, it has been demonstrated that nasal polyps from southern Chinese patients do not share the inflammatory pat- tern of polyps in white patients, as they were characterized by neutrophil infiltration but lacked increases in ECP, eotaxin, immunoglobulin E (IgE), and IL-5 as well as GATA-3 (14, 17). As these neutrophilic polyps are clinically and morphologically indistinguishable from other polyps, this indicates that eosino- philic inflammation is not essential for polyp formation. Further evidence is found in nasal polyps from patients with cystic fibrosis, which show marked neutrophilic inflammation greatly surpassing any eosinophilic marker (10, 18).
Activated T lymphocyte infiltration occurs in all subtypes of chronic sinus disease, especially in nasal polyposis; however, different T-lymphocyte subsets contribute to it. As indicated by different cytokine signals, namely IFN-g (helper T type 1 [Th1] related) and IL-5 (a helper T type 2 [Th2] cytokine), the Th1/ Th2 ratio characterizes CRSsNP as a Th1-polarized disease, whereas CRSwNP reveals a Th2 polarization (10). IL-5 plays a central role in the activation and increased survival of eosinophils in the nasal polyps of white individuals(19). Low transforming growth factor (TGF)-b1 levels in nasal polyps have been related to decreased T-regulatory cell function, as CRSwNP shows decreased levels of forkhead box protein P3 (FOXP3) expression (20). Together with increased expression of T-bet (Th1-specific) and GATA-3 (Th2-specific), this in- dicates deficient T-regulatory function in CRSwNP, which is not observed in CRSsNP. Chinese, predominantly neutrophilic polyps share the down-regulation of FOXP3 and TGF-b1 with those of white individuals; however, a mixed Th1 and Th17 pattern was observed in this group, with significantly lower GATA-3 expression and higher IL-17 concentrations compared with the polyps of white individuals. Increased levels of IL-17 expression have previously been described in nasal polyposis (21) and orchestrate a neutrophilic inflammation.
EXTRACELLULAR MATRIX REMODELING: A CONSERVED MECHANISM OF DISEASE
Striking differences exist in the histological appearance of chronic sinus disease: nasal polyps typically consist of albumin accumu- lation and edema formation, whereas CRSsNP is marked by fibrosis. This has been demonstrated by picrosirius red staining, which indicated loose connective tissue and a low collagen con- tent in CRSwNP, but excessive production of thick collagen fibers in CRSsNP (22).
TGF-b plays a crucial role in remodeling processes in the airway by the attraction and induction of proliferation of fibroblasts, and the up-regulation of extracellular matrix (ECM) synthesis. Increases in TGF-b1 protein and mRNA have been measured repeatedly in CRSsNP, in contrast to decreases or lack of increases in CRSwNP (10, 20, 22, 23). In contrast, TGF-b2 is increased in both CRSsNP and CRSwNP. Furthermore, TGF-b receptor I and III (TGF-bRI and TGF- bRIII) mRNA expression and the number of pSmad 2– positive cells were increased in CRSsNP, in contrast with decreased TGF-bRII mRNA, TGF-bRIII and pSmad 2 cells in CRSwNP. These results confirm the up-regulation of the TGF-b signaling pathway in CRSsNP in contrast with its down-regulation in CRSwNP. Of interest, these results were confirmed in a Chinese population (24), indicating that TGF-
b1 and its signaling may be a well-conserved key marker for CRS differentiation.
Remodeling is a dynamic process in both health and disease, balancing ECM production and degradation. ECM breakdown is regulated mainly by a family of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloprotei- nases (TIMPs). In sinus disease, differing results and a multitude of MMP subtypes make it difficult to interpret data. In CRSsNP, levels of MMP-9 (gelatinase B) and its inhibitor, TIMP-1, are increased. Findings of increased concentrations of MMP-9 in nasal polyps, but not of TIMP-1, suggest that the MMP-9/TIMP-1 balance is associated with ECM degradation in CRSwNP (24– 27). Again, as for TGF-b1, results in a Chinese population were analogous to those in a white population. Moreover, MMP-9 was found to be involved in wound healing and predicts poor healing after sinus surgery (28). This is illustrated by the observation that doxycycline-releasing stents, placed in the frontal recess, signif- icantly lowered MMP-9 concentrations and were associated with improved postoperative healing (29). In contrast, the roles of MMP-2 and MMP-7 are less clear. MMP-2 may be up-regulated in nasal polyp tissue (30, 31), whereas other studies could not detect changes in MMP-2 concentrations (24, 32). MMP-7 can be found up-regulated mainly in nasal polyps (26) but also in CRSsNP (30); however, in CRSsNP, the metalloproteinase is counteracted again by TIMPs. More systematic well-designed studies are underway, relating different MMPs to the phenotype of disease (33).
SUPERANTIGEN HYPOTHESIS IN THE PATHOGENESIS OF NASAL POLYPOSIS
The discovery of IgE antibodies to Staphylococcus aureus enterotoxins A and B in nasal polyp tissue homogenates (34) indicated that these bacterial superantigens could be involved in the pathogenesis of nasal polyposis. Staphylococcus aureus is a frequent colonizer of the nose, with an average persistent colonization rate in 20–30% of individuals (35). Although S. aureus can be isolated frequently in acute and chronic rhinosi- nusitis, a disease-modifying role for its presence has never been proven previously. S. aureus has been isolated at comparable rates in control subjects and patients with CRSsNP (36, 37). In nasal swab cultures from patients with CRSwNP, higher S. aureus colonization rates have been observed compared with control patients and patients with CRSsNP, with even higher rates in asthmatic and aspirin-intolerant patients (38–40), although other studies could not demonstrate increased colonization rates (41).
Although S. aureus has traditionally been regarded as an extracellular pathogen, there is increasing evidence that it has the ability to invade and survive in nonphagocytic eukaryotic cells such as keratinocytes and respiratory epithelial cells (42). An intracellular reservoir of S. aureus in patients with CRS has been shown by confocal immunofluorescence microscopy in nasal epithelial cells, mucous gland cells, myofibroblasts, and CD45-positive phagocytes (42, 43). An increased presence of intracellular S. aureus has also been detected by peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) in the nasal polyps of an aspirin-sensitive subgroup (44) and later also in the CRSwNP group in general, but not in the CRSsNP group (45).
S. aureus secretes enterotoxins (SAEs), small proteins able to mount a massive inflammatory reaction resulting from a polyclonal activation of T and B lymphocytes, independent of a specific adaptive immune response, a unique interaction for which they are known as superantigens, as first described by Marrack and Kappler in 1990 (46). SAEs directly activate T cells by bridging the major histocompatibility (MHC) class II molecule with the T-cell receptor in a nonspecific way, without
116 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 8 2011
being processed by antigen-presenting cells (47). Indirect evi- dence for the involvement of these superantigens came from reports showing the presence of immunoglobulin E specific to staphylococcal enterotoxins (SAE-IgE) in subgroups of up to 50% of patients with polyps (34, 38, 39). The colonization rates always exceeded the SAE-IgE rates, indicating that coloniza- tion may not necessarily lead to the generation of an IgE response. Nasal polyps positive for SAE-IgE have increased concentrations of eosinophils, IgE, ECP, eotaxin, and IL-5, and these patients have more asthma and aspirin-exacerbated re- spiratory disease. These results suggest that a superantigen action is related to the hallmark eosinophilic pathology of nasal polyps. SAE-IgE was previously also detected in a small fraction of control subjects and patients with CRSsNP (38, 48); however, these findings are inconsistent with a Global Allergy and Asthma European Network (Ga2len) case–control study (our unpublished data).
Although the presence of IgE directed to SAE is indirect proof of superantigen involvement, direct demonstration of superantigen presence by ELISA has been demonstrated by Seiberling and colleagues (49), who detected common staphy- lococcal toxins (staphylococcal enterotoxin A [SEA], SEB, SEC1–SEC3, SED, toxic shock syndrome toxin [TSST]-1) in 48% of patients with polyps and in 7.7% of patients with CRSsNP. In a study of Chinese patients with sinus disease, the same superantigens were detected by ELISA in 12 of 22 polyps, compared with none in patients with CRSsNP or control subjects (50). On interaction with the T-cell receptor, staphylo- coccal superantigens show specificity for one or more Vb
subdomains of the T cell receptor, expanding specific T-cell populations and creating a superantigen-specific Vb signature (51). In several studies, ‘‘skewing’’ of the T cell receptor rep- ertoire with a signature characteristic for SAE has been shown in nasal polyps by flow cytometry (52–55), supporting the hypothesis that staphylococcal enterotoxins exert their effect in nasal polyps via the superantigen mechanism.
In an ex vivo study (56), nasal polyp and inferior turbinate fragments were suspended in culture medium and stimulated with SEB and staphylococcal protein A (SpA) for 30 minutes and 24 hours. Spontaneous release of IL-5, IL-13, tumor necrosis factor- a, and IL-10 was significantly and substantially greater in polyps than in control tissue. Twenty-four–hour stimulation with SEB caused a significant increase in Th1 and Th2 cytokines (IFN-g, IL- 2, IL-4, IL-5, IL-10, IL-13) in inferior turbinates and to a greater extent in polyp tissue. By calculating the ratio of the increase in polyps to the increase in control tissue it became apparent that the increase in cytokine production was due predominantly to Th2 cytokines (IL-4, IL-5) but that T-regulatory cytokine pro- duction (IL-10 and TGF-b) was disfavored by SEB stimulation. This study clearly confirmed that SEB can polarize mucosal inflammation to a Th2 pattern.
IMMUNOGLOBULIN PRODUCTION IN NASAL POLYPOSIS
The presence of IgE in tissue is another hallmark of CRSwNP. By detailed analysis of the pattern of increased IgE in nasal polyps and in serum, three groups of nasal polyps can be discerned (34, 39): (1) a group with no detectable specific IgE and low total IgE, (2) a group with increased concentrations of total IgE and the presence of selected specific IgE antibodies to aeroallergens, corresponding to those found in serum and to skin prick test positivity, and (3) a group with a polyclonal pat- tern of IgE expression with specific IgE to a majority of allergens and increased total IgE, reflecting only partially the serum IgE response and independent of skin prick test positiv-
ity. SAE-IgE is almost exclusively found in the polyclonal group.
Although extravasation of serum proteins has been shown in nasal polyps (15), there is indirect evidence of local production of IgE rather than local reflection of systemic production. Total IgE and SAE-IgE concentrations were in all cases higher in polyp tissue compared with serum (39); SAE-IgE may be de- tected in the serum of patients with polyps, unrelated to atopic status, especially when asthma coexists (57, 58). Moreover, the IgE/albumin ratios in polyp tissue and serum were dissociated, and specific IgE antibodies in polyp tissue showed only a partial relation to serum IgE antibodies, indicating that tissue IgE is, rather, the result of local IgE production than of extravasation (39). Lymphoid aggregations and lymphoid follicular structures could be shown in nasal polyps by immunohistochemistry, supporting the hypothesis of local production of polyclonal IgE. Further evidence is pending, showing the presence of a germinal center reaction, receptor revision, and immunoglobu- lin class switching in nasal polyp tissue (59). Furthermore, the immunoglobulin production is not limited to IgE: increased local concentrations of IgA and IgG but not of IgM have been reported in nasal polyps, and the IgG4 subclass is specifically linked to SAE-IgE–positive polyps (60).
It has been shown that nasal symptoms and markers of inflammation did not increase in relation to seasonal allergen exposure even in ragweed-sensitive patients with nasal polyps, and nasal provocation was largely unsuccessful in patients with nasal polyps (61). A polyclonal IgE pattern in nasal polyps may, however, cause a permanent degranulation of mast cells by conventional aeroallergens and superantigens, maintaining polyp growth, but not giving rise to acute allergic symptoms. This hypothesis needs further study, but may be of the utmost im- portance in also explaining similar mechanisms in nonatopic but IgE-positive asthma.
CHEMOKINES AND ADHESION MOLECULES
Recruitment of inflammatory cells is a paramount property of the immune reaction and is regulated by vascular adhesion molecules and chemokines. CC chemokines eotaxin-1, -2, and -3 preferentially attract and activate eosinophils via the CCR-3 receptor. Nasal polyp fibroblasts are able to produce eotaxins after stimulation with LPS, IL-1b, and tumor necrosis factor-a (62). Increased production of eotaxins and RANTES has repeatedly been observed in CRSwNP (63–65), and may be important in promoting the local chemotaxis of eosinophils. Moreover, increased staining for vascular cell adhesion mole- cule (VCAM)-1 has been described in nasal polyps (63, 66, 67), and correlates with tissue eosinophilia, suggesting a role for VCAM-1 in eosinophil extravasation in nasal polyps.
Increased concentrations of the neutrophil attractant and activator IL-8 have been detected in tissue and nasal lavage fluid of patients with CRSsNP and to a greater extent in CRSwNP tissue (10, 68). Production of CXC chemokines IL-8 and growth- related oncogene-a (GRO-a) has been shown to be induced by Staphylococcus epidermidis supernatants in cultured epithelial cells from nasal polyps and healthy control inferior turbinates (69); however, SEB was not able to stimulate IL-8 production in nasal polyp and inferior turbinate tissue fragments (56). Macro- lide therapy has the ability to reduce IL-8 levels and neutrophil recruitment, providing therapeutic opportunities in selected patients (70). Stimulation of cultured human nasal epithelial cells with staphylococcal superantigen SEB leads to the pro- duction of interferon-inducible protein (IP)-10, monokine in- duced by IFN-g (MIG), granulocyte colony-stimulating factor (G-CSF), RANTES, and monocyte chemoattractant protein-1
Tomassen, Van Zele, Zhang, et al.: Pathophysiology of CRS 117
(MCP-1), but not of IL-8 (71). As the supernatants increased neutrophil chemotaxis and increased eosinophil survival, these results point to the importance of the epithelium in the orches- tration of granulocyte-dominated inflammation.
EICOSANOID METABOLISM AND ASPIRIN SENSITIVITY
Nasal polyposis is frequently associated with asthma and…
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