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Pathophysiology of Chronic Rhinosinusitis

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Pathophysiology of Chronic Rhinosinusitis
Peter Tomassen, Thibaut Van Zele, Nan Zhang, Claudina Perez-Novo, Nicholas Van Bruaene,
Philippe Gevaert, and Claus Bachert
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
ed
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
ct
the most frequent diseases in humans. Chronic rhinosinusitis
(CRS) is often described as a chronic inflammatory condition of
re
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
or
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
nc
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
U
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-
(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).
1 Correspondence and requests for reprints should be addressed to Claus Bachert,
jjj, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: claus.bachert@ugent.be
Proc Am Thorac Soc Vol 7. pp 1–6, 2010
DOI: 10.1513/pats.201005-036RN
Internet address: www.atsjournals.org
PATS201005-036RN_proof j 2-11-10 12:12:01
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
f
‘‘rhinosinusitis,’’ given the observation that the nasal mucosa is
oo
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
Pr
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 eosinophils and high con- 2
centrations of eosinophilic cationic protein (ECP) (10, 15, 16).
Furthermore, cytokines regulating eosinophils such as IL-5,
eotaxin, and RANTES (regulated on activation, normal T-cell
expressed and secreted) are involved in the tissue eosinophilia
of nasal polyps. Although eosinophilic infiltration and activa-
 2 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7
tion is also present in CRSsNP, this is significantly less pro-
nounced than in CRSwNP. However, myeloperoxidase-staining
cells, and myeloperoxidase and IL-8 concentrations, are in-
creased 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-
ed
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
ct
pattern was observed in this group, with significantly lower
GATA-3 expression and higher IL-17 concentrations compared
re
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.
or
EXTRACELLULAR MATRIX REMODELING: A CONSERVED
MECHANISM OF DISEASE
nc
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
U
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 fibro-
blasts, 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. Further-
more, 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-
3 bRII mRNA 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.
PATS201005-036RN_proof j 2-11-10 12:12:02
2010
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
f
counteracted again by TIMPs. More systematic well-designed
oo
studies are underway, relating different MMPs to the phenotype
of disease (33).
Pr
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
being processed by antigen-presenting cells (47). Indirect evi-
dence for the involvement of these superantigens came from
 Tomassen, Van Zele, Zhang, et al.: Pathophysiology of CRS
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-
ed
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.
ct
In an ex vivo study (56), nasal polyp and inferior turbinate
fragments were suspended in culture medium and stimulated with
re
4 SEB and 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-
or
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
nc
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 production (IL-10 and TGF-b)
U
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
PATS201005-036RN_proof j 2-11-10 12:12:02
3
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,
f
and nasal provocation was largely unsuccessful in patients with
oo
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
Pr
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 frag-
ments (56). Macrolide therapy has the ability to reduce IL-8
levels and neutrophil recruitment, providing therapeutic oppor-
tunities in selected patients (70). Stimulation of cultured human
nasal epithelial cells with staphylococcal superantigen SEB
leads to the production of interferon-inducible protein (IP)-
10, monokine induced by IFN-g (MIG), granulocyte colony-
stimulating factor (G-CSF), RANTES, and MCP-1, but not of 5
IL-8 (71). As the supernatants increased neutrophil chemotaxis
and increased eosinophil survival, these results point to the
importance of the epithelium in the orchestration of granulo-
cyte-dominated inflammation.
 4 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7
EICOSANOID METABOLISM AND ASPIRIN SENSITIVITY
Nasal polyposis is frequently associated with asthma and aspirin
hypersensitivity, commonly known as Samter’s triad or aspirin-
exacerbated respiratory disease (AERD). The syndrome is char-
acterized by a typical sequence of persistent rhinitis in young
adulthood, followed by asthma, aspirin intolerance, and nasal
polyposis (72). In patients with AERD, bronchospasm and nasal
symptoms are provoked by aspirin or other nonsteroidal antiin-
flammatory drugs, through a mechanism attributed to cyclo-
oxygenase (COX)-1 inhibition, with abundant eosinophil and
mast cell infiltration, Th2 cell activation, and a striking over-
production of cysteinyl leukotrienes, as reported in a review by
Stevenson and Szczeklik (73).
Increased S. aureus colonization rates, total local IgE,
specific IgE to SAE and ECP, and IL-5 were reported in
patients with nasal polyps and aspirin sensitivity (aspirin-
sensitive nasal polyps, ASNP) compared with aspirin-tolerant
patients with nasal polyps (aspirin-tolerant nasal polyps,
ATNPs) (38, 74, 75), suggesting a relation of staphylococcal
superantigens to aspirin sensitivity. Comparing eicosanoid pro-
duction in CRSwNP and CRSsNP, concentrations of leukotri-
ene C4 synthase, 5-lipoxygenase, and cysteinyl leukotrienes
were increased in different sinus disease subgroups (CRSsNP,
ATNP, and ASNP) in parallel and in correlation with eosino-
philic inflammation severity whereas COX-2 and prostaglandin
E2 (PGE2) were inversely correlated (76). These data confirmed
the notion that changes in eicosanoid metabolism do occur in
CRS even in the absence of clinical aspirin sensitivity and
appear to be related to the severity of eosinophilic inflamma-
tion. In cultured inferior turbinate fibroblasts, SEB significantly
ed
6 down-regulated PGE2, COX-2, and prostaglandin EP2-receptor
mRNA expression, pointing to an effect of staphylococcal
superantigens on eicosanoid metabolism in upper airway tissue
ct
(77). Taking these results together, staphylococcal enterotoxins
are thought to have an amplifying role in upper airway disease
with aspirin sensitivity, without evidence for a direct causal
re
relationship of SAE with aspirin sensitivity.
ROLE OF FUNGI IN THE PATHOGENESIS OF CRS
or
Fungi have frequently been hypothesized to be causal patho-
gens in sinusitis. Invasive fungal infection can impose severe
nc
acute and chronic rhinosinusitis in the immunocompromised
host. Evidence of fungi, eosinophilic mucin, and eosinophils in
the nose and sinuses is present in nearly all patients with CRS;
U
however, no significant difference in fungal isolation in com-
parison with healthy control subjects could be detected in
multiple studies, as reported in a review by Ebbens and col-
leagues (78). Treatment of patients with CRS with topical and
oral antifungals did not result in improvement of subjective and
objective outcome measures in the majority of blinded random-
ized controlled trials. In the ‘‘allergic fungal sinusitis’’ concept,
type I hypersensitivity to fungi, instead of direct fungal effects,
is thought to be involved in CRS pathophysiology. IgE specific
to fungi may be elevated in patients with CRS; however, results
are conflicting. Relevance of fungal IgE in the pathogenesis of
CRS is not proven yet and might represent concurrent fungal
allergy in these patients. As there is no substantial evidence for
a disease-modifying effect of fungi in CRS, fungi are currently
regarded as innocent bystanders in CRS.
IMMUNE BARRIER HYPOTHESIS
Both the staphylococcal and fungal hypotheses currently fail to
7 identify microorganisms as an etiological agent at the origin of
CRS. In most studies, SAE-IgE can be demonstrated in up to
PATS201005-036RN_proof j 2-11-10 12:12:02
2010
50% of patients with polyps, although the commonly measured
SAE-IgE cocktail might underestimate the real prevalence of
superantigen involvement (79). Moreover, attempts to eradicate
the suspected agent have not yet proven successful, and both
staphylococci and fungi are present as commensals on the upper
respiratory epithelium of healthy individuals. From this per-
spective, it is hypothesized that CRS will develop only in
susceptible individuals with altered tolerance to common or-
ganisms. This impaired immune barrier hypothesis has been
well reviewed by Kern and colleagues (80). Disrupted mechan-
ical barriers and deficiencies in both the innate and acquired
immune system make the sinonasal mucosa more susceptible to
antigenic exposition and stimulation, leading to either side of
the spectrum of chronic inflammation. Epithelial damage has
been observed in CRSwNP, and genetic deficiency or environ-
mentally induced damage in epithelial repair mechanisms may
be associated with both forms of CRS.
CONCLUSION AND PERSPECTIVES
There is ample evidence that the pathophysiology of chronic
rhinosinusitis, by its current definition, is characterized by
f
a great diversity of immunological mechanisms and possible
oo
etiological factors, reflected in the effector T-cell signature,
eosinophilic versus neutrophilic inflammation, and remodeling
profile. The inflammation in CRSwNP may be amplified by
Pr
Staphylococcus aureus enterotoxins, acting as superantigens, via
polyclonal T- and B-cell activation. This pathological diversity
seems to stand in contrast to the nonspecific clinical presenta-
tion of CRS, but the disease phenotype will, however, be of
great importance in the development and application of highly
individualized treatment. Therefore, identification of specific
disease subgroups within the broad concept of CRS, clustering
etiology, biomarkers, and optimal treatment, is an important
and challenging task in future research.
Author Disclosure: P.T. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. T.V.Z. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. N.Z. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. C.P.-N. received grant
support (institutional) from the Research Foundation Flanders (more than
$100,001). N.V.B. received grant support (institutional) from the Research Foun-
dation Flanders (more than $100,001). P.G. received grant support (institutional)
from GlaxoSmithKline and Novartis (more than $100,001) and is employed by the
Research Foundation Flanders. C.B. was on the Advisory Board for GlaxoSmithKline,
ALK, and Merck ($1,001–$5,000). He received lecture fees from FAES, Merck
($1,001–$5,000), and Schering-Plough ($5,001–$10,000). He received grant
support from Schering-Plough ($50,001–$100,001).
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Tomassen, Van Zele, Zhang, et al.: Pathophysiology of CRS 7

AUTHOR QUERIES

1 AU: M.D., Ph.D., or both?

2 AU: Please define EG2, or perhaps spell out, as it is mentioned only once in article?
3 AU: Preceding OK as ‘‘TGF-bRII’’? Earlier in same sentence TGF-bRI and TGF-bRIII are
mentioned, but not TGF-bRII?
4 AU: Define SpA? Staphylococcal protein A?
5 AU: Please define MCP-1? Monocyte chemoattractant protein-1?
6 AU: Change preceding from ‘‘prostaglandin EP2-receptor’’ to ‘‘PGE2 receptor (EP2)’’?
7 AU: ‘‘at’’ or ‘‘as’’ here?
8 AU: Please complete Reference 24?
9 AU: Please update Reference 44?
10 AU: Please update ref. 45 in proof?

PATS201005-036RN_proof j 1-11-10 15:26:45

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