Introduction
Chronic rhinosinusitis (CRS) impairs quality of life as well as work
productivity (1) and has a high socioeconomic burden (1). In the Global
Allergy and Asthma European Network (GA2LEN) European
multicentre study involving 56 000 adult subjects, a prevalence rate of
CRS of 10.9% was determined with a range from 6.9 to 27.1% in Europe
(2). The CRS comprised heterogeneous diseases and was differentiated by
the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS
2020) in phenotypes with and without nasal polyps (CRSwNP/ CRSsNP) (3).
Subtypes are non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated
respiratory disease (N-ERD), cystic fibrosis, and the allergic fungal
rhinosinusitis (3). CRS is associated with asthma (4). Evidence-based
therapies consist of nasal corticosteroids in CRSsNP and nasal/oral
corticosteroids in CRSwNP (3). In cases without improvement under
conservative treatment, surgery of nasal sinuses is recommended
according to the EPOS 2020 criteria (3). Despite the evidence-based
therapy options, an acceptable level of disease control is still not
reached in a high proportion of patients (5). There is a particularly
high risk of disease recurrence following nasal sinus surgery for
patients with CRSwNP (5, 6). New therapy concepts developed for severe
CRSwNP consist of modified nasal sinus surgeries as reboot operations
that aim to entirely remove all nasal sinus mucosa and allow healthy
reepithelialization from the preserved nasal mucosa (7). Biological
treatment options are gaining evidence as an efficient therapy (8-10) in
CRSwNP. The CRS can be characterized by a wide range of factors, such as
histopathological findings, specific inflammatory and T-cell patterns,
tissue remodeling parameters, the concentration of eicosanoids, and IgE
production (11). The current phenotyping in CRSwNP and CRSsNP might not
sufficiently reflect pathophysiological processes within the CRS
disease. Therefore, elucidation of the pathomechanisms underlying CRS,
with the aim to develop specific and personalized therapy strategies,
might improve specific therapy options. First results of the
GA2LEN Sinusitis Cohort study in the framework of the
European FP6 research initiative have already been published by Tomassen
et al. (12). This multicenter case-controlled study focused on the
analysis of immune markers of nasal sinus tissues from CRS patients.
This second cluster analysis followed the first analysis, and the CRS
patients were assigned to groups CRSsNP, CRSwNP, and asthma comorbidity.
The study included parameters regarding tissue remodeling,
proinflammatory cytokines, cytokines of type 1-, type 2 inflammation and
Th17 lymphocyte pattern, eosinophil and neutrophil activation markers as
well as Staphylococcus aureus enterotoxin-specific IgE (SE-IgE). Based
on the detected IL-5 concentrations, CRS was divided into ten clusters
with low/ undetectable IL-5 and moderate or high concentrations of IL-5.
The group of IL-5-negative clusters represented mainly the CRSsNP
phenotype, while with increasing IL-5 levels, the proportion of the
CRSwNP phenotype raised to 100 %, with high IL-5 and positive SE-IgE.
The asthma prevalence increased with the elevation of IL-5 levels and
the presence of SE-IgE (12), but the presence and concentration of
chemokines were not analyzed so far.
Chemokines are small peptides (8-14 kDa) that induce chemotactic
activity in chemokine-receptor-positive cells. Chemokines influence the
activation status of the target cells and selectively regulate the
directed migration of specific inflammatory cells. They are also
involved in cell recruitment, inflammation, angiogenesis, type 1/ type 2
inflammation, wound healing, and lymphoid trafficking (13). The
classification of chemokines is based on the positioning of the first
two cysteine residues. Following chemokine families were defined: CXC,
CC, C, and CX3C (14). These families differ in function, e.g., CC
chemokines activate monocytes, basophils, eosinophils, T-lymphocytes,
and natural killer cells, whereas CXC chemokines stimulate mainly
neutrophils (15).
The general aim of the present study was analogous to previously
published GA2LEN study ”Chronic rhinosinusitis and nasal polyposis
cohort study”, aiming to match the immune patterns with the phenotypes
CRSwNP, CRSsNP, and comorbid asthma.
The primary aim of this substudy was to characterize chemokine patterns
in the tissue of CRS patients in relation to the levels of the Th2
related parameter IL-5 primarily, and subsequently assign them to the
phenotypes CRSwNP and CRSsNP and associated comorbidities asthma and
N-ERD. We analyzed the concentration of the CC-chemokines TARC/CCL17,
PARC/CCL18, eotaxin/CCL11, MCP-3/CCL7, MIP-1α /CCL3, IP-10 /CXCL10, and
the CXC chemokine ENA-78/CCL5.
The secondary aim of the study was to examine the influences of the
additional parameters MPO, IL-17 (neutrophilic), IL-22, TNF-α, and IFN-γ
(Th1-associated) on chemokine patterns. The use of biologics for the
therapy of severe CRS with nasal polyps expands increasingly. Therefore,
improving the understanding of pathomechanisms behind CRS, and
performing systematic characterization of CRS endotypes could lead to
the discovery of new biomarkers, advancing the choice of specific
biologics for the treatment of uncontrolled severe CRSwNP.