Objectives
Nasal polyps are often characterized by type 2 inflammation and disease recurrence. We developed a new surgical technique, referred to as reboot approach, which aims to maximally remove ...all sinus mucosa and allow healthy re‐epithelialization from the preserved nasal mucosa. We here review type 2 endotype chronic rhinosinusitis with nasal polyps (CRSwNP) patients who underwent classical mucosa‐sparing endoscopic sinus surgery (ESS) or the reboot approach.
Methods
Retrospective case‐control study of 50 consecutive CRSwNP patients who underwent endoscopic sinus surgery between 2015 and 2017, either as a classical non‐reboot ESS (n = 20); a partial reboot approach removing the mucosa of the ethmoidal, sphenoidal, and maxillary sinuses (n = 18); or a complete reboot approach including Draf III and removal of all frontal sinus mucosa (n = 12). Polyp recurrence over the follow‐up period of 2 years served as the primary outcome.
Results
All patients demonstrated a type 2 inflammation of the mucosal tissue harvested during surgery. In the classical approach group (n = 20), nine patients relapsed within 2 years (45%); in the partial reboot group, three out of 18 patients (17%) relapsed; and in the full reboot group one out of 12 patients (8%) relapsed. The relapse rates were significantly different between the non‐reboot and the reboot groups (P = 0.02) but also between all treatment groups (P = 0.038).
Conclusion
Complete removal of diseased mucosa from the paranasal sinuses (reboot approach) significantly reduces the recurrence of nasal polyps for 30 months postoperatively compared to the current mucosa‐sparing approach in type 2 inflammatory CRSwNP.
Level of Evidence
3b
Laryngoscope, 129:1286–1292, 2019
Chronic rhinosinusitis without nasal polyps (CRSsNP) is mainly considered a type 1 mediated disease. The role and clinical significance of type 2 immune responses in CRSsNP have not been addressed ...sufficiently; a recent cluster analysis for CRS described the existence of a subgroup of patients with CRSsNP with a type 2 inflammation.
We aimed to characterize the underlying type 2 immune response and its clinical significance in patients with CRSsNP.
A total of 240 patients with CRSsNP were endotyped and subdivided on the basis of expression of marker cytokines. Clinical data such as recurrence, comorbid asthma and allergy, and numbers of blood eosinophils and neutrophils were collected from all patients. A selection of 15 patients was further characterized for the presence of eosinophils, neutrophils, Charcot-Leyden crystals, and eosinophil extracellular traps in the mucosae.
A type 2 immune response with increased levels of IL-4, IL-5, eosinophil cationic protein, IgE, and Staphylococcus aureus enterotoxin–specific IgE was observed in 49% of patients with CRSsNP. Those patients showed increased numbers of blood and tissue eosinophils, and they displayed a considerable eosinophilic inflammation associated with eosinophil extracellular trap cell death and Charcot-Leyden crystals. A significantly increased prevalence of recurrence and asthma was observed in patients with type 2 CRSsNP compared with in patients with non–type 2 CRSsNP. However, only 4 of 117 patients with type 2 CRSsNP developed nasal polyps within 12 years.
This study shows that type 2 immune responses in CRSsNP follow similar patterns but are less pronounced than in chronic rhinosinusitis with nasal polyps. Also CRSsNP with a moderate type 2 immune response showed a considerable eosinophilic inflammation with clinical impact.
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Chronic rhinosinusitis (CRS) is a heterogeneous disease, with patients having either a high or low type 2 inflammatory endotype. Whereas the type 2–high group is well characterized by IL-5 ...expression, the type 2–low group, consisting of approximately 20% of CRS with and 50% of CRS without nasal polyp patients, lacks a clear biomarker profile and thus specific therapeutic targets.
The aim was to identify underlying molecular pathways of type 2–low CRS, as stratification of patients may allow improvement of personalized treatments.
Luminex assays were performed to analyze proteins in nasal secretions and tissues of CRS patients. Immunostainings were analyzed for differences in neutrophils, granulocyte-colony stimulating factor (G-CSF), and its receptor in nasal tissue. Neutrophils were isolated from blood of healthy volunteers and stimulated with G-CSF. Effects on apoptosis and neutrophil activity were analyzed with flow cytometry.
G-CSF was significantly upregulated in nasal tissue and secretion fluid of type 2–low CRS patients compared to type 2–high patients. In nasal polyp tissue of type 2–low patients, a large infiltration of neutrophils expressing both G-CSF and its receptor was detected, suggesting the presence of a neutrophil-intrinsic autocrine survival mechanism. In response to G-CSF, neutrophils were in an activated state and were resistant to apoptosis, possibly contributing to a chronic inflammation. Of interest, type 2–high nasal polyp patients treated with IgE-blocking omalizumab had increased G-CSF concentrations compared to before treatment.
G-CSF is an important cytokine regulating neutrophils in type 2–low CRS and has potential in the diagnosis and therapy of the disease.
Objectives/Hypothesis
Chronic rhinosinusitis (CRS) is a heterogenic disease with different inflammatory patterns depending on the presence (CRSwNP) or absence (CRSsNP) of polyps and geographical ...location. A shift toward type 2 endotype has been seen in Asia. We aim to investigate whether there has been type 2 shift in Belgium and to further endotype CRS based on clinical markers.
Study design
Prospective descriptive study.
Methods
Four hundred and thirty eight patients with CRS undergoing sinus surgery at Ghent University Hospital between 2007 and 2018 were included and stratified based on phenotype, comorbidities, inflammatory markers in tissue, and two different time points of surgery. Tissue samples from surgery were analyzed for type 2 markers. In a subgroup of CRSwNP blood eosinophils (EBC) was available.
Results
There was an increase in type 2 inflammatory markers in the latter group versus the earlier, in non‐asthmatic, non‐allergic CRS patients regardless of phenotype. The proportion of IL‐5+ patients was elevated in the latter group in CRSwNP. Inflammatory markers and comorbidities differ between IL‐5+ CRSsNP and CRSwNP subjects, no difference was seen in IL‐5− CRS. EBC can together with information on comorbidities help identify type 2 CRSwNP in a clinical setting.
Conclusion
There is a shift toward type 2 inflammation within the CRS population over recent 8 years also in Belgium. This shift implies that we expect to see more cases of severe and difficult to treat CRS in the future. Polyp formation is not directly linked to the presence or concentrations of type 2 inflammatory markers. Clinical parameters and EBC > 300 cells/μL can be used to identify type 2 CRSwNP.
Level of Evidence
3. Laryngoscope, 131:E1408–E1414, 2021
In chronic rhinosinusitis (CRS) different phenotypes have been reported based on cytokine profile and inflammatory cell patterns. The aim of this study was to characterize the intracytoplasmatic ...cytokines of T cells infiltrating the inflamed sinonasal mucosa.
Infiltrated T cells and tissue homogenates from sinonasal mucosal samples of 7 healthy subjects, 9 patients with CRS without nasal polyp (CRSsNP), 15 with CRS with nasal polyps (CRSwNP) and 5 cystic fibrosis patients (CF-NP) were analyzed for cytokine expression using flow cytometry and multiplex analysis respectively. Intracytoplasmic cytokinesin T cells were analyzed after stimulation of nasal polyps with Staphylococcus aureus enterotoxin B for 24 hours.
The number of T cells per total living cells was significantly higher in patients with CRSwNP vs. CRSsNP and controls. 85% of the CD4(+) T cells showed to be memory T cells. The effector T cells present in all tissues have a predominant Th1 phenotype. Only in CRSwNP, a significant fraction of T cells produced the Th2 cytokines IL-4 and IL-5, while nasal polyps from CF patients were characterized by a higher CD4/CD8 T cell ratio and an increased number of Th17 cells. 24 h stimulation with SEB resulted in a significant induction of CD4(+) T cells producing IL-10 (Tr1 cells).
T cell cytokine patterns in healthy and inflamed sinonasal mucosa revealed that Th2 cells (IL-4 and IL-5 producing cells) are significantly increased in CRSwNP mucosal inflammation. Exposure to SEB stimulates Tr1 cells that may contribute to the Th2 bias in CRSwNP.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by both a chronic inflammation and tissue remodelling; as indicated by extracellular matrix protein deposition, basement membrane ...thickening, goblet cell hyperplasia and subepithelial edema, with reduced vessels and glands. Although remodelling is generally considered to be consequence of persistent inflammation, the chronological order and relationship between inflammation and remodelling in polyp development is still not clear. The aim of our study was therefore to investigate the pathological features prevalent in the development of nasal polyps and to elucidate the chronological order and relationship between inflammation and remodelling, by comparing specific markers of inflammation and remodelling in early stage nasal polyps confined to the middle turbinate (refer to as middle turbinate CRSwNP) obtained from 5 CRSwNP patients with bilateral polyposis, mature ethmoidal polyps from 6 CRSwNP patients, and normal nasal mucosal tissue from 6 control subjects. Middle turbinate CRSwNP demonstrated significantly more severe epithelial loss compared to mature ethmoidal polyps and normal nasal mucosa. The epithelial cell junction molecules E-cadherin, ZO-1 and occludin were also expressed in significantly lower amounts in mature ethmoidal polyps compared to healthy mucosa. Middle turbinate CRSwNP were further characterized by significantly increased numbers of subepithelial eosinophils and M2 type macrophages, with a distinct lack of collagen and deposition of fibronectin in polyp part. In contrast, the turbinate area of the middle turbinate CRSwNP was characterized by an increase in TGF-β activated myofibroblasts expressing α-SMA and vimentin, an increase in the number of pSmad2 positive cells, as well as increased deposition of collagen. These findings suggest a complex network of processes in the formation of CRSwNP; including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodelling. Furthermore, remodelling appears to occur in parallel, rather than subsequent to inflammation.
...the aim of this study was to investigate whether serum (s) periostin is elevated in patients with CRSwNP compared with patients with CRSsNP and controls, and to evaluate whether s-periostin and ...other inflammatory markers could be used as serum biomarkers to identify patients with CRSwNP with IL-5 and/or SE-IgE tissue (t) expression, representing moderate and severe endotypes of CRSwNP according to the formerly mentioned cluster analysis.2 In total 377 patients participating in the Global Allergy and Asthma European Network study were included, divided into CRSwNP (n = 144), CRSsNP (n = 123), and controls (n = 110) on the basis of history and nasal endoscopy. ...our results show that s-periostin is elevated in patients with CRSwNP. Measurement of inflammatory markers Nasal tissue of 0.1 g was diluted in 1 mL of 0.9% NaCl solution containing a protease inhibitor cocktail (Complete; Roche Diagnostics, Mannheim, Germany), homogenized at 1000 rpm for 5 minutes, and centrifuged at 1500g for 10 minutes at 4°C as described before.E2 Serum and tissue homogenate concentrations of total IgE, specific IgE to a mixture of S aureus enterotoxins (staphylococcal enterotoxins A and C and toxic shock syndrome toxin 1), and eosinophil cationic protein were assayed by using the UniCAP system (Phadia, Uppsala, Sweden). Parameter CRSwNP CRSsNP Controls P value CRSwNP vs CRSsNP (P value) CRSwNP vs controls (P value) CRSsNP vs controls (P value) Serum concentration, median (IQR) Periostin (ng/mL) 68.9 (57.1-86.6) 53.5 (46.4-64.3) 56.0 (48.3-67.8) <.0001∗ <.0001† <.0001† >.05† IgE (kU/L) 84.5 (36.2-231.4) 44.4 (16.1-113.5) 50.1 (13.4-131.5) <.001∗ <.001† <.01† >.05† SE-IgE (kUA/L) 0.13 (0-0.43) 0.07 (0-0.23) 0.08 (0-0.23) <.0001∗ <.001† <.0001† >.05† ECP (μg/L) 15.3 (7.7-28.9) 13.1 (6.8-21.6) 11.2 (5.5-18.9) <.01∗ <.01† <.01† >.05† sIL-5Rα (pg/mL) 318.5 (205.9-527.6) 239.4 (171.3-363) 219 (142.8-300.4) <.0001∗ <.001† <.0001† >.05† Proportion of patients above cutoff (numbers) in serum, % (n/N) Periostin > 48.5 ng/mL 93 (129/138) 72.7 (80/110) 75 (78/104) <.0001‡ <.0001§ <.0001§ >.05§ IgE >96 kU/L 44.4 (64/144) 28.4 (35/123) 30 (33/110) <.05‡ <.01§ <.05§ >.05§ SE-IgE >0.28 kUA/L 33.3 (48/144) 26 (32/123) 22.7 (25/110) >.05‡ >.05§ >.05§ >.05§ Tissue concentration, median (IQR) IgE U/g tissue 203.2 (72.1-529.7) 25.2 (7.3-76.6) 8.9 (1.9-22.3) <.0001∗ <.0001† <.0001† <.01† IL-5 pg/g tissue 132.3 (23.9-519.5) 0 (0-17.5) 0 (0-0) <.0001∗ <.0001† <.0001† <.0001† ECP μg/g tissue 4.626 (2.2-9.4) 0.83 (0.20-2.3) 0.11 (0.07-0.35) <.001∗ <.0001† <.0001† <.0001† Proportion of patients above cutoff (numbers) in tissue, % (n/N) IgE >0.35 U/g tissue 97.3 (110/113) 87.2 (82/94) 71.9 (64/89) <.0001‡ <.01§ <.0001§ <.05§ SE-IgE >0.35 UA/g tissue 20.3 (23/113) 3.2 (3/94) 0 (0/92) <.0001‡ <.001§ <.0001§ >.05§ IL-5 >6.6 pg/g tissue 83.9 (94/112) 32.3 (30/93)) 2.4 (2/84) <.0001‡ <.0001§ <.0001§ <.0001§ Table E1 Baseline characteristics of the cohort Characteristic CRSwNP CRSsNP Control Total N 144 123 110 377 Sex: male/female/missing 95/47/2 64/57/2 60/47/3 Age (y), mean (range) 45 (25-72) 40 (17-70) 32 (17-69) Body mass index, mean (range) 25.8 (18.1-34.8) 25.5 (17.1-39.6) 24.3 (17.7-33.4) Smoking pack-years, mean (range) 18.2 (1-40) 17.5 (2-41) 13.5 (1-50) Smoking ever, n (%) 83 (58) 80 (65) 52 (47) 215 (57) Smoking current, n (%) 23 (16) 46 (37) 26 (24) 95 (25) Asthma, n (%) 60 (42) 17 (14) 15 (10) 92 (24) Allergy, n (%) 63 (44) 61 (50) 39 (35) 163 (43) Allergic rhinitis, n (%) 42 (29) 39 (32) 26 (24) 107 (28) Aspirin intolerance, n (%) 14 (10) 2 (2) 1 (1) 15 (6) Table E2 Sensitivity and specificity of clinical signs for predicting the presence of IL-5 or SE-IgE in patients with CRSwNP∗ Parameter Sensitivity Specificity P value Tissue IL-5 positive Polyp score >3/6 60.7 84.6 <.005 Asthma 38 62.5 >.05 Tissue SE-IgE positive Polyp score >3/6 61.9 39.4 >.05 Asthma 54.6 64.3 >.05 1 C.A. Akdis, C. Bachert, C. Cingi, M.S. Dykewicz, P.W. Hellings, R.M. Naclerio, Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology, J Allergy Clin Immunol, Vol. 131, 2013, 1479-1490 2 P. Tomassen, G. Vandeplas, T. Van Zele, L.O. Cardell, J. Arebro, H. Olze, Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers, J Allergy Clin Immunol, Vol. 137, 2016, 1449-1456.e4 3 G. Jia, R.W. Erickson, D.F. Choy, S. Mosesova, L.C. Wu, O.D. Solberg, Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients, J Allergy Clin Immunol, Vol. 130, 2012, 647-654.e10 4 N.A. Hanania, M. Noonan, J. Corren, P. Korenblat, Y. Zheng, S.K. Fischer, Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies, Thorax, Vol. 70, 2015, 748-756 5 N.A. Hanania, P. Korenblat, K.R. Chapman, E.D. Bateman, P. Kopecky, P. Paggiaro, Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials, Lancet Respir Med, Vol. 4, 2016, 781-796 6 M. Wang, X. Wang, N. Zhang, H. Wang, Y. Li, E. Fan, Association of periostin expression with eosinophilic inflammation in nasal polyps, J Allergy Clin Immunol, Vol. 136, 2015, 1700-1703, e1-9 7 J. Milonski, H. Zielinska-Blizniewska, K. Przybylowska, P. Pietkiewicz, B. Korzycka-Zaborowska, I. Majsterek, Significance of CYCLOOXYGENASE-2 (COX-2), PERIOSTIN (POSTN) and INTERLEUKIN-4(IL-4) gene expression in the pathogenesis of chronic rhinosinusitis with nasal polyps, Eur Arch Otorhinolaryngol, Vol. 272, 2015, 3715-3720
Background The role of IgE in patients with severe asthma is not fully understood. Objective We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease ...severity in adult asthmatic patients. Methods Specific IgE antibody concentrations in serum against enterotoxins, grass pollen (GP), and house dust mite allergens and total IgE levels were measured in adult cohorts of 69 control subjects, 152 patients with nonsevere asthma, and 166 patients with severe asthma. Severe asthma was defined as inadequately controlled disease despite high-dose inhaled corticosteroids plus at least 2 other controller therapies, including oral steroids. Results Enterotoxin IgE positivity was significantly greater in patients with severe asthma (59.6%) than in healthy control subjects (13%, P < .001). Twenty-one percent of patients with severe asthma with enterotoxin IgE were considered nonatopic. Logistic regression analyses demonstrated significantly increased risks for enterotoxin IgE–positive subjects to have any asthma (OR, 7.25; 95% CI, 2.7-19.1) or severe asthma (OR, 11.09; 95% CI, 4.1-29.6) versus enterotoxin IgE–negative subjects. The presence of GP or house dust mite IgE antibodies was not associated with either significantly increased risk for asthma or severity. Oral steroid use and hospitalizations were significantly increased in patients with enterotoxin IgE and nonatopic asthma. GP IgE was associated with a higher FEV1 percent predicted value, and enterotoxin IgE was associated with a lower FEV1 percent predicted value. Conclusions Staphylococcal enterotoxin IgE antibodies, but not IgE against inhalant allergens, are risk factors for asthma severity. We hypothesize that the presence of enterotoxin IgE in serum indicates the involvement of staphylococcal superantigens in the pathophysiology of patients with severe asthma.
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