Neutrophilic inflammation in chronic rhinosinusitis.

PURPOSE OF REVIEW: Over the last years, extensive research has been done on neutrophils and their contribution in chronic rhinosinusitis (CRS), and made it clear that they are more than just a bystander in this disease. In this article, we will review all recent publications on this topic and look to what the future hold regarding therapeutics targeting the neutrophilic inflammation in CRS. RECENT FINDINGS: Evidence is growing that the presence of neutrophils are associated with a worse disease outcome in certain CRS patient groups. They are highly activated in type 2 inflammations and exhibit damaging properties through their proteases, contributing to the chronicity of the disease. Several recent studies identified useful biomarkers and targets for future therapeutics. SUMMARY: The findings we review in this manuscript are of utmost importance in unraveling the complexity of CRS and provide us with the necessary knowledge for future clinical practices.

Can patient-reported outcomes and inflammatory markers define endotype 2 in chronic rhinosinusitis without nasal polyps?

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease at the clinical phenotype level (without nasal polyp [CRSsNP] vs with nasal polyp [CRSwNP]) and at the underlying inflammatory endotype level (type 2 vs non-type 2). Whether the endotype is associated with clinical presentation in patients with CRSsNP has yet to be explored in detail. OBJECTIVE: To identify associations between endotypes and their clinical significance in patients with CRSsNP based on tissue interleukin-5 levels. METHODS: A total of 104 patients with CRSsNP who underwent functional endoscopic sinus surgery between 2013 and 2017 were endotyped. We collected immunologic and clinical parameters and evaluated whether there were associations between the endotype and clinical features using Visual Analog Scale (VAS), Sino-Nasal Outcome Test-22 (SNOT-22), Sniffin' Sticks test, Lund-Mackay CT score, and nasal endoscopy. RESULTS: Mean tissue interleukin-5 levels were used to identify type 2 inflammation (non-type 2: 3.37 vs type 2: 191.98 pg/g tissue; P < .001). There were no significant clinical differences measured by patient-reported outcome measures between patients with type 2 CRSsNP and those with non-type 2 CRSsNP preoperatively. Type 2 and non-type 2 CRSsNP did not differentiate in CT score, Sniffin' Sticks test, and nasal endoscopy. Postoperative SNOT-22 and VAS scores correlated well with each other (r = 0.75; P < .01). Postoperative VAS scores were in both groups significantly lower than before the operation (type 2: 5.07 vs 2.99; P < .01; non-type 2: 5.74 vs 3.22; P < .01), but not associated to the inflammatory subtype. CONCLUSION: The type of inflammation does not affect the symptoms, the computed tomography scan, or the postoperative results in CRSsNP in contrast to former findings in CRSwNP. TRIAL REGISTRATION: Belgian registration number (B.U.N.) No. B6702020000097.

Olfaction in nasal polyp patients after Reboot surgery: an endotype-based prospective study.

PURPOSE: To report biomarkers present in the olfactory mucosa in chronic rhinosinusitis with nasal polyps (CRSwNP) in comparison with nasal polyps and to nasal mucosal tissues from control patients. To evaluate the kinetics of smell over 6 months in patients who underwent Reboot surgery. METHODS: Cohort study from May 2021 to May 2022. We collected samples of olfactory mucosa and nasal polyps from 16 CRSwNP patients and inferior turbinate samples from 20 control subjects. The study was not randomized for surgical and/or medical treatment. Samples were analyzed by Luminex and Unicap 100 to measure biomarkers of inflammation (IL1-ß, IL4, IL5, IL6, IL17, CCL3, CCL4, G-CSF, SE-IgE, total IgE and ECP). 12 of the CRSwNP patients underwent Extended Sniffin'tests at timepoints 1-4 days pre-surgery, and 1, 3 and 6 months after Reboot surgery. RESULTS: Type-2 markers were significantly elevated in OM and polyp tissue in CRSwNP (n = 16) vs. controls (n = 20), P < 0.05. TDI scores improved already 1 month (P < 0.05) after surgery and remained stable for 6 months. Type-2 inflammation in nasal polyps was associated with decreased sense of smell and taste before surgery, but improved after surgery (P = 0.048). Type-3 inflammation was present in the olfactory mucosa and was associated with a better sense of smell before surgery, but a smaller improvement of smell afterward. CONCLUSIONS: Type-2 inflammation is present in the olfactory mucosa in CRSwNP patients and is associated with smell loss. Reboot surgery, aiming to completely remove inflamed sinus mucosa, significantly improves the smell in this group of patients.

Advances in chronic rhinosinusitis in 2020 and 2021.

Major progress has been achieved in the understanding and clinical practice of chronic rhinosinusitis, with or without nasal polyps. These advances resulted in a better understanding of the pathophysiology, the distribution into subgroups, and consequently in a better management perspective using classical approaches and biologics. Pathomechanisms, endotypes and biomarkers, and finally innovative therapeutic approaches are themes especially for the more severe forms of chronic rhinosinusitis, those with uncontrolled severe nasal polyps. Biologicals against key type 2 cytokines are gaining ground in the long-term treatment approaches of often recurrent nasal polyps, and should be integrated in care pathways making use of classical and innovative treatment pathways. These areas of interest show a fast development and will profoundly change our disease management within a decade.

Rethinking neutrophils and eosinophils in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) often is characterized by an eosinophilic inflammatory pattern, nowadays referred to as type 2 inflammation, although the mucosal inflammation is dominated by neutrophils in about a third of the patients. Neutrophils are typically predominant in 50% of patients with CRS without nasal polyps, but also are found to play a role in patients with severe type 2 CRS with nasal polyp disease. This review aims at summarizing the current understanding of the eosinophilic and neutrophilic inflammation in CRS pathophysiology, and provides a discussion of their reciprocal interactions and the clinical impact of the mixed presentation in patients with severe type 2 CRS with nasal polyps. A solid understanding of these interactions is of utmost importance when treating uncontrolled severe CRS with nasal polyps with biologicals that are preferentially directed toward type 2 inflammation. We here focus on recent findings on both eosinophilic and neutrophilic granulocytes, their subgroups and the activation status, and their interactions in CRS.

A substantial neutrophilic inflammation as regular part of severe type 2 chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with severe type 2 immune reactions in the white population. However, recent findings suggest an additional role for neutrophils in severe type 2 inflammation. OBJECTIVE: This study aimed to characterize the neutrophilic inflammation in CRSwNP and its relation to eosinophilic inflammation in severe type 2 immune reactions. METHODS: The presence and activation of neutrophils and eosinophils was analyzed in CRS without NP and CRSwNP by measuring cell and activation markers via immunohistochemistry, immunofluorescence, Luminex assay, ELISA, UniCAP, fluorescence-activated cell sorting, and PCR. Differential neutrophil migration was assessed via Boyden-chamber assay and neutrophil survival was analyzed via flow cytometry. RESULTS: Both CRS without NP and CRSwNP displayed variable degrees of eosinophilic and neutrophilic inflammation, with a profound neutrophilic infiltration and activation in type 2 CRSwNP, associated with eosinophil extracellular traps cell death and Charcot-Leyden crystals, but independent of IL-17. Neutrophil extracellular traps cell death in CRSwNP was associated with bacterial colonization, however, neutrophils were less prone to undergo neutrophil extracellular traps cell death in the tissue of patients with severe type 2 CRSwNP. Neutrophils did not show increased migration nor survival in the CRSwNP environment in vitro. CONCLUSIONS: This study demonstrated a severe neutrophilic inflammation associated with severe eosinophilic type 2 inflammatory CRSwNP, the role of which needs further study.

Unravelling the expression of interleukin-9 in chronic rhinosinusitis: A possible role for Staphylococcus aureus.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a Th2 biased inflammation, associated with nasal colonization of Staphylococcus (S.) aureus. Interleukin (IL)-9 is a pro-inflammatory Th2 cytokine with a pivotal role in asthma, allergy and chronic obstructive pulmonary disease (COPD), but is less studied in CRSwNP. We aimed to characterize the expression and cellular source of IL-9 and examined S. aureus as potential local trigger in CRSwNP. We showed increased numbers of interleukin-9 producing neutrophils and mononuclear cells in the tissue of CRSwNP patients. This interleukin-9 production was stimulated by S. aureus and its enterotoxin B in vitro. These findings underline the contribution of S. aureus and define IL-9 as another relevant cytokine in type 2 CRSwNP.

Type 2 inflammation in chronic rhinosinusitis without nasal polyps: Another relevant endotype.

BACKGROUND: 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. OBJECTIVE: We aimed to characterize the underlying type 2 immune response and its clinical significance in patients with CRSsNP. METHODS: 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. RESULTS: 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. CONCLUSION: 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.