Charcot-Leyden crystals promote neutrophilic inflammation in patients with nasal polyposis

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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.

Section: Discussionmentioning

confidence: 95%

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

Delemarre¹,

Holtappels²,

Ruyck³

et al. 2020

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“…39,40 In turn, these crystals further sustain the inflammation by enhancing the proinflammatory cytokine production from the epithelium and other inflammatory cells. 40,41 In addition, the deposition of these highly stable crystals leads to a secondary neutrophilic inflammation and NETosis, which leads to further damage to the tissue or epithelium and may lead to resistance to therapeutic interventions with glucocorticoids. [40][41][42][43] TREATMENT APPROACHES AND UNMET NEEDS Type 2 immune reactions in CRSwNP have been associated with asthma comorbidity, severity, and recurrence of nasal polyps after systemic GCS or surgical treatment.…”

Section: Type 2 Inflammation In Crswnpmentioning

confidence: 99%

“…40,41 In addition, the deposition of these highly stable crystals leads to a secondary neutrophilic inflammation and NETosis, which leads to further damage to the tissue or epithelium and may lead to resistance to therapeutic interventions with glucocorticoids. [40][41][42][43] TREATMENT APPROACHES AND UNMET NEEDS Type 2 immune reactions in CRSwNP have been associated with asthma comorbidity, severity, and recurrence of nasal polyps after systemic GCS or surgical treatment. 6 Frequent oral GCS boosts per year and repeated surgeries are therefore a clear hint for type 2 CRSwNP.…”

Section: Type 2 Inflammation In Crswnpmentioning

confidence: 99%

“…[66][67][68] Their effectiveness also has been demonstrated for CRSwNP, with mepoliumab and benralizumab currently in phase 3 trials. With the IL-5 antagonism, also secondary phenomena such as eosinophil extracellular trap release from activated eosinophils and Charcot-Leyden-crystal formation with the consecutive recruitment of neutrophils 41 should be avoided; however, it is unclear how long Charcot-Leyden-crystals can persist in the tissue and maintain a neutrophilic inflammation. In a double-blind placebo-controlled, randomized (DBPCR), 2-center safety and pharmacokinetic study, 24 subjects with bilateral CRSwNP were randomized to receive a single intravenous infusion of reslizumab, a humanized antihuman IL-5 mAb, at 3 mg/kg or 1 mg/kg or placebo.…”

Section: Antagonizing Eosinophil Activation In Crswnpmentioning

confidence: 99%

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Biologics for chronic rhinosinusitis with nasal polyps

Bachert

Zhang

Cavaliere

et al. 2020

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124

101

With the increasing recognition of the role of type 2 immune responses in chronic rhinosinusitis, its severity, recurrence, and comorbidities, several biologics targeting IL-4, IL-5, and IL-13 as well as IgE have been administered in small proof-of-concept studies. Recently, the first phase 3 trials have been reported with dupilumab, an IL-4 receptor antagonist, demonstrating a significant and clinically relevant reduction of the disease burden from polyp size and sinus involvement to symptoms and smell; these changes consecutively led to an important increase in quality of life. Finally, the biologic versus placebo treatment reduced the need for systemic glucocorticosteroids and sinus surgery significantly and clinically meaningfully. Dupilumab today is registered for the treatment of chronic rhinosinusitis with nasal polyps in Europe and the United States. Within a year, 2 further phase 3 trials with omalizumab and mepolizumab will be reported. With this development, without any doubt, a new era for the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps has begun. Questions on the indication of the biologics, the selection of patients, and finally criteria for monitoring the efficacy in individual patients need to be urgently answered, and care pathways need to be established integrating the current standard of care including surgery.

“…17,18 These CLCs, however, induce a strong neutrophilic infiltration on their own, adding to the inflammatory load of the mucosa. 19 In less severe inflammation, INF-g and IL-17 may also induce neutrophilic inflammation side to side with the presence of eosinophil granulocytes. 20,21 However, the fact that more than 80% of bilateral nasal polyps-and thus the vast majority-are type 2 with or without comorbid type 1 or 3 inflammation 10 led to the fact that non-type 2 nasal polyps were neglected in the strategy for biologic treatment.…”

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confidence: 99%

Endotypes of chronic rhinosinusitis: Impact on management

Cardell

Stjärne

Jonstam

et al. 2020

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Following the trend in asthma, endotypes for chronic rhinosinusitis with nasal polyps have been established, with type 2 immune reactions representing >80% of nasal polyp cases in Europe and the United States. Endotyping is without doubt useful to predict the natural course of disease, to determine pharmacotherapy and the extent of surgery, and lately also to select patients for treatment with type 2 biologics. However, with the opening of this new era of treatment, limitations of the current possibilities in subgrouping patients also became apparent, as (1) mixed endotypes often can be found and (2) predictions as to the best biologic to be used in an individual patient are not yet possible. Some of the questions to address in the near future are discussed. (J Allergy Clin Immunol 2020;145:752-6.)