Reviews and feature article
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

https://doi.org/10.1016/j.jaci.2013.02.036Get rights and content

Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or “endotypes,” which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti–IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.

Section snippets

Pathophysiology of CRS

The pathophysiology of CRS is complex and includes local, systemic, microbial, environmental, genetic, and iatrogenic factors (Fig 1).

Diagnosis of rhinosinusitis

CRS endotypes depend on definition of pathophysiologic mechanisms; however, phenotypes are recognized by clinical findings. Internationally, there is consensus concerning the clinical diagnosis of rhinosinusitis.1, 75, 76 Rhinosinusitis represents a symptomatic inflammation of the paranasal sinuses involving the sinonasal tract. The diagnosis of CRS is based on the presence of at least 2 sinonasal symptoms and should be supported by objective clinical or radiologic evidence of sinonasal

Contributing factors, differential diagnosis, and comorbidities of patients with CRS

There are a variety of contributing factors and comorbid conditions that should be considered when diagnosing and managing CRS or defining endotypes. The symptoms of rhinosinusitis can be aggravated by anatomic deformities, such as nasal septal deviations, nasal valve dysfunction, concha bullosa (enlarged nasal turbinate caused by internal ethmoid air cell), adenoid hyperplasia, nasal choanal narrowing, nasal or sinus mucoceles, scarring from prior nasal or sinus surgery, and septal

Treatment of CRS

Treatment of CRS is straightforward in most cases of acute exacerbations, but a significant group of subjects have persistent or recurrent disease. This challenge is most probably due to multiple phenotypes and endotypes with different underlying mechanisms that lead to chronicity and severity. The number of different treatment options and modalities in the literature is large, but there are limited treatment options with evidence of benefit. Apart from nasal irrigation/douching, nasal and oral

Phenotypes and endotypes of CRS

CRS is a heterogeneous collection of diseases.82, 85 In clinics CRS can be phenotyped according to duration (acute vs chronic), NPs (with and without), recurrent disease, severity (mild vs moderate vs severe), conventional therapy response, mucus color, presence of peripheral specific IgE, nature of triggering events, and presence of a complication (Fig 2). However, extensive scientific evidence is accumulating that justifies a differentiation of sinus disease not only by phenotype (ie, defined

Conclusion

In this report we propose that one of the major obstacles to understanding the causes of CRS and improving treatment is the failure to understand the underlying disease mechanisms in patients with different underlying pathophysiologies (Box 2). It will be necessary to classify patients into endotypes according to the underlying disease mechanism to improve our understanding of CRS. We propose that the classification of patients with CRS according to endotype will facilitate the development of

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    Disclosure of potential conflict of interest: C. A. Akdis receives research support from Novartis, PREDICTA, the Swiss National Science Foundation, MeDALL, the Global Allergy and Asthma European Network, and the Christine Kühne-Center for Allergy Research and Education; has consulted for Actellion, Aventis, Stallergenes, and Allergopharma; is president of the European Academy of Allergy and Clinical Immunology; is a fellow and interest group member of the American Academy of Allergy, Asthma & Immunology (AAAAI); is a former committee member of the Global Allergy and Asthma European Network; and is the director of the Christine Kühne-Center for Allergy Research and Education. C. Bachert has received research support from Novartis and GlaxoSmithKline. M. S. Dykewicz has consultant arrangements with Boehringer Ingelheim, Ista, and Merck. R. M. Naclerio has received travel support from AAAAI; has board memberships with Merck, TEVA, and Sunovion; has received grants from TEVA, Johnson & Johnson, and Kalypsis; and has received payment for lectures from TEVA and Sunovion. R. P. Schleimer has consultant arrangements with Intersect ENT, GlaxoSmithKline, Allakos, and Aurasense; has received research support from the National Institutes of Health; and has received stock/stock options from Allakos. D. Ledford has received travel support from AAAAI; has consultant arrangements with Genentech; and has received payment for lectures from Meda and Genentech. The rest of the authors declare that they have no relevant conflicts of interest.

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