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

Abstract

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.

FIG 1

Pathomechanisms of CRS. A, CRSwNP. In a T_H2-type microenvironment with general lack of regulatory T (Treg) cell function, IL-5 induces eosinophilia, and IL-4 and IL-13 induce local IgE production. An alternatively activated macrophage subset contributes to the inflammation. The activation of epithelium colonized by bacteria and fungi leads to release of proinflammatory chemokines and cytokines with increased thymic stromal lymphopoietin (TSLP) and IL-32 levels. Activated epithelial cells die, with apoptosis resulting in a compromised epithelial barrier. B, CRSsNP. Instead of a T_H2-skewed T-cell response, a T_H1 or a mixed T_H0 response predominates, neutrophilia is often associated, and expression of TGF-β and its receptors is increased. DC, Dendritic cell.

FIG 2

Key phenotypes in relationship to proposed endotypes and their possible associations are shown. ASA, Aspirin.

FIG 3

Algorithm for the follow-up of patients with CRSwNP (A) and CRSsNP (B). CSF, Cerebrospinal fluid.