Nasal polyposis pathophysiology: Endotype and phenotype open issues

Abstract

Purpose

Endotyping chronic rhinosinusitis with nasal polyps (CRSwNP) poses a challenge for rhinologists nowadays. Phenotyping CRSwNP proved inappropriate as an approach to their classification because of their common clinical features. Endotyping, being based on the pathogenic mechanism, provides a precise picture more appropriate for use in clinical practice. Patients' treatment and follow-up can thus be tailored to cope with the degree of aggressiveness of a specific CRSwNP endotype.

The aim of this study was to analyze the available information about the main currently accepted endotypes of CRSwNP; furthermore, we reported and commented evidence regarding some clinical conditions associated with nasal polyposis which could be related with new endotypes.

Materials and methods

Pubmed and Scopus electronic database were searched. The main available studies about CRSwNP endotyping published predominantly in the last 5 years were critically analyzed.

Results

The pathophysiological features of some asthma-related CRSwNP (allergic fungal rhinosinusitis, aspirin-exacerbated respiratory disease) are quite well understood, including them among known endotypes of CRSwNP. On the other hand, because of their known pathophysiological mechanisms, some well-known diseases associated with aggressive forms of CRSwNP, such as eosinophilic granulomatosis with polyangiitis, primary ciliary dyskinesia and cystic fibrosis, should be investigated as potentially related with CRSwNP endotypes.

Conclusions

CRSwNP comprises several inflammatory endotypes defined by different pathogenic mechanisms. These endotypes correlate with the disease's clinical manifestations and behavior. A thorough understanding of CRSwNP endotypes will enable targeted medical therapies and tailored follow-up protocols.

Introduction

Chronic rhinosinusitis (CRS) is commonly divided into two phenotype-based groups on the presence (CRSwNP) or absence of nasal polyps (CRSsNP), which are clinically diagnosed by nasal endoscopy and/or computed tomography (CT) of the paranasal sinuses. It is clear that this classification is over simple, since the same patients may or may not have nasal polyps at different times in their clinical history, even after appropriate medical or surgical treatment.

A different, more comprehensive approach is therefore needed to classify CRS more accurately. There is evidence to suggest that some forms of nasal polyposis, associated with certain conditions (e.g. allergy, asthma, aspirin sensitivity), have particular characteristics: local aggressiveness, a weak response to drugs, and high recurrence rates after surgical treatment. Such forms are quite homogeneous from the clinical viewpoint, and have been called “phenotypes”, but this classification also reveals some weaknesses in clinical practice [1,2]. In 2008, Anderson [3] observed that intrinsic bronchial asthma (which could be considered as an “unicum” in terms of its clinical profile) differed between young adult and elderly patients in terms of severity and response to therapy. Surmising that the two forms of asthma had a different pathogenesis, Anderson introduced the concept of “endotype”. Endotyping is based on the fact that some diseases have the same pathogenic mechanism even though their etiology and final clinical features may differ.

The endotyping approach prompted the idea that some forms of disease sharing the same mechanism of action could be treated with targeted therapies to interrupt their progression. Investigations revealed that some elements were capable of triggering a common inflammatory mechanism [4,5]. For example, bacteria, fungi, viruses, biofilms, and proteins are all able to activate T-helper (T_H) cells, which shift from a quiescent native state (T_H naive), through an intermediate T-helper Ø (T_HØ) stage, to reach a final T-helper specialization stage as type 1, 2 and 17 (T_H1, T_H2, T_H17). These activated lymphocytes produce a spectrum of substances called interleukins (ILs). They can regulate the activity of other blood cells in the immune system, especially eosinophils and basophils, giving rise to an inflammatory microenvironment. The cells attracted to a site of inflammation are capable of producing other cytokines that can enrich the microenvironment and facilitate the inflammatory process. Among these cytokines, at the endothelial level there are chemokines (eotaxins 1, 2 and 3) that are able to activate and recruit eosinophils, basophils, and T_H lymphocytes at the inflammatory site. Adhesins (intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) make cells adhere to vessels and tissues, and cause cellular transmigration through the endothelium. Then there are the metal proteinases 2 and 9 which locally degrade the extracellular matrix by allowing inflammatory cells to pass through and spread into the nasal polyp tissue. The final stage leads to the synthesis of DNA transcription factors, such as G-A-T-A binding core sequence transcription factors, or signal transducers and transcription activators. These proteins produced by inflammatory cells migrate into the cell nucleus, binding to specific DNA sites, and blocking or triggering the action of RNA polymerase and RNA synthesis, which results in an altered cell turnover. For example, action on eosinophils has the effect of inhibiting apoptosis, leading to an exponential increase in eosinophils in nasal polyps.

It is now believed that T helper cells are compartmentalized: interleukins 4, 5 and 13 are produced, and eosinophils are recruited in the T_H2 environment, while interleukins 17 and 22 are mainly produced, and neutrophils are recruited in the T_H1 and T_H17 environments. It has also been suggested, however, that multiple cell lines can coexist at the same site of inflammation.

We are still unable to classify all CRS endotypes. Some endotypes have been understood and associated with a clearly-defined form of CRS thanks to a close correspondence between endotype and phenotype. Different forms of CRS sometimes seem to share the same pathogenesis (i.e. there may be several phenotypes with the same endotype). Finally, as Anderson [3] suggested for asthma, if the same form of CRS shows different clinical characteristics (e.g. a phenotype with different degrees of aggressiveness), this may be due to various pathogenic mechanisms (different endotypes with the same phenotype). These complexities can only be clarified by means of a significant improvement in our understanding of the pathogenic mechanisms involved.

The need for identifying individual phenotypes and endotypes extends to the approaches that currently considered the mainstay of treatment of CRS [6]. In particular, the endotypes classificative approach has to focus on defining CRS pathogenic mechanisms rather than describing the inflammatory pattern of CRS even in an advanced biological way. The aim of this study was to analyze the available information about the main currently accepted endotypes of CRSwNP [6,7]; furthermore, we reported and commented evidence regarding some clinical conditions associated with nasal polyposis which could be related with new endotypes.