Endotypes of chronic rhinosinusitis: Relationships to disease phenotypes, pathogenesis, clinical findings, and treatment approaches

Abstract

Chronic rhinosinusitis (CRS) is a common clinical syndrome that produces significant morbidity and costs to our health system. The study of CRS has progressed from an era focused on phenotype to include endotype-based information. Phenotypic classification has identified clinical heterogeneity in CRS based on endoscopically observed features such as presence of nasal polyps, presence of comorbid or systemic diseases, and timing of disease onset. More recently, laboratory-based findings have established CRS endotype based upon specific mechanisms or molecular biomarkers. Understanding the basis of widespread heterogeneity in the manifestations of CRS is advanced by findings that the three main endotypes, Type 1, 2, and 3, orchestrate the expression of three distinct large sets of genes. The development and use of improved methods of endotyping disease in the clinic are ushering in an expansion of the use of biological therapies targeting Type 2 inflammation now and perhaps other inflammatory endotypes in the near future. The purpose of this review is to discuss the phenotypic and endotypic heterogeneity of CRS from the perspective of advancing the understanding of the pathogenesis and improvement of treatment approaches and outcomes.

Keywords: chronic rhinosinusitis; endotype; inflammation; nasal polyps; phenotype.

FIGURE 1.

Gene expression patterns in sinonasal tissues from patients undergoing surgery at Northwestern in Chicago. Data are from samples taken from patients with no sinonasal disease (Control, n = 11), CRSsNP (9 TunsNP, 5 T1sNP, 8 T2sNP, and 5 T3sNP), and CRSwNP (8 ET and 9 NP). The heatmap shows genes with more than threefold elevated levels in T1sNP, T2sNP, or T3sNP compared to controls. Inspection of the gene expression patterns shows that CRSwNP samples from ethmoid tissue and from nasal polyps are closely aligned with the T2 patterns seen in ethmoid tissue from a T2 subset of patients with CRSsNP. The figure was adapted from published studies by Klingler et al. Tun—untypeable, T1—Type 1 endotype, T2—Type 2 endotype, and T3—Type 3/17 endotype (see text). ET, ethmoid tissue; NP, nasal polyp tissue

FIGURE 2.

Characterizations of inflammatory endotypes in CRS and potential implications for clinical identification and management. Overview of the primary cytokines driving T1, T2, and T3 endotypes, the source cells producing the primary cytokines and the effector cells that are recruited to the tissue and activated. The natural targets of each immunological endotype are shown. An overview of recent studies linking clinical phenotypic signs and potential treatments with molecular endotype is also included in the figure. It is anticipated that future studies will increasingly link phenotypic signs and symptoms with an underlying endotype to better define pathogenic mechanisms and indicate appropriate treatment regimens

FIGURE 3.

Summary of the major biomarker genes whose expression is elevated in the T1, T2, and T3 endotypes of CRS (whether CRSsNP or CRSwNP). We present selected genes from our previous study that showed >3-fold significant elevation compared to control and all other CRSsNP endotypes. Genes and proteins shown in bold are currently the best markers to identify inflammatory endotypes. Also shown are the “mixed” endotypes, as indicated by T1,3, T1,2, and T2,3. Not shown are T untypeable (Tun), which do not express elevated levels of the biomarker genes, or the T1,2,3 endotype comprised of a rare group of patients that have elevated levels of all three sets of biomarker genes