The Etiology and Pathogenesis of Chronic Rhinosinusitis: a Review of Current Hypotheses

Abstract

Chronic rhinosinusitis (CRS) is a broad clinical syndrome that is characterized by prolonged mucosal inflammation of the nose and paranasal sinuses, and is typically divided into two subtypes based on the presence or absence of nasal polyps. The etiology and pathogenesis of both forms remain areas of active research. Over the last 15 years, a number of hypotheses have been proposed to explain all or part of the clinical CRS spectrum. These hypotheses reflect the concept that CRS results from a dysfunctional interplay between individual host characteristics and factors exogenous to the host. Six broad theories on CRS etiology and pathogenesis are discussed as follows: (1) the "fungal hypothesis," (2) the "superantigen hypothesis," (3) the "biofilm hypothesis," and (4) the "microbiome hypothesis," all of which emphasize key environmental factors, and (5) the "eicosanoid hypothesis" and (6) the "immune barrier hypothesis," which describe specific host factors. These theories are reviewed, and the evidence supporting them is critically appraised.

Fig. 1

The “immune barrier hypothesis” posits that the chronic inflammation associated with CRS is linked to a defective mechanical and innate immune barrier. This deficit leads to a compensatory innate effector cell recruitment and activation, coupled with a robust adaptive immune response. The nature of this compensatory response likely varies among CRS phenotypes. Describes the proposed pathway for a typical case of Caucasian nasal polyposis. Reduced host defense molecules (1) lead to an abnormal microbiome (2), likely in biofilm format. Impaired mucociliary flow and a porous mechanical barrier lead to increased access of PAMPS stimulating a compensatory response (3). In Caucasian polypoid CRS, the cytokines BAFF and TSLP have been implicated in the observed innate and adaptive response. TSLP acts on type 2 innate lymphocytes (ILC2s) to release the type 2 cytokines IL-5 and IL-13. TSLP also acts on dendritic cells, fostering Th2 lymphocyte differentiation with an amplified type 2 cytokine response. Superantigens, if present, will accentuate the T cell response expressed in the tissue; in this case, the response is skewed to Th2. BAFF drives a strong local B cell immunoglobulin response, including autoreactive antibodies in severe cases (4). Collectively, this results in the recruitment and activation of innate effector cells that possess Fc receptors for the locally produced immunoglobulins. In the presence of large amounts of antigen that penetrate the weakened barrier, this should lead to widespread effector cell degranulation and tissue damage