Understanding the aetiology and resolution of chronic otitis media from animal and human studies

Abstract

Inflammation of the middle ear, known clinically as chronic otitis media, presents in different forms, such as chronic otitis media with effusion (COME; glue ear) and chronic suppurative otitis media (CSOM). These are highly prevalent diseases, especially in childhood, and lead to significant morbidity worldwide. However, much remains unclear about this disease, including its aetiology, initiation and perpetuation, and the relative roles of mucosal and leukocyte biology, pathogens, and Eustachian tube function. Chronic otitis media is commonly modelled in mice but most existing models only partially mimic human disease and many are syndromic. Nevertheless, these models have provided insights into potential disease mechanisms, and have implicated altered immune signalling, mucociliary function and Eustachian tube function as potential predisposing mechanisms. Clinical studies of chronic otitis media have yet to implicate a particular molecular pathway or mechanism, and current human genetic studies are underpowered. We also do not fully understand how existing interventions, such as tympanic membrane repair, work, nor how chronic otitis media spontaneously resolves. This Clinical Puzzle article describes our current knowledge of chronic otitis media and the existing research models for this condition. It also identifies unanswered questions about its pathogenesis and treatment, with the goal of advancing our understanding of this disease to aid the development of novel therapeutic interventions.

Keywords: Animal models; Chronic otitis media; Genetics; Inflammation.

Fig. 1.

Otoscopic view of the right ear of a 5-year-old child with COME (‘glue ear’). An effusion is present behind (deep to) the tympanic membrane (ear drum), which appears as slight opacity. Image courtesy of Professor David Pothier, University of Toronto, Ontario, Canada.

Fig. 2.

Otoscopic view of the right ear of a child with CSOM. The image shows a perforation of the posterior tympanic membrane. This patient complained of intermittent ear discharge (otorrhoea), although at the time of this image no discharge is evident. Image courtesy of Professor David Pothier, University of Toronto, Ontario, Canada.

Fig. 3.

Inter-related phenotypes of mucosal OM, together with their known or presumed risk factors. In this schematic, white broken arrows denote postulated links between OM-related conditions and unbroken arrows represent known links. Risk factors and therapies associated with pathogen exposure (left) and with host characteristics and inflammatory response (right) for acute and chronic forms of OM are shown. There are two forms of chronic mucosal OM: COME (chronic OM with effusion) and CSOM (chronic suppurative OM). Note that OME and COME can occur without antecedent AOM. The causes of CSOM are not well understood. AOM, acute otitis media; rAOM, recurrent AOM.

Fig. 4.

Common methods to induce acute or chronic OM in mouse models. Methods shown here are for mouse models (methods to induce acute or chronic otitis media are determined by the model species and the hypothesis under test, and can be combined; for example, inoculating a genetic mutant with bacteria). (A) Inoculation with bacteria. A mouse is inoculated with bacteria, intranasally or by injection directly into the middle ear (bulla). Bacteria commonly used include pneumococcus or NTHi. (B) Surgical methods. The top inset shows surgically induced tympanic membrane perforation, and the lower inset shows surgical ligation of the Eustachian tube. (C) Genetic manipulation. This can be performed via chemical mutagenesis [typically with injection of the chemical mutagen N-ethyl-N-nitrosourea (ENU), as shown] or by targeted genetic mutation. (D) In vitro cell culture, for example of immortalised middle ear epithelial cells or mucosal explants. Following exposure to bacteria, these cell-culture models enable host-pathogen interactions at the epithelial surface to be assessed.

Fig. 5.

Gross and microscopic pathology in different subtypes of chronic OM. (A) The structures of a child's middle ear, including the ossicles (malleus, incus and stapes), tympanic membrane and Eustachian tube. The normal ciliated and non-ciliated epithelial lining of the middle ear, overlaid by a thin layer of surface mucus, is shown in a magnified view (lower panel). (B) The middle ear of a child with COME. The pale yellow shading depicts mucoid effusion. Lower panel: the inflamed lining of the middle ear features mucosal hyperplasia with secretory goblet cell proliferation. Bacteria can exist in the effusion in a planktonic state, in biofilms or intracellularly, and neutrophils and macrophages are present. (C) The middle ear of a child with CSOM. Yellow shading depicts purulent effusion, and the tympanic membrane is perforated. Lower panel: the inflamed lining of the middle ear features mucosal hyperplasia, which can be profuse and form polyps. Bacteria are present in a variety of forms and many different bacterial species can be found. Neutrophils, macrophages and lymphocytes are present in abundance.