Invasive external otitis (IEO) is an aggressive and potentially life-threatening infection. This rare disorder is commonly caused by Pseudomonas aeruginosa especially with diabetes as an associated disease (Rubin Grandis et al, 2004). However, a fungal aetiology should be considered in patients suffering from IEO when their symptoms worsen and are unresponsive to adequate and prolonged courses of broad-spectrum antibiotics even in the absence of immunosuppression. (Carfrae et al, 2008; Bhatt Y M, 2013; Marchionni et al, 2016; Pichon et al, 2020; Noroy L et al, 2020). Fungal IEO are mostly due to the Aspergillus spp. which is also reported as Aspergillus necrotizing/malignant otitis externa.
There are two patterns of invasive Aspergillus infections of the ear – chronic suppurative otitis media (CSOM) and invasive external otitis (IEO). Most probably the second follows from the first. CSOM caused by fungi has been infrequently reported (Dinçer et al, 1992; Tiwari et al, 1995; Ibekwe et al, 1997; Attallah 2000; Khanna et al, 2000).
Among Aspergillus species, A. fumigatus, A. flavus, and A. niger are the most notable Aspergillus spp. that cause this infection (Narozny et al, 2006). A. flavus is the second most frequent pathogenic species after A. fumigatus. Conidia of Aspergillus flavus are bigger than those of Aspergillus fumigatus preferentially infecting sinuses and ears (Hedayati et al, 2007; Pasqualotto, 2009; Krishnan et al, 2009).
Invasive Aspergillus otitis frequently involves necrosis of the meatal epithelium and subepithelial tissue of the auditory canal, bone erosion and perforation of the tympanic membrane (Vennewald et al, 2010). Aspergillus mastoiditis follows from invasive Aspergillus otitis (Petrak et al, 1985; Reiss et al 1991; Hanna et al, 1993; Ress et al, 1997; Parize et al, 2009).
IEO may occur as a result of impaired cellular innate immunity in cells from patients with diabetes mellitus with impaired chemotaxis, phagocytosis and killing capacities of polymorphonuclear cells (Geerlings et al, 1999). Defects in IL-17 and IL-22 production could play a role in Aspergillus IEO predisposition. Diabetes related microangiopathy and endarteritis alter the natural local host defences and facilitate the invasion of for Aspergillus into blood vessel walls. Local and systemic host defences may be affected by diabetes mellitus predisposing to this severe fungal infection (Delsing et al, 2015). However, it is still not clear what supports the massive proliferation of fungi in immunocompetent patients (Youssef M et al, 2014).
Clinical features are non specific and include otalgia, hearing loss, facial nerve paralysis, fever and otorrhea. Usually the middle ear is destroyed and infection has extended into the mastoid and/or petrous bone. The invasive process can lead to even death if IEO is not recognized and treated early. Masked mastoiditis with an intact tympanic membrane has been rarely reported (Mani, 2008).
Deep tissue biopsy remains the gold standard for invasive aspergillosis diagnosis providing reliable fungal identification due to highest yield of the organism and confirming the presence of Aspergillus spp. in culture or histopathological demonstration of septate hyphae consistent with Aspergillus spp. (Pichon et al, 2020). Other fungi can appear similar to Aspergillus in tissue sections and diffferent Aspergillus species have different antifungal susceptibility patterns Therefore, identification of Aspergillus cultured should be at species level. Molecular methods are recommended for identification of Aspergillus species within various sections (Balajee SA et al, 2009). Imaging using CT scan and MRI to determine the location and extent of diseased tissue .PET scan allows earlier identification of complications (e.g..temporomandibulozygomatic involvement, mastoiditis),aids in the management of the disease and rules out metastatic origin of the lesion (Youssef M et al, 2014; Noroy L et al, 2020). β-D glucan levels may be helpful in the diagnosis and follow up of these patients in the future, whereas serum galactommannan antigen was found to have low sensitivity (Marchionni et al, 2016). Diagnosis is often delayed because Aspergillus is very rarely involved in IOE, compared with P. aeruginosa (Carfrae et al, 2008). Early diagnosis is imperative to guide towards appropriate treatment and to improve outcome
Otological sequelae are frequent, including residual hearing impairment, dizziness, residual facial palsy or hypothesia, otalgia or pain during mastication. Infection can extend into temporomandibular joint, skull base, neck deep space and mastoid. These features may be present at presentation and be visible on imaging. Vascular involvement has been reported as well (Marchionni et al, 2016).
Historically, surgery was considered an integral part of the treatment of invasive Aspergillus otitis, however, surgical procedure is now reserved to diagnostic approach such as bone biopsy and culture. (Stodulski et al, 2006; Pichon et al, 2020). Extensive surgical debridement along with long-term systemic antifungal therapy including amphotericin B and/or itraconazole was the standard of treatment (Finer et al, 2002), until the licensure of voriconazole.
In accordance with recent guidelines, voriconazole is now currently considered the first choice of therapy in invasive Aspergillus otitis with favourable outcomes (Walsh et al, 2008, Marchionni et al, 2016). Voriconazole is a broad-spectrum azole which exhibits high anti-Aspergillus activity and good long-term tolerance. It has good bone and soft tissue diffusion (Denes et al, 2007; Mouas et al, 2005). Voriconazole shows better fungicidal activity towards A. fumigatus than itraconazole (Lewis et al, 2005) and a superior efficacy against invasive aspergillosis than intravenous amphotericin B (Herbrecht et al, 2002). Therapeutic drug monitoring of voriconazole is recommended to improve its safety and efficacy, especially in immunocompromised patients (Ashbee et al, 2014).
Early invasive Aspergillus otitis externa can be successfully treated with voriconazole without the need for surgical debridement. However, surgical debridement is still necessary for refractory Aspergillus invasive otitis externa.
Hyperbaric oxygenation has been shown to increase the oxygen partial pressure in infected tissues, enhancing oxygen-mediated leukocyte killing of pathogens. Moreover, regular exposure to hyperbaric oxygenation enhances soft-tissue and bone healing by promoting fibroblastic division, collagen production, and capillary angiogenesis. Its efficacy remains debatable (Phillips and Jones, 2005; Narozny et al, 2006; Savvidou et al, 2018).
Drug-resistant Aspergillus species do not usually emerge, and a second course of voriconazole could be used to treat the infection if relapse are to occur (Hsu-Chueh et al, 2014).
Rola Hashad MB BCh, MSc, PhD
Lecturer of Medical Microbiology and Immunology, Faculty of Medicine, Alexandria University, Egypt.
Mohammad T. Hedayati, MSc, PhD
Invasive Fungi Research Center/ Department of Medical Mycology,
Mazandaran University of Medical Sciences, Khazarabad Road,
P.O. Box: 48175-1665, Sari- Iran
August 2020
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