Eosinophils And The Upper Respiratory Tract

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In fungal disease of the upper respiratory tract the presence of eosinophils is a critical diagnostic feature. Diseases of fungal etiology in the upper respiratory tract primarily involve fungal sinusitis, and both superficial "allergic" diseases and invasive fungal sinusitis are associated with eosinophilia (Currens et al. 2002; Ferguson 2004; Granville et al. 2004. As reported by the Ponikau et al. (Ponikau et al. 1999 and subsequently by other investigators, allergic fungal sinusitis (AFS) is manifest as nasal polyposis and a strong eosinophilic response. AFS is considered to be among the most prevelant forms of chronic rhinosinusitis (Braun et al. 2003a, 2003B; Granville et al. 2004; Ponikau et al. 1999). The condition results from a superficial infection of the sino-nasal mucosal tissue by a variety of different fungal organisms, dematiaceous fungi being the most common (Clark et al. 1996; Katzenstien et al. 1983a, 1983b; Gourley et al. 1990; MacMillan et al. 1987; Torres et al. 1996).

Eosinophilia in the mucous and activation of eosinophils, as evidenced by deposition of Charcot-Leyden crystals (allergic mucin), was an original diagnostic feature of AFS and has remained important (Katzenstien et al. 1983a, 1983b; Kuhn and Swain, 2003; Waxman et al. 1987). It is not understood; however, what factors are strictly required for the induction of eosinophilia and recruitment of eosinophils to the sino-nasal tissues during fungal infection of the upper respiratory tract.

Elevated serum IgE and fungal specific IgE are often included in the major diagnostic criteria of AFS. Fungal proteases from Aspergillus have been implicated in the amplification of IgE response to fungal antigens in ABPM; however, the role of IgE-mediated hypersensitivity in the development of an eosinophilic response is not clear (Corey, 1992; Deutsch and Hevron, 2004; Khun and Swain, 2003; Reed and Kita, 2004). In some patients with AFS, systemic allergy to fungal organisms may not be present (Collins et al. 2004; Sasama et al. 2005). Local production of fungal specific IgE in the absence of elevated total serum levels has been suggested as a possible mechanism for the development of an eosinophilic response in individuals without evidence of systemic allergy (Collins et al. 2004). Because serum IgE levels, and fungal specific IgE have been traditionally considered diagnostic for AFS, it is possible to misdiagnose chronic eosinophilic rhinosinusitis in patients lacking these clinical features. Additionally, there is an emerging consensus that fungi may be responsible for non-IgE mediated chronic rhinosinusitis, where eosinophilic inflammation is linked to the presence of certain fungi in the sino-nasal passage through an IgE independent mechanism (Sasama et al. 2005). A study of fungal sinusitis using IgE-deficient mice demonstrated no difference in the recruitment of eosinophils to the nasal mucosa compared to wild type mice (van de Rijn et al. 1998). This concept is further supported by a recent study characterizing the humoral response in AFS, where fungal specific IgG3 was elevated in the study group, but IgE levels remained unchanged, suggesting other immunoglobulin isotypes can mediate eosinophilic inflammation (Pant et al. 2005). Thus, eosinophilic sinus disease with fungal etiology should not always be considered an IgE-mediated allergic condition, but rather hypersensitivity characterized by eosinophilic recruitment in a Th2 dominated response (Ferguson, 2004).

Keeping this in consideration, the cytokine and chemokine response is crucial in mediating eosinophilic inflammation in fungal sinusitis. Data regarding the mechanisms of cytokine and chemokine mediated recruitment of eosinophils in fungal sinusitis are lacking. One study examined eosinophilic recruitment in response to a protein extract from A. fumigatus, and reported that eotaxin was able to recruit eosinophils to the nasal mucosal tissues in an IL-5 dependent manner, but little else has been reported (van de Rijn, 1998).

The presence of eosinophils in the blood of patients with fungal sinus disease is associated with worse disease (Zadeh et al. 2002). This may be a result of eosinophil activation and degranulation at the site of infection. The activation of eosinophils in the sino-nasal mucosa is presumed by the presence of Charcot-Leyden crystals in allergic mucin, but there are other markers for eosinophil activity in AFS (Klatzenstien et al. 1983; Kuhn and Swain 2003; Waxman et al. 1987). Levels of MBP have been correlated with disease activity suggesting a contribution of eosinophils to the pathogenesis (Khan et al. 2000). ECP has also been detected at elevated levels in patients with AFS and this also correlated to disease severity (Feger et al. 1997; Collins et al. 2004).

Conversely, the mechanisms of eosinophil activity, and the potential contribution of eosinophils to host defense in infectious sinusitis are poorly understood. During allergic disease potentially pathogenic organisms must be prevented from invading the host. In an examination of mucin from patients with AFS, eosinophils were found to be associated with fungal hyphae, and appeared to phagocytose the cuticular substance of the fungal hyphae into a sheet-like invaginated space into which, granules were released (Watanabe et al. 2004). In nasal polyposis, recruited eosinophils were reported to phagocytose and kill fungal conidia and damage fungal hyphae, processes that were amplified by TLR-2 and TLR-4 stimulation (Pitzurra et al. 2004). There is no solid evidence; however, that the anti-fungal activity of eosinophils in upper respiratory tract mycoses is protective.

Although there is an appreciation that eosinophils participate in fungal sinusitis, the detailed mechanisms of recruitment and activation in sinusitis have not been explored. To this end, the eosinophilic response to fungal infections of the lung and other sites provides some additional information.

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