Kern et al treatments, which in turn is related to the lack of understanding of the pathophysiology of the disease (Meltzer et al 2004). This review will focus on current thinking and evidence for the pathogenesis of CRS, as well as current diagnostic methods and treatment options, including the topical intranasal use of antifungal compounds. Clinical definition The term CRS encompasses all inflammatory disorders of the nose and paranasal sinuses with a minimum duration of 12 weeks. This definition was put forth in 1996 by the Rhinosinusitis Task Force (RSTF), which was established by the American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) (Benninger et al 2003). However, this definition does not include a specific etiology for the eosinophilic inflammatory process. Etiology and pathogenesis CRS has a number of proposed causes. It is often attributed to bacterial infection; a variety of aerobic (staphylococcus spp., Gram-negative rods) and anaerobic (prevotella, fusobacterium, peptostreptococcus) bacteria have been cultured from patients with CRS (Meltzer et al 2004). However, it is unclear if bacteria are causing infection, are exposing the host to superantigens causing an inflammatory response, or are able to colonize due to pre-existing pathology of the sinus mucosa (Meltzer et al 2004). A fairly recent concept in the pathogenesis of CRS is colonization with fungi. Due to the presence of fungal spores in the air, fungus is a common f inding in the upper respiratory tract even of healthy individuals. There are, however, clinical subentities of CRS that have long been attributed to fungal etiology. Allergic fungal rhinosinusitis (AFRS) is a type of CRS in which patients have an allergic response to the fungus colonizing the mucin in their sinonasal cavities. In contrast, fungus balls are caused by overgrowth of fungus in the nose and paranasal sinuses, without an inflammatory reaction (Meltzer et al 2004). The inflammatory reaction in response to a fungus ball is more of an irritative inflammation, like a foreign body reaction, ie, giant cells, and not an eosinophilic inflammation, which is present in CRS. Recent studies have attributed a much broader role to fungi in CRS. It is postulated that in certain individuals, colonizing fungi provoke a hypersensitivity response that is non-immunoglobulin E (IgE)-mediated. Rather than an allergic response, the fungi stimulate a local inflammatory response with infiltration of eosinophils. This condition has 320 been termed eosinophilic fungal rhinosinusitis (EFRS), and it has been implicated in the majority of cases of CRS (Meltzer et al 2004). The immune response in CRS patients is commonly a partial Th2 lymphocyte response (production of interleukin [IL]-5, IL-13, a small amount of IL-4); this is the immune profile seen even among CRS patients who have a positive skin response to fungal allergens, where one would expect increased IL-4, as it is necessary for IgE synthesis (Hamilos and Lund 2004) In fact, it seems that a universal immune response in CRS is a T-cell response (a mix of Th1 and Th2 cells) with IL-5 as the most recognized mediator, IL-13, and little IL-4 (Hamilos and Lund 2004). Although allergic rhinitis can be present as a comorbid condition, the patient with CRS alone exhibits eosinophilic mucin on histology, without evidence for IgE-mediated allergy (Sasama et al 2005). The mucin of CRS patients also contains fungal hyphae. Ponikau and colleagues (1999) collected specimens from 210 patients with CRS (with or without polyposis) and found that 96% were culture positive for multiple fungi, the most common being Alternaria spp. (44.3%). Interestingly, 100% of the 14 healthy controls also had positive fungal cultures, with similar mycology. Other recent studies have found similar results using fungal DNA detection with PCR (Gosepath et al 2004). Therefore fungi are present in patients with CRS and in healthy controls. The difference between the CRS patients and the controls in this study was the presence of eosinophils in tissue specimens (96% of 101 CRS surgical cases vs none of 4 controls). Fungi, only in sensitized individuals, will initiate the eosinophilic reaction, which targets the fungi in the mucous and allows the degranulation of the eosinophils. The authors hypothesized that the patients with CRS were forming an eosinophilic reaction toward the fungal hyphae in their sinonasal mucin; the eosinophils migrate through the epithelium and degranulate in the mucin, causing the inflammatory response (Ponikau et al 1999). It is likely that it is the fungal antigen itself in patients with CRS, which is able to induce migration and degranulation of the eosinophils. This fungal antigen is derived from the germinating fungal spores. Thus, it is the airborne fungal spores, not a fungal colony itself which is required to induce the immunologic cascade. Eosinophilic degranulation is thought to cause the local tissue damage seen in CRS, mainly through release of major basic protein (MBP). It appears that MBP itself inflicts the epithelial damage directly because of its toxicity (Frigas et al 1980; Harlin et al; Motojima et al Therapeutics and Clinical Risk Management 2007:3(2)