The etiology and pathogenesis of CRS currently is unknown; however, there are several new insights into the potential mechanisms of CRS.

The hypothesis proposed by Ponikau involves fungus-dependent activation of the immune system with subsequent recruitment of eosinophils to the nasal mucus. This is supported by histopathologic studies of nasal mucus that demonstrate fungal elements surrounded by clusters of eosinophils (10). It has been hypothesized that eosinophils play a defensive role against fungal hyphae trapped in the mucus. Eosinophils release granule-associated cationic proteins, MBP, eosinophilic peroxidase, and eosinophil-derived neurotoxin, which are toxic to both fungi, and unfortunately, nasal mucosal epithelium. The weakened nasal and sinus epithelium may then be susceptible to bacterial invasion, infection, and additional tissue inflammation. Cytokines and growth factors released by the inflamed mucosa can promote the formation of nasal polyps (1). Over time, infection can involve the underlying bone with resulting low-grade osteomyelitis. The chronic inflammation and scarring contributes to permanent obstruction of the natural sinus ostia. Critics of this model point out there is inconclusive evidence that the fungi cultured in these patients are pathogenic or even colonizers of the nasal mucosa. They argue that the fungal elements seen on histopathologic analysis and the organisms cultured from the nasal mucus merely represent airborne contamination. Proponents of this model, however, have gone on to use highly sensitive polymerase chain reaction (PCR) assays on mucosal tissue removed from patients with CRS and demonstrated the presence of fungal DNA (11). They speculate this may represent true mucosal disease or even endocytosis and antigen presentation of fungal elements.

Efforts to identify the strains of fungi in patients with CRS have demonstrated a remarkable diversity. Stammberger's group reported fungal cultures on 233 subjects, in which 619 fungal strains were cultured and 81 species identified. There were up to nine separate species isolated per patient. The most prevalent isolates were Penicillium, Aspergillus species, Cladosporium, Alternaria, and Aurobasidium (12). Interestingly, Gosepath reported on 27 of 27 surgical specimens from patients with CRS and found all positive for fungal DNA. His controls, consisting of 15 patients with healthy ethmoid mucosa, however, tested positive when using pan-fungal PCR primers. Species-specific analysis revealed that many of the patients with CRS were positive for Alternaria, while none of the healthy controls were, possibly implicating Alternaria as an important pathogen (11). In an effort to establish the early and ubiquitous nature of fungal presence in nasal mucus, Lackner examined neonates. His group demonstrated that by four months of life, 17 of 18 healthy neonates had positive fungal cultures and concluded that fungi must be considered a normal content of nasal mucus. Fungi that were cultured included Alternaria alternate, A. fumigatus, Penicillium commune, Acremonium polychromum, and Cladosporium cladosporioides (13).

Immunologic studies suggest that these patients have an abnormal systemic response to fungi. Interleukin-5 (IL-5) and interleukin-13 (IL-13) are known to be key cytokines for eosinophilic reactions and play a role in eosinophil chemotaxis. In 2004, Shin obtained peripheral blood lymphocytes from patients with CRS and exposed them to fungal antigens from Alternaria, Aspergillus, Cladosporium, and Penicillium species. He demonstrated that over 90% of these patients exhibited a peripheral blood lymphocyte response by producing IL-5 and IL-13. Control lymphocytes from healthy patients, however, did not produce IL-5 and IL-13 (14). Interestingly, less than 30% of the patients in the CRS group had specific IgE antibodies to the fungi tested. These observations suggest that there is a systemic immune response to fungal antigens in patients with CRS, and it may not require the presence of IgE-specific antibodies.

If CRS is the result of chronic bacterial infection, a neutrophilic infiltrate would be expected. Histomorphologic analysis of mucosal tissue from patients with CRS, however, reveals an eosinophilic infiltrate. Eosinophils are known to be involved in host defenses against fungi and parasites but are not part of the defense against bacteria (15). This also correlates with the contention that the immune response to fungi plays a role in CRS.

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