News -> January, 2002 News
Jens Ponikau, MD
Rochester, MN
Chronic rhinosinusitis (CRS) is a confusing disease for the practicing Otorhinolaryngologist. It usually presents histologically as an eosinophilic inflammation that is complicated by periods of acute exacerbation. These acute exacerbations are presumed to be of bacterial origin. Bacterial infections trigger a neutrophilic inflammation. The eosinophilic inflammation seen in chronic sinusitis is not likely to be caused by bacteria. Eosinophils are understood to play a role in the host defense against larger, non-phagocytosable organisms such as parasites.
The original aim of our research on chronic sinusitis was to prospectively determine the incidence of Allergic Fungal Sinusitis (AFS). Through novel culture, histologic and antigen detecting methods we were able to demonstrate the presence of fungi in every patient with chronic rhinosinusitis (n=46), and in every healthy control person without the disease (n=14).
By studying the tissue and mucin from chronic sinusitis sufferers more closely we observed that the eosinophils were present nearly entirely intact in the tissue. Further the eosinophils migrated into the mucin, formed clusters around fungi and degranulated. Since this was observed in the majority (96%) of consecutive surgical CRS cases (n=101), the questions was raised whether the eosinophils play an immunologic defensive role against those fungi in CRS patients.
Immunologic testing further showed that the chronic sinusitis patients peripheral blood T-lymphocytes, when presented with certain fungal antigens, reacted with the production of the cytokines, which recruit (IL-13) and activate (IL-5) eosinophils (n=18). Lymphocytes from healthy controls (n=15) did not demonstrate this immune response. We conclude that the T-lymphocytes in chronic sinusitis patients recruit eosinophils in response to fungal antigens, while T-lymphocytes in normal people do not. This underlying reaction to fungi occurred independent of IgE-mediated allergy. Thus, the immunologic response is not IgE mediated allergy, and the term "allergic" in AFS is incorrect. As a consequence, the term Eosinophilic Fungal Rhinosinusitis (EFRS) was introduced.
Our working hypothesis of the immunologic mechanism of EFRS, based on the research findings in the laboratory, is that eosinophils are recruited as a defense to fight of fungi in the nose, where healthy controls are lacking this specific immunity. The eosinophils migrate through the nasal tissue and into the mucin of the nose. There the cells cluster around the fungi in a similar fashion as they group around parasites. The eosinophils destroy the fungal organisms through the release of their toxic proteins. As a result, the mucin contains eosinophilic Major Basic Protein (MBP) in a quantity large enough to damage the nasal mucosa. This mucosal destruction allows residential nasal bacteria to secondarily invade the patient's mucosa and cause an acute exacerbation of chronic sinusitis.
Currently we are developing new treatments protocols based on our understanding of the etiology of CRS. Intranasal antifungals have been demonstrated to be safe and appear to demonstrate efficacy in open trials and are now tested in a double blinded, placebo-controlled fashion.
It should be mentioned that this non-invasive disease is a hypersensitivity to fungi, and not a fungal infection. EFRS needs to be differentiated from other forms of fungal sinusitis, such as fungus balls (non-invasive) and invasive fungal sinusitis (acute fulminant or chronic form).
A most striking finding for us is the fact that the T-lymphocytes of chronic sinusitis patients are sensitized in the peripheral blood and recruit and activate eosinophils when they sense a fungal antigen. This finding indicates that CRS is a systemic hypersensitive disease. Further research into the pathophysiology of CRS along this new paradigm will hopefully lead us to new treatments and ultimately better care for our patients.
Figure 1.
Numerous eosinophils cluster around a fungal hyphae in cross section (arrow) in the mucin of CRS patient (Transmission Electron Microscopy x 7125)
Figure 2.
Immuno-fluorescence staining for Major Basic Protein (MBP) demonstrates striking release of toxic protein in the mucus of CRS patient. Note the intact eosinophils in the tissue (right side of image) and the eroded epithelium (arrows). (x200)
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