540 Letters to the Editor Role of Fungi in Allergic Fungal Sinusitis and Chronic Rhinosinusitis To the Editor: In the recent study by Ponikau et al,' the authors describe a new and more efficient method of nasal mucus collec- tion. They subsequently used this method to demonstrate that of 2 IOpatients diagnosed as having chronic rhinosinusitis (CRS), 202 patients (96%) had fungi (representing 40 different genera) in their nasal mucus. They further found that 100% of their control patients (14114) also had fungi (from 8 different genera) in their mucus. A subset of 101 CRS patients was also treated surgically, and nasal samples were subjected to histopathological examination. Fungal elements were found in 82 (81%) of the 101 samples examined. They also found that eosinophil "presence" was de- tectable in 96% (97/101) of these cases . In contrast, tissue from 4 control patients subjected to histopathological examination contained no evidence for the presence of eosinophils. Based on their findings, the authors conclude that allergic fungal sinusitis (AFS) is significantly underdiagnosed and is in fact present in the majority of patients suffering from CRS. They also suggest that immunoglobulin E (lgE)-mediated type I hyper- sensitivity is not the dominant pathophysiological factor in AFS. They indicate that such a role is played by eosinophils and suggest that AFS be renamed eosinophilic fungal rhinosinusitis (EFRS). For the most part, the article presents some thoughtful, intrigu- ing, and provocative findings. However, it is also somewhat per- plexing how the authors arrive at their conclusion that fungi play an important role in the onset of AFS. In part this is due to the fact that their reported findings violate Koch's postulates on causation of disease and that the authors actually demonstrate that the "causative agents," ie, fungi, are present in both diseased and control patients. Furthermore, the authors did not demonstrate that the same symp- toms can be induced in a healthy subject after infection with the pathogen, in this case the fungus. Hence, it is rather difficult to accept, based on the preliminary data presented, the authors' asser- tion that fungi are important in the etiology of AFS and CRS. The authors' finding that 96% of the individual CRS surgical tissue examined revealed the presence of eosinophils appears to be important, since this finding contrast s with the fact that tissue specimens from all 4 control patients contained no eosinophil presence . However, this is not a new finding. Harlin et af reported in 1988 on a study of 26 patients suffering from chronic sinusiti s that tissue from such patients "was extensively infiltrated with eosinophils.' Indeed, Hansel,' back in 1929, was the first to report such infiltration by eosinophils. Furthermore, this contrast in eosinophil infiltration between CRS vs control patients would have been more compelling if the authors had carried out exami- nations on a clearly defined control population. I also noted that a Mayo Clinic news release! issued immedi- ately after the article was published stated that "Mayo Clinic researchers say that they have found the cause of most chronic sinus infections-an immune response to fungus." The release went on to state that the authors of the article say "this discovery opens the door to the first effective treatment for this problem." The study findings' and these claims" were criticized in a Washing- ton Post article published in late November 1999. 5 Experts in Mayo Clin Proc, May 2000,Vol75 otolaryngology expressed concern that if "100% of controls have fungi, why does it [Mayo findings) mean anything?" Furthermore, the Washington Post article' raised the issue that patient expecta- tions to be treated successfully for CRS had been elevated unduly. It would appear with hindsight that the Mayo findings' may have been reported prematurely. This has already resulted in both criticism and skepticism of the work. On reflection this is some- what unfortunate, since even the critics of the work" agree that more comprehensive studies should be done to explore the pos- sible role of fungi in AFS and CRS. However, I would hope that all of us continue to strive for candid and objective assessment of work. This is particularly important in regard to those findings that may impact patients' hopes and expectations regarding treat- ment of a particular illness or disease. We should all err on the side of caution in terms of conclusions we draw and report based on a very preliminary data set. Stephen Naylor, PhD, DSc Mayo Clinic Rochester Rochester, Minn I. Ponikau JU, Sherris DA, Kern EB, et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc. 1999;74:877-884. 2. Harlin SL, Ansel DG, Lane SR, Myers J, Kephart GM, Gleich GJ. A clinical and pathologic study of chronic sinusitis: the role of the eosinophil. J Allerg y Clin Immunol . 1988;81:867-875. 3. Hansel FK. Clinical and histopathologic studies of the nose and sinuses in allergy. J Allergy. 1929;1:43-47. 4. Mayo Clinic Rochester News. Mayo Clinic study implicates fungus as cause of chronic sinusitis [news release], September 9, 1999. Available at: www.mayo.edulcomrnlmcr/news/news_773.htmI.Ac- cessed April 7, 2000. 5. Boodman SG. Mayo report on sinusitis draws skeptics; some experts challenge fungal basis for many infections. Washington Post. Novem- ber 23, 1999:Z07. Available at: www.newslibrary.comldeliverccdoc .asp?SMH=313919. Accessed February 17,2000. In reply: As Dr Naylor states, extramucosal fungi were found in almost all patients with CRS and also in all controls.' To conclude for this reason that fungi do not cause disease is flawed. We know that the bacteria responsible for most cases of acute sinusitis are always present in normal, healthy hosts. An event (such as an upper respiratory tract infection) occurs that causes swelling and leads to a cascade of events that allow infection by the same bacteria . From an infectiou s disease point of view, assuming that the mere presence of organisms causes disease, the conclusions we drew from our study can certainly be challenged. But from the perspective of a hypersensiti vity reaction, which is not IgE medi- ated, our hypothesis seems plausible. For example, everyone inhales pollens, but only a sensitized patient develops the symp- toms of hay fever (in that case, IgE mediated) . Thus, the term infection is not applicable for the disease, EFRS, which we are describing. An infection is defined by microorganisms entering tissue, usually through the skin or a mucus membrane. In EFRS, the fungal organisms arc always present extramucosally in the mucus and are not themselves causative for this disease. As Naylor also states, the presence of eosinophils in the tissue in CRS is not new, nor is it reported as new in our article. What we reported is the observation that the eosinophils are leaving the tissue and form the typical clusters in the eosinophilic mucin. A key point of our article, besides the presence of fungi in the mucus, is For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.