Until recently, the cause of chronic rhinosinusitis (CRS) was not fully understood. Beginning with their work in 1999, researchers at the Mayo Clinic in Rochester, Minnesota discovered that fungus plays a major role in CRS.(1)

Fungus, like pollen and dust mites, is present in the air and is normally found in the nasal passages and mucus of healthy people and those with CRS. In patients with CRS, it is an immunologic response to the fungi that results in the symptoms of the disease. T-cells (or lymphocytes) and eosinophils play a major role in the disease process. View examples of the eosinophilic inflammation.

In CRS patients, the presence of fungal antigens triggers lymphocytes to produce cytokines, including IL-13 and IL-5. These cytokines are responsible for the recruitment, migration, activation and life prolongation of eosinophils, which are cells that are predominantly involved in the body's defense against larger organisms such as parasites and which are also the hallmark of inflammation in CRS.(2) This reaction to the fungi does not occur in healthy controls. In the mucus of CRS patients, eosinophils are activated, cluster around the fungal hyphae, and a resulting degranulation and release of cytotoxic proteins occurs on the fungi (View Animation). Thus eosinophils appear to target fungi in the mucus of CRS patients.

One such protein is eosinophilic major basic protein (MBP), a substance that is directly toxic to the fungi (View Image) (View Video). However, the toxic proteins also damage the nasal epithelium. Over time this damage leads to inflammation and airway remodeling.(3) (View Image) More immediately, this damage can lead to secondary infections because the damaged tissue is vulnerable to invasion by bacterial and viral organisms (View Image).

Prior to the research done at the Mayo Clinic, the presence of fungi in the nasal mucus was theorized, but primarily undetected. This was primarily due to two factors: the unavailability of a sensitive staining method to detect the presence of fungal hyphae and improper handling of specimens. A study conducted at the Mayo Clinic and published in 2002 describes a new process used to identify fungus in the mucus of patients with CRS.(4) The study evaluated a fluorescein-labeled staining technique that targets chitin, a substance that is found in fungal cell walls, but not in mammalian cells. Using this new technique, the researchers found that 100% of patients with CRS had fungus in their mucus (View Image). Alternaria and Aspergillus were the most common fungi isolated. Other fungal organisms identified in both healthy controls and CRS patients include Cladosporium and Penicillium.(1,4) These results were confirmed in a European study published in 2003. In this study, the presence of fungal organisms in both healthy and CRS patients was demonstrated by positive fungal cultures in 91% of individuals in each group. By histology, fungal components and eosinophilic mucus were found in 75% and 95% of CRS patients, respectively.(5) A 2004 study published in the American Journal of Rhinology provided additional support for the fungal etiology of CRS when fungal DNA from Alternaria (a black mold) was detected in 100% of tissue samples from CRS patients, but not from healthy controls.(6)

Clinical Studies

• Chronic Rhinosinusitis: An Enhanced Immune Response to Ubiquitous Airborne Fungi (DocuRights® Service )
  In this study, patients with CRS demonstrated an exaggerated humoral and cellular immune response to airborne fungi. Peripheral blood mononuclear cell (PBMC) cultures obtained from patients with CRS produced IL-5 and IL-13 when exposed to four common airborne fungi—Alternaria, Aspergillus, Cladosporium, and Penicillium. The greatest response was seen with Alternaria to which approximately 90% of samples produced IL-5 and IL-13. Production of IFN-gamma was also increased in response to Alternaria. Level of IgG antibodies were increased compared to controls in response Alternaria and Cladosporium, while less than 30% of samples exhibited specific IgE antibodies. The researchers concluded that the chronic inflammatory nature of the condition results from patients' abnormal immune and inflammatory response to the fungi.
  
  For more information, the complete citation for this study is: Shin SH, Ponikau JU, Sherris DA, et al. Chronic rhinosinusitis: an enhanced immune response to ubiquitous airborne fungi. J Allergy Clin Immunol. 2004; 114(6) 1369-75.
  
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• The Diagnosis and Incidence of Allergic Fungal Sinusitis
  This study conducted at the Mayo Clinic describes a novel specimen collection and culture technique used to improve the accuracy of diagnosing CRS. Fungal cultures were positive in 202 of 210 CRS patients (96%) and the diagnosis of allergic fungal sinusitis (AFS) was made in 94 of 101 consecutive surgical cases (93%). Furthermore, results from this study rebutted the theory that atopy was an essential element of CRS and demonstrated an immune-mediated reaction caused by the infiltration of eosinophils. Based on these results, the researchers proposed a change in terminology from AFS to eosinophilic fungal rhinosinusitis.
  
  
• The Chemotactic Behavior of Eosinophils in Patients with Chronic Rhinosinusitis.
  In this prospective, controlled, ex vivo study, researchers studied the migration of eosinophils in the mucus and nasal tissue extracts harvested from ten patients with CRS at the time of sinus surgery. This was compared to the statistically significant, lower concentration of eosinophils in samples obtained from ten healthy patients. The authors concluded that nasal mucus and tissues of patients with CRS contain chemoattractants that cause the eosinophilic migration.
  
  For more information, the complete citation for this study is: Wei JL, Kita H, Sherris DA, et al. The chemotactic behavior of eosinophils in patients with chronic rhinosinusitis. Laryngoscope. 2003;113:303-6.

Microbiology

• Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein.
  This article reports the results of a study at the Mayo Clinic in which two staining techniques were compared in their ability to detect the presence of fungal hyphae in the mucus of patients with CRS. The researchers found that fluorescein-stained chitinase was superior to Grocott methanamine silver stain, with a 100% versus 76% detection rate.

References

1. Ponikau JU, Sherris DA, Kern EB et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc. 1999;74:877-84.
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2. Shin SH, Ponikau JU, Sherris DA, et al. Chronic rhinosinusitis: An enhanced immune response to ubiquitous airborne fungi. J Allergy Clin Immunol.; 2004;114(6):1369-75.
   
   
3. Ponikau JU, Sherris DA, Kephart GM, et al. Features of airway remodeling and eosinophilic inflammation in chronic rhinosinusitis: Is the histopathology similar to asthma? J Allergy Clin Immunol. 2004;114(6):1369-75.
   
   
4. Taylor MJ, Ponikau JU, Sherris DA, et al. Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein. Otolaryngol Head Neck Surg. 2002;127:377-83.
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5. Braun H, Buzina W, Freudenschuss K, et al. Eosinophilic fungal rhinosinusitis: a common disorder in Europe? Laryngoscope. 2003;113(2):264-9.
   
   
6. Gosepath J, Brieger J, Vlachtsis K, et al. Fungal DNA is present in tissue specimens of patients with chronic rhinosinusitis. Am J Rhinology. 2004;18(1):9-13.