New Horizons for Allergic Fungal Rhinosinusitis
Amber Luong, MD, PhD
Chronic rhinosinusitis represents a syndrome characterized by nasal symptoms including discolored nasal drainage, nasal obstruction or congestion, and pain or tenderness over the sinuses; this syndrome resulting results from a number of possible etiologies. It is estimated that chronic sinusitis accounts for over 24 million patient visits annually and over $200 million in expenditures for treatment.1 A severe subtype of CRS is allergic fungal rhinosinusitis (AFRS), whose hallmarks include a nasal polyps, elevated fungal-specific IgE levels, and thick eosinophilic mucin containing fungal elements. With warm and humid temperatures, Houston not surprisingly has a significant number of patients suffering from AFRS.
Despite its name, the etiology of AFRS remains unknown. Allergic fungal rhinosinusitis was named for its clinical similarities to the pulmonary disease allergic bronchopulmonary aspergillosis (ABPA), which is also characterized by thick tenacious eosinophilic excretions.2 Correlations in the fungal species identified in the mucin with elevated fungal-specific IgE levels and positive skin test to the same fungal antigen have supported an IgE-mediated response in the pathophysiology of AFRS.3
Recent data presented at the 2008 American Rhinologic Society spring meeting provided more direct evidence that AFRS represents an allergic response to fungal antigens. Allergic responses are characterized by the activation of Th2 cytokines such as IL-5, IL-4 and IL-13 that are responsible for the local infiltration of eosinophils and mast cells and for the increase in IgE production. Mast cells are activated to release effector molecules such as histamine upon antigen recognition of bound IgE receptors leading to local inflammatory changes. This is in contrast to antigens that incite a Th1 cytokine response characterized by IFN-gamma and IL-2 that leads to infiltration of neutrophils and an increase in IgG levels. The study showed that peripheral blood mononuclear cells (PBMCs) harvested from AFRS express Th2 cytokines when challenged with common fungal antigens in vitro. In contrast, PBMCs from healthy controls either had no reaction or responded with a Th1 cytokine profile. This is one of the first studies to demonstrate a direct effect of fungal antigens on inflammatory cells from AFRS patients that is not reproduced in healthy controls.4
An exciting observation that may have implications in the treatment of AFRS is that some fungal antigens incited an expression of IL-10 from PBMCs from only healthy controls. IL-10 is a cytokine known to have regulatory effects on the inflammatory response. This finding suggests that IL-10 expression in healthy controls is protective, inhibiting a Th2 response to fungal antigen challenges. Allergen immunotherapy, a common treatment for severe allergic rhinitis, induces an increase in IL-10 levels by T regulatory cells. The current consensus believes that allergen immunotherapy works by increasing IL-10 that ultimately reduces the late-phase response to the allergen. Similarly, future treatment for AFRS can be aimed at increasing fungal specific T-regulatory cells activity and an increase in IL-10 levels.
Recently, thymic stromal lymphopoietin (TSLP) has been identified as the master switch for the Th2 response. Upon TSLP expression incited by allergen exposure, dendritic cells are activated which in turn stimulate the conversion of Th0 cells to Th2 cells.5 This mechanism has been characterized in asthma and atrophic dermatitis. We plan to investigate the role of TSLP in AFRS. If TSLP should be important in initiating the Th2 response in AFRS, blocking the TSLP represents another possible avenue of treatment.
Although more research will be necessary to fully characterize the molecular pathophysiology of AFRS, we are dedicated to these studies as we believe it will lead to not only a better understanding of the disease but also enlighten us to new treatment possibilities.
- Van Cauwenberge P, Watelet JB. Epidemiology of chronic rhinosinusitis. Thorax 2000;55 S20-1.
- Katzenstein AL, Sale SR, Greenberger PA. Allergic aspergillus sinusitis: A newly recognized form of sinusitis. J Allergy Clin Immunol 1983;72:89-93.
- Manning SC, Holman M. Further evidence for allergic pathophysiology in allergic fungal sinusitis. Laryngoscope 1998;108:1485-96.
- Luong A, Davis LS, Marple BF. Peripheral Blood Mononuclear Cells from Allergic Fungal Rhinosinusitis Adults Elicit a Th2 Cytokine Response to Fungal Allergens. Presented at the 2008 Spring Meeting of the American Rhinologic Society 2008:May 1, 2008.
- Liu YJ. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J Allergy Clin Immunol 2007;120:238-44.