The Role of Fungi in ChronicRhinosinusitis

Amber Luong, MD, PhD, Bradley Marple, MDDepartment of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center

Otolaryngologic Clinics of North America vol.38 (2005)1203-1213

Introduction

Fungi can interact with and influence the upper respiratory tract in various fashions.Common finding in both normal and diseased states.Conditions supporting fungal growth formation of fungal balls or fungal mycelia within the nose and paranasal sinus.

Characteristics of fungusEukaryotic organisms Aiding in the decomposition and recycling of organic matter. Produce spores enhancing survival in harsh environmental conditions and retain the ability to germinate when the environment becomes more favorable for fungal growth.Dispersed easily into the atmosphere.

Characteristics of fungus

Only about 300 have been documented as playing a role in human disease.To cause disease by

invading and proliferating within host tissue (infection)inducing an allergic (or nonallergicimmunologic) responseproduction of toxins

Characteristics of fungus

Potential fungal pathogens primarily are confined to three major groups

ZygomycetesAspergillus speciesVarious dematiaceous genera ( Bipolaris, Helminthosporium,Curvularia, Dreschslera, Fusarium, Cladosporium, Epicoccum, Exserohilum,andAlternaria)

Allergic fungal inflammation

Fungal exposure and its effect upon airway inflammationDegree of fungal exposure vary based upon environmental conditions.Moisture and temperature appear to be the most important determinants affecting the potential for fungal growth.Several studies have noted an increased prevalence of respiratory symptoms among children and adults living in moist conditions.

Ren studied ,No correlation between childhood development of asthma and exposure to moisture.Epidemiological studies suggest that fungal exposure cannot be predicted reliably based upon the characteristics of the environment, but rather actual air samples are necessary to determine fungal exposure

Savilahti studied :Association between environmental fungal exposure and the subsequent development of atopy ( elevate IgEand symptomatic allegies )

Fungal allergiesProtein components of fungi can stimulate the respiratory tract through IgE-mediated allergic mechanism.Fungal antigens also lead to delayed reactions in the form of Gell and Coombs types III and IV reactions.Desensitization to fungal antigens has been shown to be useful in the control of symptoms in patients who are sensitized to these antigens.

Immunotherapy ,may contribute to variances in the antigens that are available within extracts used for treatment and evaluation.Allergenic similarities have been noted among numerous different fungal genera - demonstrate a broad IgE-mediated cross-reactivity to a range of fungal species.

Allergic fungal rhinosinusitis (AFRS)

Initially recognized for its similarities to allergic bronchopulmonaryaspergillosis(ABPA).AFRS possesses unique clinical, radiographic, pathologic, and immunologic characteristics.Bent and Kuhn : Patients with AFRS uniformly demonstrated five characteristics.

Allergic fungal rhinosinusitis (AFRS)

Gross production of eosinophilic mucincontainingNoninvasive fungal hyphaeNasal polyposisCharacteristic radiographic findingsImmunocompetenceAllergy

Allergic fungal rhinosinusitis (AFRS)

The diagnosis of AFRS is most simply dependent upon identifyingA combination of histologic evidence of fungi within eosinophilic mucinAnd host allergy to that fungus

Pathophysiology of allergic fungal rhinosinusitis

Manning and colleagues ; several inter-related factors and events lead to the developmentandperpetuation of the disease.Atopic host is exposed to fungiTrigger eosinophilic inflammatory response ( type 1,3) Inflammation leads to obstruction of sinus ostia + anatomical factors Stasis within sinusesIncrease proliferation of fungal, antigenic exposure, production of allergic mucinSuffering from AFRS

The link between AFRS and fungal allergy Manning and Holman :patients with AFRS had positive skin test reactions to Bipolaris antigen and positive RAST and ELISA inhibition to Bipolaris-specific IgE and IgG.Implicating the importance of allergy to fungal antigens (both in vivo and in vitro) in the pathophysiology of AFRS.

Manning et al: Levels of fungal-specific IgE were elevated uniformly in all patients who had AFRS, and these corresponded with the results of fungal cultures.Link between AFRS and IgE-mediated hypersensitivity to fungus ?

Why does fungal-specific IgE remain elevated after prolonged fungal immunotherapy when normally it would be expected to decrease? Why does the incidence of AFRS fail to parallel the incidence of fungal allergy?Why does one fail to see the eventual rise in specific IgG levels because of development of IgG-blocking antibodies in response to fungal immunotherapy?

Other factors such as T helper cells, anatomy, genetics, or exposures contribute to the development of the disease.

Nonallergic fungal inflammation

In 1999 at the Mayo Clinic, which hypothesized a broader role for fungi in the pathogenesis of chronic rhinosinusitis.Using this combination of histologicallyidentified eosinophilic inflammation and positive fungal cultures as a less stringent set of diagnostic criteria for AFRS, it was proposed that virtually all forms of chronic rhinosinusitis were related in some fashion to nonallergic eosinophilicinflammation caused by fungal exposure

Allergy to fungi failed to correlate with their definition of AFRS.Suggested that the term AFRS be replaced with EFRS (eosinophilic fungal rhinosinusitis).Nonallergic (non-IgE–mediated) fungal inflammatory process occurring within susceptible individuals.

Shin and Kita: Increased production of interleukin (IL)-5, IL-13, and interferon-g was observed when peripheral blood monocytes from patients who had CRS were exposed to alternaria species.These findings were thought to be supportive of direct simulation of peripheral blood monocytes by certain specific fungi resulting in a specific pattern of cytokine secretion favorable to eosinophil chemotaxis and survival.

Role of immunotherapy for treating chronic rhinosinusitis

Evidence supporting fungal hypersensitivity in the pathogenesis of AFRSFungal immunotherapy was proposed as a possible adjuvant therapy.A cohort of patients treated with immunotherapy, followed for three years, showed a significant decrease in disease recurrence and dependence on systemic and topical corticosteroids

Immunotherapy after surgical removal of allergic mucin resulted in a significant decrease in rate of reoperation.In a 10-year follow-up study,immunotherapy failed to show a significant impact on long-term control of disease ( quality of life ,IgE levels )Immunotherapy has limited long-term effects .

Role of topical antifungals

Local elimination of fungi in the nasal cavities should improve or halt the disease.Ponikau and colleagues treated 51 patients who had CRS refractory to other therapies with nasal lavages containing amphotericin every other day for at least 3 months. A decrease in symptoms, an improvement on CT findings, or an improvement on endoscopic examwasnoted for 75% of the patients.

Ricchetti and colleagues evaluated the efficacy of nasal lavages with amphotericin in a subgroup of CRS patients with nasal polyps. After 1 month of treatment, 29 out of the 74 (39%) patients had complete resolution of nasal polyps.A caveat in these studies is that nasal lavages with saline alone have been shown to improve CRS symptoms .

Wescheta and colleagues, in a double-blind randomized controlled study, treated 60 patients who had CRS and nasal polyps refractory to common medical therapy, excluding patients with allergic fungal sinusitis, with either nasal saline sprays or with nasal saline spray containing amphotericin B for 1 month.The 28 who received nasal saline with amphotericin (at a dose of 200 mg per nostril four times per day), only two (7%) reported an improvement in their symptoms.

CT scans and nasal endoscopic evaluations were unchanged after the 1-month treatment.This study suggests that antifungals are not effective for treating CRS.The inclusion of patients who have AFRS in the Ponikau and Richetti studies may explain their success with local antifungals partially. Elimination of fungi by antimycotics should relieve symptoms in patients who have AFRS.Kanda and colleagues revealed that antifungalssuppress the production of IL-4 and IL-5 by T-cells.

Summary

Fungi may play in developing and perpetuating inflammatory disease of the respiratory tract.Review of the current literature appears to offer strong evidence to support both allergic and nonallergic forms of noninvasive fungal inflammation. As investigation focusing upon these new concepts continues,it should lead to better understanding of chronic inflammatory disease of the respiratory tracts.

Thank you for your attention

Thank you for your attention