Allergic Fungal Sinusitis (Feb.1996)

ALLERGIC FUNGAL SINUSITIS
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds
DATE: FEBRUARY 7, 1996
RESIDENT PHYSICIAN: Ramtin Kassir M.D.
FACULTY: Brian Driscoll M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.

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"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

History

1981- Millar et al. recognize histologic resemblance between chronic fungal sinusitis and allergic bronchopulmonary aspergillosis

1983- Katzenstein et al. - resemblance between ABPA (allergic bronchopulmonary aspergillosis) and seven cases of chronic sinusitis associated with fungal hyphae (allergic Aspergillus sinusitis)

1988- Sher and Schwartz report the first case of concurrent ABPA and AFS

1991- Allphin et al. and Manning et al. - fungi of the Dematiaceae family, not Aspergillus species, were the primary etiologic agent in AFS

1994- Kinsella et al - double density sign

1995- Rassekh et al - Skull base allergic fungal sinus disease

Fungal sinusitis

Invasive-

1. acute fulminant - pt immunocompromised, usually caused by Mucormycosis Aspergillus, life threatening

2. chronic indolent - immunocompetent host, disease escapes confines of sinus cavities and invades tissue. Rx includes surgery and antifungals

Noninvasive -

1.mycetoma - proliferation of fungal elements, no immune response, simple debridement sufficient

2. AFS - intense immune reaction to fungal antigen, requires surgical debridement and steroid therapy

Approximately 7% of chronic sinusitis cases requiring surgery are caused by AFS. As the entity is gaining recognition, reports of its incidence are increasing. Most series of AFS reports are from medical centers in the southern United States. A warm humid climate may enhance fungal growth and amplify disease prevalence.

Mycology

Most common etiologic agent in ABPA is Aspergillus. In AFS, fungi in the Dematiaceae (black) family (Curvularia, Bipolaris, Alternaria, Exserohilum) are responsible in the majority of cases.

Pathophysiology

Predisposing factors: 1. Atopic host
2. mechanical obstruction (deviated septum, mucosal hypertrophy, polyps, OMC disease)
3. Exposure to ubiquitous fungus

Mucus- allergic mucin very tenacious, thick, and pasty and resembles peanut butter. Color ranges from light green to dark brown.

Histology- layers of mucus mixed with sheets of eosinophils Can see Charcot Leyden crystals (necrotic eosinophils) on high power

Fungal hyphae can be seen on H&E stain but best seen on methanamine silver stains If allergic mucin with hyphal element is seen, the diagnosis of AFS can be made. However, fungal elements in AFS are relatively scarce and do not dominate the histologic specimen as in mycetoma. The surgical specimen must be analyzed promptly as the scant fungal elements deteriorate in vitro. The morphology of various fungi is similar on tissue examination, therefore fungal cultures must be obtained. The absence of fungal invasion in to removed mucosa and bone is necessary to rule out invasive fungal sinusitis.

Immunology

ABPA - elevated levels of IgE and IgG to the specific fungal agent. AFS is the counterpart of ABPA manifested in the sinuses, so it is also thought to represent Gell and Coombs type I and type III responses.

Type I immunity - emphasized by Manning et al. who demonstrated elevated levels of total IgE and Bipolaris specific IgE in nine consecutive patients.

Type III - IgG antibodies (in addition to IgE antibodies) to the specific fungus in the serum can be demonstrated. There is no cytotoxic event associated with these IgG antibodies (as in type II), therefore it is thought to be a type III, non IgE mediated, noncytotoxic, antibody-dependent immune response. Complement mediated immune response has not been demonstrated in AFS.

The role of hypersensitivity vs. true infection in the pathogenesis of AFS is still controversial. Clinical, histologic and serologic support for allergic causes include the incidence of AFS in young immunocompetent atopic patients, allergic mucin and lack of invasion on histology, serologic and skin test evidence of IgE mediated fungal hypersensitivity, and the presence of IgG and precipitating antibodies to fungal antigens. Mabry and Manning recently showed not only elevated total IgE levels in patients with AFS but also a significant degree of allergen-specific IgE for other inhalants such as grasses, weeds, trees, and dust mite. This also supports the idea that AFS is a true allergic rather than infectious disease.

Radiology

The CT and MRI findings in AFS is important for distinguishing fungal sinusitis from bacterial sinusitis and sinus neoplasms. Serpiginous areas of increased attenuation on noncontrast CT, particularly on bone windows are characteristic of AFS. These hyperdense and heterogenous densities in an opacified sinus are also referred to as the “double density” sign and most likely represent higher levels of magnesium, manganese, and iron in fungal mucin. T1-weighted MRIs of fungal sinusitis demonstrate isointense or slightly hypointense regions surrounded by mucosal inflammation; T2 images often have a signal void and are black. This is in contrast to MRIs of neoplasms and bacterial infections which are hyperintense. AFS tends to affect multiple sinuses with a unilateral predominance. It is a slow growing and chronic entity, and bone erosion is not uncommon. This occurs in the same manner as mucoceles and polyps. Evidence of bony erosion on radiography should not be interpreted as invasion without histologic evidence of invasion..

Clinical Presentation and Diagnosis

AFS occurs in adolescents and young adults who often have asthma that is exacerbated by their sinusitis. There is no male or female predominance. All patients are immunocompetent and have a strong history of atopy. All have nasal polyps and chronic sinusitis; many have had multiple sinus surgeries. There is no increased aspirin sensitivity despite the association with asthma and nasal polyps. Patients typically present to the otolaryngologist with acute worsening of their chronic sinusitis with nasal obstruction, headache, proptosis, and at times intracranial erosion.

Diagnostic criteria have been suggested by Bent and Kuhn and include
(1) type I hypersensitivity confirmed by history, skin tests, or serology;
(2) eosinophilic mucus without fungal invasion of sinus tissue;
(3) positive fungal stains of sinus contents removed during surgery.

Treatment

The current therapy for AFS involves surgical extirpation of all allergic mucin if possible with aeration of diseased sinuses. Endoscopic surgical decompression with adjunctive steroids are considered initially. Most patients will experience rapid relief of nasal congestion, drainage, headache and other associated symptoms; however, this is transitory as the polyps and associated AFS symptomatology almost always recurs. The hallmark of this disease is multiple sinonasal surgeries (including external approaches and frontal sinus obliteration) with recurrence of symptoms. These recurrences may be treated with adjunctive steroids and office debridement. Other patients may require repeat radiographic studies and repeat operative debridement. Total and fungal-specific IgE levels are useful laboratory studies and can be used to follow the course of the disease.

Steroids Systemic steroids are the mainstay of therapy in ABPA flairs and have been used successfully in recurrent cases of AFS. However, steroids have multiple side effects and their use is controversial. Since surgical drainage and ventilation is possible in the sinuses but not in the lungs, some authors reserve systemic steroids for difficult or refractory cases of AFS. Others believe that systemic low dose steroids should be used indefinitely. Topical intranasal steroid sprays and saline irrigations have minimal side effects and are used routinely in the postoperative management of AFS. However, the duration and effectiveness of steroid sprays in AFS has not been proven scientifically.

Antifungal therapy

The use of topical and systemic antifungal agents is controversial. No indication exists for the use of toxic antifungal agents (amphotericin B, Fluconazole) to treat noninvasive fungal sinusitis. Both amphotericin B and Fluconazole are ineffective against the Dematiaceous fungi and Aspergillus species. Since AFS is thought to be an allergic disease caused by an extrinsic fungal antigen rather than a true infection, systemic antifungals should be ineffective. Itraconazole, a relatively benign and oral antifungal agent, has had some usefulness in treatment of ABPA and may be of adjunctive use in management of AFS associated with Aspergillus. However, the efficacy of itraconazole against dematiaceous has not been studied.

Immunotherapy

Immunotherapy based on mold desensitization with serial end point titration would theoretically blunt the type I immune response. However, antigen injections, while blunting type I hypersensitivity, increase IgG levels as blocking antibodies are made.This increase in IgG could theoretically potentiate the pathologic type III response. However, the role of the type III response in AFS is debated. Immunotherapy for other inhalants is recommended to reduce the antigenic load presented to the patient.

Summary

AFS is a newly recognized noninvasive disease that accounts for approximately 7% of all chronic sinusitis requiring surgical intervention. The vast majority of causative fungal agents belong to the Dematiaceae family. AFS should be suspected in any atopic patient with refractory nasal polyposis and characteristic radiographic signs. Thick, tenacious, allergic mucin encountered at surgery can be confirmed histologically and hyphae can be demonstrated on special fungal stains or confirmed by a positive fungal culture. Current therapy includes conservative but complete removal of all allergic mucin, which usually can be accomplished endoscopically. Although the use of steroids is controversial, adjunctive systemic steroids are used short term and topical nasal steroids long term. Recurrence of AFS with associated symptomatology is common, necessitating close clinical, endoscopic, and radiographic follow-up.

BIBLIOGRAPHY

Mabry RL, Manning S. Radioallergosorbent microscreen and total immunoglbulin E in allergic fungal sinusitis. Otolaryngol Head Neck Surg 1995 Dec; 113(6):721-3.

deShazo RD, Swain RE. Diagnostic criteria for allergic fungal sinusities. J Allergy Clin Immunol 19995 Jul; 96(1): 24-35.

Corey JP, Delsupehe KG, Furgeson BJ. Allergic fungal sinusitis; allergic, infectious, or both? Otolaryngol Head Neck Surg 1995 Jul; 113 (1)110-9.

Roth M. Should oral steroids be the primary treatment for allergic fungal sinusitis? Ear Nose Throat J 1994 Dec; 73 (12):928-30.

Bent JP III, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1994 Nov: 111(5): 580-8.

Lydiat WM et al. Allergic fungal sinusitis with intracranial extension and frontal lobe symptoms: a case report. Ear Nose Throat J 1994 Jun; 73 (6): 402-4.

Cody DT II et al. Allergic fungal sinusitis: the Mayo Clinic experience. Laryngoscope 1994 Sep; 104 (9) : 1074-9.

Manning SC, Mabry RL, Schaefer SD, Close LG. Evidence of IgE -mediated hypersensitivity in allergic fungal sinusitis. Laryngoscope 1993 Jul; 103(7):717-21.

Kinsella JB, Rassekh CH, Bradfield JJ et al. Allergic fungal sinusitis with skull base erosion. Head and Neck, In Press, 1995.