T= ITLE: Fungal Sinusitis<= span style=3D'mso-bookmark:OLE_LINK1'>
SOURCE: Grand Rounds Presentation,
The University of Texas Medical Branch (utmb Health)
Department of Otolaryngology
DATE: January 30, 2012
RESIDENT PHYSICIAN: David Gleinser, MD
FACULTY PHYSICIAN: Patricia Maeso, MD
DISCUSSANT: Patricia Maeso, MD
SERIES EDITOR: Francis = B. Quinn, Jr, MD
ARCHIVIST: Melinda Stoner Quinn, M= SICS

"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 Sur= gery 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 accurac= y, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be u= sed for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

Introduction

Fungal organisms are ubiquitous, and our exposure to t= hese organisms occurs on a daily basis. A common location for these organisms to enter the human body is through the = sinonasal cavity. Luckily, our immune system= helps to prevent infection by these organisms. In those who do develop infection, a benign, noninvasive process usu= ally occurs. However, in some patients, invasive disease does occur. As in= vasive fungal infections can lead to serious morbidity and mortality, it is import= ant for the clinician to be able to recognize the difference between noninvasive and invasive fungal disease

Basic Mycology

There is an estimated 20,000 to 1.5 million different = fungal species. However, only a few dozen actually cause infectious disease in humans. There are two main forms of a fungus, yeasts and molds. The yeast is a unicellular organism rou= ghly 3-15 µm in diameter. They reproduce asexually by budding. If these buds do not detach, a chain of fungal cells results. This chain is known as a pseudohyphae. The mold = is a multicellular organism measuring 2-10 µm in diameter. These organisms grow = by branching into structures termed hyphae.

Another important component of the fungal organism is = the spore. The spore is a reproductive structure that can be produced in the presence of unfavorable conditions. These spores can withstand many adverse conditions, and are dispersed widely throughout the environment. Once these spores are exposed to a favo= rable environment, they begin to grow. Inhalation of spores is thought to be the primary means by which fun= gal organisms gain access to the sinonasal tract.

Classification of Fungal Sinus Disease

Fungal sinus disease can be broken in two categories, noninvasive and invasive. Noninvas= ive disease includes saprophytic fungal infestation, sinus fungal ball, and allergic fungal sinusitis. Invasive disease includes acute fulminant invasive fungal sinusitis, chronic invasive fungal sinusitis, and granulomatous invasive fungal sinusitis.

Saprophytic Fungal Infestation

Saprophytic fungal infestation within the sinonasal ca= vity occurs when fungus grows on mucus crusts without the involvement of the surrounding mucosa. Patients typic= ally have minimal to no sinonasal symptoms. Diagnosis is done by direct examination, and the treatment involves removal of the crusting with sinonasal rinses. In addition, patients should undergo weekly endoscopy with removal of further crusting until the disease process resolves.

Sinus Fungal Ball (Mycetoma)

A fungus ball is the sequestration of fungal hyphal elements within a sinus without invasive or granulomatous changes. The disease begins with the inhalation = of spores that then become sequestered in a specific location, usually the maxillary sinus (69-86% of cases). Growth of the fungus then occurs while evading the host immune system. In most cases, the offendi= ng agent is an Aspergillus species.

Signs and symptoms of the disease are the result of ma= ss effect by the fungal ball and sinus obstruction. However, the symptoms are not specific = as they mimic signs of chronic rhinosinusitis; facial pressure, pain, nasal congestion, rhinorrhea. Physical examination typically reveals mild to no mucosal inflammation, with 10% of patients having polyps. Diagnosis = is done through physical examination, imaging, and biopsy. The most common imaging modality utiliz= ed is computed tomography. On CT scans, = the disease involves a single sinus in 59-94% of cases with complete or subtotal opacification of the involved sinus. Bony sclerosis is usually seen, however, in 3.6-17% of cases bony destruction can be seen. On biopsy= , the fungal component is noted. In the = case of Aspergillus, one will see y-shaped, fungi with 45-degree branching.

The treatment of choice for a sinus fungal ball is com= plete surgical removal of the disease with creation of appropriate drainage pathw= ays for the sinus. In addition, sinona= sal irrigations should be instituted. Antifungal therapy is usually not required unless there is recurrenc= e of disease or the patient is at high risk for invasive disease. Topical antifungals should be instituted first followed by the least toxic medications if they are required.

Allergic Fungal Sinusitis=

Allergic fungal sinusitis occurs when a fungus coloniz= es a sinus cavity and then causes allergic mucosal inflammation through an IgE response to fungal protein. Patien= ts present with nasal obstruction, rhinorrhea, facial pressure, sneezing, watery/itchy eyes, and periorbital edema. There are five major criteria used to make the diagnosis of AFS. These are the presence of eosinophilic = mucin containing noninvasive fungal hyphae, nasal polyposis, allergy to the offen= ding fungus, immunocompetance of the patient, and the classic radiographic findi= ngs associated with AFS.

Eosinophilic mucin is pathognomonic for AFS, and is described as a thick, tenacious and highly viscous material that is tan to brown or dark green in appearance. Under microscopic examination, the mucin contains branching fungal hyphae, sheets of eosinophils, and charcot-leyden crystals. Charcot-leyden crystals are slender and pointed crystals consisting of a pair of hexagonal pyramids joined at their bases. They result from the breakd= own of cells by enzymes that are released by eosinophils.

The classic radiographic findings of AFS are best note= d by CT imaging. The disease will usual= ly be unilateral in 78% of cases. The in= volved sinuses are typically expanded, with rare cases of bony destruction. Bone destruction, if present, is usuall= y seen in advanced or bilateral disease. = Within the involved sinuses, one will see the presence of “double densities.” This is a heterogeneity of signal due t= o the increased presence of heavy metals (iron, manganese) and calcium salts. On MRI, there is a variable signal dens= ity noted on T1 weighted images. On T2 weight images, there is a hypointense central region within the affected si= nus due to the low water content of the mucin. In addition, there is a peripheral enhancement due to tissue edema.<= /p>

As stated previously, patients with AFS typically exhi= bit allergy to the fungus causing their disease. In a prospective study by Manning et al, 8 patients with proven cult= ure positive Bipolaris AFS were compared to 10 controls with chronic rhinosinusitis. Both groups underw= ent RAST, ELISA, and skin testing. All= 8 patients with AFS showed positive skin testing, RAST, and ELISA to Bipolari= s. Eight of the ten controls were negative= in their tests for Bipolaris. Authors concluded that AFS patients were more often likely to exhibit a fungal allergy. In addition to the positi= ve allergy testing, patients also tend to exhibit higher levels of IgE.

The treatment of AFS begins with the surgical removal = of all mucin while providing permanent drainage and ventilation of the affected sinuses. Following this, systemic steroids are utilized. Multiple st= udies have shown that the addition of systemic steroids helps to decrease the rat= e of recurrence of disease. There is no clear consensus on the length of treatment, but the usual length 2-3 months. Schubert examined steroid treatment for AFS looking at treatment lengths from 2-12 months. It was noted that longer treatment cour= ses resulted in much fewer recurrences, but more side effects.

As AFS is an allergic response, immunotherapy has also= been used as a treatment. One prospecti= ve study examined patients with AFS who were given immunotherapy consisting of= all fungal and nonfungal antigens to which each patient was sensitive following surgical removal of the mucin. Aft= er one year, the patients did not require systemic steroids, and the recurrence ra= tes were significantly better than patients who had not received immunotherapy.= In a retrospective study by Folker et = al, 22 patients with AFS were treated with surgery and steroids. Eleven were treated with immunotherapy = while the other eleven were not. The re= sults showed that the immunotherapy did not result in fewer recurrences. However, immunotherapy did result in be= tter quality-of-life scores and decreased mucosal edema.

Acute Fulminant Invasive = Fungal Sinusitis

Acute fulminant invasive fungal sinusitis (AFIFS) occu= rs when fungal infection begins to invade the mucosal tissues. Patients are typically immunocompromise= d with illnesses such as diabetes mellitus, AIDS, hematologic malignancies, aplast= ic anemia, organ transplantation, or on chemotherapy or steroids. The most common fungi involved are Aspergillus, Mucor, Rhizomucor, Absidia, and Rhizopus. Less common fungi are Candida, Bipolari= s, and Fusarium.

In AFIFS, fungi gain access to the sinonasal cavity typically by way of spores that are inhaled. The fungi then grow and begin to invade neural and vascular structures. This leads to thrombos= is of vessels with resultant mucosal necrosis and loss of sensation. Eventually, the fungi extend beyond the affected sinus via bony destruction, perineural and perivascular spread.

Fever is one of the most common signs of initial infec= tion as it is seen in 90% of cases of AFIFS. Other signs and symptoms include rhinorrhea, nasal congestion, facial pain, facial numbness, diplopia, headaches, seizures, cranial nerve deficit= s, and ulcerations of the nasal, facial, or palatal mucosa. As the disease can result in mortality = in days, it must be recognized early. Any immunocompromised patient with fever and one other sinonasal symptom should undergo evaluation for fungal sinusitis.

As part of a good examination, patients must undergo endoscopic examination of the sinonasal cavity. Changes in the appearance and anesthesia of the mucosa are the most consistent findings of AFIFS. In t= he early stages of the disease, the mucosa may just appear pale. In later stages, the mucosa will become ulcerative and black. Biopsies sho= uld be obtained whenever one suspects fungal disease or notes changes in mucosal appearance or sensation. If the bi= opsies return back normal, or there are no changes noted with the mucosa, biopsies should be taken from the middle turbinate and nasal septum as both of these areas are the most common sites of involvement.

Imaging is an important part of the work-up, and should include CT and MRI. CT is better at detecting bony destruction while MRI is better at detecting mucosal/skin invasion as well as orbital or intracranial involvement. On CT scans, classically there is bony erosion and extrasinus extension. = One may also note severe, unilateral mucosal thickening and thickening of periantral fat planes. MRI will al= so detect periantral fat obliteration, which should alert the clinician to the possibility of fungal invasion. Ot= her findings include leptomeningeal enhancement with intracranial involvement a= nd granuloma formation. Granulomas wi= ll appear hypointense on both T1 and T2 weighted images.

The treatment of AFIFS involves a combination of medic= al and surgical therapy. One of the most important aspects of medical management is the correction of the underlying immunocompromised state. In diabet= ics who are suffering from diabetic ketoacidosis (DKA), DKA should be corrected as = soon as possible as this will improve survival by 80% if corrected promptly. Using white blood cell transfusions and granulocyte stimulating factor to maintain an absolute neutrophil count gre= ater than 1000/mm³ is important as counts less than this are associat= ed with a much worse prognosis.

Systemic antifungals should also be started. Until mucormycosis is ruled out, amphot= ericin B at a dose of 1 mg/kg/day should be started. Close monitoring of renal function is imperative at this time as 80%= of patients will suffer nephrotoxicity. A lipid-based form of amphotericin B is available, but is more expensive. However, it has less side effects, and = higher concentrations of the drug can be maintained. If mucormycosis is not involved, less toxic antifungals such as voriconazole and itraconazole can be used; mucormycosis are resistant to th= ese drugs. In addition to systemic antifungals, amphotericin B sinus rinses should be started as well. Results are mixed when it comes to the effectiveness of these rinses, but the potential benefits of such rinses greatly outweigh any risks.

Surgical therapy for AFIFS helps to decrease pathogen = load, removes devitalized tissue, and establishes pathways for sinus drainage. Debridement should occur until clear, bleeding margins are obtained. In earlier stages of disease, endoscopic approaches should be utilized as they= are less morbid, and survival rates are similar to open approaches. Advanced disease (orbital, skin, and pa= latal involvement) requires open approaches. The prognosis of the patient should be considered when extensive resection is going to be required. For instance, skull base/intracranial involvement results in mortality in great= er than 70% of patient regardless of surgical treatment.

The overall mortality rate for AFIFS is 18-80% and dep= ends on how early treatment can begin. Patients who are treated very early in their disease course do much better than those who present with= advanced disease. The single most predictive indicator for mortality is intracranial involvement with a 70%+ mortality rate. An ANC < 1000/mm^{3 is
associated with a worse prognosis.
Recovery from neutropenia is the most predictive indicator for
survival. Mucor infection tends to=
worse
than Aspergillus as Mucor tends to be more aggressive with earlier orbital =
and
intracranial involvement. Diabetic=
s do
worse than those of other immunocompromised states. This is thought to be because mucormyco=
sis is
more often seen in diabetics.}

<= b>Chronic Invasive Fungal Sinusitis

Chronic invasive fungal sinusitis (CIFS) has a very si= milar clinical appearance as AFIFS, but is much slower, occurring over months to years. Patients with this disease = tend to be immunocompetent. The most co= mmon pathogen is Aspergillus, seen in about 80% of cases. Other fungi include Mucor, Rhizopus, Bipolaris, and Candida.

The signs and symptoms of CIFS are very similar to chr= onic rhinosinusitis, which makes it difficult to recognize until late in the dis= ease course. Unresponsiveness to antibi= otics, epistaxis, facial anesthesia, visual changes, altered mental status, and seizures should all increase suspicion for fungal infection. Once a detailed history has been obtain= ed, a thorough head and neck examination with nasal endoscopy should be performed. Unlike AFIFS, nasal endoscopic findings in CIFS are very subtle and include mucosal edema, crusting, and the presence of polyps. Rarely will ulceration and eschar formation be noted. Imaging is a key to making the diagnosi= s of disease. This is done with the use= of CT and MRI. CT scans will show hyperattenuating soft tissue within one or more sinuses with bony destructi= on and extrasinus spread. MRI finding= s are very similar to that found with AFIFS except there will be no granuloma formation. Biopsies should be obta= ined just as with AFIFS to assess for mucosal invasion. On microscopic evaluation, invasion of vascular and neural structure= s as well as mucosa is noted as is the case with AFIFS. However, with CIFS, there are few, if a= ny, inflammatory cells. In addition, o= ne will note the absence of granulomas, a key difference between CIFS and granulomatous invasive fungal sinusitis.

The treatment of CIFS is similar to AFIFS with a combi= nation of surgical and medical treatments. Surgical resection should include all involved tissues until clear, bleeding margins are obtained. Sys= temic and topical amphotericin B should be started until cultures prove that the offending agent is not a Mucor species. If not a Mucor species, the clinician can use voriconazole or itraconazole to help limit side effects; Mucor species tend to be resistant= to these drugs. Patients should be fo= llowed closely with examination and debridement. Biopsies should be taken from any suspicious areas as asymptomatic recurrence is not uncommon.

Granulomatous Invasive = Fungal Sinusitis

Granulomatous invasive fungal sinusitis (GIFS) appears nearly identical to CIFS. The differences come in the pathogen involved, location that the disease is fou= nd, and the microscopic findings. GIFS= is very rare, and is caused by Aspergillus flavus. The disease is almost exclusively found in North Africa and Southeast Asia. The workup for the disease is exactly like CIFS. On microscopic evaluation, one will note the presence of multinucleated giant cell granulo= mas.

The treatment of GIFS involves surgical resection of involved tissues to bleeding margins and the use of systemic and topical antifungals. As the disease is cau= sed by Aspergillus flavus, one may start treatment with voriconazole. Close follow-up with debridement is mandatory. As with CIFS, one should biopsy any suspicious lesions.

Conc= lusion

Fungi are ubiquitous, and exposure to these organisms = occurs on a daily basis. Our immune syste= ms are usually able to clear the pathogens within the sinonasal cavity prior to the development of infection. When inf= ection does occur, the process is typically benign. However, if treatment fails to resolve the disease process, an invas= ive infection should be suspected. Any immunocompromised patient with sinonasal symptoms and fever should be suspe= cted of having invasive fungal disease, and a thorough workup should be performed with a low threshold for biopsy.

The mainstay = of treatment of fungal sinus disease is surgical debridement. When the disease is invasive, the debri= dement should continue until one obtains clear, bleeding margins. However, one must weigh extensive surgi= cal resection with the prognosis of the patient. In addition to surgical resection, systemic antifungals should be utilized when invasive disease is present. Once the disease has been cleared, close follow-up with debridement = of crusts is mandatory to help with healing and to detect early recurrence. Biopsies of any suspicious lesions shou= ld be performed as asymptomatic recurrence may occur.

Discussion

Patricia Maeso, MD

Dr. Maeso: Just a couple of points: Just remember that AFS is an allergic reaction. It has been defined as a Type I hypersensi= tivity reaction. I think it was first des= cribed at MCV and then UTHSC at Dallas they have the largest experience. You brought in some CT scans and you mentioned the pushing aspect. I wa= nted to bring in some scans that were a little bit different but are still AFS.<= span style=3D'mso-spacerun:yes'> Because this can be frequently confused= with a tumor. You have to know what it= looks like, both in soft tissue and bone windows . There are subtle differences, and they can be confused with a tumor. So, yes, there is expansion, absolutely. But there can also be erosion. Because of the expansion = there can also be erosion, and I'll show you this. You can see how this side is completely displaced. That was the bone window and now you se= e the double density that Dr. Gleinser was describing. This is typical AFS. The Mecca for this is really in Georgia, where I trained and the first time they showed me an image like this I said "tumor!"

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