대한비과학회

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Mycotic Rhinosinusitis

Hun-Jong Dhong, M.D.

Though mycotic infections of the paranasal sinuses are not common, their increasing frequency has been recognized over the past two decades.^1-3) Stammberger reports the incidence of mycotic infection as existing in almost 10 percent of all patients requiring surgical management for sinusitis.⁴⁾ Recently, Ponikau et al.,⁵⁾ reported that improved culture and tissue handling techniques increase the yield of mycology and pathology in identifying fungi from the nose and sinuses. They believe that nearly all patients with chronic rhinosinusitis have eosinophilic fungal rhinosinusitis.

Technical advances in computed tomography and ma- gnetic resonance scanning and improvements in serology testing have enhanced diagnostic capabilities, which enable more frequent identification. However, the most important factor in the increasing incidence of mycotic infections has been the growing number of immunosu- ppressed individuals. These include：diabetics, patients with defective immune response following radiation or chemotherapy for treatment of malignancy, immunosuppressive drugs after organ transplantation, use of long term antibiotics, immunodeficiency diseases such as AIDS. Fungal infections of the paranasal sinuses most often include coccidiomycosis, histoplasmosis, candidi- asis, zygomycosis, and aspergillosis. The principal fungi amid them are species of Aspergillus and Zygomyce- tes,⁶⁾ which are ubiquitous soil saprophytes or even normal human commensals. They are capable of causing isolated limited disease if local defense mechanisms are compromised such as with an obstructed sinus or an

implanted foreign body, but in general, invasive disease is possible only in the presence of immunodeficiency.

CLASSIFICATION

The classification systems for fungal sinusitis have been both confusing and inconstant. Most do not ac- count for all of the cases reported in the literature. When McGill et al. first described fulminant Aspergillus sinusitis in 1980,⁷⁾ they suggested the presence of three forms of Aspergillus sinusitis；1) noninvasive local disease (aspergilloma), 2) slowly progressive, indolent disease, and 3) fulminant soft tissue invasion in imm- unocompromized. As late as 1988, Washburn et al.

considered fungal sinusitis as acute, chronic invasive, and chronic non invasive.⁸⁾ Since Katzenstein et al. su- ggested a new type of Aspergillus sinusitis in 1983,⁹⁾¹⁰⁾ fungal rhinosinusitis has been classified into 2 major groups upon the basis of clinical and/or pathologic evidence of tissue invasion. They are extramucosal (noninvasive) and invasive fungal rhinosinusitis. There are three forms of non-invasive fungal rhinosinusitis. They are superficial sinonasal mycosis, fungal ball, and allergic fungal rhinosinusitis. There are two forms of invasive fungal rhinosinusitis. They are chronic invasive fungal rhinosinusitis and acute (fulminant) fungal rhinosinusitis. All subtypes of these mycotic infections may be viewed as distinct pathological entities with certain clinical behaviors and they are reviewed below. Depending on the variable factors such as local sinonasal environ- ment, the inoculum size of the fungi, the immune status of the host, there exists a wide spectrum of immune response to fungal pathogens. As such, fungal rhinosinusitis may also be viewed as a continuum of disease.

This continuum starts with superficial sinonasal mycosis, the most benign form, and may progress to acute fungal rhinosinusitis, the most lethal form. Based on the immune status of patients, one end of the spectrum is seen Department of Otorhinolaryngology and Head and Neck Sur-

gery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

Address correspondence and reprint requests to Hun-Jong Dhong, M.D., Department of Othorhinolaryngology and Head and Neck Surgery, Samsung Medical Center, 50 Irwon-dong, Kangnam-ku, Seoul, Korea

Tel：82-2-3410-3579, Fax：82-2-3410-3879 E-mail: [email protected] Accepted for publication on October 18, 2000

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in the leukemic bone marrow transplant patient who is severely immunocompromized.

DIAGNOSIS

The best way to make a diagnosis of a fungal infection is to obtain biopsy material for staining and for culture by the physician’s suspicion based on an awareness of the types of patients at greatest risk and the typical clinical presentation of fungal illness. Any patient who has acute or chronic sinusitis that is unresponsive to appropriate antibiotics or who has pain out of extent to the radiographic findings should be evaluated for a possible fungal infection. Overall, the most sensitive fungal stains are the methenamine silver stains, alth- ough fungi can be seen with the usual hematoxylin and eosin staining. The routine fungal culture medium is Sabouraud’s agar, consisting 2% or 4% glucose, 1%

neopeptone, and 2% agar. Routine cultures are incu- bated at 25℃ to 30℃ and must be retained for several weeks before they are reported as negative.

The preoperative diagnosis of paranasal mycosis is sometimes difficult, especially with regard to differen- tiating it from malignant lesions because of frequent unilaterality and multiplicity of the affected sinus and/

or extensive bone destruction and formation of fungus balls. The clinician must keep in mind that many other disease entities such as squamous carcinoma, chronic sinusitis with osteomyelitis, rhinoscleroma, and Wege- ner’s granulomatosis may imitate fungal infections.¹¹⁾

Zinreich et al. reviewed the CT and MRI scans of patients with documented fungal sinusitis.¹²⁾ They found the CT scans to show increased attenuation, which is significantly higher than that seen in chronic bacterial sinusitis with polyposis. In general, CT revealed a rim of soft tissue attenuation of variable thickening along the bony walls of the isolated paranasal sinus, or mo- ttled hyperdense foci of variable size. However, these characteristics may induce clinical misdiagnosis. Dhong et al. reported that the sensitivity of CT evaluation was 62%, and specificity was 99%.¹³⁾ The false-positive and false-negative rate were 22% and 2%, respectively.

The MRI scans demonstrated isointense or slightly decreased intensity on T1-weighted images while the T2-weighted images were decreased. This is definite evidence of a fungal infection because all any other inflammatory disease show intensified T2-weighted images.

They suggested that this could be related to the presence

of calcium, manganase, magnesium, or ferromagnetic elements, for which fungi have a great affinity.

SUPERFICIAL SINONASAL MYCOSIS

This condition is present when fungus in the nose or sinuses is detected either grossly during nasal endoscopy or upon culture of suspicious crusts. It looks like much like mold growing on old bread. Patients may be asy- mptomatic or may also report the presence of crusts/

chunks of debris upon nose blowing. A tuft of fungal material is seen in areas of high airflow such as the anterior edge of turbinates but can also appear in surgi- cally widened sinus cavities. Typically, but not exclusively, these are post-surgical patients who have either dry nasal passage-ways or have some mucous stasis.

Endoscopic removal of the encrusted material reveals underlying pus, as well as mucosal erythema and edema.

Treatment is as simple as removal of fungal material.

If there exists any devitalized bone below the crust in the post-operative patient and remove them. Treat any underlying bacterial infection and humidify the nasal passages with nasal irrigation, sprays and or mucous thinning agents (guaifenesin). Anti-fungal agents are not typically used to treat this condition. Superficial sinonasal mycosis tend to recur and repeated endoscopy is indicated to monitor the results of treatment. It has the potential to be a nidus for more significant rhinosinusitis.

FUNGAL BALL

Fungal ball, which was also misnamed as aspergilloma and mycetoma by the analogy to the pulmonary mycetoma, is an isolated noninvasive disease defined as the presence of a solitary fungal ball. According to the mycology literature this term describes a discrete syndrome which is invasive and not related to an extramucosal process. By definition, mycetoma is a chronic infection and is characterized by the formation of tume- factions, exudate with granules of variable colors, and multiple draining sinuses within the involved tissues.¹⁴⁾ In 1966, British pathologists were first to use the term aspergilloma for paranasal sinus disease where they noted Aspergillus related granulomatous disease afflic- ting the Northern Sudanese.¹⁵⁾ The term aspergilloma was later incorrectly adopted by many otolaryngologists to describe a variety of Aspergillus related fungal con-

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ditions including AFS & fungal balls.

Fungi within the sinus, which are entrapped by inha- ling air, may provide soluble antigens or irritants which increase mucosal inflammatory reaction. Possibly, a mycelia containing mass could obstruct the sinus ostium, favoring episodes of acute bacterial sinusitis. Alterna- tively, obstruction of the sinus ostium from mechanical or inflammatory causes leads to a low oxygen environ- ment favorable for fungal growth and the fungus may be simple growing in the nutritionally ample source of sinus mucus and not causing any of the clinical manifestations.⁸⁾ In either case, a local inflammatory response may accompany the fungal mass, but fungi do not des- troy the local architecture. The most commonly cultured organism is Aspergillus fumigatus.

These patients do not seem to have a characteristic clinical presentation other than chronic, recurring sinusitis of a single sinus that has failed to respond to conventional medical therapy and antral lavage. The symptoms are usually unilateral nasal obstruction, pressure sensation, gelatinous oily rhinorrhea, postnasal drip, accompanied by increased pain and fever during intermittent episodes of acute bacterial sinusitis.^16-18) These symptoms do not provide specifically pathogno- mic findings of mycotic sinusitis. Antral secretions collected by antral lavage are thick, viscid, gelatinous or“membrane-like”with a very offensive odor.¹⁶⁾ The discharge may exhibit unusual gray, greenish brown colors. A small amount of decaying friable masses obtained from antral irrigation has a more significant meaning, suggesting a fungal ball.

In plain radiography, the affected sinus is demonstrated as a nodular mucoperiosteal thickening, homo- geneous opacification. Computed tomography revealed rim of soft-tissue attenuation of variable thickening along the bony walls of the paranasal sinuses. Several well-defined hyperdense foci with a variable size (4- 25 mm) can be detected, which are occasionally misin- terpreted as metallic pieces, misplaced dental fillings, or posttraumatic foreign bodies.¹²⁾

Chronic disease of a single maxillary sinus without evidence of bone destruction can be cured by a surgical debridement and aeration.¹⁹⁾ The operating surgeon finds a thick or cheese like friable mass within the sinus, readily separated from a sometimes thickened or hypertrophic mucosa, with intact bony structures. With an adequate sinus drainage and the restoration of mucociliary clear- ance, recurrence is unusual. Concurrent medical therapy

such as antibiotics and mucolytics aimed at reducing associated mucosal edema is initiated.

ALLERGIC FUNGAL RHINOSINUSITIS

Allergic fungal rhinosinusitis is a chronic condition characterized by three features：1) Fungi present in allergic mucin (preponderance of eosinophils in sinonasal mucinous debris) documented by either mycology or histopathology；2) Absence of sub-epithelial tissue invasion by fungi documented by histopathology；3) Do- cumented IgE mediated allergy to the identified fungus or its family.

In 1981, Millar et al. first suggested a relationship between“allergic aspergillosis of the paranasal sinuses”

and allergic bronchopulmonary aspergillosis (ABPA).²⁰⁾ Two years later, Katzenstein and coworkers proposed a relatively new diagnostic category which they called

“allergic Aspergillus sinusitis”.¹⁰⁾ Upon retrospective analysis of sinus biopsy slides, they found septate fungal hyphae in a background of a particular mucinous material containing eosinophils, Charcot-Leyden crystals from seven young adult patients with a history of asthma, chronic nasal polyposis, multiple prior sinus surgery and radiologic evidence of pansinusitis. Sinus debris from patients was histologically similar to allergic mucoid impaction of the bronchi familiar with allergic bronchopulmonary aspergillosis, a well-known entity first described by Hinson, et al.²¹⁾ Allergic Aspergillus sinusitis may be thought of as the sinus counterpart of allergic bronchopulmonary aspergillosis. In 1987, Wax- man et al., further reported eight additional patients with clinical and histological evidence of allergic Aspergillus sinusitis.²²⁾ Though fungal cultures were negative as with the former series, Aspergillus was the presumed causative agent based on histologic resemblance to allergic bronchopulmonary aspergillosis.

The term“allergic fungal sinusitis (AFS)”rather than allergic Aspergillus sinusitis is now popularly used, because Curvularia lunata as well as other fungi have been shown to induce a clinical picture similar to that found with Aspergillus species. Since the first isolated report of the culture-positive, non-Aspergillus-allergic case,²³⁾ several other fungal organisms, such as Alterna- ria, Exserohilum, Curvularia, Drechslera and Bipolaris, have been reported to cause AFS.^24-28) The prevalence of AFS is not known. The retrospective review of other authors found that the prevalence of AFS among patients

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with chronic sinusitis may be as high as 7%.¹⁰⁾²⁶⁾ Some argue AFS is an IgE mediated allergy, others suggest it may be an infection and yet others ask if it could be both. Researchers who use IgE mediated allergy as part of the diagnostic criteria for AFS find evidence of this in their study population and those who do not use evidence of allergy as part of the definition do not find allergy to be nearly as prevalent. Despite the speculation that AFS and allergic bronchopulmonary aspergillosis have similar mechanisms, it is very rare to find cases of both occurring in the same patient at different times or at once. Safirstein reported a patient with ABPA who initially presented with sinusitis and nasal polyps.²⁹⁾ Sher described fully documented case in which these two syndromes coexist in the same patient.³⁰⁾ The fact that a case of concomitant ABPA and AFS is almost nonexistent suggests that other factors may play a role in their respective pathogenesis.²²⁾³¹⁾

This relatively newly described entity is most commonly seen in young patients with nasal polyps and history of asthma and pansinusitis that is refractory to medical treatment. Up to 75% of the patients have a history of asthma.³²⁾ Spectrum of this disease clearly exists ranging from mild allergic symptoms, polyps, and scant allergic mucin with a few scattered hyphae, to an extreme atopic state with massive expansile disease which is so commonly recurrent over many years that it may cause bony erosion and facial deformity.³¹⁾ Grossly, the sinuses are filled with dense, inspissated, greenish-brown, peanut butter-like mucus that makes surgeons aware of the possibility of fungal disease. And sinus mucosa is hypertrophied with/without polyps.

Plain film radiography shows non-specific thickening and clouding of several or all paranasal sinuses. Al- most twenty percent of reported cases demonstrated evidence of bony displacement or erosion in computed tomography.^23)33)34) Though there is some confusion with the finding of bony erosion without any evidence of tissue invasion by hyphae, pressure necrosis by ex- panding mass of polyps and inspissated mucin or the toxic effect of locally released inflammatory enzymes and mediators, such as major basic protein from eosinophils, are thought to be causative factors. However, this erosion is clearly not associated with tissue invasion by hyphae. Computed tomography demonstrates a very characteristic picture of diffuse expansile sinus involvement with areas of dense concretions. Contrast to the most common finding seen with bacterial sinusitis

on CT scan, i.e., presence of soft tissue mass of low attenuation or low density in the paranasal sinuses, AFS shows areas of high attenuation or increased heteroge- nous density as other type of fungal sinusitis. The soft tissue hyperdensity ranged from 100 to 125 Hounsfield units.²⁶⁾ The increased density of allergic mucin relative to that of mucosal thickening or fluid cannot be appre- ciated by plain radiographic films alone. Though chest films generally show normal findings, they should be taken to detect a chance of ABPA.

The histological feature of this condition is scattered Aspergillus hyphae in mucinous material with abundant eosinophils and Charcot-Leyden crystals (“allergic mucin”).³⁴⁾³⁵⁾ Allergic mucin is characterized by clumps of necrotic eosinophils and other cellular debris, free eosinophil granules within a background of pale, eosinophilic-to-basophilic, amorphous mucin.¹⁰⁾ It is distin- guished from nonallergic inflammatory mucin in which neutrophils were prominent. Because most pathologists are not yet familiar with looking for allergic mucin, many cases are initially reported as“chronic inflam- mation. If fungal cultures reveal an organism or AFS is highly suspected from clinical findings, a surgeon should request to re-scrutinize or identify the allergic mucin.³²⁾ Allergic mucin could be identified with standard hematoxylin and eosin (H & E) stain, while Charcot-Leyden crystals were demonstrated both with H & E and Brown and Brenn stains.²⁵⁾ The fungal elements tended to be sparse without invasion of the mucosa or fungal ball formation. Pathologists should be alert to look for fungal hyphae when a distinctive, if not constant, laminar layering of the cells and cellular debris in the mucoid matrix is found.³³⁾ Hyphae are easily detected using a Gomori’s methenamine silver stain. These crystals are formed from the membrane of released granules within eosinophils and are made up almost entirely of lysoph- ospholipase. They appear hexagonal in cross-section and bipyramidal, spindle shaped in longitudinal section.¹⁰⁾²⁵⁾

An effective treatment strategies for AFS is not yet known. Careful and complete surgical drainage and restoration of sinus aeration are important. This can be accomplished in many cases by either a traditional external approach or a functional endoscopic sinus surgery, according to the preference of the individuals imvolved.

This procedure also helps decrease the fungal antigen load and theoretically can decrease the stimulus leading to immediate and late-phase allergic symptoms. However, recurrence of disease despite sufficient surgical drainage

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and aeration of the sinuses is common. Medical therapy may include culture directed antibiotics, mucolytic therapy, antihistamines, systemic steroids, immunotherapy, and/or anti-fungal agents. Systemic corticosteroids are suggested postoperatively in many patients with AFS, especially with extensive recurrent disease and severe atopy because of their ability to reduce inflammatory responses.⁹⁾²²⁾ Whether topical intranasal steroids alone can prevent recurrence after surgical drainage remains to be proved. They have been ineffective when used alone, but may have a long term preventive role after a course of oral corticosteroids.³¹⁾

Safirstein et al. reported an 80% remission rate with use of systemic corticosteroids in allergic bronchopulmonary aspergillosis.³⁶⁾ It would seem that high remission rates can be expected with AFS. The current suggested therapy for allergic bronchopulmonary aspergillosis is prednisone (0.5 mg/kg/day) for 2 weeks, then alternate day therapy for 3 to 6 months followed by a tapering dose.³⁶⁾³⁷⁾ The author of this chapter also prefers to initiate dosing with prednisone at 0.5 mg/kg/

day. Then prednisone is tapered based upon endoscopic findings, not based upon symptomatic improvement.

Prednisone doses ranging between 2-5 mg of prednisone (0.07-0.02 mg/kg/every other day) every other day has been required to maintain disease free intervals.

The use of a corticosteroid inhalant and disodium cro- moglycate is of limited benefit through an impaired airway in patients with ABPA because of the inability of the drugs to reach the affected areas in the lung due to air way obstruction secondary to bronchodialators and mucus plugging.

Another controversial point is the role of systemic antifungal agents such as amphotericin B in noninvasive fungal sinusitis. The role of specific immunotheraphy or local antifungal therapy has not been defined. Before this type of fungal disease was well recognized, many patients were treated with systemic antifungal agents.⁸⁾²²⁾ In severe cases in the literature, which were suspected to be AFS, recurrences were reported despite treatment with intravenous amphotericin B.⁸⁾ However, antifungal therapy has not been of benefit in the treatment of ABPA.³⁶⁾ Regardless, antifungal agents are unwarranted in the allergic disease state without tissue invasion.³⁴⁾³⁸⁾ If pathologic evidence of allergic mucin is found, with or without fungi as seen on fungal stain or culture, initiation of topical intranasal corticosteroids and a complete allergic surveillance are recommended.

CHRONIC INDOLENT ((((CHRONIC INVASIVE)))) FUNGAL RHINOSINUSITIS

This is a relatively rare invasive fungal disease that can span months to years in its clinical course and is described to be more common in immunocompetent patients.

It presents clinically as an enlarging mass which can erode insidiously through anatomic barriers such as the cheek, orbit, hard palate, brain, or pituitary.^15)38-42) Com- plaints of visual changes, including proptosis, external facial deformity, and cranial nerve dysfunction can de- velop. Headache, nasal congestion and other symptoms of a chronic rhinosinusitis may be present. This disease occurs in patients without obvious immune deficiency.⁸⁾ Indolent fungal disease may be either slowly progressive or fulminant. Slowly progressive disease should be suspected in an apparently immunocompetent person with chronic sinusitis that progresses despite multiple medical and surgical treatments.

Diagnosis is based on a biopsy demonstrating tissue invasion by fungal hyphae. Aspergillus is the most common organism associated with this condition. Fungal hyphae are scarce and not easily seen with routine stains, appearing as holes in giant cells, but can be easily identified with silver stain.³⁵⁾ The indolent form often is invasive but may be noninvasive early in its course.

Histologically, there is a chronic inflammatory reaction with giant cells and granulation formation within the tissue. The allergic mucin is absent.

Nasal endoscopy may only reveal nasal cavity findings similar to what appears with a fungal ball. CT scan imaging is recommended and typically demonstrates significant soft tissue thickening and evidence of altered adjacent bone. Rarely the altered bone may present with a paucity of mucosal disease. This may be more likely to appear in individuals with some measure of altered immunity. MRI is recommended for impending complication of the eye and brain.

Once diagnosis is confirmed, this infection is handled much like a malignant neoplasm since persistent disease is common. Wide local resection is preferred in conjun- ction with systemic anti-fungal agents. Depending upon the nature of the sinus involvement and the experience of the surgeon, the surgery may be approached through minimally invasive techniques or traditional open surgery. The anti-mycotic agent of choice is based upon

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the fungus that is present. Amphotericin is the agent that is typically initiated. The duration of therapy is based upon location of residual disease, ability to reverse any underlying sources of immunosuppression, and response to treatment. Recurrence is not uncommon despite systemic antifungal therapy following surgery.

As stated earlier, this disease can invade neighboring structures such as the orbit and brain and may be fatal.⁸⁾⁴³⁾

FULMINANT FUNGAL RHINOSINUSITIS

This is a rapidly progressive, tissue invasive fungal disease that appears almost exclusively in immunocompromised patients such as those who have been diagnosed with acute leukemia, lymphoma, or aplastic anemia. Patients who received corticosteroids, cytotoxic drugs, irradiation, or broad-spectrum antibiotics, organ transplantation, other surgical procedures, or who have experienced immunologic disorders, chronic infections, low granulocyte counts, or prolonged hospitalization are predisposed to opportunistic infections. Kavanagh et al. reported that forty two percent of patients with leukemia had abnormal sinus radiographs and eight out of thirty six operated cases were proved as fungal sinusitis.⁴⁴⁾ It is most commonly associated with Mucor but is also seen in association with Aspergillus and many other forms of fungi.

The diagnosis of fulminant fungal rhinosinusitis de- pends on an awareness of the disease by both oncol- ogist and otolarygologist. The clinical presentation is often initiated by a severe spiking febrile illness that does not respond to antibiotics and localized, predomi- nantly painless cutaneous induration and erythema.⁴⁵⁾ Nasal obstruction with granular, bloody nasal discharge, and swelling over the involved sinuses are highly suspicious findings.⁶⁾ A characteristic earliest lesion indi- cating involvement of the nose and sinuses is crusting of the anterior end of the inferior turbinate or adjacent part of the cartilaginous septum and underlying discolo- ration of the nasal mucous membrane. Black intranasal eschar is the pathognomonic finding that describes acute fulminant fungal rhinosinusitis and it is most typically seen when Mucor is the predominant fungal organism.

It is by no means universally present and can only be seen when there is advanced disease with vessel invasion. Unfortunately, a black eschar in a severely ill

patient is often ignored and can be mistaken as dried blood. In some patients with an earlier phase of acute fungal rhinosinusitis the mucosa may not appear to be black but instead it will appear pale or blanched white.

This mucosal appearance is more typically seen in patients with non-Mucor acute fungal rhinosinusitis. This may progress to a whitish necrotic mass in the nose.

Within two or three days, the lesion progresses to involve the lateral nasal wall with a rapidly progressive gangrenous mucoperiostitis. Facial swelling rapidly occurs. Proptosis, chemosis and opthalmoplegia signify orbital involvement. The palate often becomes eroded and necrotic. Necrosis of the facial skin can occur. Any crusting in the nasal cavity should be removed and stained with methenamine silver technique. Removal of this crusting reveals an underlying gangrenous inferior turbinate which is insensitive. Even if a fungal infection is suspected, cultures are frequently negative. And even though culture may be positive, assessment of that meaning can be difficult because of their ubiquitous nature.

The only reliable means of confirming the diagnosis is the histological demonstration in infected tissue of micro- organisms morphologically consistent with species. Any finding suggestive of an invasive process warrants biopsy either at the bedside or in the operating room. Early nasal or oral examination may demonstrate areas of pale gra- yish, relatively insensitive mucosa. The physician should not wait for the appearance of the classic turbinate or palatal black necrosis to confirm the diagnosis. Because of underlying bleeding diathesis (eg. thrombocytopenia) and the patients general condition, an operating room biopsy may be preferred. Biopsy is obtained at the leading edge of involved tissue. Biopsy from the center of a necrotic area is not likely to be as fruitful. Any crusting in the nasal cavity should be removed and stained with methenamine silver technique.

Similarly sinus radiographs may be unremarkable due to the lack of immune response. CT is indicated as soon as the possibility of invasive disease is considered in order to attempt demonstrate bony erosion or soft tissue involvement. Sinus radiographs may be very non- specific. Emergent MRI is indicated in these patients to determine occult extension of disease and is especially helpful in evaluating the orbit, cavernous sinuses, and brain.

An aggressive treatment needs to be taken in these patients, with antifungal and antibacterial agents given at the same time of onset of symptoms.⁴⁴⁾ When diag-

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nosis is established, amphotericin B and surgical debridement are recommended. The optimum total dose of amphotericin B and and duration of treatment with amphotericin B remains unknown. Traditionally, textbooks have recommended a 1 mg test dose in 5% dextrose on the first day of therapy, followed by a progressive escalation of dose by daily increments of 5 mg until a daily dose of 1 mg/kg of body weight is reached. How- ever, in seriously ill patients with rapidly progressing mucormycosis, a 1-mg test dose during several hours to be followed immediately by repeated doses every 12 hours at 10 to 15 mg increments until a daily dose of about 0.7 to 1.0 mg/kg of body weight daily is reached.

The same daily dose of 0.7 to 1.0 mg/kg can be given every other day since patient's condition stabilizes or improves.⁴⁶⁾ All patients should be followed with labo- ratory studies of serum creatinine, BUN, electrolytes, and complete blood counts on a regular basis because of their nephrotoxicity. Fever, chills, headache, nausea, and vomiting have been reported in up to 80% of patients, and hypokalemia in up to 20%. If the serum creatinine becomes greater than 3.0 mg/dL, dosage of amphotericin be delayed until the patient’s renal function stabilizes or improves.⁴⁶⁾

Rifampin, itraconazole or 5-flucytosine can be added when the initial response is poor. In certain circumstances, aggressive life-saving adjunctive therapies have been associated with variable success. These measures include the use of granulocyte colony-stimulating factor (G- CSF), white blood cell transfusions, bone marrow transplantation, and hyperbaric oxygenation.⁴⁷⁾ The most effective treatment, though it is not often possible, con- sists of prompt resolution of the underlying immunodeficiency.

Immediate surgical debridement of devitalized tissue and aeration of involved sinuses is indicated for all patients as soon as possible except for those who have an early lesion with prompt response to antifungal therapy because this disease is so fulminant that there is frequently not enough time to obtain an actual thera- peutic effect.⁷⁾ Following surgery, continuous irrigation of the nasal cavity and sinuses must be instituted to prevent crusting and further invasion by aspergillosis.

Amphotericin B (50 mg/L of water) irrigations (20 ml four times a day) may be performed via a rubber cathe- ter left in the maxillary sinus. Further debridement may be required if persistent crusting or recurrent disease becomes clinically evident.

The overall response to amphotericin B is about 50%；however, regardless of therapy, the mortality in patients with bone marrow transplants or cerebral disease is over 90%. The prognosis with favorable initial response to treatment often show recurrence when additional immunosuppressive therapy becomes necessary.

REFERENCES

1) Axelsson H, Carlsii B, Weibring J, Winblad B. Aspergillosis of the maxillary sinus. Acta Otolaryngol 1978;86:303-8.

2) Holt GR, Standefer JA, Brown WE, Gates GA. Infectious diseases of the sphenoid sinus. Laryngoscope 1984;75:768-73.

3) Stammberger H. Endoscopic surgery for mycotic and chronic recurring sinusitis. Ann Otol Rhinol Laryngol 1985;94(suppl, 119):

1-11.

4) Stammberger H. Functional Endoscopic Sinus Surgery. B.C. Decker, Philadelphia, PA, p398, p409.

5) Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA, Roberts GD. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 1999 Sep;74(9):877-84.

6) Stevens MH. Primary Fungal Infections of the Paranaal Sinuses.

Am J Otolaryngol 1981;2:348-57.

7) McGill TJ, Simpson G, Healy GB. Fulminant aspergillosis of the nose and paranasal sinuses; a new clinical entity. Laryngoscope 1980;90:748-54.

8) Washburn RG, Kennedy DW, Begley MG, Henderson DK, Bennett JE. Chronic fungal sinusitis in apparently normal hosts. Medicine 1988;67(4):231-47.

9) Katzenstein AA, Sale SR, Greenberger PA. Pathologic findings in allergic Aspergillus-sinusitis. Am J Surg Pathol 1983;7:439-43.

10) Katzenstein AL, Sale SR, Greenberger PA. Allergic Aspergillus Sinusitis: A newly Recognized Form of Sinusitis. J Allergy Clin Immunol 1983;72:89-93.

11) Tanaka T, Nishioka K, Naito M, Masuda Y, Ogura Y. Coexistence of Aspergillosis and Squamous-Cell Carcinoma in the Maxillary Sinus Proven by Preoperative Cytology. Acta Cytologica 1985;29 (1):73-8.

12) Zinreich SJ, Kennedy DW, Malat J, Curtin HD, Epstein JI, Huff LC, Kumar AJ, Johns ME, Rosenbaum AE. Fungal sinusitis; diagnosis with CT and MRI imaging. Radiology 1988;169:439-44.

13) Dhong J, Jung JY, Park JH. Diagnostic accuracy in sinus fungus balls: CT scan and perative findings. Am J Rhinol 2000:14:227-31.

14) Sredman’s medical dictionary. 23red Ed. Baltimore: Willians &

Wilkin, 1976.

15) Milosev B, Mahgoub ES, Abdel Aal O, El Hassan AM. Primary aspergilloma of the sinuses in the Sudan. Br J Surg 1969;56:132-7.

16) Bassiouny A, Maher A, Bucci TJ, Moawad MK, Hendawy DS.

Noninvasive antromycosis. J Laryngol Otol 1982;96:215-28.

17) Kopp W, Fotter R, Steiner H, Beaufort F, Stammberger H. Asper- gillosis of the paranasal sinuses. Radiology 1985;156:715-6.

18) Levine PA, Yanagisawa E. Aspergillosis of the maxillary sinus.

Arch Otolaryngol 1977;103:560-3.

19) Simmons BP, Johnson G, Aber RC. Fungus ball of the sphenoid sinus in an immunecompetent host. South Med J 1982;75:762-5.

20) Millar JW, Johnston A, Lamb B. Allergic aspergillosis of the maxillary sinuses (abstract). Thorax 1981;36:710.

21) Hinson KFW, Moon AJ, Plummer WS. Bronchopulmonary As- pergillosis. Thorax 1952;7:317

22) Waxman JE, Spector JG, Sale SR, Katzenstein AA. Allergic As- pergillus sinusitis: Concepts in treatment of a new clinical entity.

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Laryngoscope 1987;97:261-6.

23) Brummard W, Kurup VP, Harris GJ, et al. Allergic Sino-orbital Mycosis. A Clinical and Immunologic Study. JAMA 1986;256:

3249-53.

24) Bartynski JM, McCaffrey TV, Frigas E. Allergic Fungal Sinusitis Secondary to Dermatiaceous Fungi-Curvularia lunata and Alternaria.

Otoraryngol Head Neck Surg 1990;103:32-9.

25) Ence, BK, Gourley DS, Jorgensen NL, Shagets FW, Parsons DS.

Allergic Fungal Sinusitis. Am J Rhinol 1990;4(5):169-78.

26) Gourlry DS, Whisman BA, Jorgansen N, Martin ME, Reid MJ.

Allergic Bipolaris sinusitis: clinical and immunopathologic characteristics. J Allergy Clin Immunol 1990;85:583-91.

27) Killingsworth SM, Wetmore SJ. Curvularia/Drechslera Sinusitis Laryngoscope 1990;100:932-7.

28) Macmillan RH, Cooper PH, Body BA, Mills AS. Allergic fungal sinusitis due to Curvularia lunata. Hum Pathol 1987;18:960-4.

29) Safirstein B. Allergic bronchopulmonary aspergillosis with obstruction of the upper respiratory tract. Chest 1976;70:788-90.

30) Sher TH, Schwartz HJ. Allergic Aspergillus sinusitis with con- current allergic bronchopulmonary Aspergillus; report of a case. J Allergy Clin Immunol 1988;81:844-6.

31) Allphin AL, Strauss M, Abdul-Karim FW. Allergic Fungal Sinu- sitis; Problems in Diagnosis and Treatment. Laryngoscope 1991;

101:815-20.

32) Schwietz LA, Gourley DS. Allergic Fungal Sinusitis. Allergy Proc 1992;13:3-6.

33) Hartwick RW, Batsakis JG. Sinus Aspergillosis and Allergic Fungal Sinusitis. Ann Otol Rhinol Laryngol 1991;100:427-30.

34) Manning SC, Schaefer SD, Close LC, et al. Culture positive Allergic Fungal Sinusitis. Arch Otolaryngol Head Neck Surg 1991;

117:174-8.

35) Milroy CM, Blanshard JD, Slucas, Michaels L. Aspergillosis of the nose and paranasal sinuses. J Clin Pathol 1989;42:123-7.

36) Safirstein B, D’Souza M, Simon G, et al. Five-Year Follow-up of Allergic Bronchopulmonary Aspergillosis. Am Rev Respir Dis 1973;108:450-9.

37) Harwig J, Greenberger P, Patterson R. Allergic Bronchopulmonary Aspergillosis. Immun Allerg Prac 1984;6:292-301.

38) Shugar MA, Montgomery WW, Hyslop NE. Alternaria sinusitis.

Ann Otol Rhinol Aryngol 1981;90:251-4.

39) Crivelli G, Riviera LC. Unilateral blindness from aspergilloma at the right optic foramen. J Neurosurg 1970;33:207-11.

40) Goldhammer Y, Smith JL, Yates BM. Mycotic intrasellar abscess.

Trans Am Ophthalmol Soc 1974;72:65-78.

41) Hora JF. Primary aspergillosis of the paranasal sinuses and associated areas. Laryngoscope 1965;75:768-73.

42) McGill TJI. Mycotic infection of the temporal bone. Arch Otola- ryngol 1978;104:140-4.

43) Frenkel L, Kuhls TL, Nitta K, Clancy M, Howard DH, Ward P, Cherry JO. Recurrent Bipolalis sinusitis following surgical and antifungal therapy. Pediatr Infect Dis 1987;6:1130-2.

44) Kavanagh KT, Hughes WT, Parham DM, Chanin LR. Fungal Sinu- sitis in Immunocompromised Children with Neoplasms. Ann Otol Rhinol Laryngol 1991;100:331-6.

45) Weingarten JS, Cockett DM, Lask RP. Fulminant aspergillosis:

Early cutaneous manifestations and the disease process in the immunocompromized host. Otolaryngol Head Neck Surg 1987;97:

495-9.

46) Lehrer RI, Howard DH, Sypherd PS, Edwards JE, Segal GP, Win- ston DJ. Mucormycosis. Ann Intern Med 1980;93:93-108.

47) Kajs-Wyllie M. Hyperbaric oxygen therapy for rhinocerebral fungal infection. J Neurosci Nurs 1995 Jun;27(3):174-81.