Fungal infections of the head and neck: an update

Fungal infections of the head and neck: an update

Otolaryngol Clin N Am 36 (2003) 577–594 Fungal infections of the head and neck: an update Richard D. Thrasher, MD, Todd T. Kingdom, MD, FACS* Departm...

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Otolaryngol Clin N Am 36 (2003) 577–594

Fungal infections of the head and neck: an update Richard D. Thrasher, MD, Todd T. Kingdom, MD, FACS* Department of Otolaryngology, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, B-205, Denver, CO 80262, USA

Much has been written in the recent literature on fungal infections and their pathogenic mechanisms. This interest may reflect increased knowledge arising from improved technology and diagnostic capabilities or the increased experience with the organisms as more immunosuppressant medications are used. This article provides an update on the topic and discusses the current management options for these infections.

Fungal infections: background Fungi are eukaryotic organisms comprising molds, yeasts, mushrooms, and similar organisms. More than 100,000 species of fungi have been described. Only about 0.1% are recognized as human pathogens, although the number capable of producing disease in the immunocompromised host continues to increase [1]. Most organisms are soil saprophytes; only the dermatophytes are capable of host-to-host transmission [2]. Mycosis is defined as an infection caused by fungi and is categorized into four major groups based on portal of entry and the major site of infection (Table 1) [2]. Human defense against fungal infections is mediated on several levels, any of which may break down and allow a route for infection (Table 2).

Anti-fungal therapy: a review Common sense guides the general principles of antifungal therapy. Prevention is a realistic goal only in those who are immunosuppressed, * Corresponding author. E-mail address: [email protected] (T.T. Kingdom). 0030-6665/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0030-6665(03)00029-X


R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594

Table 1 Types of mycoses Type





Limited to the keratinized tissues Localized to subcutaneous structures Disseminated widely Local or disseminated

Topical Broken skin

Tinea pedis Tinea captitis Rhinospordiosis

Inhalation Cell-mediated immune compromise

Histoplasmosis Candidiasis Mucormycosis


Systemic Opportunistic

because avoidance is rarely required or even possible in healthy individuals. Prevention in immunocompromised individuals ranges from physical avoidance to meticulous hygiene to prophylaxis. Surveillance is also a significant preventative measure in those at most risk. For example, patients with an absolute neutrophil count less than 500 have a significantly increased likelihood of acquiring an invasive fungal infection. Thus, in these patients, a thorough work up is required for patients who develop a fever of unknown origin lasting 48 hours or more. Correction of local and systemic predisposing factors (eg, diabetic ketoacidosis) is both reasonable and mandatory. Without optimization of host defense, medical and surgical therapy will certainly be less effective. This dogma is clearly demonstrated by the possibility of clearance of invasive fungal disease when diabetic ketoacidosis is corrected. Medication becomes the mainstay of antifungal therapy when host defense is penetrated, again most commonly in the immunocompromised individual. Antifungal agents are limited to amphotericin, the azoles, nystatin, flucytosine, terbinafine, and the echinocandins (or glucan synthesis inhibitors) (Table 3). Table 2 Host defenses against fungi and potential causes of circumvention Host defense

Mechanism of circumvention

Mucocutaneous barriers

Wounds, burns, intravenous catheters, sores, ulcerations, nonfungal infection Diabetes, steroid administration, HIV infection, chemotherapy, cancer (especially those involving cells of the immune system) Granulocytopenia Chronic granulomatous disease Myeloperoxidase deficiency Congenital deficiency

General cellular immunity

Phagocytosis Polymorphonuclear Leukocytes Monocytes Humoral Immunity: complement and immunoglobulins Normal bacterial flora


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Table 3 Antifungal medications Medication

Mechanism of action

Amphotericin B

Fungicidal. Binds to ergosterol in fungal cell membranes increasing permeability Fungistatic. Inhibits an enzyme required to produce ergosterol Fungicidal. Binds to ergosterol in fungal cell membranes increasing permeability Fungistatic. Interrupts DNA synthesis Fungicidal. Inhibits an enzyme required to produce ergosterol Fungicidal. Glucan synthase inhibitors which prevent fungal cell wall maintenance and repair Yet to be studied

Azoles Nystatin Flucytosine Terbinafine Echinocandins Sodarins

Amphotericin B was introduced more than 40 years ago and remains the criterion standard for combating the most severe fungal infections. It has a broad spectrum of coverage but also has significant toxicities that limit its use to the most difficult infections. Amphotericin B disrupts fungal cell membranes through its affinity for ergosterol, a protein found in fungal cell membranes but not in those of bacterial or human membranes. Attachment allows increased permeability and leakage of intracellular components, resulting in cell death. Because amphotericin B also has a limited affinity for cholesterol, side effects may include nephrotoxicity in up to 80% of patients, anemia, fever, chills, nausea, and vomiting. Lipid-based amphotericin B was designed to decrease the risk of nephrotoxicity and maintain the same antifungal activity. Amphotericin B is administered either intravenously as 0.3 to 1.5 mg/kg/day in 5% dextrose over 2 to 4 hours (for systemic or invasive disease) or orally as a lozenge or in a 100-mg/mL solution taken four times per day (for topical infections). Nystatin, like amphotericin B, is a polyene antifungal that because of its toxicity is used as a topical agent. Its mechanism of action is similar to that of amphotericin B, attaching itself to sterols in the cell membrane to disrupt regulation of cell permeability. It is generally administered in 100,000 to 200,000 U/day taken by swish-and-spit four times per day for oropharyngeal candidiasis. The azoles, fungistatic agents, include imidazoles (clotrimazole, ketoconazole, miconazole) and triazoles (fluconazole and intraconazole). This group of medications does not carry the same nephrotoxic side effects that accompany amphotericin B, but they still exert effect on systemic mycoses. The triazoles as a class have superior pharmokinetics, better safety profiles, and more studies documenting clinical efficacies and are therefore more commonly used for systemic disease. All azoles work by inhibiting a cytochrome P-450–dependent enzyme that is required to convert lanosterol to ergosterol. Of the triazoles, fluconazole is administered both orally and intravenously in typical doses of 200 mg/day; however, doses as high as 1600 mg/day have been used for more significant infections.


R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594

Itraconazole dosage ranges from 100 to 400 mg/day depending on the infection. The imidazoles are used primarily for the treatment of Candida albicans topical infections. Clotrimazole comes as an oral troche (10 mg administered up to five times per day for 7 days) or as a topical cream for skin infections. Miconazole is rarely used in the treatment of head and neck fungal infections. Ketoconazole is used for oropharyngeal candidiasis but less commonly than clotrimazole, fluconazole, or nystatin. Flucytosine, originally designed as a chemotherapeutic agent, enters into yeast cells where it is converted to 5-fluorouracil that through its metabolites interrupts DNA synthesis. Administered orally, it is often given in conjunction with amphotericin B. Bone marrow suppression is its most significant side effect but is much less common than diarrhea, nausea, vomiting, and rash formation. Flucytosine has demonstrated strong efficacy against Cryptococcus and Candida species. A common dose for serious infections is 100 mg/kg/day divided four times per day. Of the remaining antifungal agents, terbinafine is a fungicidal medication that inhibits an enzyme used in the production of ergosterol. It is administered orally with great success against dermatophyte infections of the hair, skin, and nails. Echinocandins, otherwise known as glucan synthesis inhibitors, are a new class of fungicidal agents that inhibit a key component of fungal cell wall maintenance. Their activity is most consistently strong against Candida, Aspergillus, and Pneumocystis carinii. An even newer class of antifungal agent that has yet to be reported in human trials is the sordarins that inhibit fungal cell protein synthesis. Little is known about these agents and their efficacy in vivo [3–7].

Otomycosis Meyer in 1844 first described fungal infections of the external auditory canal (EAC) a location that supplies the ideal warm humid environment for the proliferation of these organisms [8]. Multiple studies have shown that fungi can be a primary pathogen in the EAC rather than simply an opportunistic secondary pathogen [9–12]. Candida and Aspergillus are the most common fungi isolated from the EAC in several series, although more than 60 species have been identified [9,13]. The most common complaints in otomycosis according to Than et al [14] are a deep itching (70%), often followed by a dull, deep pain (54%) with or without tinnitus (50%), hearing loss (35%), or discharge (35%). No demonstrable increase in otomycosis has been found with topical aural steroid drops [8]. The mainstay of treatment of otomycosis remains drying and acidifying the EAC. The single greatest change over the last decade in the treatment of otomycosis is the development of over-the-counter clotrimazole preparations. Other medication options for fungal infections of the EAC include

R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594


nystatin, Domeboro otic solution (Bayer Corp., West Haven, CT), gentian violet, ethyl alcohol, and miconazole. In a recent study, clotrimazole had the greatest efficacy against the common aural fungi (Aspergillus niger, Candida species, Penicillum, and Alternaria) [8]. Oral and intravenous preparations of antifungal agents are available for severe infections in immunocompromised persons. In this subpopulation of patients malignant otitis externa can, rarely, present as an aggressive angioinvasive fungal infection of the temporal bone.

Fungal infections of the oral cavity, pharynx, and esophagus Almost all fungal infections of the mouth are caused by candidal species with most of these secondary to C. albicans. Indeed up to 60% of the healthy population can have C. albicans cultured from the oral mucosa without having evidence of disease [15]. Other rare fungal infections occurring in the mouth include blastomycosis, histoplasmosis, coccidioidmycosis, cryptococcosis, geotrichosis, and phycomycosis. This update focuses on Candida. Generally speaking, candidal infections require the presence of a preexisting immunosuppressed condition to become pathogenic. This immunosuppression can range from seemingly benign conditions such as decreased salivation to the more commonly known diabetes, pernicious anemia, chemotherapy, human immunodeficiency virus (HIV), and radiation therapy to the oral cavity. Oropharyngeal candidiasis is frequently associated with HIV, diabetes, the use of dentures, orally inhaled steroids, and chemotherapy [16]. The clinical presentation can vary widely. Patients may be relatively asymptomatic or experience dysphagia, odynophagia, burning or pain in the mouth, tongue, or pharynx, and white patches on the oropharyngeal mucosa [16]. Additional findings may include subtle erythematous patches or even simple irritation presenting like a mild mucositis. Diagnosis can be elusive and may require mucosal scraping with potassium hydroxide (KOH) preparation or even biopsy, in addition to a high degree of suspicion. A number of available medications have reasonable efficacy against Candida, but it is inappropriate to disregard the inciting factor. Therefore, before administration of antifungal agents, the clinician should ensure that the underlying cause is treated first. This treatment may include relatively simple measures such as appropriate cleaning of dentures or more complex management issues such as optimizing glucose control in the diabetic patient. The most commonly used antifungal agents for thrush are a nystatin swish-and-spit or a clotrimazole oral troche (1 to 2 tabs providing 200,000 U per tab four to five times per day) continued until symptoms have resolved for 48 hours [3]. Other oral preparations that are effective include amphotericin B, miconazole, itraconazole, and fluconazole. Fluconazole and itraconazole work systemically rather than topically and are held in reserve for cases of topical failure.


R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594

Candidal esophagitis can present without oral candidiasis up to 50% of the time [4]. There are four grades for the esophagitis, with presentations ranging asymptomatic to severely odynophagic. Diagnosis is made by esophagogastroduodenoscopy (EGD), which allows the clinician to visualize the severity of the mucosal involvement and take brushings or biopsies as needed. Treatment depends on the severity of the disease and the overall health of the patient. It can include topical medications for immunocompetent individuals or oral systemic medications such as fluconazole (100 mg/ day for up to 14 days) or itraconazole in those who are immunocompromised. When candidiasis is invasive, fluconazole is administered in a loading dose of 800 mg followed by 400 mg/day orally or intravenously until clearance is achieved.

Fungal infections of the larynx A rare disease, fungal laryngitis is almost exclusively attributable to the yeast group of fungi that include Candida, Cryptococcus, Blastomyces, Paracoccidioides, and Coccidioides. The mold forms, Aspergillus and Mucormycoses, are rarely found and when present are nearly universally secondary pathogens [17]. Candida has been reported as isolated to the epiglottis, true vocal folds, voice prostheses, and false vocal folds in addition to global involvement of the entire larynx [17]. Laryngeal candidiasis primarily is observed in hematologic malignancies. Hoarseness is the most common clinical symptom, but its severity does not indicate the extent of laryngeal involvement [18,19]. Similarly, odynophagia, although often present, does not indicate severity. Diagnosis is probably more urgent in the larynx than in the oral cavity alone because of the increasing complications that can occur in this area including scarring of the true vocal folds and airway compromise from glottic edema. Diagnosis cannot be made with simple history and physical examination (flexible nasopharyngoscopy is suggestive) but requires tissue for culture and histopathology. Treatment is similar to that for oropharyngeal candidiasis. Histoplasmosis is nearly always a presentation of chronic progressive disseminated disease. In fact, two thirds of patients with chronic disseminated disease display laryngeal and oropharyngeal ulcers, which are often the initial presenting complaint [17]. Two reports have shown that the lesions are more likely involve the anterior larynx rather than the posterior predilection shown in tuberculosis [20]. Because histoplasmosis is a manifestation of disseminated disease, amphotericin B, 35 mg/kg, is the most common treatment. Ketoconazole is an alternative treatment for patients who are not immunocompromised. Of the remaining fungi, Coccidioides is manifest in the larynx in the disseminated form of the disease similar to that found in histoplasmosis.

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The treatment usually consists of amphotericin B; ketoconazole has a high relapse rate. Blastomyces can be isolated from any level of the larynx. In one study of 460 patients infected with the fungus, the larynx was involved in 8, or in slightly less than 2% [21]. Ketoconazole is an effective treatment. Paracoccidioides can present with crusted granulomatous lesions in the nose, oral cavity, pharynx, or larynx. It can be treated with sulfadiazine, amphotericin B, itraconazole, or ketoconazole. Finally, Cryptococcus can present in the larynx but usually in the presence of disease elsewhere. It has been described in immunocompetent individuals, however. Treatment consists of combination therapy, usually of flucytosine and amphotericin B.

Fungal infections of the sinuses By far the greatest advances in the last decade as well as the greatest topic of controversy in head and neck mycoses has revolved around fungal rhinosinusitis. This limited discussion reviewing the current concepts of fungal rhinosinusitis should form a solid basis for further reading and investigation.

Classification of fungal sinusitis There are five recognized forms of fungal sinusitis, each with its own pathophysiology and clinical presentation. They include acute fulminant invasive fungal sinusitis, chronic invasive fungal sinusitis, granulomatous invasive fungal sinusitis, fungus ball, and allergic fungal rhinosinusitis (AFS). Recent work, however, has suggested that this traditional classification list should be changed by including or even substituting the diagnostic category of eosinophilic fungal rhinosinusitis for AFS and by adding the entity eosinophilic mucin rhinosinusitis. Acute fulminant invasive fungal sinusitis is less than 4 weeks in duration and nearly universally involves patients who have some form of immunosuppression [22]. This incompetence may result from diabetes mellitus, immunosuppressive drugs, primary or secondary immunodeficient conditions, or cancer. The fungus, most commonly of the Mucoraceae family (usually Rhizopus) or Aspergillus fumigatus, is angioinvasive and destroys both bone and tissue. It has a relatively high mortality rate and requires extensive surgical de´bridement of all nonviable tissue as well as systemic intravenous antifungal medication, typically amphotericin B. If possible, the underlying causative immunocompromised state should be reversed. Because recovery of normal neutrophil count is mandatory for survival, new adjunctive therapies such as granulocyte infusion or administration of granulocyte colony-stimulating factor are being investigated.


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Chronic invasive fungal sinusitis (also known as nongranulomatous chronic invasive fungal sinusitis) is most commonly found in patients with diabetes mellitus; Aspergillus fumigatus is the most common pathogen. De Shazo [23] has reported that all patients in his series with this form of fungal sinusitis had diabetes mellitus. Granuloma formation requires an appropriate cell-mediated immune response that may be limited in diabetes. Patients often have little or no immunosuppression. The disease is characterized by a low-grade inflammatory reaction with tissue necrosis but minimal or no evidence of vascular invasion. Its duration is longer than 4 weeks. Extension into the orbit often produces proptosis. Like acute fungal sinusitis, chronic invasive fungal sinusitis demands wide surgical de´bridement with systemic intravenous antifungal medication, often of prolonged duration (6 weeks or more) [24]. Granulomatous invasive fungal sinusitis has also been called indolent fungal sinusitis. It is considered the counterpart to chronic invasive fungal sinusitis, but with an intact cell-mediated immune response. It is clinically indistinguishable from the nongranulomatous form; histologic examination is required to distinguish the two. It also predominates in immunocompetent individuals. The immune response limits the invasion to the superficial mucosa. Granulomas surround the invasive fungal elements and limit deeper penetration. Multinucleated giant cells, pallisading nuclei, and eosinophils can be seen surrounding the granulomas. Treatment is somewhat controversial: some authors suggest surgical de´bridement alone as effective, whereas others cite the need for antifungal medications in addition to surgery [24]. Antifungal treatment consists of intravenous amphotericin B followed by itraconazole. If P. boydii is the pathogen, imidazole may be the preferable intravenous agent [25]. Although prognosis is hard to ascertain in many patients, in general it is considered to be better than for the nongranulomatous form because of the intact cell-mediated immunity. Fungus balls, or mycetomas, usually present as a unilateral opacification of either the maxillary or sphenoid sinus [26]. Only rarely are they found in the ethmoid or frontal sinuses. There are no reported pediatric patients, and women are more predominately affected, accounting for about two thirds of patients. Patients are classically immunocompetent without evidence of atopy. The fungus ball is composed of tightly packed hyphae most often from Aspergillus, Alternaria, or P. boydii [26]. Treatment is surgical and must include removal of debris and wide ventilation of the involved cavity. Medical therapy is of little utility, and recurrence is unusual after appropriate surgical management.

Allergic fungal sinusitis Allergic fungal sinusitis (AFS), more appropriately called allergic fungal rhinosinusitis, is the fifth classification of fungal sinusitis. Indeed, a large

R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594


amount of controversy exists regarding the etiology and pathogenesis of this entity. In fact, recent research challenges the current definition and pathophysiology of allergic fungal sinusitis. The history of AFS itself is somewhat convoluted. Safirstein [27] first noted the combination of nasal polyposis, crust formation, and positive sinus cultures for Aspergillus in 1976. In 1981, Millar et al [28] noted the histologic similarities between AFS and allergic bronchopulmonary aspergillosis (ABPA). Even this first description noted that some patients had all the histologic features of AFS without identifiable fungal hyphae. Robson et al [29] introduced the term allergic fungal sinusitis in 1989 to describe the findings now associated with the disease. The noted lack of fungal hyphae in some patients foreshadows a recent debate in AFS pathophysiology. First, however, researchers set out to determine that AFS represented an immunologically mediated disorder rather than a precursor to invasive fungal disease. Extensive work by Manning [30], Schubert and Goetz [31,32], Mabry [33,34], and Bent and Kuhn [35] suggests that AFS is an IgE-mediated disease. Allergic fungal sinusitis is typically a disease of younger patients; the average age at diagnosis ranges in the literature from 21.9 to 42.4 years [30,36–38]. It has been estimated that 5% to 10% of patients with chronic rhinosinusitis carry a diagnosis of AFS [38–41]. Certainly, however, the incidence depends on location. A review by Ferguson et al [42] on the geographic variation in the United States revealed a higher incidence in the southern central region of the country. Diagnostic criteria vary by author, but the most widely accepted are the five described by Bent and Kuhn [35]: (1) type I hypersensitivity to fungi, (2) nasal polyposis, (3) characteristic radiographic findings, (4) eosinophilic mucin demonstrating noninvasive fungus, and (5) positive fungal stain or culture. The clinical presentation of AFS can vary from mild to dramatic. Significant changes may include acute visual loss, gross facial dysmorphia, and complete nasal obstruction. The more typical patient presents with progressive nasal obstruction, rhinorrhea, nasal cast formation, and chronic rhinosinusitis. Classic radiographic findings include unilateral involvement with paranasal sinus cavity expansion. Bone erosion may be present in up to 20% of cases, and a heterogeneous appearance with areas of increased signal intensity highly suggestive of inspissated fungal debris can be seen (Fig. 1) [43]. Laboratory findings are quite variable and are a source of controversy. Several studies have reported elevated levels of both total and fungal-specific IgE levels in addition to evidence of type I allergy in patients with AFS. On the other hand, several investigators have failed to demonstrate these findings, especially elevated fungal specific IgE levels. These later data call into question the IgE-mediated basis for the disease. Work by Bent and Kuhn [35] and Schubert and Goetz [54,55] has demonstrated that changes in total IgE levels in the serum may reflect disease activity and predict recurrence. Based on these data, the underlying


R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594

Fig. 1. CT scan of a patient with allergic fungal sinusitis.

mechanism for disease in AFS was believed to be an IgE-mediated hypersensitivity to fungal antigens. This process would lead to eosinophilic infiltration with cellular degranulation and start a cycle that perpetuates the formation of allergic mucin. This cycle was outlined by Marple [44] demonstrating the contributing factors responsible for AFS and the possible cites of treatment (Fig. 2).

Eosinophilic fungal rhinosinusitis Recent work by Ponikau et al [45,46] describes an alternative theory that proposes a different mechanism for AFS and could be applied more universally to encompass chronic rhinosinusitis (CRS) as well. Using a sensitive detection method, their initial study demonstrated that 96% of patients with CRS had fungi present in tissue specimens. Moreover, the control group was found to have a 100% fungal detection rate. Unlike AFS, however, they did not find type I allergy, elevated total IgE levels, or

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Fig. 2. The cycle of allergic fungal rhinosinusitis and the rationale for its various treatments. (From Marple BF. Allergic fungal rhinosinusitis: current theories and management strategies. Laryngoscope 2001;111:1006–19.)

elevated fungal-specific serologies to be prevalent in their study group. Thus, they offered the hypothesis that CRS is in fact a cell-mediated response to fungal elements and suggested the new term eosinophilic fungal rhinosinusitis. Subsequent work by Ponikau et al [43,47] has demonstrated eosinophilic migration from the endovascular space into the extramucosal space in the sinus where the allergic mucin is found (Fig. 3). Sensitive laboratory techniques have demonstrated clustering of the eosinophils around the fungal elements with a robust elaboration of several factors such as major basic protein (MBP) and various interleukins (Fig. 4). Furthermore, their work has also shown that T lymphocytes taken from patients with CRS elaborate these same factors when exposed to various fungal antigens in the laboratory, whereas T lymphocytes from a normal control do not have this response. These data seem to support their original hypothesis that states that CRS is a cell-mediated disease directed against fungal elements in the extramucosal space and allergic mucin in some patients. The elaboration of cytotoxic factors from the recruited eosinophils leads to mucositis, rhinosinusitis, and quite possibly bacterial disease. Although publication of their latest data is pending, Ponikau’s group has presented these findings at various scientific meetings [43,47]. Other investigators have also presented data that supports the Mayo group’s findings [48,49]. Many questions remain, however, because this response is not present in all patients who have fungi in the nose and paranasal sinuses. Much work is required before the role and importance of fungi in CRS is clearly defined.


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Fig. 3. Numerous eosinophils cluster around a fungal hyphae in cross section (arrow) in the mucin of a CRS patient (transmission electron microscopy 7125). (From Ponikau JU. Chronic rhinosinusitis: the war of the immune system against fungi. American Rhinologic Society Newsletter 2002;21(2):6.)

Given the diagnostic criteria proposed by Bent and Kuhn, patients with AFS have a distinct presentation apart from those with chronic bacterial rhinosinusitis, but several questions eloquently stated by Marple [44] remain. Why does AFS present so frequently as a unilateral disease if it is indeed IgE mediated? Why does fungal-specific IgE remain elevated despite prolonged fungal immunotherapy? Why is there no IgG-specific rise in response to immunotherapy? Is there a separate, unrecognized form of nonallergic fungal eosinophilic inflammation that can lead to a similar clinical presentation? Eosinophilic mucin rhinosinusitis In an attempt to further subclassify patients with CRS and add to the limited understanding of this disease, Ferguson [50] described eosinophilic mucin rhinosinusitis (EMRS) as a distinct entity. Following up on what Cody et al [37] had called allergic fungal sinusitis-like syndrome, in 2000 she published a strong argument proposing that EMRS represented a diverse group of pathophysiologic mechanisms in which the driving force is not a fungal hypersensitivity but rather is a systemic dysregulation associated with both upper and lower airway eosinophilia. Eosinophilic mucin could be present and cause sinusitis without the presence of fungi. She documented

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Fig. 4. Immunofluorescence staining for major basic protein (MBP) demonstrating striking release of toxic protein in the mucus of a patient with chronic rhinosinitis. Note the intact eosinophils in the tissue (right side of image) and the eroded epithelium (arrows). (200) (From Ponikau JU. Chronic rhinosinusitis: the war of the immune system against fungi. American Rhinologic Society Newsletter 2002;21(2):6.)

a number of differences in the presentation of AFS and EMRS (Table 4). The difference in treatment between the two groups remains to be investigated. The limited understanding of this disease remains a reason for humility. Recent research has demonstrated what rhinologists have long accepted, namely, the diagnosis of CRS covers several pathologic conditions that may indeed be distinct diseases with similar yet differing underlying mechanisms. The definition of these subgroups of patients with CRS is far from complete.

Table 4 Comparison of allergic fungal sinusitis and eosinophilic mucin rhinosinusitis Allergic fungal sinusitis

Eosinophilic mucin rhinosinusitis

Underlying disorder

Allergic response to fungi

Unilaterality Allergic markers Age Associated disorders

Unilateral (55%) Higher total IgE levels Younger patients (30.7 years) No known link to aspirin sensitivity Asthma (50%) Fungal immunotherapy promising

Systemic dysregulation of immunologic control (non-allergic mechanism) Always bilateral disease IgG1 deficiency (50%) Older patients (48.0 years) Aspirin sensitivity (54%) Asthma (93%)


Unstudied, but suggestive of poor response to immunotherapy

Data from Ferguson BJ. Eosinophilic mucin rhinosinusitis: a distinct clinicopathological entity. Laryngoscope 2000;110:799–813.


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Improved diagnosis and management of patients with CRS depends on unraveling these mechanisms of disease. Management issues Allergic fungal sinusitis, as defined by Bent and Kuhn [35], has a number of contributing factors associated with its progression and therefore has multiple modalities of treatment. Marple [44] has described a cycle for AFS pathophysiology following the mechanism described by Manning and Homan [30] in which atopy, continuous antigenic exposure, and inflammation all play roles in the perpetuation of the disease (see Fig. 3). The mainstay of any combination treatment for AFS remains surgical removal of the allergic mucin and fungal elements along with creation of patent sinus ostia that are large enough to provide postoperative access to the sinuses [24,44,51–53]. As a single modality, functional endoscopic sinus surgery results in a high rate of recurrence, and therefore medical therapy is mandatory. This intervention can occur preoperatively in the form of corticosteroid administration to decrease the intranasal polyposis and inflammation. In addition, corticosteroids should be administered postoperatively both topically and systemically, but the duration and optimal dosing remain unclear [24,53]. Multiple studies [24,31,32,44] have shown improvement in symptoms as well as increased time to recurrence and improvement in overall recurrence rates with corticosteroid administration, and the data seem to support a longer period than a shorter one. Kuhn and Javer [53] have a postoperative protocol using oral prednisone. They recommend 0.4 mg/kg/day for 4 days. This dosage is decreased by 0.1 mg/kg/day in cycles of 4 days until a dose of 20 mg/day or 0.2 mg/kg/day, whichever is greater, is reached. This dose is continued for 1 month postoperatively and is then adjusted to 0.2 mg/kg/day. This dose is maintained while the patient is followed monthly with nasal endoscopy and IgE levels. The corticosteroid level is adjusted to maintain the patient on a stage 0 mucus membrane appearance described by Kupferberg et al [54]. This system is described in Table 5. If stage 0 is maintained for 4 consecutive months, the prednisone dosage is reduced to 0.1mg/kg/day, and a nasal steroid spray is begun. If stage 0 continues to be maintained for 2 more Table 5 Mucosal staging by endoscopy in allergic fungal sinusitis Stage

Endoscopic Mucosal


No mucosal edema or allergic mucin Mucosal edema with or without allergic mucin Polypoid edema with or without allergic mucin Sinus polyps with fungal debris or allergic mucin

Data from Kupferberg SB, Bent JP. Allergic fungal sinusitis in the pediatric population. Arch Otolarngol Head Neck Surg 1998;124:1179–80.

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months, the prednisone is tapered off completely, and the nasal steroid spray is continued for 1 year. Patients need to be followed for at least 5 years according to this protocol. Systemic antifungal preparations have been studied with at best mixed results; in fact, prospective, controlled studies do not exist, and the risks of these medications may outweigh the benefits for noninvasive fungal disease [44]. Ponikau and colleagues [55] are testing topical antifungal medications on chronic rhinosinusitis patients to determine if this treatment supports the mechanism they have proposed for the disease. Prospective, controlled trials are also underway to determine whether topical medications affect a response in patients with the diagnosis of allergic fungal rhinosinusitis. One study published by Ricchetti et al [56] reports improvement in nasal polyposis with amphotericin B nasal lavage. These patients were not specifically given a diagnosis of AFS, nor was there a control group; nevertheless, it is apparent that further investigation is warranted based on their findings. Mabry et al [33,34,57] have rigorously investigated immunotherapy in the treatment of AFS. In their initial report, 11 patients receiving immunotherapy demonstrated less crusting and polyposis as well as a decreased need for corticosteroid therapy [33]. There was no control group in this initial study. More recently, they have reported similar results in a study in which a control cohort was used [34]. Both groups received surgical intervention and postoperative corticosteroid treatment. The patients receiving immunotherapy showed a reduced reliance on both systemic and intranasal corticosteroids. Mabry et al [57] have now published data indicating no evidence of recurrence in eight patients who had received and subsequently discontinued immunotherapy for at least 3 years. In contrast, Ferguson [58] had earlier reported a retrospective review of seven patients with AFS who received immunotherapy; five of these patients either did not improve or even worsened. These patients, however, did not receive maximal surgical or corticosteroid treatment. Clearly, further investigation is required to delineate fully both the pathophysiology and the treatment of fungal rhinosinusitis and its related disorders. Ever-advancing laboratory technology is likely to shed light on this complex set of pathologies. Much work remains to be completed, but it seems that multiple underlying triggers for chronic rhinosinusitis exist, fungal included. As these mechanisms are elucidated, patient subgroups will be better defined.

Summary Despite the vast literature regarding fungal infections of the head and neck, little has changed in diagnosis or management of these infections except in the nose and sinuses. Three main points regarding fungal


R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594

involvement in the paranasal sinuses are evident now. First, fungi may be important in a significant percentage of patients with chronic rhinosinusitis. Second, the pathophysiologic mechanism responsible for fungal rhinosinusitis remains unclear. It may represent an allergic IgE response, a cellmediated reaction, or a combination of the two. Finally, there is certainly a spectrum of disease thus far defined: allergic fungal sinusitis as defined by Bent and Kuhn [35], eosinophilic mucin rhinosinusitis defined by Ferguson [50], and eosinophilic fungal rhinosinusitis as proposed by Ponikau [45]. Fungal infections of the head and neck are panoramic in distribution and pathophysiology. They represent a broad range of disease of which medical science has only recently begun to uncover the surface. As research begins to unravel the complex host defense mechanisms against these pathogens from a cellular and even genetic level, the body of knowledge will continue to increase exponentially and the ability to treat patients suffering from fungal infections will improve.

References [1] Kwon-Chung KJ, Bennett JE. Medical mycology. Philadelphia: Lea & Febiger; 1992. [2] Bottone EJ, Hong T, Zhang DY. Basic mycology underscoring medically important fungi. Otolaryngol Clin North Am 1993;26(6):919–40. [3] Scully C. Candidiasis, mucosal. eMedicine Journal 2002;3(1). Available at http://¼2&Topic¼68&id¼3781& accttype¼P. Date accessed 9/17/02. [4] Ansari S, Mukherjee S. Esophagitis. eMedicine Journal 2002;3(8). Available at http://¼6&Topic¼735&id¼3781& accttype¼P. Date accessed 9/17/02. [5] Loftus BC. General principles of management of fungal infections of the head and neck. Otol Clin North Am 1993;26(6):1115–22. [6] Neibart E, Gumprecht J. Antifungal agents and the treatment of fungal infections of the head and neck. Otol Clin North Am 1993;26(6):1123–32. [7] Beatriz L, Drew RH, Perfect JR. Agents for treatment of invasive fungal infections. Otol Clin North Am 2000;33(2):277–300. [8] Lucente FE. Fungal infections of the external ear. Otolaryngol Clin North Am 1993; 26(6):1995–2005. [9] Nielsen PG. Fungi isolated from chronic external ear disorders. Mykosen 1985;28:234–7. [10] Sood VP, Sinha A, Mohaoatra LN. Otomycosis: a clinical entity–clinical and experimental study. J Laryngol Otol 1967;81:999–1003. [11] Stern JC, Lucente FE. Otomycosis. Ear Nose Throat J 1988;67:804–10. [12] Stern JC, Shah MK, Lucente FE. In vivo effectiveness of 13 agents in otomycosis and review of the literature. Laryngoscope 1988;98:1173–7. [13] Mugliston T, O’Donoghue G. Otomycosis–a continuing problem. J Laryngol Otol 1985; 99:327–33. [14] Than KM, Naing KS, Min M. Otomycosis in Burma, and its treatment. Am J Trop Med Hyg 1980;29:520–3. [15] Arendorf TM, Walker DM. The prevalence and intra-oral distribution of Candida albicans in man. Arch Oral Biol 1980;25(1). [16] Lynch DP. Oral candidiasis: history, classification, and clinical presentation. Oral Surg Oral Med Oral Pathol 1994;78(2):189–93.

R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594


[17] Vrabec DP. Fungal infections of the larynx. Otolaryngol Clin North Am 1993;26(6): 1091–114. [18] Kobayashi RH. Candida esophagitis and laryngitis in chronic mucocutaneous candidiasis. Pediatrics 1980;66:380–4. [19] Lawson R, Bodey G, Luna M. Candida infection presenting as laryngitis. Am J Med Sci 1980;280:173–7. [20] Bickard RE, Kotzen S. Histoplasmosis or the larynx. South Med J 1973;66: 1311–2. [21] Chapman SW. Blastomyces dermatitidis. In: Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious disease. 3rd edition. New York: Churchill Livingstone; 1990. p. 1999–2008. [22] Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am 2000; 33(2):227–35. [23] de Shazo RD. A new classification and diagnostic criteria for invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 1997;123:1181–8. [24] Schubert MS. Medical treatment of allergic fungal sinusitis. Ann Allergy Asthma Immunol 2000;85:90–7. [25] Stringer SP, Ryan MW. Chronic invasive fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33:375–87. [26] Ferguson BJ. Fungus balls of the paranasal sinuses. Otolaryngol Clin North Am 2000;33:389–98. [27] Safirstein B. Allergic bronchopulmonary aspergillosis with obstruction of the upper respiratory tract. Chest 1976;70:788–90. [28] Millar JW, Johnston A, Lamb D. Allergic aspergillosis of the maxillary sinuses. Thorax 1981;36:710. [29] Robson JMB, Hogan P, Benn R. Allergic fungal sinusitis presenting as a paranasal sinus tumor. Aust N Z J Med 1989;19:351–3. [30] Manning SC, Homan M. Further evidence for allergic pathophysiology in allergic fungal sinusitis. Laryngoscope 1998;108:1485–96. [31] Schubert MS, Goetz DW. Evaluation and treatment of allergic fungal sinusitis. I. Demographics and diagnosis. J Allergy Clin Immunol 1998;102(3):387–94. [32] Schubert MS, Goetz DW. Evaluation and treatment of allergic fungal sinusitis. II. Treatment and follow-up. J Allergy Clin Immunol 1998;102(3):395–402. [33] Mabry RL, Manning SC, Marple BF. Immunotherapy in the treatment of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1997;116:31–5. [34] Mabry RL, Marple BF, Folker RJ. Immunotherapy for allergic fungal sinusitis: Three years’ experience. Otolaryngol Head Neck Surg 1998;119:648–51. [35] Bent J, Kuhn F. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1994;111:580–8. [36] Bent JP, Kuhn FA. Antifungal activity against allergic fungal sinusitis organisms. Laryngoscope 1996;106:1331–4. [37] Cody DT, Neel HB, Ferreiro JA. Allergic fungal sinusitis: the Mayo clinic experience. Laryngoscope 1994;104:1074–9. [38] Ence BK, Gourley DS, Jorgensen NL. Allergic fungal sinusitis. Am J Rhinol 1990;4: 169–78. [39] Allphin AL, Strauss M, Abdul-Karim FW. Allergic fungal sinusitis: problems in the diagnosis and treatment. Laryngoscope 1991;101:815–20. [40] Kupferberg SB, Bent JP. Allergic fungal sinusitis in the pediatric population. Arch Otolarngol Head Neck Surg 1998;124:1179–80. [41] Morpeth JF, Rupp NT, Dolen WK. Fungal sinusitis: an update. Ann Allergy Asthma Immunol 1996;76:128–40. [42] Ferguson BJ, Barnes L, Bernstein JM, et al. Geographic variation in allergic fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33:441–9.


R.D. Thrasher, T.T. Kingdom / Otolaryngol Clin N Am 36 (2003) 577–594

[43] Ponikau JU, Sherris DA, Kern EB. Chronic rhinosinusitis: an immune response to fungi. Presented at Nose 2000, a division of the American Rhinologic Society Meeting. Washington DC, September:21, 2000. [44] Marple BF. Allergic fungal rhinosinusitis: current theories and management strategies. Laryngoscope 2001;111:1006–19. [45] Ponikau JU, Sherris DA, Kern EB. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 1999;74:877–84. [46] Ponikau JU, Sherris D, Homburger HA. Immunologic aspects of allergic fungal sinusitis. Presented at the Meeting of the American Rhinologic Society, Palm Beach, May 11, 1998. [47] Burton LK, Panikau JU, Kita H, et al. Fungal specific immunoglobulins levels in nasal mucus and peripheral blood in patients with chronic rhinosinusitis and healthy controls [abstract]. Presented at the Meeting of the American Rhinologic Society. San Diego, September 21, 2002. [48] Gosepath J, Brieger J, Mann WJ. Fungal elements are present in the tissue specimens of patients with chronic rhinosinusitis [abstract]. Presented at the Meeting of the American Rhinologic Society. San Diego, September 21, 2002. [49] Buzina W, Braun H, Freudenschuss K, et al. Fungal cultivation and identification techniques in EFRS patients. Presented at Nose 2000, a division of the American Rhinologic Society meeting. Washington DC, September 21, 2000. [50] Ferguson BJ. Eosinophilic mucin rhinosinusitis: a distinct clinicopathological entity. Laryngoscope 2000;110:799–813. [51] Houser SM, Corey JP. Allergic fungal rhinosinusitis: pathophysiology, epidemiology, and diagnosis. Otolaryngol Clin North Am 2000;33:399–408. [52] Marple BF. Allergic fungal rhinosinusitis: surgical management. Otolaryngol Clin North Am 2000;33:409–18. [53] Kuhn FA, Javer AR. Allergic fungal rhinosinusitis: perioperative management, prevention of recurrence, and role of steroids and antifungal agents. Otolaryngol Clin North Am 2000;33:2. [54] Kupferberg SB, Bent JP. Prognosis for allergic fungal sinusitis. Otolaryngol Head Neck Surg 1997;117:35–41. [55] Ponikau JU. Chronic rhinosinusitis: the war of the immune system against fungi. American Rhinologic Society Newsletter 2002;21(2):6. [56] Ricchetti A, Landis BN, Maffioli A, et al. Effect of anti-fungal nasal lavage with amphotericin B on nasal polyposis. J Laryngol Otol 2002;116:261–3. [57] Mabry RL, Marple BF, Mabry CS. Outcomes after discontinuing immunotherapy for allergic fungal sinusitis. Otolaryngol Head Neck Surg 2000;122:104–7. [58] Ferguson BJ. Immunotherpy and antifungal therapy in allergic fungal sinusitis. Presented at the Annual Meeting of the American Academy of Otolaryngic Allergy. Minneapolis, September 14, 1993.