Allergic Fungal Sinusitis 

Updated: Mar 16, 2018
Author: John E McClay, MD; Chief Editor: Arlen D Meyers, MD, MBA 

Overview

Practice Essentials

Over the past few decades, allergic fungal sinusitis (AFS) has become increasingly defined.[1] Historically mistaken for a paranasal sinus tumor, allergic fungal sinusitis (AFS) now is believed to be an allergic reaction to aerosolized environmental fungi, usually of the dematiaceous species, in an immunocompetent host. This is in contrast to invasive fungal infections that affect immunocompromised hosts, such as patients with diabetes mellitus and patients with AIDS. Most patients with allergic fungal sinusitis (AFS) have a history of allergic rhinitis, and the exact timing of allergic fungal sinusitis (AFS) development can be difficult to discern. Thick fungal debris and mucin, as shown below, are developed in the sinus cavities and must be surgically removed so that the inciting allergen is no longer present. Recurrence is not uncommon once the disease is removed, but anti-inflammatory medical therapy and immunotherapy are being employed to help prevent recurrence.[2]

Left middle meatus with suctioning of thick allerg Left middle meatus with suctioning of thick allergic mucin from the ethmoid bulla in the center of the picture; the end of the suction is in the inferior portion of the picture.

Diagnosis

Laboratory studies

Total immunoglobulin E (IgE) values generally are elevated in allergic fungal sinusitis (AFS), often to more than 1000 U/mL (normal values are < 50 U/mL), and have been proposed as a useful indicator of allergic fungal sinusitis (AFS) clinical activity.

Patients with allergic fungal sinusitis (AFS) generally demonstrate positive skin tests and in vitro radioallergosorbent test (RAST) responses to fungal and nonfungal antigens. Preliminary information suggests that methods of quantitative skin testing (in vivo) may provide even greater sensitivity ratings than RAST in patients with the disease.

Gell and Coombs type I hypersensitivity in patients with allergic fungal sinusitis (AFS) can be demonstrated by elevation of serum total and fungal-specific IgE and by positive skin test results for fungal and nonfungal antigens. However, this reaction does not appear to be fungal specific.

CT scanning

Accumulation of allergic fungal mucin eventually leads to the increasingly well-recognized radiographic findings characteristic of allergic fungal sinusitis (AFS). Heterogeneous areas of signal intensity within paranasal sinuses filled with allergic fungal mucin frequently are identified on computed tomography (CT) scans.

Expansion, remodeling, or thinning of involved sinus walls is common in allergic fungal sinusitis (AFS) and is thought to be caused by the expansile nature of the accumulating mucin. Areas of high attenuation are found within the expanded paranasal sinuses in all patients. Similar radiographic findings can be caused by rare osteoid/chondroid matrix-producing sinonasal sarcomas or meningiomas.

MRI

Magnetic resonance imaging (MRI) also can provide information useful in preoperative identification of allergic fungal mucin, but it usually is not necessary when making the diagnosis unless the disease has extended into the intracranial cavity or confusion exists with the diagnosis.

Histologic findings

Allergic fungal mucin normally is first encountered at surgery. Therefore, recognition of its presence is the initial step in establishing an accurate diagnosis of allergic fungal sinusitis (AFS). Examination of mucosa and polyps obtained from involved paranasal sinuses reveals findings consistent with the inflammation of a chronic inflammatory process and should be performed to exclude fungal invasion.

Management

On the basis of a postulated schema of the pathophysiology of allergic fungal sinusitis (AFS), a variety of treatment plans addressing its multiple contributing factors has emerged. Medical control of the disease has made use of various combinations of antifungal medications, corticosteroids, and immunotherapy, with varying degrees of disease control.

The invariable components of combination therapy still are surgical removal of the inciting fungal allergic mucin and marsupialization of the involved sinuses. For this reason, surgery has played an important role in the management of allergic fungal sinusitis (AFS) since its earliest reports.

Increased acceptance of specific immunologic hypersensitivity as the cause of allergic fungal sinusitis (AFS) has led to changes in its management. These changes have involved the medical and surgical arms of therapy. While systemic use of antifungal medications largely has been replaced by immunomodulation, radical surgery for allergic fungal sinusitis (AFS) has given way to more conservative, tissue-sparing approaches.

History of the Procedure

Several decades ago, fungal disease in the nose and paranasal sinuses represented an invasive deadly disease. Management consisted of extensive surgical debridement followed by therapy with systemic and topical antifungal agents. Early on, Aspergillus, a fungus known to cause invasive disease in the sinuses, was the only fungus recovered from the paranasal sinuses in patients with allergic fungal sinusitis (AFS) because of the limitation of culture techniques and the lack of knowledge that dematiaceous fungi caused disease in the paranasal sinuses. Therefore, the disease was treated aggressively.

In 1976, Safirstein noted that the combination of polyposis, crust formation, and sinus cultures yielding Aspergillus was similar to the constellation of findings observed in allergic bronchopulmonary aspergillosis (ABPA), a benign allergic process.[3] Safirstein's description was duplicated and expanded on by reports of allergic aspergillosis of the paranasal sinuses and allergic Aspergillus sinusitis. In the late 1980s, the disease was more widely accepted as a benign fungal process and often confused with a paranasal sinus tumor on imaging studies because allergic fungal sinusitis (AFS) creates expansion of affected sinus cavities.

In 1989, Robson et al introduced the term allergic fungal sinusitis following reports that this condition could be caused by a number of different fungi, not only Aspergillus.[4] Although the disease is becoming more recognized, confusion remains regarding diagnosis and treatment.

Problem

No consensus exists among rhinologists concerning diagnostic criteria for allergic fungal sinusitis (AFS). Several authors have made observations.

  • In 1991, Allphin and colleagues described certain features that they felt differentiated allergic fungal sinusitis (AFS) from other forms of fungal sinusitis, including radiographic presence of multiple opacified paranasal sinuses, characteristic histologic findings of allergic mucin, and laboratory evidence of allergy.

  • In 1993, Loury and Schaefer proposed multiple diagnostic criteria, including eosinophilia, immediate skin reactivity or serum immunoglobulin G (IgG) antibodies to fungal antigen, elevated total immunoglobulin E (IgE) level, nasal mucosal edema or polyposis, histopathologic findings of allergic mucin containing noninvasive fungal hyphae, and characteristic CT or MRI findings.[5]

  • In 1994, in reporting the Mayo Clinic experience, Cody et al simplified the diagnostic criteria to include only characteristic allergic mucin and either noninvasive fungal hyphae within the collected mucin or positive fungal cultures.[6]

  • In 1994, Bent and Kuhn described what probably are the most widely accepted criteria for diagnosis. On the basis of the analysis of 15 cases, 5 common characteristics were observed, including Gell and Coombs type I (IgE-mediated) hypersensitivity to fungi, nasal polyposis, characteristic radiographic findings, eosinophilic mucin without fungal invasion into sinus tissue, and positive fungal stain of sinus contents removed at the time of surgery.[7]

  • In 1997, deShazo proposed a similar set of 5 criteria, including radiographic evidence of sinusitis, presence of allergic mucin (identified grossly or histopathologically), positive fungal stain or culture from the sinus at the time of surgery, absence of contributory factors (eg, diabetes mellitus, immunodeficiencies), and absence of fungal invasion.[8]

A positive fungal culture does not confirm the diagnosis of allergic fungal sinusitis (AFS), nor does a negative culture exclude it. For example, fungi may proliferate as saprophytic growth in diseased sinuses. Furthermore, mycology laboratories vary in capability, and specimen handling significantly influences the rate of positive fungal cultures in a clinical setting. Allergic mucin remains the most reliable indicator of allergic fungal sinusitis (AFS). Because nasal polyposis and fungal disease in the sinuses are not unique to allergic fungal sinusitis (AFS), other mycotic diseases in the differential diagnosis must be defined and include the following:

  • Invasive fungal sinusitis: This condition typically is encountered in patients who are immunocompromised or have diabetes mellitus and is characterized by angioinvasive fungal penetration of tissue. Hypesthesia, local pain, and intranasal necrosis (in an immunocompromised person) strongly suggest invasive fungal sinusitis and help to differentiate this disease from allergic fungal sinusitis (AFS).

  • Saprophytic fungal growth: This growth may be found in one or more paranasal sinus cavities of patients who have chronic suppurative rhinosinusitis. Similar growth may occur within nasal debris of patients who have undergone aggressive sinonasal surgery or those who have rhinitis sicca. Although fungal cultures may be positive, the absence of gross and histiologic findings of allergic mucin and the lack of clinical manifestations of invasive fungal sinusitis suggest saprophytic fungal growth.

  • Mycetoma, aspergilloma, or fungus ball of the sinuses: This clinical entity differs from allergic fungal sinusitis (AFS) in presentation. Rather than involving multiple sinuses, a fungus ball typically involves a single sinus, most often the maxillary antrum or sphenoid. Patients affected by this condition are not necessarily allergic and generally do not exhibit nasal polyps. On histologic examination, the material removed from the sinuses demonstrates only fungal hyphae without eosinophils. Surgery in such patients generally is curative.

  • Eosinophilic mucin sinusitis: Pansinusitis, polyposis, and mucin that is clinically indistinguishable from that of allergic fungal sinusitis (AFS) are characteristic. However, examination of mucin reveals no fungal hyphae. Allergy is not as constant a feature in this condition as it is in allergic fungal sinusitis (AFS), but asthma is observed more frequently. Ferguson has suggested that this condition may represent a variant of the Samter triad.

Epidemiology

Frequency

Approximately 5-10% of patients affected by chronic rhinosinusitis actually carry a diagnosis of allergic fungal sinusitis (AFS). Atopy is characteristic of the disease; approximately two thirds of patients report a history of allergic rhinitis, and 90% of patients demonstrate elevated specific IgE to one or more fungal antigens. Approximately 50% of patients in a series by Manning et al had asthma. No linkage to aspirin sensitivity has been established.

Incidence of allergic fungal sinusitis (AFS) appears to be impacted by geographic factors. Review of world literature reveals that most sites reporting cases of allergic fungal sinusitis (AFS) are located in temperate regions of relatively high humidity. However, incidence of allergic fungal sinusitis (AFS) varied remarkably based on the location of reporting sites. Allergic fungal sinusitis (AFS) in the United States was encountered most commonly within the Mississippi basin, the Southeast, and the Southwest. The reason for this geographic difference remains unexplained.

Allergic fungal sinusitis (AFS) is most common among adolescents and young adults; the mean age at diagnosis is 21.9 years. The male-to-female (M/F) ratio of allergic fungal sinusitis (AFS) differs slightly between published reports but is believed to be equal when all ages are evaluated together. A literature review of 98 cases in the 1980s and early 1990s from 29 published journal articles reported an equal M/F incidence. A review by the author and colleagues of 151 patients at the University of Texas (UT) at Southwestern also revealed an equal M/F ratio, with ages ranging from 5-75 years.[9]

However, the M/F ratio may be age dependent and different in children and adults. In the review of patients at UT Southwestern, in children, males dominated (M/F ratio 2.1:1; average age, 13 y), and in adults, females dominated (M/F ratio 1:1.4; average age, 36 y). When evaluating the average ages and sex ratios of other studies, series with younger average ages are more likely to have a male predominance. The average ages in the male-dominated series were 25 and 27 years, while the average age in the female-dominated series was 33 years. The only other pediatric series consisted of 10 patients and had an M/F ratio of 1.5:1, with a mean age of 13.6 years. Interestingly, when 2 series of patients from a single institution were reviewed over time, an early study had an M/F ratio of 1.5:1, with an age range of 13-51 years (average age, 27.5 y), and a later review had an M/F ratio of 1:1.4, with an age range of 13-69 years (no average age given).

Etiology

Most rhinologists believe that allergic fungal sinusitis (AFS) is an allergic reaction to fungi, in which fungal debris, allergic mucin, and nasal polyposes are formed in the nasal cavity and paranasal sinuses. The causative fungi in allergic fungal sinusitis (AFS) are usually dematiaceous fungi, consisting of the genera Bipolaris, Curvularia, Exserohilum, Alternaria, Drechslera, Helminthosporium, and Fusarium, with a small component of allergic fungal sinusitis (AFS) caused by Aspergillus. In a 1996 review of English literature performed by Manning, 263 cases of allergic fungal sinusitis (AFS) were identified, of which 168 cases yielded positive fungal cultures. Of these 168 positive cultures, 87% were from the dematiaceous genera, while only 13% yielded Aspergillus.

The largest reported single institutional experience to date is at the UT Southwestern Medical Center in Dallas, Texas. The fungi recovered from the paranasal sinuses in that evaluation by the author and colleagues revealed that Bipolaris, followed by Curvularia, is the most common pathogen present, seen with similar incidence in adults and children, see Table 1 below. Most large reviews agree, indicating that Bipolaris and Curvularia species are the most common fungi recovered.

When geographic location is specifically reviewed, the further west and inland the series, the more likely that Bipolaris species dominated the fungi recovered. When the series was performed in the Southeast, Curvularia species were more likely to be recovered. Interestingly, in the UT Southwestern experience, Aspergillus was recovered in 13% of adults but in no children. A report from India found only Aspergillus species identified in all 11 patients with allergic fungal sinusitis (AFS) in whom fungus was recovered.

Table 1. Causative Fungus Identified at UT Southwestern Medical Center (Open Table in a new window)

Fungus

Children (n=44)

Adults (n=107)

Bipolaris

21 (66%, 21/32)

40 (57%, 40/70)

Curvularia

7 (22%, 7/32)

12 (17%, 12/70)

Exserohilum

2

2

Alternaria

1

3

Aspergillus (niger/flavus)

0

9 (13%)

Acremonium

0

1

Chrysosporium

0

1

Helminthosporium

0

1

No Growth

2

21

No Data

12

16

Combination

1 Bipolaris/Curvularia

1 Aspergillus/Acremonium

Controversy has existed over whether the disease is infectious or allergic. Manning and Holman objectively addressed this controversy in 2 separate studies.[10] In the first study, 8 patients with culture-positive Bipolaris allergic fungal sinusitis (AFS) were prospectively compared with 10 control subjects who did not have allergic fungal sinusitis (AFS). Both groups were evaluated with (1) radioallergosorbent test (RAST) and enzyme-linked immunosorbent assay (ELISA) inhibition to Bipolaris -specific IgE and IgG antibodies and (2) skin testing with Bipolaris antigen. All 8 patients had positive skin test reactions to Bipolaris antigen and positive RAST and ELISA inhibition to Bipolaris -specific IgE and IgG. Eight of the 10 control subjects had negative results on both skin and serologic testing, implicating the importance of allergy to fungal antigens (both in vivo and in vitro) in the pathophysiology of allergic fungal sinusitis (AFS).

In a complementary study, sinus mucosal specimens from 14 patients with allergic fungal sinusitis (AFS) were compared with those from 10 control subjects who did not have allergic fungal sinusitis (AFS). Immunohistochemical analysis for eosinophilic mediators (major basic protein and eosinophilic-derived neurotoxin) and a neutrophil-derived mediator (neutrophil elastase) was performed to assess the underlying nature of inflammation. Eosinophilic-derived mediators were much more common (P< 0.00001) than neutrophil-derived mediators in the allergic fungal sinusitis (AFS) group, whereas significant differences were not observed in the control group. The predominance of eosinophilic-derived mediators further supports the association between noninfectious (ie, allergic) inflammation and allergic fungal sinusitis (AFS).

The concept of eosinophilic activation associated with allergic fungal sinusitis (AFS) was further emphasized by Feger et al, who studied eosinophilic cationic protein levels in the serum and mucin of patients with allergic fungal sinusitis (AFS). No differences in serum eosinophilic cationic protein were detected between patients with allergic fungal sinusitis (AFS) and control subjects, but eosinophilic cationic protein levels were significantly higher in the mucin of patients with allergic fungal sinusitis (AFS); P < 0.01).

Studies such as those by Manning et al and Feger et al offer strong immunologic and histologic data to support the argument that allergic fungal sinusitis (AFS) represents an immunologically mediated disorder rather than a point on the spectrum of infectious fungal disease.[11]

A study by Lu-Myers et al found that socioeconomic factors differed between patients with allergic fungal rhinosinusitis and those with chronic rhinosinusitis, with the latter tending to be white and older, with a higher income and greater access to primary care. The study, which involved a total of 186 patients (93 patients in each group), also found that patients with allergic fungal rhinosinusitis tended to have greater quantitative serum IgE levels and higher Lund-Mackay scale scores than did patients with chronic rhinosinusitis.[12]

A study by Mostafa et al found serum levels of vitamin D3 to be significantly lower in patients with allergic fungal rhinosinusitis than in controls. The investigators suggest that the agent may serve as a prophylactic against the disease. The study included 25 patients with allergic fungal rhinosinusitis and 19 controls.[13]

Pathophysiology

Currently, the pathophysiology of allergic fungal sinusitis (AFS) is postulated to be similar to that of allergic bronchopulmonary fungal disease (a term replacing bronchopulmonary aspergillosis). Manning and colleagues have suggested that several interrelated factors and events lead to the development and perpetuation of allergic fungal sinusitis (AFS). First, an atopic host is exposed to fungi, theoretically via normal nasal respiration, which provides the initial antigenic stimulus. An initial inflammatory response ensues as the result of both a Gell and Coombs type I (IgE-mediated) and type III (immune complex–mediated) reaction, causing subsequent tissue edema. The resulting obstruction of sinus ostia, which may be accentuated by anatomic factors such as septal deviation or turbinate hypertrophy, results in stasis within the sinuses. This creates an ideal environment for further proliferation of the fungus, thus increasing the antigenic exposure to which the host is allergic.

At some point, the cycle becomes self-perpetuating, resulting in the eventual product of this process, allergic mucin, the material that fills the involved sinuses of patients with allergic fungal sinusitis (AFS). Accumulation of this debris obstructs the involved sinuses and propagates the process.

The production of this allergic mucin and its eventual clinical, histologic, and radiographic characteristics are unique to allergic fungal sinusitis (AFS) and serve as a hallmark of the disease. Grossly, allergic fungal mucin is thick, tenacious, and highly viscous. Its color may vary from light tan to brown or dark green, as depicted in the images below. Its characteristic gross appearance has resulted in the use of such descriptive terms as peanut butter and axle grease when referring to allergic fungal mucin.

Left middle meatus with suctioning of thick allerg Left middle meatus with suctioning of thick allergic mucin from the ethmoid bulla in the center of the picture; the end of the suction is in the inferior portion of the picture.
The viscosity of a thick allergic mucin being suct The viscosity of a thick allergic mucin being suctioned from the nasal cavity and vestibule in a patient with allergic fungal sinusitis.

In a study of 74 patients, White et al indicated that in cases of allergic fungal sinusitis, younger patients and African Americans are more likely to suffer bony erosion, suggesting that these individuals have a more severe inflammatory response in the disease.[14]

Presentation

Patients with allergic fungal sinusitis (AFS) normally present with signs and symptoms of nasal airway obstruction, allergic rhinitis, or chronic sinusitis that includes nasal congestion, purulent rhinorrhea, postnasal drainage, or headaches. Often, presentation of allergic fungal sinusitis (AFS) is subtle. Patients typically complain of gradual nasal airway obstruction and production of semi-solid nasal crusts that, upon inquiry, match the gross description of allergic fungal mucin. Development of nasal airway obstruction may have been so gradual that the patient is unaware of its presence. Because of the slow progression of allergic fungal sinusitis (AFS), if facial dysmorphia is present, its progression often is so slow that it is unrecognized by the patient and family members. Pain is uncommon among patients with allergic fungal sinusitis (AFS) and suggests the concomitant presence of a bacterial rhinosinusitis.

Patients with allergic fungal sinusitis (AFS) are atopic, but generally their symptoms have been unresponsive to antihistamines, intranasal corticosteroids, and prior immunotherapy. Use of systemic corticosteroids may produce some relief of symptoms, but relapse is typical following completion of therapy. In contrast to patients who have invasive fungal sinusitis, patients with allergic fungal sinusitis (AFS) always are immunocompetent.

The range of physical findings on examination is typically broad, from nasal airway obstruction resulting from intranasal inflammation and polyposis, as depicted in the 1st image below, to gross facial disfigurement and orbital or ocular abnormalities. The author and colleagues reported that facial dysmorphism, consisting of proptosis, as depicted in the 2nd image below, telecanthus, and malar flattening, more often was seen in children than in adults (42% vs 10%) in their series of 151 patients, including 107 adults aged 18 years or older and 44 children aged 17 years or younger, as depicted in Table 2 below.

View just inside the nasal vestibule showing diffu View just inside the nasal vestibule showing diffused polyposis extending into the anterior nasal cavity and vestibule; the septum is on the right, and the right lateral vestibular wall (nasal ala) is on the left. The polyps all are in the center. The polyps almost hang out of the nasal vestibule.
A 15-year-old boy with allergic fungal sinusitis c A 15-year-old boy with allergic fungal sinusitis causing right proptosis, telecanthus, and malar flattening; the position of his eyes is asymmetrical, and his nasal ala on the right is pushed inferiorly compared to the left.
A 9-year-old girl with allergic fungal sinusitis d A 9-year-old girl with allergic fungal sinusitis displaying telecanthus and asymmetrical positioning of her eyes and globes.

Usually, when proptosis was present in patients in this study, telecanthus and malar flattening could be identified, as depicted in the first image above, depending on the amount of proptosis. Because development of proptosis usually occurs over long periods, no diplopia or visual loss generally is seen.

However, diplopia and visual loss were encountered in a study by Alaraj et al. The retrospective study, of 100 patients with allergic fungal sinusitis (AFS), reported that 34 individuals had associated eye problems. Proptosis was the most common ophthalmic presentation, occurring in 21 patients (61.8%). The next most frequent were epiphora (5 patients, 14.7%), visual loss (4 patients, 11.8%), diplopia (3 patients, 8.8%), and dystopia (1 patient, 2.9%). Intraorbital extension existed in 17.6% of patients.[15]

At times, extension of allergic fungal sinusitis (AFS) into adjacent anatomic spaces can produce a dramatic clinical presentation, such as visual loss. Visual loss from allergic fungal sinusitis (AFS) caused by compression of the ophthalmic nerve, described by Marple et al in 3 of 82 patients he encountered, was reversible with immediate surgical removal of fungal disease.[16] Return occurred over weeks to months.

A study by Gupta et al indicated that allergic fungal rhinosinusitis tends to be more severe when granulomas are present. The study involved 57 patients with allergic fungal rhinosinusitis, including nine patients with granulomas, with the investigators finding that those with granulomas had a tendency toward orbital and skull base erosion, as well as telecanthus, diplopia, exophthalmos, and facial pain.[17]

Table 2. Facial Asymmetry Characteristics (Open Table in a new window)

Condition

Children

Adults

Presence of facial asymmetry (44 children, 107 adults studied)

15/36 (42%) (8 unknown)*

10/103 (10%) (4 unknown)*

Proptosis (obvious) with telecanthus, with/without malar flattening

8/15

7/10

Proptosis (measured, not obvious, £2 mm)

0/15

2/10

Telecanthus alone

6/15

1/10

Malar flattening alone

1/15

0/10

*Not all initial clinical records mention the presence or absence of facial asymmetry or vision problems.

Indications

All patients with allergic fungal sinusitis (AFS) should undergo surgical debridement of their sinuses. The inciting fungal antigen must be removed for immunotherapy to be successful. Any recurrent disease also should be surgically removed.

Relevant Anatomy

Relevant anatomy is the same as in any endoscopic sinus surgery procedure. Often, anatomy is distorted because of expansion of the sinuses secondary to the disease process. The lateral nasal wall is pushed medially, obliterating the nasal cavity on the affected side, and the inferior and middle turbinates are pushed inferomedially, as depicted in the 1st two images below. If the ethmoid sinuses are involved, the roof often is expanded superiorly into the anterior cranial fossa, and the lateral wall is expanded into the orbit, as depicted in the last image below.

A 9-year-old girl with allergic fungal sinusitis d A 9-year-old girl with allergic fungal sinusitis displaying telecanthus and asymmetrical positioning of her eyes and globes.
Coronal CT scan showing extensive allergic fungal Coronal CT scan showing extensive allergic fungal sinusitis involving the right side with mucocele above the right orbit and expansion of the sinuses on the right.
Typical view of a middle meatus in a patient with Typical view of a middle meatus in a patient with allergic fungal sinusitis with expansion of the ethmoid complex and extension of the middle turbinate more inferiorly. This is a postoperative view.

Contraindications

No specific contraindications exist to surgical removal of fungal debris and polyps in patients with allergic fungal sinusitis (AFS). Normally, these patients are healthy immunocompetent individuals.

 

Workup

Laboratory Studies

See the list below:

  • Total immunoglobulin E

    • Total IgE values generally are elevated in allergic fungal sinusitis (AFS), often to more than 1000 U/mL (normal values are < 50 U/mL).

    • Total IgE level traditionally has been used to monitor the clinical activity of allergic bronchopulmonary fungal disease.

    • On the basis of similar IgE behavior associated with recurrence of allergic fungal sinusitis (AFS), total IgE levels have been proposed as a useful indicator of allergic fungal sinusitis (AFS) clinical activity.

  • Immunologic testing for allergens

    • RAST versus skin testing

      • Patients with allergic fungal sinusitis (AFS) generally demonstrate positive skin tests and in vitro (RAST) responses to fungal and nonfungal antigens. Manning et al, who compared 16 patients with histologically confirmed allergic fungal sinusitis (AFS) with a control group of patients with chronic rhinosinusitis, first demonstrated the sensitivity of RAST. Levels of fungal-specific IgE were uniformly elevated in all patients with allergic fungal sinusitis (AFS) and corresponded to the results of fungal cultures. In contrast, levels of fungal-specific IgE were not elevated within the control group. Moreover, patients with allergic fungal sinusitis (AFS) appear to demonstrate a broad sensitivity to a number of fungal and nonfungal antigens. Mabry et al have reported their experience, which indicates that patients with allergic fungal sinusitis (AFS) are allergic to multiple fungal antigens and to many typical nonfungal antigens.

      • Preliminary information suggests that methods of quantitative skin testing (in vivo) may provide even greater sensitivity ratings than RAST in patients with allergic fungal sinusitis (AFS). RAST traditionally has been considered less sensitive than skin testing during the investigation of atopy involving fungi. This has been attributed to technical problems, such as difficulty in binding the mold antigen to the carrier substrate.

      • To study the validity of this concept, Mabry et al prospectively evaluated 10 patients with allergic fungal sinusitis (AFS) for sensitivity to 11 pertinent fungi by both RAST and dilutional intradermal testing. A predictable correlation between RAST and skin test scores was observed in many, but not all, patients. Most often, this disparity was in the form of greater sensitivity indicated by skin testing than by RAST, sometimes differing by as many as 3 classes.

      • The lack of concordance was not confined to testing for fungi cultured from the sinuses, nor was it more or less pronounced in the case of dematiaceous fungi. The most likely causes for the disparity were thought to involve subtle differences in antigens used in skin test material as compared to RAST standards. Additionally, skin testing allowed observation of delayed and late-phase reactions, a measure not possible by specific IgE testing with RAST. This study appears to emphasize the importance of both skin testing and specific IgE testing via RAST in initial evaluation of patients in whom allergic fungal sinusitis (AFS) is suspected.

    • Nonspecific allergy testing

      • Gell and Coombs type I hypersensitivity in patients with allergic fungal sinusitis (AFS) can be demonstrated by elevation of serum total and fungal-specific IgE and by positive skin test results for fungal and nonfungal antigens. However, this reaction does not appear to be fungal specific.

      • Sensitivity to numerous fungi has been indicated both by in vitro (RAST) and in vivo methods (skin testing), although generally, only a single fungus is isolated by culture of corresponding allergic fungal mucin. This previously has been thought to represent either a common fungal epitope or a genetic predisposition toward fungal allergy in allergic fungal sinusitis (AFS).

      • Recent work by Chrzanowski et al identified the presence of an 18-kd protein in allergic mucin obtained from patients with allergic fungal sinusitis (AFS), which may represent such a pan-antigen.

Imaging Studies

See the list below:

  • Computed tomography[18]

    • Accumulation of allergic fungal mucin eventually leads to the increasingly well-recognized radiographic findings characteristic of allergic fungal sinusitis (AFS). Heterogeneous areas of signal intensity within paranasal sinuses filled with allergic fungal mucin frequently are identified on CT scans, as depicted in the image below.

      Coronal CT scan showing extensive allergic fungal Coronal CT scan showing extensive allergic fungal sinusitis involving the right side with mucocele above the right orbit and expansion of the sinuses on the right.
      Coronal CT scan showing typical unilateral appeara Coronal CT scan showing typical unilateral appearance of allergic fungal sinusitis with hyperintense areas and inhomogeneity of the sinus opacification; the hyperintense areas appear whitish in the center of the allergic mucin.

      See the list below:

      • Although these findings are not specific for allergic fungal sinusitis (AFS), they remain relatively characteristic of the disease and may provide preoperative information supportive of a diagnosis of allergic fungal sinusitis (AFS). This characteristic, which is best identified using soft-tissue algorithms on CT scan, has been the focus of some interest.

      • An initial theory proposed that the role of hemosiderin occurring within inspissated mucin is responsible for the areas of increased signal intensity. This was disputed by Zinreich et al, who were unable to identify increased hemosiderin within typical allergic fungal mucin. Current evidence points to the presence of accumulations of heavy metals (eg, iron, manganese) and calcium salt precipitation within inspissated allergic fungal mucin as the most likely causes of these radiographic findings.[19]

    • Expansion, remodeling, or thinning of involved sinus walls is common in allergic fungal sinusitis (AFS) and is thought to be caused by the expansile nature of the accumulating mucin. Areas of high attenuation are found within the expanded paranasal sinuses in all patients. Similar radiographic findings can be caused by rare osteoid/chondroid matrix-producing sinonasal sarcomas or meningiomas.

    • Bony erosion of the sinus walls and extension into adjacent cavities have been mentioned in many reports, usually focusing on intracranial extension, as depicted in the 1st image above.[20] In most series, a rate of approximately 20% bony erosion with extension into surrounding vital cavities is reported.

      • A recent review at UT Southwestern focusing on patterns of bony erosion in all the authors' patients found a 20% rate of erosion with extension. Sites of extension included the nasopharynx and pterygomaxillary space and intracranial and intraorbital areas.

      • A statistically significant association was identified between expansion of paranasal sinuses involved with disease and the presence of bone erosion.

      • The ethmoid sinus was the most commonly involved sinus, while the adjacent lamina papyracea was the most common bone to exhibit demineralization, as depicted in the image below. Extension of allergic fungal sinusitis (AFS) beyond the confines of the paranasal sinuses most commonly occurred into the orbit, followed by the anterior, middle, and posterior cranial fossae, respectively.

        Coronal CT scan showing typical unilateral appeara Coronal CT scan showing typical unilateral appearance of allergic fungal sinusitis with hyperintense areas and inhomogeneity of the sinus opacification; the hyperintense areas appear whitish in the center of the allergic mucin.
      • When evaluating children and adults in the authors' population separately, no difference was observed in the amount or location of bony erosion with extension, as depicted in the Table below.

      • Despite the sometimes-remarkable extension into adjacent anatomic spaces, no cases of histologic invasion of fungus into the adjacent barriers of the orbital periosteum or dura of the brain were identified on histologic review.

    • Although bilateral in 51% of cases reviewed in a large interinstitutional trial of 45 patients, allergic fungal sinusitis (AFS) caused asymmetric involvement of the paranasal sinuses in 78% of patients. Asymmetrical involvement actually is more pronounced in children. In a review of 151 children and adults, the author and colleagues demonstrated that children have more asymmetrical involvement than adults (88% vs 58%) and have a much greater incidence of unilateral disease on presentation than adults (70% vs 37%). Adults in this study presented most often with bilateral disease, but as in the interinstitutional study, asymmetrical disease was seen more often.

    • Table 3. Sites of Extension of Allergic Fungal Sinusitis From the Paranasal Sinuses*

      Table. (Open Table in a new window)

      Site

      Children (n=10) (25%, 10/40)

      Adults (n=23) (23%, 23/100)

      Intracranial anterior cranial fossa

      3

      9

      Middle cranial fossa

      1

      4

      Posterior cranial fossa

      2

      2

      Orbit

      6

      17

      Pterygopalatine fossa

      1

      3

      Nasopharynx

      3

      2

      *Multiple sites were affected in some patients.

  • Magnetic resonance imaging[18]

    • MRI also can provide information useful in preoperative identification of allergic fungal mucin, but it usually is not necessary when making the diagnosis unless the disease has extended into the intracranial cavity or confusion exists with the diagnosis. Som and Curtin have pointed out that protein concentrations exceeding 28% cause a decreased signal on T1- and T2-weighted MRI images because of protein cross-linking and slower macromolecular motion. This effect is more pronounced on T2-weighted images because of prolonged magnetic field relaxation times. The high protein and low water concentration of allergic fungal mucin, coupled with the high water content within surrounding edematous paranasal sinus mucosa, gives rise to rather specific MRI characteristics, as depicted in the image below.

      Coronal MRI showing expansion of the sinuses with Coronal MRI showing expansion of the sinuses with allergic mucin and polypoid disease; the hypointense black areas in the nasal cavities are the actual fungal elements and debris. The density above the right eye is the mucocele. The fungal elements and allergic mucin in allergic fungal sinusitis always look hypointense on MRI scanning and can be mistaken for absence of disease.
    • In a series of 10 patients with allergic fungal sinusitis (AFS), Manning et al demonstrated that hypointense central T1 signal, central T2 signal void, and the presence of increased peripheral T1/T2 enhancement were highly specific for allergic fungal sinusitis (AFS) when compared to other forms of fungal sinusitis (invasive fungal sinusitis, fungal ball) and mucocele. On MRI, the hypointense signal looks black and can be mistaken for absence of disease in the paranasal sinuses because a black signal in the sinuses on CT scan indicates the absence of disease. Compare the two images below. The combined CT scan and MRI findings provided a radiographic appearance that was highly specific for allergic fungal sinusitis (AFS).

      Coronal CT scan showing extensive allergic fungal Coronal CT scan showing extensive allergic fungal sinusitis involving the right side with mucocele above the right orbit and expansion of the sinuses on the right.
      Coronal MRI showing expansion of the sinuses with Coronal MRI showing expansion of the sinuses with allergic mucin and polypoid disease; the hypointense black areas in the nasal cavities are the actual fungal elements and debris. The density above the right eye is the mucocele. The fungal elements and allergic mucin in allergic fungal sinusitis always look hypointense on MRI scanning and can be mistaken for absence of disease.

Histologic Findings

Allergic fungal mucin, as depicted in the images below normally is first encountered at surgery. Therefore, recognition of its presence is the initial step in establishing an accurate diagnosis of allergic fungal sinusitis (AFS). Realizing that mucin, rather than paranasal sinus mucosa, demonstrates the histologic appearance consistent with allergic fungal sinusitis (AFS) is important. Examination of mucosa and polyps obtained from involved paranasal sinuses reveals findings consistent with the inflammation of a chronic inflammatory process and should be performed to exclude fungal invasion. Once mucin is collected, culture and pathologic examination are undertaken.

Left middle meatus with suctioning of thick allerg Left middle meatus with suctioning of thick allergic mucin from the ethmoid bulla in the center of the picture; the end of the suction is in the inferior portion of the picture.
The viscosity of a thick allergic mucin being suct The viscosity of a thick allergic mucin being suctioned from the nasal cavity and vestibule in a patient with allergic fungal sinusitis.

Initially described by Millar and Lamb and Katzenstein et al, histologic examination of allergic mucin reveals a constellation of characteristic findings.[21] Branching noninvasive fungal hyphae are identified within sheets of eosinophils and elongated eosinophilic bodies (Charcot-Leyden crystals), which represent the product of eosinophilic degradation. Use of various histologic staining techniques helps to identify the variety of components within allergic fungal mucin. Hematoxylin and eosin (H&E) staining accentuates the mucin and cellular components of allergic fungal mucin. Using this stain, background mucin often takes on a chondroid appearance, while eosinophils and Charcot-Leyden crystals are heavily stained and become easily detectable.

Fungi fail to stain using this technique and therefore may be difficult to identify. The presence of fungi may be implicated on H&E stain by the resulting negative image against an otherwise stained background. However, fungal hyphae and elements are often rare, scattered, and fragmented within allergic mucin, rendering identification difficult unless specific histologic stains are used. Fungal elements are recognized for a unique ability to absorb silver. This property is the basis for various silver stains, such as the Grocott-Gomori methenamine silver (GMS) stain, which turns fungi black or dark brown. The use of a fungal stain complements the findings of initial H&E stain and is extremely important in the identification of fungi.

 

Treatment

Medical Therapy

On the basis of a postulated schema of the pathophysiology of allergic fungal sinusitis (AFS), a variety of treatment plans addressing its multiple contributing factors has emerged. Medical control of the disease has made use of various combinations of antifungal medications, corticosteroids, and immunotherapy, with varying degrees of disease control. Attempts to control this disease by only partially addressing the underlying causes likely have contributed to a high rate of recidivism. Successful treatment of allergic fungal sinusitis (AFS) requires that the treatment plan account for each factor responsible for the propagation of the disease.

The allergic fungal sinusitis (AFS) cycle suggests that atopy, continuous antigenic exposure, and inflammation all have key roles in the perpetuation of the disease. In theory, individually accounting for each of these factors provides for the best chance of long-term disease control. This comprehensive approach to management depends on complete removal of all fungal mucin (usually requiring surgery) and long-term prevention of recurrence through either immunomodulation (immunotherapy and/or corticosteroids) or fungistatic antimicrobials.

Corticosteroids

The origin of corticosteroid therapy for long-term management of allergic fungal sinusitis (AFS) arose directly from the success of this strategy in the treatment of ABPA. The potent anti-inflammatory and immunomodulatory effects of corticosteroids appear to be well suited to control recurrence of disease. This concept was emphasized by Bent and Kuhn, who noted eventual universal recurrence of allergic fungal sinusitis (AFS) in their patients who were not treated with systemic corticosteroids.[22]

Schubert and Goetz further studied the role of systemic corticosteroids in postoperative management of allergic fungal sinusitis (AFS), demonstrating a significant increase in the time to revision sinus surgery in patients with allergic fungal sinusitis (AFS) who received prolonged courses of postoperative corticosteroids.[23, 24] Postoperative corticosteroid therapy in this study ranged from 2-12 months, with improved outcomes recorded among patients who were placed on longer courses of therapy. However, at present, the optimal dosing regimen and length of therapy remain unclear.

Topical corticosteroids are accepted as standard therapy in the postoperative treatment of allergic fungal sinusitis (AFS), but they possess a limited benefit before surgery because nasal access is restricted. However, after surgery, they may be effective in controlling local inflammation.

Complications of corticosteroids

The well-recognized benefits of systemic corticosteroids are counterbalanced by numerous potential adverse effects, including growth retardation, diabetes mellitus, hypertension, psychotropic effects, gastrointestinal side effects, cataracts, glaucoma, osteoporosis, and aseptic necrosis of the femoral head. Schubert and Goetz noted no adverse effects in their series of 67 patients with allergic fungal sinusitis (AFS) who were treated for up to 1 year with systemic corticosteroids, but long-term follow-up study for this form of therapy is lacking. The adverse effect profile of systemic corticosteroids warrants careful consideration when they are used in a long-term fashion to control allergic fungal sinusitis (AFS).

Topical corticosteroids generally present fewer adverse effects than systemic corticosteroids, based on their limited bioavailability. Long-term use, especially when topical corticosteroids are used at high dosages or in combination with inhaled corticosteroids, presents a risk of hypothalamic-pituitary-adrenal axis suppression, cataract formation, growth retardation, nasal bleeding, and nasal septal perforation in rare cases. As with individuals on any form of long-term therapy, patients using topical corticosteroid sprays should be monitored.

Immunotherapy

The similarity between allergic fungal sinusitis (AFS) and ABPA led to an empiric and theoretical concern that immunotherapy using specific fungal antigens in patients with either of these diseases might incite further allergic reactions by adding to the patient fungal antigenic stimulus. This concern specifically addressed the possible exacerbation of immune complex development and deposition. However, in allergic fungal sinusitis (AFS), surgery is able to remove the inciting fungal load from the paranasal sinuses. Therefore, it recently was postulated that immunotherapy may be beneficial, rather than harmful, as a component of treatment for allergic fungal sinusitis (AFS).

To investigate the safety of fungal immunotherapy as an adjunct to allergic fungal sinusitis (AFS) treatment, a prospective study was performed to examine the response of patients with allergic fungal sinusitis (following adequate surgery) to immunotherapy with all fungal and nonfungal antigens to which the patients were sensitive. In the first year of this study, clinical status was not shown to worsen, patients did not require systemic corticosteroids, most patients were able to discontinue topical corticosteroid therapy, and allergic fungal sinusitis (AFS) recurrence was markedly diminished among patients compliant with the regimen. The follow-up study revealed similar findings at 2 and 3 years.

A complementary study retrospectively compared 11 patients treated in this manner with 11 age- and diseased-matched control subjects who received the same surgical and medical treatment but no immunotherapy. A statistically significant difference was noted between the 2 groups. The cohort receiving immunotherapy as part of their treatment performed better in quality-of-life scores and objective endoscopic measures of mucosal edema.

In a series of 8 patients in whom immunotherapy was given for 3-5 years and then discontinued, no recurrences were seen up to 17 months after discontinuation. Additional study is necessary, but initial work suggests that a role may exist for immunotherapy in the overall treatment strategy for allergic fungal sinusitis (AFS).

Technique of immunotherapy in allergic fungal sinusitis

In initial studies, only immunotherapy for positive fungal antigens was administered for the first 6 months to be certain that any effects (either positive or negative) on the disease process were caused by the administration of fungal antigens. Later, both fungal and nonfungal antigens to which the patient was found to be allergic were included in the treatment mix. However, administering these in 2 separate vials for the first several months of treatment remains advisable to more easily assess the source of any untoward local reaction and to more efficiently advance treatment dosage. After maintenance levels are achieved, the fungal and nonfungal antigens may be combined into one vial.

A common misconception is that only immunotherapy for those fungi identified by culture from allergic fungal mucin should be included in the testing/treatment regimen for a patient. Because of variability in mycology laboratories and circumstances, a positive culture is not obtained for all patients. Conversely, the presence of fungi on culture of sinus contents does not confirm the diagnosis of allergic fungal sinusitis (AFS). One successful approach has been to test for a wide variety of molds (the choice being dictated by experience gained in testing and treating allergy patients in the region) and to include all positive reactors in the treatment set.

Advancement and adjustment of dosage are performed in the usual fashion. Although late local reactions (induration of >30 mm in diameter occurring 24-48 h after an injection) are said to be more common when administering immunotherapy for molds than for other antigens, this has not been the reported experience in treating patients with allergic fungal sinusitis (AFS). Systemic reactions to immunotherapy likewise have not been observed in the UT Southwestern experience.

On the basis of experience, administration of immunotherapy to patients with allergic fungal sinusitis (AFS) is currently recommended for the same duration as that recommended for patients with allergies in general, ie, 3-5 years. Mabry and Marple's protocol at UT Southwestern is listed in Table 4 below. The antigens for which they test and treat are listed in Table 5 below.

Table 4. Protocol for Immunotherapy in Allergic Fungal Sinusitis (Open Table in a new window)

Protocol

1. After successful surgical exenteration of sinuses and confirmation of diagnosis, perform allergy evaluation and testing (RAST or quantitative skin test) for typical panel of nonfungal antigens appropriate for the area. Test (RAST or quantitative skin test) for all relevant molds (fungi) available. Discuss treatment protocol with the patient and obtain informed consent.

2. Instruct the patient in avoidance measures for molds. Adjust pharmacotherapy as necessary.

3. Prepare a vial of all positive nonfungal antigens and a second vial of all positive fungal antigens. Perform a vial test with each.

4. Administer immunotherapy weekly, with dosage advancement as tolerated, placing 1 injection from each vial in a different arm. This allows for accurate recognition of the cause of any local reactions noted.

5. Observe the patient regularly and adjust dosage as necessary if local reactions or adverse changes in nasal signs/symptoms occur. Regularly examine the patient with endoscopy to detect reaccumulation of allergic mucin or reformation of polyps and to ensure that cleaning, medical management, etc, are carried out.

6. As dosage advancement permits (generally by second vial), antigens may be combined into 1 vial; continue for a 3- to 5-year regimen according to standard practice.

Reproduced from Mabry RL, 1998.

Table 5. Antigens From Fungal Genera in Current Testing and Treatment Protocol at the University of Texas Southwestern Medical Center at Dallas (Open Table in a new window)

Antigens From Fungal Genera in Approximate Relative Order of Local (Dallas, TX) Importance

Helminthosporium

Alternaria

Stemphyllium

Curvularia

Aspergillus

Epicoccum

Fusarium

Mucor

Pullularia

Cladosporium

Penicillium

Reproduced from Mabry RL, 1998.

Complications of immunotherapy

Currently, no treatment-related complications have been identified when immunotherapy follows appropriate surgical extirpation of all allergic mucin. However, this finding should not promote a sense of false security concerning this form of therapy because immunotherapy continues to represent a new and incompletely understood treatment modality. In general terms, immunotherapy may lead to worsening of local or systemic disease, specifically if the patient continues to be exposed to a significant antigenic load.

Ferguson reported 7 patients who received immunotherapy for the treatment of allergic fungal sinusitis (AFS). The 5 patients who received immunotherapy before surgical removal of all allergic mucin either symptomatically worsened or failed to improve in response to therapy. In contrast to these findings, the 2 patients who underwent surgery before initiation of immunotherapy responded well to this treatment modality. This small study supports the concept that immunotherapy administered in the presence of an ongoing antigenic load (in this case, fungus) raises the risk of untoward complications of therapy (eg, immune complex deposition, delayed or late-phase reactions, local reactions).

Another permutation of this concern occurs when allergic fungal sinusitis (AFS) presents concomitantly with ABPA. Unlike in allergic fungal sinusitis (AFS), the fungi within the lower respiratory tract of patients with ABPA cannot be surgically removed, thereby resulting in a retained antigenic load. Moreover, while clinical manifestations of allergic fungal sinusitis (AFS) sometimes are dramatic, they rarely are life threatening. The threat of ABPA potentially is much greater. Given the lack of information regarding the effects of immunotherapy on ABPA, great care should be taken when immunotherapy is given in this situation.

Antifungals

Systemic antifungal therapy for allergic fungal sinusitis (AFS) initially was proposed to control the theoretical potential for progression to invasive forms of fungal sinusitis. As the unacceptably high rate of recidivism following surgery alone was recognized, antifungal therapy often was used in an attempt to provide some degree of control over recurrence of allergic fungal sinusitis (AFS). Early use of amphotericin B yielded to the use of less toxic agents, such as ketoconazole, itraconazole, and fluconazole, but the poor in vivo activity of these agents against dematiaceous fungi soon was discovered.

Objective data on the effects of this form of therapy for allergic fungal sinusitis (AFS) have been limited. Denning et al studied the effect of systemic itraconazole in patients with ABPA and demonstrated a decrease in total IgE (used as a marker of disease severity) and in systemic corticosteroid requirements.[25] Anecdotal reports of systemic itraconazole to prevent allergic fungal sinusitis (AFS) recurrence offer mixed results. Ferguson points out that the expense, limited available data, and potential drug-related morbidity of systemic antifungal therapy may limit the usefulness of this form of treatment for noninvasive fungal disease.

Topical application of antifungal agents may hold some benefit in the control of postoperative recurrence, and studies of this form of treatment currently are underway. Bent and Kuhn studied the in vitro susceptibility of fungi commonly encountered in patients with allergic fungal sinusitis (AFS) and determined that minimal inhibitory concentrations can be exceeded with certain antifungal agents when applied topically. Similarly, Ponikau et al support the use of topical antifungal agents. Supportive data are pending.

Complications of antifungal therapy

Antifungal medications are recognized for some potentially serious adverse effects, which warrant consideration when these medications are used as a form of treatment for AFS. The well-known complications associated with amphotericin B include acute renal failure, anemia, agranulocytosis, acute liver failure, cardiopulmonary hypertension, and hemorrhagic gastroenteritis. Itraconazole and fluconazole offer a slightly safer form of antifungal therapy but still may give rise to drug-induced cardiac dysrhythmias, hepatic dysfunction, urticaria, and anaphylaxis.

Surgical Therapy

The invariable components of combination therapy still are surgical removal of the inciting fungal allergic mucin and marsupialization of the involved sinuses. For this reason, surgery has played an important role in the management of allergic fungal sinusitis (AFS) since its earliest reports. An aggressive surgical posture initially was adopted because of a perceived risk of fungal invasion. This frequently was accomplished through the use of open antrostomies with radical removal of mucosa, intranasal sphenoethmoidectomies, and Lynch frontoethmoidectomies. Despite such aggressive therapy, recidivism remained high, and most patients required multiple surgical procedures.

Clinical appearance of the disease often confused the underlying diagnosis, further influencing surgeons to adopt a more radical stance. Radiographic evidence of invasion (which really was extension) into adjacent spaces (eg, orbit, intracranial cavity) frequently was interpreted as evidence of malignancy or invasive fungal disease. It logically followed that surgical approaches appropriate for these serious conditions (eg, lateral rhinotomy, facial degloving approaches, craniofacial resection) would be performed.

Increased acceptance of specific immunologic hypersensitivity as the cause of allergic fungal sinusitis (AFS) has led to changes in its management. These changes have involved the medical and surgical arms of therapy. While systemic use of antifungal medications largely has been replaced by immunomodulation, radical surgery for allergic fungal sinusitis (AFS) has given way to more conservative, tissue-sparing approaches. Mabry et al refer to this surgery as conservative but complete, relying almost completely on endoscopic techniques.

A retrospective study by Masterson et al indicated that for patients with allergic fungal rhinosinusitis, quality-of-life improvement following endoscopic sinus surgery is significantly greater than for patients with nonfungal chronic rhinosinusitis without nasal polyposis, at 9- and 12-month follow-up. Quality of life was evaluated via the 22-item Sino-Nasal Outcome Test (SNOT-22).[26]

Preoperative Details

To minimize recurrence of disease, treatment of allergic fungal sinusitis (AFS) is directed at removal of the inciting antigenic material via complete surgical removal of allergic mucin and debris while also ameliorating the underlying inflammatory process through the use of limited systemic and topical steroid preparations. One accepted preoperative medical regimen is to initiate systemic corticosteroid therapy (prednisone dosed at 0.5-1 mg/kg/d) approximately 1 week before surgery to decrease intranasal inflammation and nasal polyp volume. Bleeding encountered at surgery following preoperative steroids also is reduced. Additionally, preoperative antibiotics are instituted because of the frequency of concomitant postobstructive bacterial sinusitis.

Intraoperative Details

At surgery, 3 surgical goals should be achieved: (1) complete extirpation of all allergic mucin and fungal debris, (2) permanent drainage and ventilation of the affected sinuses while preserving the integrity of the underlying mucosa, and (3) postoperative access to the previously diseased areas.

First, surgery should result in complete extirpation of all allergic mucin and fungal debris, thus greatly reducing or eliminating the antigenic inciting factor within the atopic individual, as depicted in the image below. At times, this may be challenging because the nasal polyposis inherent in allergic fungal sinusitis (AFS) can range from subtle to extensive, causing distortion of local anatomy and loss of useful surgical landmarks. Bleeding often occurs in response to surgical manipulation of the polyps, increasing the potential for disorientation. The operating surgeon must recognize that these factors, in combination with the high likelihood of bony dehiscence, increase the risk of iatrogenic injury.

Immediate postoperative 30° angled view showing th Immediate postoperative 30° angled view showing the complete removal of polyps with a widened frontal sinus recess superiorly and widened ethmoid cavity in the mid portion. The middle turbinate is on the right, pushed against the septum. The lateral nasal wall is on the left.

Aside from these problems, polyps can provide an important intraoperative role by serving as a marker of disease. Allergic fungal sinusitis (AFS) causes a relatively consistent configuration of disease. The involved paranasal sinus, acting as a reservoir for allergic fungal mucin, is the epicenter of the disease process. Allergic fungal mucin completely occupies the sinus cavity and almost always is mixed with fungal elements, as depicted in the images below, while the lining mucosa, demonstrating only mild-to-moderate inflammation, remains an intact barrier to the fungus. More significant inflammation located at the sinus ostia gives rise to polyps that extend into the infundibulum, middle meatus, sphenoethmoid recess, and nasal cavity. Recognition of this allows the surgeon to follow the polyps to the disease.

Fungal ball in the right maxillary sinus. Fungal ball in the right maxillary sinus.
Fungal debris being removed from the ethmoid compl Fungal debris being removed from the ethmoid complex. A suction device is seen in the right lower corner of the picture.
Allergic mucin, fungal debris, and polyps are show Allergic mucin, fungal debris, and polyps are shown after removal from the patient. The scale is in inches.

The allergic mucin, not the polyps, should be sent to a pathologist to confirm the diagnosis of allergic fungal sinusitis (AFS; see Histologic Findings). The fungal elements and mucin can be sent for culture and pathologic stain to help make the diagnosis and identify the fungus responsible for the disease. Fungal stains are positive more often than fungal cultures, but both should be attempted.

Resulting nasal polyposis also can facilitate surgical treatment of allergic fungal sinusitis (AFS) in another fashion. The expansile behavior of allergic fungal sinusitis (AFS) increases access to involved paranasal sinuses. As revealed radiographically, the combination of slowly growing nasal polyps and accumulating allergic fungal mucin expands the involved paranasal sinuses and the surgical route to the involved sinuses. Enlargement of the nasal cavity, middle meatus, and frontal recess provides the surgeon with access adequate to address the disease, even in the most difficult areas, such as the lateral area of the frontal sinus, which once was thought to require a traditional nonendoscopic approach, as depicted in the image below.

Coronal CT scan showing extensive allergic fungal Coronal CT scan showing extensive allergic fungal sinusitis involving the right side with mucocele above the right orbit and expansion of the sinuses on the right.
Coronal CT scan showing the postoperative view fol Coronal CT scan showing the postoperative view following removal of disease after significant disease recurred on both the right and left sides of the nasal cavity and sinuses; mild mucosal thickening of all involved sinuses is present, with some moderate thickening of the left maxillary sinus. All disease, even the lateral mucocele, was removed or drained endoscopically.

After surgical access to the involved sinus is achieved, a dilated cavity filled with allergic fungal mucin is encountered. This material is thick, tenacious, and viscous and may vary in color from light tan to black. Because of its noninvasive behavior, it may be removed in a blunt fashion, leaving the involved sinus completely lined with intact mucosa. Preservation of mucosa provides protection of adjacent anatomic structures, even in the face of large areas of bony dehiscence.

The next goal of surgery is to produce permanent drainage and ventilation of the affected sinuses while preserving the integrity of the underlying mucosa. This has been aided greatly by the recent advent of tissue-sparing instrumentation. Even in the setting of significant dissolution of the fovea ethmoidalis, lamina papyracea, clivus, and sphenoid planum, wide marsupialization of diseased areas can be achieved without causing trauma to the underlying mucosa. Careful preservation of mucosa ensures that underlying periosteum, dura, and/or periorbita remain free of penetrating injury. Sinonasal polyposis initially may preclude orientation, but removal in a controlled fashion using powered microdissection provides the operating surgeon with eventual access to areas of fungal presence. After adequate ventilation and drainage are achieved, the preserved underlying mucosa is able to revert to its normal state.

Adequate ventilation and drainage also provide for the final goal of surgery, postoperative access to the previously diseased areas. Even under ideal conditions, small residua of fungus may remain in situ, inciting recurrence if not controlled postoperatively. Surgery should be performed with facilitation of postsurgical care in mind. This goal can be attained reliably in most patients while preserving the integrity of important intranasal structures, such as the middle and inferior turbinates.

These surgical goals can be accomplished through a number of approaches and techniques, the choice of which ultimately is influenced by the experience and training of the surgeon. Endoscopic powered instrumentation has demonstrated its effectiveness; this technique allows for removal of soft tissue and thin bone while maintaining superb visibility. Exercise great care when using powered instrumentation because the well-recognized bone dissolution associated with allergic fungal sinusitis (AFS) increases the potential risk of inadvertent orbital and/or intracranial penetration. In the event of extensive remodeling or bone erosion, image-guided systems (eg, Stealth, InstaTrak) may be of benefit.

Postoperative Details

Postoperative care begins immediately following surgery with nasal saline irrigation with bulb irrigations or Water-Pic, with or without the Grossan adaptor. Sinus packing usually is not needed, but the need is evaluated on an individual basis. Weekly clinic visits for about a month initially are required to allow regular inspection of the operative site and debridement of crusts and retained fungal debris.

Systemic corticosteroids, which were initiated before surgery, are continued during the postoperative period and slowly tapered during the process of healing. The length of corticosteroid treatment and the form of postoperative adjunctive medical management used to further control the disease are at the discretion of the managing physician. The authors typically treat the patients with 3-4 weeks of steroids postoperatively, starting with a similar dose of steroids received preoperatively for 10-14 days. The steroids then are tapered over the next 10-14 days. Topical nasal steroids are started at the first postoperative visit, continued until immunotherapy is well established, and used thereafter as needed.[27]

Follow-up

Postoperative follow-up care for the first month is noted above. No set interval is established for follow-up visits after the postoperative regimen. However, the author has started requesting patient follow-up visits at 3-month intervals to detect recurrences early because recurrence is not uncommon. Immunotherapy is always recommended for these patients, thus they are monitored closely by the physician, usually an allergist, who is instituting the injections. If symptoms of sinusitis or nasal airway obstruction return, rigid or flexible rhinoscopy in the clinic or CT should be performed to evaluate for recurrent disease.

Complications

In most patients, surgery is performed without incident, but the pathologic behavior of allergic fungal sinusitis (AFS) theoretically increases surgical risk. Nasal polyposis, expansile accumulations of allergic mucin, and poor intraoperative hemostasis may increase spatial disorientation. Additionally, areas of bony dehiscence may confuse or distort anatomic boundaries while offering little protection to the orbit and intracranial cavities. Conversely, a less than complete surgical procedure (in an attempt to decrease iatrogenic injury) is likely to lead to incomplete retrieval of allergic fungal mucin and rapid recurrence of allergic fungal sinusitis (AFS).

On the basis of currently accepted pathophysiology of allergic fungal sinusitis (AFS), little risk of fungal invasion into adjacent tissues should exist in an immunocompetent host. However, rare exceptions may occur. Tsimikas et al report a single case of an Aspergillus frontal lobe abscess that occurred following surgical treatment of allergic fungal sinusitis (AFS) that had expanded into the anterior cranial fossa.[28, 29] This case may represent seeding of the intracranial cavity as a result of inadvertent dural penetration, and it emphasizes the importance of mucosal preservation.

In addition to fungal or bacterial seeding, penetration of the dura or periorbita iatrogenically during surgery may result in injury of structures within the orbit or intracranial cavities. Such transgressions can cause diplopia, blindness, hemorrhage, stroke, intracranial hemorrhage, encephalocele, and/or cerebrospinal fluid (CSF) rhinorrhea (see the Medscape article Pediatric Sinusitis Surgery).

Erosion by allergic fungal sinusitis (AFS) of the osseous boundaries separating the intracranial fossa from the sinonasal cavities may increase the risk of subsequent encephalocele formation. The otologic community commonly accepts that dural exposure in the absence of dural injury along the tegmen mastoideum rarely results in development of an encephalocele. Unfortunately, no analogous information within the rhinologic literature exists. However, it is logical to assume that eventual encephalocele formation may occur as a result of a combination of factors, including dural injury, location of bony dehiscence, and/or size of the bony dehiscence. In rare cases, accumulations of allergic fungal mucin actually may appear to support intracranial structures. Monitoring for development of encephaloceles is important, because their occurrence may require subsequent repair of bony dehiscence.

Outcome and Prognosis

A retrospective study in North Carolina by Miller et al indicated that various socioeconomic factors, including low income, residency in rural areas, low-quality housing, and reduced access to health care, are associated with the severity of allergic fungal sinusitis (AFS). The investigators, whose study involved 93 patients, determined that the prevalence of AFS-associated bone erosion was greater in patients living in counties with a lower per-capita income or with older, poorer-quality housing, while patients with orbitocranial involvement tended to be found in rural counties with fewer primary care providers per capita. The study also concluded, however, that disease severity did not correlate with patients’ race, age, gender, or insurance status.[30] The potential for AFS recidivism is well respected and ranges from 10% to nearly 100%. Recurrence can be in the form of mucosal edema, as depicted in the first image below, polyps as depicted in the second image below, scarring, allergic mucin, or fungal debris. However, published rates of allergic fungal sinusitis (AFS) recurrence can be misleading and are highly dependent on length of follow-up study. To emphasize the importance of long-term surveillance, Bent and Kuhn pointed out that, in their experience, the often-dramatic initial response to surgical therapy eventually was replaced by recurrence of allergic fungal sinusitis (AFS) in the absence of ongoing therapy.

Two-week postoperative endoscopic picture showing Two-week postoperative endoscopic picture showing polypoid thickening already in the ethmoid cavities while the patient was still on tapering steroids; on the left is the lateral nasal wall. The right shows the middle turbinate next to the septum.
A polypoid recurrence in the center of the ethmoid A polypoid recurrence in the center of the ethmoid cavity. The septum is on the left.

Similarly, Kupferburg et al monitored the appearance of sinonasal mucosa of 24 patients treated with combined medical and surgical therapy for allergic fungal sinusitis (AFS). Of the 24 patients, 19 eventually developed recurrence of disease after discontinuation of systemic corticosteroids, but the authors observed that endoscopic evidence of disease generally preceded return of subjective symptoms.

Allergic fungal sinusitis (AFS) recidivism appears to be influenced by long-term postoperative therapy. Schubert and Goetz reported the long-term clinical outcome of 67 patients following initial surgical therapy for allergic fungal sinusitis (AFS). Patients treated with at least 2 months of oral corticosteroids were compared to those who received no corticosteroids. At 1 year following initial surgery, patients treated with oral corticosteroids were significantly less likely to have experienced recurrent allergic fungal sinusitis (AFS; 35%) than those who had not (55%). However, allergic fungal sinusitis (AFS) recidivism remains high despite appropriate postoperative medical therapy. Fungal and nonfungal specific immunotherapy holds some potential as a form of postoperative treatment in patients with allergic fungal sinusitis (AFS), but clinical failures can arise during immunotherapy.

In a review of 42 patients who had received immunotherapy following surgery, Marple et al reported 4 recurrences of disease, which were attributed to noncompliance with immunotherapy or inadequate operative extirpation of allergic fungal mucin.

A study by AlQahtani et al found that in patients with unilateral allergic fungal rhinosinusitis (AFRS), the risk of contralateral postoperative development of the condition was increased when, prior to endoscopic sinus surgery, the contralateral side was symptomatic and demonstrated signs of inflammation. Contralateral sinus involvement was decreased in patients in whom budesonide irrigation was used postoperatively.[31]

Future and Controversies

Controversy still exists regarding the exact criteria for diagnosis and the exact regimen for treatment. Although not perfected, recent evidence supports the theory that allergic fungal sinusitis (AFS) represents an immunologic, rather than infectious, disease process. An improved understanding of this underlying disease process has led to an evolution in the treatment of allergic fungal sinusitis (AFS).

Medical therapy has begun to shift from an emphasis on systemic antifungal therapy to various forms of topical treatment and immunomodulation. Likewise, surgical treatment of allergic fungal sinusitis (AFS), still a crucial component of the overall treatment plan of the patient, has shifted from radical to a more conservative but complete, usually endoscopic, approach. Although important, surgery alone does not lead to a long-term disease-free state. A comprehensive management plan incorporating medical, surgical, and immunologic care remains the most likely means of providing long-term disease control for allergic fungal sinusitis (AFS). The exact combination continues to be debated strongly.

 

Questions & Answers

Overview

What is allergic fungal sinusitis (AFS)?

What is the role of lab testing in the diagnosis of allergic fungal sinusitis (AFS)?

What is the role of CT scanning in the diagnosis of allergic fungal sinusitis (AFS)?

What is the role of MRI in the diagnosis of allergic fungal sinusitis (AFS)?

Which histologic findings are characteristics of allergic fungal sinusitis (AFS)?

How is allergic fungal sinusitis (AFS) treated?

How has the diagnosis and treatment for allergic fungal sinusitis (AFS) evolved over time?

What are the diagnostic criteria for allergic fungal sinusitis (AFS)?

Which conditions are included in the differential diagnoses of allergic fungal sinusitis (AFS)?

What is the prevalence of allergic fungal sinusitis (AFS)?

What causes allergic fungal sinusitis (AFS)?

What is the evidence to support an immunologic theory of the etiology of allergic fungal sinusitis (AFS)?

What is the pathophysiology of allergic fungal sinusitis (AFS)?

Which clinical history findings are characteristic of allergic fungal sinusitis (AFS)?

Which physical findings are characteristic of allergic fungal sinusitis (AFS)?

When is surgical debridement indicated for the treatment of allergic fungal sinusitis (AFS)?

Which nasal anatomy is relevant to allergic fungal sinusitis (AFS)?

What are the contraindications to surgical debridement for the treatment of allergic fungal sinusitis (AFS)?

Workup

What is the role of total immunoglobulin E (IgE) measurement in the workup of allergic fungal sinusitis (AFS)?

What is the role of immunologic testing in the workup of allergic fungal sinusitis (AFS)?

What is the role of nonspecific allergy testing in the workup of allergic fungal sinusitis (AFS)?

What is the role of CT scanning in the workup of allergic fungal sinusitis (AFS)?

What are the sites of extension of allergic fungal sinusitis (AFS)?

What is the role of MRI in the workup of allergic fungal sinusitis (AFS)?

Which histologic findings are characteristic of allergic fungal sinusitis (AFS)?

Treatment

How is allergic fungal sinusitis (AFS) treated?

What is the role of corticosteroids in the treatment of allergic fungal sinusitis (AFS)?

What are the adverse effects of corticosteroids in the treatment of allergic fungal sinusitis (AFS)?

What is the role of immunotherapy in the treatment of allergic fungal sinusitis (AFS)?

What is the protocol for immunotherapy to treat allergic fungal sinusitis (AFS)?

What are the adverse effects of immunotherapy for allergic fungal sinusitis (AFS)?

What is the role of antifungal therapy in the treatment of allergic fungal sinusitis (AFS)?

What are the adverse effects of antifungal therapy for allergic fungal sinusitis (AFS)?

What is the role of surgery in the treatment of allergic fungal sinusitis (AFS)?

What is included in preoperative care for allergic fungal sinusitis (AFS)?

How is surgery performed for allergic fungal sinusitis (AFS)?

What is included in postoperative care following surgery for allergic fungal sinusitis (AFS)?

What is included in the long-term monitoring for allergic fungal sinusitis (AFS)?

What are the possible complications of allergic fungal sinusitis (AFS) surgery?

What is the prognosis of allergic fungal sinusitis (AFS)?

What are the controversies regarding the treatment of allergic fungal sinusitis (AFS)?