INTRODUCTION — Allergic fungal rhinosinusitis (AFRS) is a distinct type of chronic rhinosinusitis (CRS), accounting for between 5 and 10 percent of all CRS cases. AFRS is believed to result from chronic, intense allergic inflammation directed against colonizing fungi. Patients with AFRS are immunocompetent and show evidence of allergy to one or more fungi. Definitive diagnosis is usually confirmed after sinus surgery. Successful treatment involves a combination of surgical and medical management.
The pathogenesis, clinical manifestations, diagnosis, differential diagnosis, and management of AFRS are reviewed here. More general topics about CRS are found separately. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis" and "Chronic rhinosinusitis without nasal polyposis: Management and prognosis" and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
DEFINITION — AFRS is defined as a specific subtype of chronic rhinosinusitis (CRS). All forms of CRS are defined as inflammatory conditions involving the paranasal sinuses and linings of the nasal passages that last 12 weeks or longer. The diagnosis of all forms of CRS requires objective evidence of mucosal inflammation. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Definition'.)
AFRS is a distinct subtype of CRS that arises as a result of a localized allergic reaction to noninvasive fungal growth in areas of compromised mucus drainage [1,2]. AFRS is defined as an intense, localized allergic/eosinophilic inflammatory sinus disease that results in the accumulation of eosinophilic (allergic) mucin (a thick, tenacious eosinophilic secretion that contains fungal hyphae), intense eosinophilic inflammation, and characteristic radiographic findings. The diagnostic criteria for AFRS require:
●The presence of CRS with nasal polyposis (NP), unless the patient has undergone surgery or aggressive medical therapy with systemic glucocorticoids to remove or shrink the polyps.
●The presence of eosinophilic mucin (with pathology showing fungal hyphae and degranulating eosinophils).
●Evidence of immunoglobulin (Ig)E-mediated allergy to fungus (documented either by skin testing or in vitro IgE immunoassays).
●No evidence of invasive fungal disease, diabetes mellitus, or immunodeficiency.
●Characteristic radiographic findings.
Diagnosis is discussed in more detail below. (See 'Diagnosis' below.)
PATHOGENESIS — The pathophysiology of AFRS is most consistent with chronic, intense T helper type 2 (Th2) allergic inflammation directed against colonizing fungi. The sinuses become filled with thick, inspissated mucus that is dense with degranulating eosinophils .
Key steps in the pathogenesis are outlined below, although this sequence of events is largely theoretical (modified from ):
●Fungal spores become trapped in nasal or sinus mucus. This is known to occur in healthy subjects, depending on geographic and climatic conditions.
●The host becomes sensitized to fungal antigens.
●Some of the fungal spores germinate into hyphae. The hyphae provide the local antigenic stimulus for the allergic response.
●The large local load of fungal antigen elicits a localized Th2-allergic immune response. This likely explains the localization of disease to one or more sinuses (AFRS is often a unilateral process).
●Chronic allergic inflammation results in local fungal-specific IgE production, mast cell degranulation, and late-phase allergic inflammation, with an influx of large numbers of eosinophils.
●The eosinophils attack the fungal hyphae, degranulate and release inflammatory mediators, cytokines, and growth factors that amplify the inflammatory process, and may contribute to airway remodeling, nasal polyp formation, and possibly to bony demineralization.
●The sinonasal mucosa becomes damaged, which facilitates bacterial penetration of the mucosa, leading to bacterial infection, biofilm formation, and further perpetuation of the inflammatory process.
The Th2-derived cytokines, interleukin-5 (IL-5) and interleukin-13 (IL-13), are likely involved in the local eosinophil accumulation and subsequent eosinophil-mediated attack of fungal hyphae in mucus. In an in vitro study, peripheral blood lymphocytes from patients with AFRS produced greater amounts of IL-5 when stimulated by fungal antigens from Alternaria and Cladosporium, compared with lymphocytes from healthy control subjects .
The role of allergy — Patients with AFRS are, by definition, allergic to one or more fungi, as determined by skin testing or in vitro testing for fungal-specific IgE. However, one study found that AFRS patients were not distinguishable from patients with allergic rhinitis and fungal allergy in the following parameters: total serum IgE, serum levels of Alternaria alternata-specific or Aspergillus fumigatus-specific IgE, IgG, or IgA levels, or the percent of fungal-specific serum IgE relative to total serum IgE measurements . Furthermore, the prevalence of fungal allergy to A. alternata or A. fumigatus in AFRS and AFRS-like patients was no different from that observed in allergic rhinitis with fungal allergy. These findings suggest that allergy to fungus by itself is not sufficient to explain the pathophysiology of AFRS. The other factors that determine why one patient with allergy to fungus develops AFRS while another has uncomplicated allergic rhinitis are undefined.
Fungi implicated in AFRS — The most common fungi reported to cause AFRS are Bipolaris, Curvularia, Aspergillus, Exserohilum, and Drechslera species, with a wide variety of other fungi implicated in case reports [7,8]. Newer culture techniques and identification of the fungal microbiome will undoubtedly improve our understanding of fungi and their role in AFRS [9,10]. When AFRS was first recognized in the 1970s, it was believed to represent an upper airway manifestation of allergic bronchopulmonary aspergillosis (ABPA) . However, the co-occurrence of these two conditions is infrequent, and Aspergillus is just one of the many fungi that cause AFRS, although it may be a more common culprit in other parts of the world [7,12].
The fungi that most commonly cause AFRS belong to the "dematiaceous" or "melanized" group of fungi, sometimes called "dark" fungi . The reasons for this are not known, and nondematiaceous fungi can also cause AFRS. Dematiaceous fungi have brown pigmented hyphae that are often discernible in tissue specimens without the use of staining procedures . However, the presence of melanin alone is insufficient for inclusion in this group, as some amount of melanin is also present in nondematiaceous fungi. The vast majority of dematiaceous fungi are of no clinical significance, although some cause opportunistic infections (local or systemic) in immunocompromised hosts . In the absence of dark pigment in the cell wall of hyphae, a special stain called Fontana-Masson (FM) can be used to observe melanin pigment in the fungal cell walls. Many Aspergillus species, which are nondematiaceous, and some zygomycetes also stain positively with FM, whereas other fungi showed either weak intensity or no staining . The stains typically used in diagnosis are discussed below. (See 'Detection of fungi' below.)
Controversial issues — Fungi have been proposed to play a much broader role in the pathogenesis of other forms of chronic rhinosinusitis (CRS), namely CRS without nasal polyposis (NP) and CRS with NP [9,16-18]. Some studies have reported that fungi are present in the mucus of the vast majority of patients with CRS and that peripheral blood T lymphocytes from CRS patients produce eosinophil-promoting cytokines, including IL-5 and IL-13, when exposed in vitro to certain fungi, most notably Alternaria . However, this theory is controversial, and other studies have reported that fungal hyphae are not universally found in the mucus of non-AFRS CRS cases . In addition, other studies failed to confirm that fungi elicit strong immunologic responses in CRS patients [20,21].
Bacterial coinfection — Although AFRS is not caused by bacterial infection, it has been observed that bacterial coinfection in AFRS cases is not uncommon. Indeed, a higher rate of mucosal colonization with enterotoxin-producing Staphylococcus aureus has been reported in AFRS compared with non-AFRS CRS with NP, and a pathologic role for S. aureus has been proposed in AFRS [22,23]. It is possible that such enterotoxins contribute to the Th2 microenvironment in these patients. The microbiology and antimicrobial therapy of CRS are reviewed in more detail separately. (See "Microbiology and antibiotic management of chronic rhinosinusitis".)
EPIDEMIOLOGY AND POSSIBLE RISK FACTORS — AFRS occurs worldwide, although most published reports are from the southern United States. In a systematic review of studies from around the world, the prevalence of AFRS among patients with chronic rhinosinusitis with nasal polyposis (CRS with NP) in 35 cities across 5 continents was approximately 8 percent, with a range of 0.2 to 27 percent . Climactic factors that were associated with a higher prevalence of AFRS were hotter, less humid, and less windy climates. No correlations were found with presence of water bodies, forests, average rainfall, or altitude.
The majority of cases of AFRS have been reported in the southern United States, specifically along the Mississippi River basin . This distribution has not been definitively tied to specific geographic conditions, such as differences in ambient mold spore counts, although it unlikely to be simply a selection bias resulting from the research interests of investigators from these areas. Another important epidemiologic feature of AFRS in the United States is a higher prevalence in younger patients, African Americans, uninsured or Medicaid patients, and patients residing in counties with higher poverty rates . It is possible that lower socioeconomic status may play a role through delayed access to care, differences in quality of care, or poor housing quality, although this association requires further study [26,27]. A study of mold exposure in the homes of patients with AFRS compared with those with CRS w NP did not reveal significant differences, despite the presence of socioeconomic differences .
Signs and symptoms — The symptoms of AFRS are similar to chronic rhinosinusitis with nasal polyposis (CRS with NP), since AFRS patients uniformly have NP. Early disease may present with innocuous-sounding nasal congestion or obstruction, anosmia, and postnasal drainage. Fever is uncommon. Patients may report that semisolid nasal crusts or rubbery globs of dark-colored mucus are periodically expelled from the nose .
The four cardinal symptoms of CRS are:
●Anterior and/or posterior nasal mucopurulent drainage
●Nasal obstruction, nasal blockage, congestion
●Facial pain, pressure, and/or fullness
●Reduction or loss of sense of smell
At least two of the four cardinal symptoms of CRS are required for the diagnosis of AFRS, similar to other forms of CRS . The cardinal CRS symptoms and the diagnosis of CRS are discussed in greater detail separately. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Signs and symptoms'.)
Some patients may have multiple symptoms, including anosmia, rhinorrhea, and cough. However, none of these are specific for AFRS. Occasionally, AFRS presents dramatically with complete nasal obstruction, gross facial asymmetry, and/or visual changes [29,30]. Children present with proptosis more commonly than adults .
Warning signs and complications — Moderate and severe AFRS can lead to bony expansion and bony erosion, with extension to extrasinus areas, such as the orbit, skin, and brain. This happens more with AFRS than with other forms of CRS. The following symptoms may develop as a result of bony expansion or erosion: double or reduced vision, proptosis, dramatic periorbital edema, ophthalmoplegia, facial dysmorphia, other focal neurologic signs, severe headache, meningeal signs, or significant or recurrent epistaxis [7,32-34]. Urgent referral to an otolaryngologist/head and neck surgeon is indicated in the presence of these symptoms, even if they have developed gradually. (See 'Findings on imaging studies' below.)
Impact on quality of life — The impact of AFRS upon quality of life is similar to other forms of CRS, and AFRS has similar clinical outcomes [35,36]. One study documented that patients with CRS had significantly lower quality of life scores for social functioning as well as physical and overall health, compared with the general population, with decrements similar to chronic lung or heart illnesses .
EVALUATION — The evaluation of AFRS is similar to that of chronic rhinosinusitis (CRS). It involves a clinical history, objective documentation of mucosal disease (with sinus imaging or nasal endoscopy), allergy evaluation, consideration of immunologic defects and infectious complications, and in most cases, endoscopic sinus surgery (ESS). These components of diagnosis, as they apply to all forms of CRS, are summarized separately. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)
Laboratory findings — Patients with AFRS may have elevations of total serum IgE and peripheral blood eosinophilia, although these abnormalities are not required for the diagnosis. In one study of 99 patients with either AFRS or CRS, total IgE in patients with AFRS was significantly higher than in those with CRS (mean levels, 1146 versus 247 kU/L) .
Allergy evaluation — Patients with AFRS must demonstrate IgE-mediated allergy to fungus either by skin testing or in vitro immunoassays. Both epicutaneous (ie, prick/puncture) and intradermal test results are relevant . Most patients with AFRS show allergy to more than one fungus, although sensitization to multiple fungi is not required for the diagnosis. Skin testing for other perennial allergens (dust mite, cockroach, and animal danders) is also recommended, as these are potentially relevant to any patient with CRS.
Findings on imaging studies
Sinus CT — Any patient with CRS who has failed conservative treatment, who is being considered for sinus surgery, or who is suspected of having AFRS based on physical examination findings should have a computed tomography (CT) study of the paranasal sinuses. Characteristic findings are usually present despite previous medical therapy, including both antibiotics and oral glucocorticoids.
Sinus CT usually reveals nasal polyposis (NP) with opacification of one or more sinuses. In the majority of cases, multiple sinuses are involved [39,40]. There may be unilateral or bilateral sinus involvement in AFRS, with up to one-half of cases presenting with unilateral disease. AFRS is an important consideration in the evaluation of a child with a unilateral sinus disease or unilateral nasal mass . Similar to CRS with NP, sinus opacification is typically found in the absence of facial pain, pressure, and headaches.
A characteristic CT finding in AFRS is differential densities (hyperattenuated areas) within the opacified sinuses, which indicates the presence of dense accumulations of eosinophilic mucin in those sinuses (image 1). Local pressure on the bony walls of the sinus cavity may result in expansion of this sinus cavity and bony demineralization over time. True bone erosion is less common, occurring in 20 percent of cases .
Both mucus accumulation and mucosal thickening contribute significantly to sinus opacification and are difficult to differentiate with sinus CT imaging. The main distinguishing features of AFRS on sinus CT include:
●One or more opacified sinuses with foci of increased density ("hyperdensities") corresponding to the presence of eosinophilic mucin – Eosinophilic mucin has areas of high protein content and low water content that give rise to characteristic hyperdense appearance on sinus CT (image 2). These same areas appear "hypointense" on T2-weighted magnetic resonance images (MRIs). Although this is considered a pathognomonic feature of AFRS, it actually signifies the presence of "allergic mucin," which can be found in other disorders. (See 'Eosinophilic mucin rhinosinusitis' below.)
●Bony demineralization of the sinus wall resulting in sinus expansion – Occasionally, sinus cavity opacification in AFRS may be associated with local pressure effects on bone. Bony demineralization of the sinus wall may ensue, resulting in expansion of the sinus and possibly mucocele formation. A study of this process concluded that bony demineralization was caused by intense, local mucosal allergic inflammation adjacent to areas of eosinophilic mucin accumulation .
●True bone erosion – Expansile bone erosion occurs in 20 to 30 percent of AFRS cases in most series and is far more common in AFRS than in other forms of CRS (image 3 and image 4 and image 5) [40,41,43-46]. Males appear to be at higher risk . When bone destruction is present, it is imperative to rule out invasive fungal sinusitis, although the bony destruction seen with invasive fungal sinusitis is not typically expansile in nature. Nearly any malignancy can also cause bone destruction, and if there is concern, biopsy and clinical correlation should be considered. (See 'Acute or chronic invasive fungal sinusitis' below.)
●Nasal cavity expansion – In addition to erosion and expansion of the sinus bone, AFRS can also expand within the nasal cavity. While this can be evident upon CT, it can also lead to widening of the piriform aperture and hypertelorism that is visible externally.
●Expansion of soft tissue disease into the orbit, soft tissue of the face, or brain – In some cases, the expansion of soft tissue disease results in gross facial dysmorphia.
Sinus MRI — The combination of CT and magnetic resonance imaging (MRI) techniques can provide a more precise differentiation of mucus accumulation and mucosal thickening within sinus cavities . This is particularly useful for distinguishing the eosinophilic mucin of AFRS from other material in an opacified sinus (such as infected fluid or trapped secretions in a mucocele). Eosinophilic mucin produces characteristic hyperdensities on CT, which appear as hypoattenuated (or hypointense) areas on T2-weighted MRIs (image 5) . MRI is also more sensitive in differentiating inflammatory conditions from neoplastic processes and in detecting subtle or obvious intracranial spread of disease . For these reasons, it is sometimes advisable to obtain both a CT and MRI before performing sinus surgery.
The decreased signal intensity on T1-weighted MRIs and the very decreased signal intensity on T2-weighted MRIs were previously thought to be due to calcium, iron, and manganese within the mucin . However, it is believed that the presence of inspissated mucus within the sinus cavity or along the crevices of polyps results in a markedly hypointense T2-weighted signal [31,40]. Therefore, hyperdensities on sinus CT scan are most consistent with the presence of eosinophilic mucin and suggestive but not actually pathognomonic of AFRS [49,50].
Histologic findings — Eosinophilic mucin is generally identified at the time of surgery, and its presence is required for the diagnosis.
Eosinophilic mucin — Eosinophilic mucin is thick, inspissated material that occupies one or more sinuses in AFRS and ranges in color from light tan to brown to dark green (picture 1) . It contains sheets of degranulating eosinophils and Charcot-Leyden crystals . Eosinophilic mucin is not specific to AFRS, as it can also be seen in the other subtypes of CRS . However, in AFRS, the eosinophilic mucin contains fungal hyphae demonstrable by staining or fungal culture, as discussed in the next section.
Detection of fungi — The eosinophilic mucin in AFRS contains fungal hyphae, which is indicative of fungal colonization. To make a diagnosis of AFRS, it is necessary to confirm the presence of fungi in the eosinophilic mucin, either by a positive fungal stain or a positive fungal culture. By contrast, in invasive fungal sinusitis, fungal hyphae can be shown histologically to penetrate the underlying mucosa. Therefore, to exclude invasive fungal sinusitis, pathologic examination must confirm that there are no fungal hyphae invading tissue or bone.
●Documentation of fungal hyphae in mucus samples requires specific staining, such as Grocott or Gomori methenamine silver (GMS) stain, which stain fungal hyphae black or dark brown. Silver-based stains have high specificity but low sensitivity. The insensitivity of this stain for detecting fungi has led to a proposed modification involving predigestion of the mucin with trypsin . Using this technique, one group identified fungal hyphae in 91 percent of CRS mucus samples, whereas fungal hyphae were identified in only 27 percent of specimens using conventional GMS staining . We believe this modified staining technique deserves consideration for more widespread use by pathologists, although it has not been widely adopted. (See "Fungal rhinosinusitis", section on 'Invasive fungal sinusitis'.)
●The Fontana-Masson (FM) stain may increase the sensitivity for identifying dematiaceous fungi in allergic mucin when used in conjunction with standard GMS staining, although confirmation of fungal species still requires fungal culture or a polymerase chain reaction (PCR)-based assay .
●Fungal cultures are typically performed in parallel with fungal staining of eosinophilic mucin. However, routine fungal cultures have a low yield, even in cases of AFRS. Methods to increase the yield of fungal cultures of CRS patients of all types were described by investigators from the Mayo Clinic (the "Mayo technique"). This technique involves pretreatment of the mucus sample with a 50/50 mixture of dithiothreitol (DTT 1.055 mg/mL) for 15 minutes at room temperature, centrifugation of the sample at 3000 RPM for 10 minutes, homogenization of the sample by vortexing, and inoculation of the sample on three different culture media, each in duplicate: Sabouraud glucose agar, malt extract agar, and Czapek-Dox agar. One set of cultures is incubated at 20°C (68°F) and the other set at 30°C (86°F) for up to six weeks in laminar flow box . Confirmatory results of fungal cultures using this technique were reported in a study of CRS patients from Austria . Finally, a study of AFRS patients confirmed an increased yield of fungal cultures using a modification of this technique from 16 to 64 percent . It should be acknowledged that there is no consensus on the optimal methods for culturing fungi from sinus specimens, and the "Mayo technique" has yet to be widely adopted into clinical practice.
●Another study treated specimens with dembrexine hydrochloride (a phenolic benzylamine mucolytic agent) and chloramphenicol, plating on Sabouraud, CHROMagar/Candida, Mycosel, and Niger seed agar plates and incubating at 30°C (86°F) (or 37°C [98.6°F]) for up to one month . These various methods of fungal staining and fungal culture are not widely adopted in clinical practice but serve to underscore that there is a need for more sensitive techniques for the diagnosis of AFRS.
●A rapid in-situ hybridization diagnostic probe for dematiaceous fungi has been reported but is not widely used . This probe may be useful in confirming cases of AFRS by examination of mucus samples. However, a positive probe test can also be seen in other conditions, such as a fungus ball or invasive fungal sinusitis.
The diagnosis of AFRS can be made when all of the following criteria are satisfied:
●The subject has symptoms of chronic rhinosinusitis (CRS) (anterior and/or posterior nasal mucopurulent drainage; nasal obstruction, blockage or congestion; facial pain, pressure, and/or fullness and reduction or loss of sense of smell), although it has been observed that the clinical presentation in AFRS patients can be subtle despite evidence of extensive sinus disease on imaging studies .
●The presence of eosinophilic mucin in one or more sinus cavities confirmed during sinus surgery. (See 'Eosinophilic mucin' above.)
●Noninvasive fungal hyphae are demonstrated in the eosinophilic mucin (note that it is essential to confirm histologically that the fungal hyphae do not invade the mucosa in order to exclude invasive fungal sinusitis).
●The patient is immunocompetent with no evidence of uncontrolled diabetes, drug-induced immunosuppression, unexplained weight loss, or impaired cellular immunity (ie, abnormal T cell subsets, history of excessive or unusual infections outside of the sinuses).
●Characteristic computed tomography (CT) findings are present with differential densities on soft tissue windowing. (See 'Findings on imaging studies' above.)
●Fungus-specific IgE is demonstrated. (See 'Allergy evaluation' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AFRS includes the following disorders.
Allergic rhinitis with fungal allergy — Fungal allergy is present in 2.7 to 44 percent of patients with allergic rhinitis, depending on geographic area and which types of fungi were included in the survey . However, the prevalence of fungal allergy is likely underestimated owing to the multitude of different types of ambient fungal spores, many of which are not included in fungal allergy testing panels. An example is the basidiomycetes species, which is not widely included in allergy skin testing panels . Patients with uncomplicated allergic rhinitis can be easily distinguished from AFRS because they do not have nasal polyposis (NP) or symptoms suggestive of chronic rhinosinusitis (CRS). (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis".)
Chronic rhinosinusitis with fungal allergy — Fungal allergy is found in about 20 percent of CRS cases overall. Incidental fungal colonization may occasionally be found in sinus mucus by stain or culture in the absence of eosinophilic mucin and may vary depending upon the sensitivity of culture technique. Patients with CRS with NP may present similarly to those with AFRS. However, CRS (with or without NP) is distinguished from AFRS by the absence of eosinophilic mucin containing fungal hyphae (as demonstrated by fungal staining or culture) and the absence of computed tomography (CT) findings suggestive of AFRS. In addition, CRS with NP is almost always bilateral. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)
Fungus ball — Fungal balls occur in patients with normal immune function and represent a noninvasive collection of mucus and fungus unaccompanied by an immunologic response . Type I hypersensitivity to fungi may be present, although it is incidental and does not play a role in the pathophysiology. Consequently, there is no eosinophilic inflammation and no eosinophilic mucin. The fungal species found in fungus balls and AFRS can be similar. CT findings of fungus balls can also show differential densities, and magnetic resonance imaging (MRI) will have decreased signal intensity, but fungus balls less commonly cause bony erosion/expansion. In addition, fungus balls are usually limited to single sinuses (most often the maxillary and sphenoid) (image 6). (See "Fungal rhinosinusitis", section on 'Fungus balls'.)
Acute or chronic invasive fungal sinusitis — This is the most important disease to distinguish from AFRS because invasive fungal sinusitis is potentially lethal, and delays in the diagnosis can be catastrophic. In acute or chronic invasive fungal sinusitis, fungal hyphae are located within the sinus mucosa, submucosa, blood vessels, or bone . Acute invasive fungal sinusitis generally occurs only in diabetics or immunocompromised hosts [62-64]. A study of 179 patients with the condition found that 70 percent had diabetes and 26 percent had underlying diseases, such as leukemia, renal disease, or transplant-related immunosuppression . Chronic forms of invasive fungal sinusitis also occur predominantly in immunocompromised hosts, and most reports have been from outside of the United States [63,64]. (See "Fungal rhinosinusitis", section on 'Invasive fungal sinusitis'.)
There may be some radiographic features that distinguish invasive fungal sinusitis from AFRS. In a prospective series of 29 patients with these disorders, AFRS cases were more likely to show heterogenous hyperdensities on CT, corresponding isointense/hypointense or signal void areas on T1-weighted and T2-weighted MRIs, sinus expansion, extensive bone erosion, lack of contrast enhancement, multiple sinus involvement, and predominantly intrasinus rather than extrasinus disease . In contrast, imaging in patients with invasive fungal sinusitis was more likely to show homogenous attenuation on CT without areas of hyperattenuation, unilateral involvement of one to two sinuses or bilateral involvement of the sphenoid sinus, and bony erosion localized to the site of extrasinus extension.
Eosinophilic mucin rhinosinusitis — This is the form of CRS that most closely mimics AFRS. Eosinophilic mucin rhinosinusitis (EMRS) patients have eosinophilic mucin but no detectable fungi in the mucus and sometimes no demonstrable type I allergy to fungus [6,66]. The sinus CT scan in these cases can also show hyperdensities (image 7). However, in EMRS, the warning signs that may be present in AFRS, such as bony expansion and/or bony erosions or facial dysmorphia, are typically not present, and the sinus opacification is usually bilateral and extensive. One study comparing AFRS with EMRS found that T2-weighted MRI signal loss was present in 100 percent of AFRS cases but in only 4.8 percent of EMRS cases .
Although it is possible that some of these cases actually have AFRS, patients with EMRS frequently do not have fungal-specific IgE by skin test or immunoassay and sometimes do not test positive to any allergens. This supports EMRS as a distinct entity, since AFRS patients always have fungal allergy and may also have other inhalant allergies. As many as 50 percent of EMRS cases have Samter's triad of NP, asthma, and aspirin-induced respiratory disease, and many such patients are nonallergic, but this is largely dependent upon how strict clinicians are in diagnosing aspirin sensitivity . EMRS is almost always bilateral, whereas AFRS is unilateral in up to one-half of cases. Estimates of the prevalence of EMRS are lacking, but it was reported to be more common than AFRS in one study  and in the authors' experience.
Unconfirmed or "AFRS candidate" cases — These patients have eosinophilic mucin and some but not all of the criteria to fulfill the diagnosis of AFRS. For example, the patient may have no fungi detectable in eosinophilic mucin but have fungal allergy. Alternatively, the patient may have fungi detected in eosinophilic mucin but no evidence for systemic fungal allergy (uncommon). In both instances, the patient can be considered to be an "AFRS candidate" . This categorization also requires examination of specimens obtained during sinus surgery. The major implication of this distinction is in terms of disease classification, as treatment of such patients is likely to be similar or identical to that of an AFRS patient, except perhaps for use of systemic antifungal medication.
TREATMENT — Based on consensus reports, treatment of AFRS includes both surgical and medical interventions [70,71].
Our approach — The approach of the authors may be summarized as follows. When the diagnosis of AFRS is entertained and invasive fungal sinusitis is very unlikely, then medical therapy for chronic rhinosinusitis with nasal polyposis (CRS with NP) can be offered as an initial intervention. This is detailed separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
If that fails, the patient should undergo endoscopic sinus surgery (ESS) to remove accumulated mucin and debris, create adequate drainage, and collect samples of sinus contents for analysis and definitive diagnosis. The authors differ in their preference for a course of presurgical glucocorticoids, although most patients have received these at some point already prior to the diagnosis of AFRS being considered. At the time of surgery, the presence of eosinophilic mucin is confirmed, based on the characteristic appearance of the mucus. The collected mucin as well as sinus tissue is evaluated histologically to determine the presence of eosinophils and fungal elements. Fungal cultures are performed. If there is a concerning clinical picture, it is important that the sinus tissue be examined to rule out invasive fungal sinusitis. Immediately following surgery, oral glucocorticoids are initiated. Glucocorticoid instillations are begun as soon as possible after surgery, with some surgeons beginning instillations on postoperative day 1 and others waiting until the mucosa is healed. The combination of oral and topical glucocorticoids forms the foundation of treatment to suppress local allergic inflammation. After one to three months, we attempt to taper and discontinue oral glucocorticoids, while maintaining the patient on instillations. (See 'Systemic glucocorticoids' below and 'Topical glucocorticoid instillations' below.)
●The use of antifungal therapy is controversial and is discussed below. (See 'Antifungal agents' below.)
●We also encourage patients to undergo a three- to five-year course of subcutaneous injection immunotherapy to address the underlying fungal allergy. (See 'Immunotherapy for fungal allergy' below.)
Each of these treatment elements is discussed in detail below, with available evidence about efficacy.
Endoscopic sinus surgery — Endoscopic sinus surgery (ESS) addresses two treatment objectives, in addition to its role in diagnosis (see 'Histologic findings' above):
●The first objective is removal of polyps, inflammatory mucin, and fungal debris. AFRS tends to be recurrent, especially if all affected tissue mucin and polyps are not removed and aeration of affected sinuses is incomplete. It is critical to open the sinuses widely when doing this, as mucin in AFRS is very tenacious, and leaving residual fungal elements or loculated pockets will result in disease recurrence. Surgery with wide marsupialization improves postoperative debridement and delivery of topical glucocorticoids [72,73]. Reported surgical revision rates vary, but a meta-analysis reported that AFRS had higher revision rates of 28.7 percent compared with 18.6 percent for all chronic rhinosinusitis (CRS) with nasal polyposis (NP) patients . A large retrospective review of 536 CRS with NP patients also reported that among AFRS patients, risk factors for revision surgery included younger age (odds ratio [OR] 1.07), male gender (OR 2.60), and previous surgery (OR 2.99) .
●The second objective is reversal of bony expansion into the orbit and brain. Successful surgical and medical management has been shown to reverse proptosis and orbital remodeling in patients with AFRS . Complete bone regeneration in areas of bony erosion has been reported in two-thirds of AFRS cases within 18 months postoperatively .
Medical management — Medical management consists of systemic and topical glucocorticoids. Other therapies (ie, systemic or topical antifungals, immunotherapy for fungal allergy) are controversial.
Systemic glucocorticoids — Systemic glucocorticoids are used preoperatively in some cases and postoperatively in all patients.
●Preoperatively – Short courses of systemic glucocorticoids may be given at the surgeon's discretion prior to surgery in some patients with suspected AFRS and extensive polypoid disease, in an effort to "debulk" the polyps, reduce mucosal thickening, and decrease bleeding and edema, thus improving surgical landmarks. However, other surgeons do not favor this, and the best approach is not known. In a series of eight patients with suspected AFRS treated with 1 mg/kg prednisone for 10 days before sinus surgery, there was significant improvement in computed tomography (CT) scan Lund-MacKay scoring and "normalization" of sinus mucosal appearance on imaging performed the day before surgery . Lesser doses of prednisone, such as 40 mg daily for 5 to 10 days, are used by some clinicians (DH's preference). Another study found that prednisone 30 mg daily for 5 days improved visualization of the surgical field during the surgical procedure , whereas 15 mg of prednisolone daily for 10 days preoperatively appeared to have minimal benefit .
●Postoperatively – Systemic glucocorticoids are the mainstay of postoperative management of AFRS and are started immediately following sinus surgery or once the diagnosis is established . In the authors' experience, prednisone is usually dosed at 0.5 mg/kg daily and tapered over a few weeks to approximately 10 mg daily. Thereafter, the dose is slowly reduced by 1 to 2.5 mg/week to the lowest dose that maintains control of sinus symptoms. The duration of systemic glucocorticoid treatment postoperatively is not well-established. In a retrospective series of 67 postsurgical patients, protracted courses (several months) of oral prednisone delayed the need for repeat surgery . However, in the authors' experience, the use of topical glucocorticoid instillations can reduce the duration of systemic glucocorticoid treatment to one to three months.
The benefit of postoperative glucocorticoids was demonstrated in a single, randomized controlled trial, although the doses used in this study were higher than those suggested above. In this trial, 24 subjects with AFRS were randomized either to oral prednisone 50 mg/day for six weeks, followed by six additional weeks of tapering prednisone or to placebo . All subjects also received systemic itraconazole 200 mg/day and glucocorticoid nasal spray for 12 weeks in the postoperative period. At six weeks, complete relief of preoperative symptoms was reported by eight patients receiving prednisone and none of the patients receiving placebo. Nasal endoscopy showed that 8 of 12 patients who had received oral glucocorticoids and 1 patient who had received placebo were free of disease. At 12 weeks, symptom relief was complete in all patients who received prednisone but in only 1 patient who received placebo. However, significant steroid-induced side effects were noted in the prednisone-treated patients, including weight gain, cushingoid features, acne, and glucocorticoid-induced diabetes. Therefore, most expert reports advocate using lower doses and shorter durations of systemic glucocorticoids in the postoperative management of AFRS, such as those described previously.
Topical glucocorticoid instillations — As soon as possible after surgery, instillations of topical intranasal glucocorticoids, such as budesonide, should be initiated . Some surgeons start these instillations on postoperative day 1, while others wait until the sinus mucosa has healed (usually within two weeks postoperatively), and the best approach has not been studied. Topical glucocorticoid instillations have been highly effective in AFRS patients in the authors' experience, although controlled studies are lacking. After the mucosa has remained normal for 2 to 3 years, we typically attempt to wean patients from their steroid instillations, as AFRS seems to burn itself out as patients reach the age of 30 to 40 years. (See 'Prognosis' below.)
Detailed instructions on how to perform sinus instillations are provided separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Intranasal corticosteroids'.)
Therapies of uncertain benefit — Therapies that are not supported by high quality evidence include immunotherapy for fungal allergy and systemic and topical antifungal treatments.
Immunotherapy for fungal allergy — Fungal immunotherapy, using a mixture of fungal allergens based on the results of skin testing or in vitro testing, has been used as an adjunct to surgical and medical therapy in patients with AFRS, and the authors believe this is a rational approach. Although no controlled clinical trials have been performed, fungal immunotherapy has been shown to be safe, with evidence for reduced rates of disease recurrence in some patients [83-87], although the evidence supporting the use of immunotherapy in AFRS is quite limited . The magnitude of effect relative to glucocorticoids is unclear.
We would suggest subcutaneous immunotherapy (SCIT) instead of oral forms of immunotherapy, as the efficacy of SCIT is better established. We encourage patients to complete a three- to five-year course of SCIT, as this duration of therapy has been shown to provide lasting benefit in some patients. Although the primary purpose of immunotherapy is to address the underlying fungal allergy, we would include any other environmental allergens to which the patient is sensitized as well. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)
Antifungal agents — The rationale for antifungal treatment is to stabilize the marked sinus inflammation present in AFRS and reduce long-term use of systemic glucocorticoids.
Several studies have examined the postoperative use of systemic antifungals for AFRS, although these are limited to open-label trials [89,90] or retrospective case series in adults and children [91,92]. Taken together, these have not shown convincing benefit, and more rigorous studies are needed. There is also limited studies of the use of topical antifungals for treatment of AFRS . Based on the paucity of supportive data, consensus guidelines do not advocate use of oral or topical antifungal agents in AFRS [71,93-95].
Studies evaluating the effects of systemic antifungal therapies on the postoperative management of AFRS include the following:
●In a retrospective series of 23 patients with AFRS that recurred despite medical and surgical therapy, repeat surgery was followed by itraconazole 100 mg twice daily for six months . The majority of patients responded to itraconazole treatment, with improvement in symptoms and a reduction of "fungal mucin" on nasal endoscopy, and had a simultaneous reduction in oral steroid use. Furthermore, many of the patients were rendered "disease-free." This study most closely evaluated the manner in which one of the authors (DH) has found oral antifungal therapy to be helpful (ie, in selected patients with recurrent or recalcitrant disease).
●In the largest case series of 139 patients, treatment with itraconazole (average dose 276 mg/day; average duration of therapy 4.3 months) was generally safe, and only 6 patients (4.3 percent) had significant liver enzyme elevation (>2 times the upper limit of normal) . Unfortunately, the data presented in this study did not allow for an assessment of whether itraconazole provided a clinical benefit, although the authors routinely tapered and discontinued patients' prednisone, suggesting that the incorporation of itraconazole into the postoperative management may have facilitated this.
One study preliminarily evaluated medical therapy for AFRS. Preoperative treatment with oral itraconazole was evaluated in a prospective study of 27 patients compared with 25 matched control patients, all of whom were considered at study entry to have AFRS. A concern about this study is that it is unclear how patients were suspected of having AFRS prior to sinus surgery . Further evaluation of this approach is needed before it can be recommended as a treatment option.
Investigational therapies — Investigational therapies include biologics:
●Dupilumab, an anti-IL-4/IL-13 monoclonal antibody, is approved by the US Food and Drug Administration for treatment of refractory nasal polyposis (see "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Anti-IL-4RA (dupilumab)' and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Biologic therapies'). It has not yet been studied in controlled clinical trials for AFRS, but there are case reports of its use [100,101]. Until further studies are done, the criteria for use of biologics for AFRS should follow established guidelines for their use for refractory nasal polyposis. In cases where the diagnosis of AFRS is suspected and there is bony expansion and/or bony erosions, extension of sinus disease to extrasinus areas (such as the orbit, skin, or brain), double or reduced vision, proptosis, dramatic periorbital edema, ophthalmoplegia, facial dysmorphia, other focal neurologic signs, severe headache, meningeal signs, or significant or recurrent epistaxis or unilateral sinus disease, we recommend adhering to the standard approach (see 'Our approach' above). This includes performing endoscopic sinus surgery (ESS) to remove accumulated mucin and debris, create adequate drainage, and collect samples of sinus contents for analysis and definitive diagnosis. Following this, if the patient has a recurrence of polyposis, use of a biologic agent might be an appropriate treatment option. Ongoing clinical trials for patients with AFRS can be found at clinicaltrials.gov.
●Omalizumab, an anti-IgE monoclonal antibody, was found to be beneficial for AFRS in a case report and in a retrospective chart review of seven AFRS patients who also had moderate or severe asthma [102,103]. A single dose of omalizumab was found to be superior to treatment with an intranasal corticosteroid nasal spray (100 mcg twice daily) over the first six months following sinus surgery in a small single-blinded clinical trial .
PROGNOSIS — AFRS nearly always recurs if patients are not treated with postsurgical glucocorticoids or are not compliant with therapy. For those who are treated appropriately and are consistent with topical therapies, symptoms can usually be controlled to a degree that is satisfactory to the patient. Most can eventually discontinue therapy after a few years without the problem recurring. The disorder seems to be most aggressive in young adults and becomes easier to control as the patient enters his/her 30s or 40s.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic rhinosinusitis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Chronic rhinosinusitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition and pathogenesis – Allergic fungal rhinosinusitis (AFRS) is a distinct subtype of chronic rhinosinusitis (CRS), which accounts for 5 to 10 percent of CRS cases. It is important to recognize, as the approach to diagnosis and treatment of AFRS always involves a combination of surgical and medical management. AFRS arises as a result of localized polypoid inflammation in response to noninvasive fungal growth in areas of compromised mucus drainage. The affected sinuses become packed with eosinophilic mucin, which is a thick, tenacious eosinophilic secretion. This mucin contains fungal hyphae, but there is no fungal invasion of the underlying mucosa or bone. Affected patients are immunocompetent and have demonstrable allergy to fungi. (See 'Definition' above and 'Pathogenesis' above.)
●Signs and symptoms – The cardinal symptoms of AFRS are the same as those of CRS with nasal polyposis (CRS with NP), namely mucopurulent drainage, nasal obstruction, facial pain and/or pressure, and decreased olfaction. Some patients with AFRS present with proptosis or gross facial dysmorphia due to local pressure effects on the bone, although even with severe disease, symptoms may be relatively mild, as the condition often develops slowly over time. (See 'Clinical manifestations' above.)
●Epidemiology – The majority of cases of AFRS have been reported in the southern United States, specifically along the Mississippi River basin, although the disorder is reported worldwide. It disproportionately affects younger patients, African Americans, and patients of lower socioeconomic status for reasons that are not entirely understood. (See 'Epidemiology and possible risk factors' above.)
●Evaluation – The evaluation of AFRS involves a clinical history and objective documentation of mucosal disease with either rhinoscopy or nasal endoscopy with decongestion or with sinus computed tomography (CT) imaging. AFRS has characteristic findings on CT. Allergy evaluation is needed to establish the presence of fungal allergy, and immunologic evaluation should exclude diabetes or immune defects. (See 'Evaluation' above.)
●Diagnosis – Endoscopic sinus surgery (ESS) is indicated in all patients with suspected AFRS to establish the presence of eosinophilic mucin and obtain samples for histologic evaluation and fungal culture, which are required for diagnosis. Diagnostic criteria for AFRS have been proposed. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis includes several entities, but acute and chronic invasive fungal sinusitis are the most critical to exclude. In invasive forms of fungal sinusitis, hyphae can be seen histologically to invade the sinus mucosa, submucosa, blood vessels, or bone. Acute invasive fungal sinusitis typically occurs only in patients with diabetes mellitus or immunodeficiency and can be life-threatening. (See 'Differential diagnosis' above and "Fungal rhinosinusitis", section on 'Invasive fungal sinusitis'.)
●Treatment – The primary components of AFRS management are ESS, in combination with systemic and/or topical glucocorticoids. (See 'Treatment' above.)
•ESS is indicated in all patients with suspected AFRS to remove inflammatory mucin, fungal debris, and nasal polyps and to relieve any pressure on bones of the orbit and skull. We suggest wide marsupialization of the affected sinuses to improve postoperative debridement and delivery of topical medications, rather than more conservative procedures (Grade 2C). (See 'Endoscopic sinus surgery' above.)
•Oral glucocorticoids are sometimes given preoperatively to improve visualization of the surgical field, although this practice is variable and is usually left to the discretion of the surgeon. In contrast, we recommend that all patients with AFRS receive systemic glucocorticoids postoperatively (Grade 1B). A common regimen is oral prednisone (0.5 mg/kg daily), tapered over a few weeks to approximately 10 mg daily. Thereafter, the dose is slowly reduced by 1 to 2.5 mg per week to the lowest dose that maintains control of sinus symptoms. The usual duration of systemic treatment is one to three months. (See 'Systemic glucocorticoids' above.)
•We also suggest instillations of topical intranasal glucocorticoids (Grade 2C). These should be initiated as soon as possible after surgery and continued indefinitely, at least for the next few years. (See 'Topical glucocorticoid instillations' above and 'Prognosis' above.)
●Therapies of uncertain benefit – Therapies of uncertain efficacy include subcutaneous immunotherapy (SCIT) for fungal allergy, systemic antifungal agents, and biologic agents. (See 'Therapies of uncertain benefit' above and 'Investigational therapies' above.)
●Prognosis – AFRS nearly always recurs if patients are not treated with postsurgical glucocorticoids or are not compliant with therapy. For those who are treated appropriately and are consistent with ongoing instillations of glucocorticoids, symptoms can usually be controlled to a degree that is satisfactory to the patient. Most can eventually discontinue therapy after a few years without the problem recurring. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel L Hamilos, MD, who contributed to earlier versions of this topic review.
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