Allergic Fungal Sinusitis Workup

  • Author: John E McClay, MD; Chief Editor: Arlen D Meyers, MD, MBA   more...
 
Updated: Mar 12, 2012
 

Laboratory Studies

  • 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.
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Imaging Studies

  • Computed tomography[12]
    • 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 appearaCoronal 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.
      • 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.[13]
    • 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. 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 appearaCoronal 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*

      (Open Table in a new window)

      SiteChildren (n=10) (25%, 10/40)Adults (n=23) (23%, 23/100)
      Intracranial anterior cranial fossa39
      Middle cranial fossa14
      Posterior cranial fossa22
      Orbit617
      Pterygopalatine fossa13
      Nasopharynx32
      *Multiple sites were affected in some patients.
  • Magnetic resonance imaging[12]
    • 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.
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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 allergLeft 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 suctThe 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.[14] 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.

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Contributor Information and Disclosures
Author

John E McClay, MD  Associate Professor of Pediatric Otolaryngology, Department of Otolaryngology-Head and Neck Surgery, Children's Hospital of Dallas, University of Texas Southwestern Medical School

John E McClay, MD is a member of the following medical societies: American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, and American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Bradley Marple, MD  Vice Chairman, Department of Otolaryngology, University of Texas Southwestern Medical Center

Bradley Marple, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, American Rhinologic Society, Texas Medical Association, and Triological Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Lanny Garth Close, MD  Chair, Professor, Department of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons

Lanny Garth Close, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Physicians, American Laryngological Association, American Society for Head and Neck Surgery, and New York Academy of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Stephen G Batuello, MD  Consulting Staff, Colorado ENT Specialists

Stephen G Batuello, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Physician Executives, American Medical Association, and Colorado Medical Society

Disclosure: Nothing to disclose.

Christopher L Slack, MD  Private Practice in Otolaryngology and Facial Plastic Surgery, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders

Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA  Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society

Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation Unrestricted gift Unknown; Axis Three Corporation Ownership interest Consulting; Omni Biosciences Ownership interest Consulting; Sentegra Ownership interest Board membership; Medvoy Ownership interest Management position; Cerescan Imaging Consulting; Headwatersmb Consulting fee Consulting; Venturequest Royalty Consulting

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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 suctioned from the nasal cavity and vestibule in a patient with allergic fungal sinusitis.
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 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 displaying telecanthus and asymmetrical positioning of her eyes and globes.
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 allergic fungal sinusitis with expansion of the ethmoid complex and extension of the middle turbinate more inferiorly. This is a postoperative view.
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.
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.
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.
Fungal ball in the right maxillary sinus.
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 shown after removal from the patient. The scale is in inches.
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.
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 cavity. The septum is on the left.
Table 1. Causative Fungus Identified at UT Southwestern Medical Center
FungusChildren (n=44)Adults (n=107)
Bipolaris21 (66%, 21/32)40 (57%, 40/70)
Curvularia7 (22%, 7/32)12 (17%, 12/70)
Exserohilum22
Alternaria13
Aspergillus (niger/flavus)09 (13%)
Acremonium01
Chrysosporium01
Helminthosporium01
No Growth221
No Data1216
Combination1 Bipolaris/Curvularia1 Aspergillus/Acremonium
Table 2. Facial Asymmetry Characteristics
ConditionChildrenAdults
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 flattening8/157/10
Proptosis (measured, not obvious, £2 mm)0/152/10
Telecanthus alone6/151/10
Malar flattening alone1/150/10
*Not all initial clinical records mention the presence or absence of facial asymmetry or vision problems.
Table 3
SiteChildren (n=10) (25%, 10/40)Adults (n=23) (23%, 23/100)
Intracranial anterior cranial fossa39
Middle cranial fossa14
Posterior cranial fossa22
Orbit617
Pterygopalatine fossa13
Nasopharynx32
*Multiple sites were affected in some patients.
Table 4. Protocol for Immunotherapy in Allergic Fungal Sinusitis
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. Fungal Antigens in Current Testing and Treatment Protocol at the University of Texas Southwestern Medical Center at Dallas
Fungal Antigens 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.
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