Allergic Fungal Rhinosinusitis Management: From Clinic to Operating Room

Aida Nourbakhsh, MD, PhD, Amber U. Luong, MD, PhD, and Corinna G. Levine, MD, MPH

The following article provides highlights from and expands upon the Panel Presentation “Allergic Fungal Rhinosinusitis Clinical Management: From Clinic to Operating Room,” presented at the AAO-HNSF 2024 Annual Meeting & OTO EXPO^SM. A webcast of the panel is also available on OTO Logic, the AAO-HNSF learning platform.

Allergic fungal rhinosinusitis (AFRS) falls under the broader category of chronic rhinosinusitis with nasal polyps and type 2 inflammation, but it has distinct disease characteristics.¹ AFRS has an insidious nature, with patients initially experiencing nasal obstruction or allergic symptoms. However, patients usually only seek specialist care when more severe symptoms emerge, such as vision changes, proptosis, or facial deformities. At the time of diagnostic imaging, patients often already have advanced expansile disease and eroded bone of the orbit or skull base. Many AFRS patients present emergently, when their chronic condition is complicated by bacterial superinfection that can lead to orbital or intracranial morbidity. Therefore, it is essential for primary care physicians (PCPs) and comprehensive otolaryngologists to have a strong understanding of epidemiology and pathophysiology of AFRS and an effective treatment plan, which may include referral to rhinologic specialist, to manage the disease and prevent complications.

Keep an eye out for the upcoming “Clinical Practice Guideline: Surgical Management of Chronic Rhinosinusitis,” which will publish online later this month in the June issue of Otolaryngology–Head and Neck Surgery.
 

Pathophysiology

The pathophysiology of AFRS was delineated when Safirstein published a case report in 1976 highlighting immunologic similarities between allergic pulmonary aspergillosis and AFRS,² including IgE-mediated hypersensitivity to the fungal elements and eosinophilic inflammation.³ In 1994, Bent and Kuhn established a set of diagnostic criteria for AFRS, which includes five major and five minor features.¹ For a definitive diagnosis, patients must meet all the major criteria:

• type I hypersensitivity to fungi,
• presence of nasal polyp,
• CT imaging showing the “double-density” sign caused by attenuated sinus ferromagnetic fungal elements contrasting with the hypodense inflamed mucosa,
• eosinophilic mucus without fungal invasion, and
• positive fungal stains of sinonasal content collected during surgery.

Minor criteria, which serve to support the diagnosis, encompass:

• radiographic bone erosion,
• positive fungal cultures,
• predominance of unilateral disease,
• identification of Charcot-Leyden crystals from degranulated eosinophils, and
• peripheral eosinophilia.

The diagnostic criteria for AFRS are stringent, and there are often patients who meet most criteria, but it may not be possible to obtain all the tests reliably. Some studies show that the preparation of samples can impact the reliability of fungal stains and cultures, while others indicate that the presence of fungal elements is not as specific to AFRS. Diagnostic uncertainty is compounded by ongoing debates about whether AFRS is part of a broader disease spectrum, such as eosinophilic mucin rhinosinusitis, or if they represent distinct entities, with environmental and host factors playing crucial roles in the complex pathophysiology.

Epidemiology

AFRS impacts immunocompetent patients, usually teens and young adults with an average age of 22 years, who have a history of atopy.⁴ AFRS has a geographic predilection for warm and humid regions, such as the Mississippi River basin in the United States, and a demographic predilection for African Americans and some Hispanic patients in these geographic regions who can experience more severe forms of the disease.^5,6 Given the geographic and demographic trend, providers need to consider epidemiological data, especially when treating younger patients in southern states who may be at elevated disease risk with persistent sinonasal symptoms despite treatment.

Workup and Diagnosis

A workup for AFRS begins with a detailed patient history, including allergies and comorbidities such as asthma, along with a thorough physical examination and endoscopic evaluation. Additionally, understanding home and work exposures, particularly to mold, can be helpful. Allergy testing can reveal comorbid allergies including to fungus. Imaging is essential to assess the extent of the disease. CT imaging (Figure 1a-c) can delineate the extent of disease, expansion of the sinuses, and areas of bone erosion and deformity. Impacted sinuses are opacified with hypodense inflamed mucosa and central hyperattenuating areas of eosinophilic mucin (Figure 1d). Bony erosion and expansile disease into surrounding compartments can lead to compression of the orbit and brain. In more advanced cases, MRI is useful, with particular attention to T1 and T2 weighted images, which can show pathognomonic features of AFRS, such as central hypointensity on T1 and signal voids (Figure 1e-f) on T2 owing to the high protein concentration of allergic mucin. It is crucial to examine both T1 and T2 imaging sequences for an accurate understanding of the disease process.

Figure 1. Radiological features of AFRS from CT (1a-c), endoscopic surgery (1d) and MRI imaging (1e-f). 

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Treatment: Medical and Surgical Management

Surgery is the first-line treatment for AFRS, followed by medical management to reduce recurrence. The primary surgical goal is to remove nasal polyps and allergic mucin, thereby alleviating obstruction, restoring sinus ventilation and drainage, and preventing further expansile effects of the disease. Additionally, creating large antrostomies during surgery facilitates the use of steroid irrigations and topical therapies to reduce risk of infection and recurrence. In severe cases, extended sinusotomies may be necessary to access and remove the disease, facilitate topical therapies, and enable in-office observation. Mucin removal should be done carefully with blunt instrumentation and copious irrigations, preserving the underlying mucosa, particularly over areas with thinned or eroded bone; mucosa should only be removed when there are submucosal micro-abscesses or polyps. While significant disease expansion can occur, cerebrospinal fluid (CSF) leaks are rare, as bony expansion is often a slow process, and the mucosal lining and a thin layer of bone are often intact.

Mainstays of AFRS medical management focus on control of inflammation^7,8 and include addressing superimposed bacterial infections, reducing inflammation with steroids, treating comorbid allergies, and targeting inflammatory pathways. AFRS inflammation responds well to steroids. Landsberg et al. demonstrated the benefits of a short-term 1 mg/kg dose of oral corticosteroids for 10 days prior to surgery, with near normalization of the mucosa at the time of surgery.⁹ Short-term oral steroid bursts can be used postoperatively and during disease flares, but due to potential side effects, only short-term use is recommended. Topical intranasal corticosteroids, such as sprays, nebulizers, and high-volume irrigation additives, are useful in maintaining inflammation control with a low side-effect profile.

For non-steroid treatments, oral and topical antifungals are not central to treatment as the primary goal is inflammation control.¹⁰ Intravenous antifungals are not indicated. Treating other sources of inflammation, such as allergies, particularly fungal allergies or asthma, may improve disease control, though studies on its effectiveness remain limited.¹¹ Biologics targeting the Type 2 inflammatory pathway, including omalizumab for AFRS patients with asthma, showed promise, and the Liberty-AFRS-AI trial on dupilumab is expected to report encouraging results by mid-2025.^12,13

Research and Future Directions

Future research directions for AFRS should focus on two key areas:

• addressing and reducing frequent delays in diagnosis and care, and
• understanding and targeting the pathophysiology of immune response.

Delayed diagnosis of AFRS and advanced disease presentation, especially in Black and Hispanic populations, is a major barrier to effective treatment.¹² Early research suggests that many AFRS patients first see their PCP for persistent sinus symptoms, which are mistakenly diagnosed as allergies (Dr. Levine, unpublished data). This is particularly concerning as early intervention can prevent disease progression. To address this, increasing awareness among PCPs, allergists, and otolaryngologists is essential. Continuing medical education and updated clinical guidelines could help healthcare providers recognize AFRS in patients with chronic, treatment-resistant sinus symptoms. Additionally, developing screening tools, such as symptom checklists or risk-stratification tools, could assist PCPs in identifying red flags for AFRS and prompting timely referrals or further diagnostic testing.

Although some patients respond to allergy treatment, others may not, indicating that there are additional immunologic factors contributing to the disease. The immune system likely plays a central role in AFRS. AFRS tissues have a higher expression of Type 2-promoting receptors compared to those from healthy subjects, suggesting a potential role in the disease’s inflammatory response.¹⁴ Correspondingly, the Type 3 immune response is downregulated in AFRS, which is crucial in combating bacterial and fungal infections that target the epithelial barrier. Dr. Luong’s lab found that dysregulation of antimicrobial peptides, particularly Histatin 1, highlights the T-cell differentiation dysregulation found in AFRS.¹⁵ Promoting correct T-cell differentiation holds significant promise. Finally, research into exogenous cytokines, vitamin D, or butyrates as immune modulators to promote endogenous antimicrobial peptide production could pave the way for new therapies.

References

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2. Safirstein BH. Allergic bronchopulmonary aspergillosis with obstruction of the upper respiratory tract. Chest 70, 788-790 (1976). https://doi.org/10.1378/chest.70.6.788
3. Bent JP, 3^rd, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 111, 580-588 (1994). https://doi.org/10.1177/019459989411100508
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8. Fokkens WJ, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 58, 1-464 (2020). https://doi.org/10.4193/Rhin20.600
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10. Gan EC, et al. Medical management of allergic fungal rhinosinusitis following endoscopic sinus surgery: an evidence-based review and recommendations. Int Forum Allergy Rhinol 4, 702-715 (2014). https://doi.org/10.1002/alr.21352
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12. Luong AU, Chua A, Alim BM, Olsson P, Javer A. Allergic Fungal Rhinosinusitis: The Role and Expectations of Biologics. J Allergy Clin Immunol Pract 10, 3156-3162 (2022). https://doi.org/10.1016/j.jaip.2022.08.021
13. Bolk KG, Wise SK. Biologic Therapies across Nasal Polyp Subtypes. J Pers Med 14 (2024). https://doi.org/10.3390/jpm14040432
14. Ebert CS, Jr. et al. Expression of protease-activated receptors in allergic fungal rhinosinusitis. Int Forum Allergy Rhinol 4, 266-271 (2014). https://doi.org/10.1002/alr.21295
15. Sun H, et al. Allergic fungal rhinosinusitis linked to other hyper-IgE syndromes through defective T(H)17 responses. J Allergy Clin Immunol 154, 1169-1179 (2024). https://doi.org/10.1016/j.jaci.2024.06.022