Allergic Fungal Rhinosinusitis 

Allergic Fungal Rhinosinusitis – 11 Interesting Facts

1. AFRS (allergic fungal rhinosinusitis) is a chronic inflammatory condition of the nasal and paranasal sinus mucosa and is a unique clinical entity under the broader umbrella of chronic rhinosinusitis with nasal polyposis (CRSwNP)
2. Main symptoms include nasal obstruction, discharge, olfactory loss, or facial pressure
3. Symptoms may be disproportionately mild compared with the burden of inflammatory and polypoidal disease
4. Endoscopic findings are crucial in evaluating the degree of nasal polyposis; if atypical features are found, biopsy should be considered
5. Imaging is useful in assessing for orbit and skull base erosion, anatomical distortion, and the presence of the “double-density” sign
6. Diagnosis is made with the Bent and Kuhn criteria, consisting of clinical, imaging, and histopathologic features
7. All 5 major criteria required: Gell and Coombs type I hypersensitivity to fungal elements (IgE mediated), nasal polyposis, characteristic CT findings, eosinophilic mucin without invasion of fungi, and positive fungal stain
8. Minor criteria support diagnosis but are not pathognomonic: unilateral disease, asthma, bone erosion/sinus expansion on CT, positive fungal cultures, peripheral eosinophilia, and Charcot-Leyden crystals in mucin
9. Although imaging findings may be alarming, referral to otolaryngologist can be made on a routine basis (rather than emergently) if there are no red flags for invasive disease (eg, malignancy, invasive fungal sinusitis)
10. Management consists of surgery and medical therapy, with corticosteroids being the cornerstone
11. Recurrence is common and may prompt clinicians to consider using fungal-specific allergen immunotherapy, biologics, or antifungals along with revision sinus surgery

Alarm Signs and Symptoms

• Orbital complications:
  • Acute visual loss
  • Diplopia
• Intracranial complications:
  • Altered mental status
  • Intractable headache
  • Neurologic deficits

Introduction

• Allergic fungal rhinosinusitis (AFRS) is a chronic inflammatory condition of the nasal cavity and paranasal sinuses (ie, maxillary, ethmoid, sphenoid, frontal)
• It is a noninvasive form of fungal sinusitis, occurring in immunocompetent individuals
• A subset of chronic rhinosinusitis with nasal polyposis (CRSwNP) and a type 2 inflammatory endotype characterized by cytokines such as interleukin-4, interleukin-5, and interleukin-13; and immune effector cells, eosinophils, and mast cells
• Distinguished by nasal polyposis, extremely thick eosinophilic mucin (previously termed allergic mucin), characteristic imaging findings, positive fungal smear, and a type I hypersensitivity to fungal elements

Epidemiology

• Patients typically present before age 30 years,¹ with a male predominance (1.5-2.6x)²
• Associated with atopy and asthma
  • Asthma in approximately 23% AFRS patients, which is significantly less when compared with other forms of CRSwNP (about 48%)³
• Most common in geographic regions with warm climates⁴
  • In the United States it is most common around the southern Mississippi River basin
• Possible association with lower socioeconomic status⁵

Etiology

• Precise pathophysiology remains unclear; thought to represent an exuberant local inflammatory response to extramucosal fungi within the nasal and paranasal sinus cavities
• Hypothesized to be an interplay of the following:⁶
  • Germination of inhaled fungal spores
    • Typically Aspergillus spp. or Dematiaceous fungi (eg, Bipolaris, Curvularia, Alternaria)
  • Breakdown in the epithelial cell barrier and release of epithelial cell–derived cytokines interleukin-33, interleukin-25, and thymic stromal lymphopoietin
  • Activation of type 2-dependent inflammatory processes
    • Upregulation of interleukin-4, interleukin5, and interleukin-13
    • Increased IgE production
  • Impaired production of antimicrobial peptides (eg, histatin)⁷
  • Leads to mucosal edema and polyposis and entrapment of eosinophilic mucin in sinuses
  • Vicious cycle is established: entrapped eosinophilic mucin and fungal elements perpetuate further inflammation
• Further details of pathophysiology still under investigation, including the roles of:
  • Interleukin-33
  • Deficiency of local endogenous antimicrobial peptides with antifungal activity⁷
  • Limited local type 3 immune response with exaggerated type 2 immune response to fungi²
  • Concurrent Staphylococcus aureus colonization⁸

Risk Factors

• Associations identified:
  • Living in warm environments⁹

Diagnosis

Approach to Diagnosis

• History
  • Unlike patients with CRSwNP (chronic rhinosinusitis with nasal polyposis), patients wih AFRS (allergic fungal rhinosinusitis) generally present younger than age 30 years
  • Patients are atopic and immunocompetent
  • 12 weeks or more of any 2 of the following:
    • Nasal obstruction
    • Mucopurulent nasal drainage (anterior or posterior)
    • Hyposmia or anosmia
    • Facial pressure
  • Patients can present with predominantly unilateral symptoms
• Physical examination
  • Facial deformity (eg, telecanthus, proptosis) can be present in AFRS
  • Nasoendoscopy reveals nasal polyposis
  • Presence of thick and tenacious secretions within or between polyps should prompt consideration of AFRS
• Allergy testing
  • Skin prick test result is positive for wheal and flare for fungal antigens or blood test result is positive for raised fungal-specific IgE
  • Atypically elevated serum total IgE levels should prompt consideration of AFRS
• Imaging
  • CT of the sinuses is commonly obtained in patients with symptoms of chronic rhinosinusitis
  • Presence of opacified expanded sinuses with bone erosion and “double-density” within the sinuses is associated with AFRS and not typical of other causes of CRS with nasal polyps
• Surgery
  • Encountering extremely thick eosinophilic mucin entrapped within sinuses and between layers of edematous mucosa should warrant consideration of AFRS diagnosis
  • Histology of specimens shows classic features of eosinophilic mucin and fungal elements

Diagnostic Criteria

• Diagnosis is made based on clinical and histopathologic features described in the 1994 Bent and Kuhn criteria¹⁰
  • Major criteria – all 5 features required to make diagnosis
    • Type I hypersensitivity to fungal elements (IgE mediated), confirmed by skin tests or serology
    • Nasal polyposis
    • Characteristic CT findings
    • Eosinophilic mucin without invasion of fungi into sinus tissue
    • Positive fungal stain of sinus contents
  • Minor criteria – supportive of diagnosis; not pathognomonic
    • Unilateral disease
    • Asthma
    • Bone erosion/sinus expansion on CT
    • Cultures positive for fungi
    • Peripheral eosinophilia
    • Charcot-Leyden crystals in mucin
• 1995 DeShazo criteria¹¹ are less widely used
• Recent work has recognized limitations of Bent and Kuhn criteria
  • Some components may lack specificity¹
    • Type I hypersensitivity to fungi can be found in patients who have allergic rhinitis (with fungal sensitization) and concurrent CRSwNP (non-AFRS)
    • Positive fungal cultures may be found in up to 60% of patients who have CRSwNP and do not otherwise meet criteria for AFRS
    • Eosinophilic mucin can also be found in patients who have CRSwNP with type 2 inflammatory endotype not meeting criteria for AFRS

Workup

History

• Symptoms tend to be disproportionately minimal compared with endoscopic and imaging findings
• Symptoms of chronic rhinosinusitis
  • Any 2 of the following for 12 weeks or more:¹²
    • Nasal obstruction or congestion
    • Nasal discharge (rhinorrhea or postnasal drip)
      • Thick, tenacious mucus
      • Nasal discharge can be yellow-brown and thick
      • Symptoms do not improve with oral antihistamines or intranasal corticosteroids
    • Hyposmia
    • Facial pressure or pain
    • Cough (in pediatric chronic rhinosinusitis)
• Locoregional symptoms of more extensive disease
  • Diplopia or other changes in vision
  • Facial swelling/eye deformity
• Symptoms of associated conditions
  • Allergic rhinitis
    • Sneezing
    • Nasal pruritis
  • Asthma
    • Present in approximately 23% of patients with AFRS (allergic fungal rhinosinusitis) (lower prevalence of asthma compared with non-AFRS CRSwNP patients in whom asthma prevalence is about 48%)³
    • Dyspnea
    • Chest tightness
    • Cough
    • Wheezing

Physical Examination

• Nose
  • Turbinate hypertrophy
  • Congested mucosa
  • Polyps – can be unilateral
• Throat
  • Cobblestoning of the oropharynx suggestive of postnasal drainage
• Locoregional examination: possible findings with severely expanded sinuses:¹³
  • Proptosis
  • Hypertelorism
  • Hyper- or hypoglobus
  • Gross facial deformity

Laboratory Tests

• Serum IgE level
  • Markedly elevated and often more than 1000 units/mL¹⁴¹⁵
  • Elevated fungal-specific IgE, often to antigens of multiple fungi
• Serum eosinophils
  • Frequently normal; peripheral eosinophilia may suggest higher risk for recurrence¹⁶

Imaging Studies

• CT scan of paranasal sinuses without contrast is the initial imaging modality and provides the following crucial information:
  • Number of sinuses involved and extent of disease
  • Shows typical features of AFRS:
    • Affected sinuses are opacified and frequently appear expanded¹⁷
    • “Double-density” sign
      • Sinus contents appear hyperdense due to eosinophilic, fungal-laden mucin, which is juxtaposed against surrounding hypodense inflamed mucosa
    • Evaluates orbit and skull base for erosion
      • Erosion of lamina papyracea and skull base reported in up to 56%¹⁸
  • Can be loaded onto surgical navigation systems for image-guided surgery
  • IV contrast may be useful if there is strong suspicion for neoplasia as a differential diagnosis
• MRI scan should be considered if skull base or orbital erosion seen on CT scan
  • Better soft-tissue resolution versus CT gives the clinician additional information about degree of expansion towards critical orbital or intracranial areas
  • Typical findings are:
    • Mucosal edema
    • Central hypointensities, noted on T2 weighted sequences
      • Due to high protein and low water content of eosinophilic mucin¹⁹
      • Presence of paramagnetic elements (eg, iron, magnesium, manganese)²⁰
  • Gadolinium contrast useful where neoplasia is strongly suspected as a differential diagnosis

Diagnostic Procedures

• Nasal endoscopy
  • Performed in the office/nonsurgical setting
  • Findings can include:
    • Nasal polyposis
      • Unilateral or bilateral (latter is more common)
    • Eosinophilic mucin – thick and very tenacious¹³
      • “Peanut butter” or “rubbery” consistency
      • Variety of colors described (eg, green, brown, black)
• Endoscopic biopsy
  • May be useful to exclude differential diagnoses such as benign neoplasia or malignancy, especially if the patient presents with atypical features (eg, epistaxis, facial numbness) or if imaging does not show typical findings consistent with AFRS
• Endoscopic sinus surgery
  • Sinus surgery is first line treatment for suspected AFRS and provides opportunity to obtain samples for fungal smear and mucin histopathology to confirm diagnosis
  • Fungal smear
    • Typical fungal pathogens responsible for AFRS (Aspergillus species and dematiaceous fungi [eg, Bipolaris, Curvularia, Alternaria]) can be difficult to detect on routine hematoxylin and eosin stains⁵
    • Gomori methenamine silver or periodic acid–Schiff stains show the fungal cell walls better²¹
    • Fontana-Masson stains may highlight dematiaceous fungi more clearly²²
  • Fungal culture
    • May be positive for typical fungal pathogens as above
    • Positive cultures represent 1 of the Bent and Kuhn minor criteria; supportive of diagnosis but not pathognomonic, and not necessary to confirm diagnosis¹⁰
  • Mucin histopathology
    • Generally serves to confirm the clinical diagnosis
    • Surgery usually required to obtain entrapped eosinophilic mucin for histopathologic analysis
    • Characteristic appearance of eosinophilic mucin:²³²⁴
      • Inflammatory immune cells with prominence of eosinophils
      • Necrotic cellular debris
      • Charcot-Leyden crystals
      • Background of amorphous eosinophilic mucin
      • Scattered fungal hyphae without evidence of tissue invasion

Other Diagnostic Tools

• Allergy skin prick testing
  • Can be used to show Gell and Coombs type I hypersensitivity to fungi as an alternative to serum testing¹⁰

Differential Diagnosis

Table

Table 1. Differential Diagnosis: Allergic fungal rhinosinusitis.⁶

Condition	Description	Differentiated by
CRSwNP–non-AFRS variant	Chronic inflammatory disease of sinuses resulting in nasal polyposis; AFRS is regarded as a unique clinical entity under the broader umbrella of CRSwNP	-Patients generally report more significant symptoms (eg, nasal obstruction, mucopurulent rhinorrhea, hyposmia, facial pain/pressure) proportionate to their polyp burden, compared with AFRS -More likely to be associated with asthma (up to 48%) compared with AFRS (23%) -Orbital or facial deformity is extremely rare -Disease is usually equally severe bilaterally (as compared with AFRS, which can present with unilateral predominance) -In those with fungal or other allergies, total serum IgE tends to be lower25 as compared with AFRS patients
Sinonasal tumor – benign or malignant	-Benign (eg, inverted papilloma) -Malignant (eg, squamous cell carcinoma)	-Patients may report epistaxis and facial numbness -Tumors may appear necrotic and ulcerated -Biopsy is crucial in making the diagnosis of sinonasal tumor
Allergic rhinitis with fungal sensitization	Allergic inflammation of the nasal airway due to Gell and Coombs type I hypersensitivity reaction to fungi	-Cardinal symptoms of nasal obstruction, clear rhinorrhea, sneezing, and nasal itching -No nasal polyposis
Fungus ball	Collection of entrapped fungal material within paranasal sinuses	-Usually involves single sinus -No Gell and Coombs type I hypersensitivity reaction to fungi
Acute invasive fungal sinusitis	-Severe, invasive inflammation with necrosis -Typically caused by Zygomycetes and Aspergillus -Occurs in severely immunocompromised hosts (eg, patients in diabetic ketoacidosis, or with neutropenia from hematologic malignancy or chemotherapy)	-Acute onset with aggressive tempo of disease -Rapid spread with significant risk of mortality -Patients report typical symptoms of sinusitis but are usually not allergic to fungi -Necrotic, pale mucosa on endoscopy with eschar and areas of anesthesia -Palatal and facial numbness -Orbital swelling and vision loss if the orbit is affected -Fungal hyphae shown to invade sinus tissue, angioinvasion may be seen
Chronic invasive fungal sinusitis	-Indolent disease course -Typically caused by Aspergillus fumigatus -Tends to occur in mildly immunosuppressed hosts, such as patients with poorly controlled diabetes mellitus or those who use chronic exogenous steroids	-Patients may report fever and epistaxis, on top of other typical sinusitis symptoms -Not usually allergic to fungi -As disease progresses, invasion of cribriform plate may occur, leading to altered mental status, neurologic deficits -May have soft tissue masses on nasal endoscopy -Not typically associated with thick eosinophilic mucin -Main distinguishing factor on histology is fungal invasion of soft tissue
Granulomatous invasive fungal sinusitis	-Indolent disease course -Typically caused by Aspergillus flavus -Tends to occur in immunocompetent patients, especially in North Africa and India	-Symptoms may be similar to chronic invasive fungal sinusitis -Usually not allergic to fungi -Endoscopy may show soft tissue masses representing granulomas -Not typically associated with thick eosinophilic mucin -Histology shows noncaseating granulomas, dense fibrosis, giant cells

Caption: AFRS, allergic fungal rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyposis.

From Dykewicz MS et al: Allergic fungal rhinosinusitis. J Allergy Clin Immunol. 2018;142;(2)341-351.

Treatment

Approach to Treatment

• Surgery is the critical foundation for successful therapy
  • Endoscopic sinus surgery is carried out under general anesthesia
  • Aims:
    • Thorough removal of all eosinophilic mucin and fungal debris (trigger for inflammation)²
    • Opening all diseased sinuses to restore ventilation and facilitate effective delivery of topical corticosteroid therapy²⁶
    • Removal of nasal polyps to restore nasal airway and improve symptoms
  • Anatomy is often distorted and as such, use of intraoperative image-guided surgical navigation is useful
• Medical therapy is needed to maintain disease remission
  • Corticosteroids are the cornerstone of medical therapy (Table 2)²²⁷
    • Suppression of inflammation leads to improved symptoms, endoscopic scores, and biochemical profile (decreased serum IgE and interleukin-5 levels)
    • Intranasal corticosteroids: Strong Recommendation on International Consensus Statement on Allergy and Rhinology 2021¹²
      • Topical delivery options:
        • Metered dose sprays
        • Nasal irrigations: strong recommendation in patients postoperatively if disease not controlled by standard metered dose sprays
        • Exhalational fluticasone effective in CRSwNP, but not proven to be superior to metered dose sprays; there are no data specific to AFRS (allergic fungal rhinosinusitis)
      • Can be initiated once diagnosis is suspected
    • Systemic corticosteroids: strong recommendation for short-term use¹²
      • Short courses (eg, oral pulse prednisone for 2-3 weeks) are effective pre- or postoperatively, but need to weigh long-term risks versus benefits
  • Nasal saline irrigations: option to mechanically remove mucus
  • Mixed evidence for antifungal therapy¹²
    • Oral itraconazole
      • Mixed evidence on overall effectiveness
      • May be an alternative to systemic corticosteroids and decrease their usage
      • Risk of hepatotoxicity
    • Topical fluconazole (spray and irrigation) and itraconazole (spray) have been investigated with inconclusive findings
    • International Consensus Statement on Allergy and Rhinology 2021 recommends considering antifungals as an option in patients recalcitrant to maximal steroid therapy and immunotherapy¹²
  • Biologics show early promise¹⁵²⁸
    • There are no double-blind randomized controlled trial data; there is 1 double-blind randomized controlled trial ongoing for dupilumab (NCT04684524)
    • A single-blind randomized controlled trial shows effectiveness for omalizumab²⁹
    • Retrospective observational series showing improved symptoms with omalizumab, dupilumab, and mepolizumab
• Possible role for fungal-specific allergen immunotherapy¹²²⁷
  • Theoretical basis for fungal-specific allergen immunotherapy , to address Type-1 hypersensitivity pathway
  • Data from retrospective series show limited effectiveness, but norandomized controlled trials have been reported in the literature
  • International Consensus Statement on Allergy and Rhinology 2021 suggests that fungal-specific allergen immunotherapy can be a reasonable treatment option¹²

Nondrug and Supportive Care

• Nasal saline irrigation¹²
  • Mechanically removes mucus and thins secretions
  • Overall minimal harm and cost
  • 1 to 2 irrigations daily

Drug Therapy

Table

Table 2. Drug Therapy: Allergic fungal rhinosinusitis.¹²

Drug	Dosage	Considerations
Intranasal corticosteroids (metered dose)	2 sprays per nostril once daily, or 1 spray per nostril twice daily	-Existing guidelines incorporate initial treatment recommendations for AFRS under broader category of CRSwNP1230 -Intranasal steroids improve symptoms and endoscopic scores
Intranasal corticosteroids (nasal irrigation)	Nasal irrigation: 1 – 2 irrigations per day, titrated to effect	-Nasal irrigation is compounded by adding corticosteroids (eg, budesonide, mometasone) to nasal saline rinses. This is commonly prescribed but remains an off-label use of corticosteroids -Nasal irrigations may improve drug delivery to paranasal sinuses, especially in post-operative patients12
Oral corticosteroids	-Prednisone 30-60 mg PO daily (starting dosage) -Prednisolone 30-60 mg PO daily (starting dose) -Methylprednisolone 32 mg PO daily (starting dose)	-Multiple dosages and regimens have been used with good effect -Starting dose can be adjusted depending on patient’s body weight and severity of disease -Treatment is generally tapered down over 2 to 3 weeks -Need to balance benefits against risks of repeated or long-term systemic use

Caption: AFRS, allergic fungal rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyposis.

Treatment Procedures

• Endoscopic sinus surgery
  • Objectives are:
    • Restoration of nasal airway
    • Thorough removal of all eosinophilic mucin and fungal elements
    • Widening of sinus drainage pathways to provide access for topical therapies, remove polyps, and fully clear eosinophilic mucin
• Fungal-specific allergen immunotherapy¹²²⁷
  • If used, duration of several years may be necessary
  • Mixed evidence for its use; consider in refractory cases

Persistent or Recurrent Disease

• Systematic approach to determine reason for persistent or recurrent disease
  • Surgical factors²
    • Remnant cells or residual eosinophilic/fungal mucin
  • Medical optimization
    • Suboptimal patient compliance with regimen
    • Suboptimal patient technique with nasal sprays or irrigations
    • Inadequate drug delivery, requiring escalation (eg, from steroid sprays to irrigations)
    • Insufficient drug dosage (eg, patient may need nasal steroid irrigations twice daily instead of once daily)
  • Disease factors
    • Recalcitrant disease despite medical optimization should lead to a consideration for use of biologics, antifungals, or fungal-specific allergen immunotherapy¹²
• Note that after treating unilateral AFRS, disease can develop on the contralateral side at a later time (can be years after)

Admission Criteria

• Orbital complications
  • Acute visual loss
  • Orbital infections (eg, orbital cellulitis, abscess)
• Intracranial complications
  • Infections (eg, meningitis, intracranial abscesses)

Special Considerations

Children

• Clinical characteristics of AFRS (allergic fungal rhinosinusitis) are similar to those in adults but may progress more quickly and aggressively³¹³²³³
  • May present with facial deformity more frequently
  • Disease has a higher chance of being unilateral and asymmetrical
  • Total serum IgE levels may be higher than in adults
  • Limited data available; further studies needed to evaluate treatment protocols

Follow-up

Monitoring

• Immediate postoperative period
  • Usual follow-up (1-2 weeks after surgery) and endoscopic debridements by an otolaryngologist in an outpatient setting
• Regular in-office endoscopic surveillance
  • To ensure no recurrence of mucosal inflammation
  • Typically, every 2 to 4 weeks for the first 1 to 3 months, then spaced out to every 3 to 6 months over the next year
  • Follow-up intervals can be adjusted according to symptoms and endoscopic findings
  • Subsequent follow-up can be on a yearly basis if symptoms and endoscopic appearance are stable

Complications

• Although expanded sinuses in AFRS (allergic fungal rhinosinusitis) are frequently associated with orbital and skull-base erosion, infective spread to these areas and associated complications are relatively rare
  • Orbital complications: diplopia, globe displacement, visual impairment
  • Intracranial complications: meningitis, intracranial abscesses
• Obstructed sinuses may lead to mucocele formation

Prognosis

• AFRS is well known to have a high recurrence rate (more than 60% quoted in some studies)²⁴ and revision surgical rate of 28%³⁴
• Disease history over time remains unclear, but mucosal inflammation and symptoms may wane

Referral

• Otolaryngologist
  • Referral is necessary as nasal endoscopy is an integral part of the diagnostic workup
  • Imaging findings may appear alarming and mimic a more sinister pathology (eg, invasive tumor) but AFRS itself is not an emergency
  • If there is sufficient evidence for a confident diagnosis of AFRS, referral can be made on a routine basis rather than an emergent one
  • Ultimately, sinus surgery is usually required as part of the long-term treatment strategy
  • Serial endoscopic evaluations are also necessary to assess for recurrence
• Allergist
  • When fungal-specific immunotherapy is being considered

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