Allergic Fungal Rhinosinusitis Diagnosis, Management, Associated Conditions, Pathophysiology, and Future Directions: Summary of a Multidisciplinary Workshop

Abstract

Allergic fungal rhinosinusitis (AFRS) is a unique endotype of chronic rhinosinusitis with nasal polyps (CRSwNP). Despite high recurrence rates and often more severe presenting signs compared with other subtypes of CRSwNP, research dedicated to AFRS has been lacking. Diagnostic criteria are outdated, the mechanistic relationship of AFRS to other associated diseases is unclear, and the pathophysiology of disease and risk factors for recurrence have not been well studied. In December 2023, a multidisciplinary group of rhinologists, otolaryngologists, pulmonologists, allergists, immunologists, scientists, and infectious disease experts met at the National Institute of Health to discuss unmet needs for future AFRS research and care, including patient management, diagnostic criteria, severity, pathophysiology, and related conditions. A summary of these clinical and associated research discussions is included below.

1. Clinical Information

1.1. Presentation of Disease

The clinical presentation of allergic fungal rhinosinusitis (AFRS) has both similarities to those of other forms of chronic rhinosinusitis with nasal polyps (CRSwNP) and unique characteristic features that give it a distinct presentation [1]. The distinctive aspects of the clinical presentation of AFRS include a younger age at presentation, the high association with environmental atopy, a lower-than-expected association with asthma, bony sinus expansion, asymmetric or unilateral disease, higher recurrence rates versus other subtypes of CRSwNP, and a significant impact on olfaction.

Like other forms of chronic rhinosinusitis (CRS), patients with AFRS generally report nasal airway obstruction, anterior or posterior nasal drainage, loss of smell/taste, and/or facial pressure/headaches. However, the timeframe over which AFRS patients develop symptoms is often more protracted with a very gradual onset of nasal obstruction and production of large discolored nasal debris [2]. A distinctive feature of AFRS is that it generally presents in a younger population compared with CRS with a mean age of less than 30 years while the prevalence of other forms of CRS is more closely associated with older patients. AFRS typically presents in the young adult population; various studies reported a mean age of 26–32 years at diagnosis [3–5]. The prevalence of CRS increases after the age of 50 years and patients older than 60 years are twice as likely to have CRS than those aged 19–39 years [6].

Unlike most forms of CRS, AFRS has a high association with atopy. Almost two-thirds of patients report a history of allergic rhinitis (AR), and about 90% of patients demonstrate elevated specific immunoglobulin (Ig) E to one or more fungal antigen [7]. Laboratory tests typically reveal extremely high total serum IgE levels (>500 IU/mL) while peripheral eosinophilia may be present but is less common [8, 9]. The only subtype of CRS with a similarly high association with atopy is central compartment atopic disease (CCAD). Marcus et al. [10] reported that of 356 patients with CRSwNP, the prevalence of allergy was significantly higher in AFRS (100%), CCAD (97.6%), and aspirin exacerbated respiratory disease (AERD, 82.6%) when compared with unspecified CRSwNP (56.1%) (p < 0.001). To further delineate this point, a systematic review of CRSwNP found that seven out of 18 studies showed no relationship between allergy and CRSwNP; 10 studies demonstrated a relationship between allergy and CRSwNP; and one study was equivocal [11]. While there is a strong association between atopy and AFRS, there is a weaker relationship between AFRS and asthma. Up to 24% of patients with AFRS have asthma, which is significantly lower than in other forms of CRSwNP where asthma can coexist in up to 50% of patients [12]. In a study of 410 patients with CRS, 48.3% of CRSwNP patients, 16.5% of patients with CRSsNP, and 23.6% of AFRS patients had asthma diagnosed by pulmonary function tests [13]. In another study, asthma prevalence was highest in AERD (100%) and unspecified CRSwNP (37.1%), but substantially lower in AFRS (19.0%) and CCAD (17.1%) [10].

Patients with AFRS also tend to present with characteristic radiographic findings. Characteristic computed tomography (CT) findings include multiple opacified sinuses with a combination of osseous expansion and/or bony erosion or decalcification. Heterogeneous signal intensities within the sinuses are hallmark of the disease that arises from highly attenuated sinus contents among hypodense inflamed mucosa [14]. In a study by Ghegan et al. [15], AFRS patients were 12.6 times more likely to have bony erosion than non-AFRS patients. Furthermore, up to 56% of AFRS patients may present with extensive radiographic evidence of skull base erosion or intraorbital extension compared with only 5% in other causes of CRS [15]. Intriguingly, pediatric AFRS patients tend to have more anterior ethmoid skull base erosion (23.8 vs. 6.7%; p = 0.047) than adult AFRS patients [16]. The severe expansion of the osseous borders of the sinuses with extensive orbital or cranial expansion may result in facial disfigurement. Patients may present with proptosis, telecanthus, malar flattening, and visual disturbances in severe cases [16]. Because of the indolent expansion of the orbital confines, vision loss and diplopia are not a common presenting feature. However, in a retrospective study of 100 patients with AFRS, Alaraj et al. [17] reported that 11.8% of patients presented with vision loss; 8.8% with diplopia; and 2.9% with dystopia. Fortunately, there is some evidence to suggest that bony changes, especially those which cause proptosis, may not be permanent. In a study of the orbital volume of patients with AFRS and proptosis, bony orbital volumes that were significantly decreased (to approximately 70% of normal) returned to 90% of normal within 7–11 months after successful medical and surgical management [18]. While magnetic resonance imaging (MRI) is not necessary to diagnosis AFRS, many patients have MRIs performed due to the extensive bony erosion and expansion seen on CT imaging. MRI findings in patients with AFRS generally include a low signal on T1 and T2 imaging in the sinuses, corresponding to areas of eosinophilic mucin, with peripheral high-signal intensity corresponding to inflamed mucosa. The heterogeneity of the signal is likely related to the existence of deposited heavy metals, such as iron and manganese [19]. AFRS may present as unilateral disease only with similar findings as presented above. Interestingly, children are more likely to present with unilateral disease/asymmetric disease, with up to 70%ofAFRS pediatric patients presenting with unilateral disease as compared with only 37% of adults [9].

1.2. Recurrence and Severity of AFRS

Following treatment, AFRS seems to have higher recurrence rates following treatment than other forms of CRSwNP. In a recent meta-analysis that included 34,220 subjects with a mean follow-up of 89.6 months, AFRS patients had higher rates of revision surgery at 28.7% than other patients with CRSwNP at 18.6% [20]. There may be many factors that contribute to these differences including socioeconomic status, access to physicians and varying levels of medication compliance. Even in patients with unilateral disease, there is a risk for recurrence on both the ipsilateral and contralateral sides. In a study by Alghomaim et al. [21] assessing recurrence patterns over 10 years, overall recurrence was found to be 28% in AFRS patients, and the pattern of recurrence in the previously unilateral disease was 18% ipsilateral and 27% bilateral.

Like other forms of CRS, disturbances of smell and taste are common but perhaps more severe in AFRS. Morse et al. [22] found that anosmia was associated with more severe forms of CRSwNP - noted to be 33% in AERD and 50% in AFRS. In another study by Philpott et al. [23], patients with AFRS had lower mean threshold, discrimination, and identification scores revealing hyposmia, with a significant correlation between patients’ performance on the Sniffin’ Sticks test and endoscopic staging, as well as their reported olfactory ability. Overall, AFRS patients have unique aspects of presentation and disease progression, which warrant attention and further research.

1.3. Diagnostic Criteria

The current diagnostic criteria for AFRS primarily revolve around two widely used publications, namely the Bent and Kuhn criteria [24] and the Deshazo and Swain criteria [5]. Bent and Kuhn developed their criteria based on common clinical features observed in only 15 patients from a single clinical practice in Savannah, Georgia, indicative of AFRS. Similarly, Deshazo and Swain criteria share similarities with Bent and Kuhn but emphasized the absence of an immunocompromised status. The latter’s strength lies in a broader patient inclusion, with 98 cases from published reports and seven locally from Alabama. While these criteria provide a foundation for AFRS diagnosis, their limitations stem from small sample sizes and potential regional bias, raising concerns about generalizability.

Saravanan et al. [25] attempted to address the diagnostic challenges associated with AFRS in their study titled “Allergic Fungal Rhinosinusitis: An Attempt to Resolve the Diagnostic Dilemma.” Their findings suggested three key characteristics that effectively identified AFRS: type 1 hypersensitivity, bony erosion evident on CT sinus scans, and heterogeneous opacity with sinus expansion in imaging studies. This research adds valuable insights to the existing criteria, emphasizing the importance of incorporating specific clinical and radiological features for a more comprehensive diagnosis.

Analyzing the components of the Bent and Kuhn criteria reveals both necessary and questionable elements. Nasal polyps, though common, lack specificity and may be absent in treated AFRS patients. Fungal hypersensitivity becomes more meaningful when associated with elevated total serum IgE levels [26], which are typically significantly higher in AFRS patients than those with AR alone. Characteristic imaging features, including expanded sinus cavities with heterogeneous signals and bony erosion, stand out as specific and sensitive criteria. On the other hand, eosinophilic mucin, while present, lacks specificity, as it is also found in AERD. Positive fungal culture, as a criterion, is deemed unreliable, as demonstrated by Ponikau et al. [27], who showed that fungal components can be present in healthy controls, rendering it nonspecific.

The current diagnostic criteria for AFRS exhibit limitations, prompting the need for refinement. A more streamlined approach could involve the presence of fungal hypersensitivity with elevated total serum IgE levels, coupled with specific CT characteristics like expanded sinus cavities, heterogeneous signals, and bony erosion. By addressing the shortcomings of the existing criteria and incorporating advancements in understanding AFRS, the medical community can enhance diagnostic accuracy and ensure more effective management of this complex condition. Figure 1 shows a representation of presenting features and diagnostic criteria for AFRS.

FIGURE 1.

Presenting features and diagnostic criteria.

1.4. Epidemiology

Epidemiological studies on AFRS are relatively limited compared with other forms of CRS. It is generally estimated that AFRS occurs in approximately 6–7% of patients with CRS [28, 29]. Several researchers from various countries have tried to examine the prevalence of AFRS, with variable results depending on geographic location. Authors in the USA and India estimate that approximately 5–10% of CRS patients meet the criteria for AFRS [24, 30, 31]. A recent study by AlQahtani et al. [29] analyzed 35 cities across five continents and concluded that the worldwide average rate of AFRS in CRS cases is 7.8%, with a range of 0.2–26.7%. However, it is essential to note that these estimates vary widely depending on the geographical region and the population studied. For example, studies from India have shown AFRS prevalence of 56–79% in parts of Tamil Nadu [32]. Further work is needed to understand the epidemiology and geographic variation of AFRS.

The sex distribution among patients with AFRS varies. Manning and Holman [33] reported a higher prevalence of AFRS in males in the United States as did Awan et al. [34] in Pakistan. Ferguson et al. [35]. and others have supported this observation, further suggesting that males may spend more time outdoors, and may work in dustier environments, thereby exposing them to more mold counts than females, and potentially contributing to the increased male prevalence. However, it is important to note that other researchers have reported a similar incidence of AFRS in both males and females [36, 37].

Several studies from the United States have found a greater incidence of AFRS in Black Americans compared with Caucasians [15, 33, 38–41]. Wise et al. [39] found ethnicity to be a statistically significant predictor of bone erosion in AFRS, with more Black Americans presenting with erosion of bony sinus walls. They also found a statistically significant difference in age of presentation for Caucasians when compared with Black Americans, with Caucasians presenting on average 11.7 years later than Black Americans.

In the context of socioeconomic disparities, geographic location and access to care play a crucial role in the prevalence and management of both AFRS and CRS. In the southeast USA, CRS patients had higher annual income per capita than AFRS patients. This highlights a potential association between economic status and disease prevalence within different populations [41].

Most sites reporting cases of AFRS are historically located in temperate regions with relatively high humidity [31, 42], theoretically favoring an increased mold count. However, no reports in the literature have directly tested this hypothesis [29]. In a survey of the geographic distribution of practices across the United States, it was noted that the highest incidence of AFRS existed along the drainage basin of the Mississippi River and the southern United States, including both the Southwest and the Southeast, with an incidence of up to 22% of CRS patients exhibiting AFRS in Memphis, TN. AFRS seems common in Southern North America, Southern Asia, the Middle East and Sudan but is relatively rare in Northern Europe, Canada, and Japan (0–4%) [35, 43].

Despite the conclusions mentioned in the previous sections, a recent study by AlQahtani et al. [29] shows some interesting but contradictory data. Their study found no relationship between climate type and AFRS prevalence but established a significant relationship between AFRS prevalence and ambient temperatures. They also found a significant association between AFRS prevalence, humidity, and wind speed. Unexpectedly, humidity and wind speed were higher in the low AFRS prevalence group. Such studies are difficult to accomplish and a significant amount of their climate and socioeconomic data were obtained from centralized databases, which may not appropriately differentiate between the micro-regions where AFRS might occur versus national data. They identify this shortcoming appropriately and therefore suggest that further studies with specific demographics and socioeconomic status are needed to assess possible associations and etiology.

Finally, it is important to note that the etiological fungal species associated with AFRS are diverse and seem to be highly dependent on geographical and weather conditions: of 168 positive cultures studied by Manning and Holman in the United States, 87% were secondary to dematiaceous fungi, and 13% yielded Aspergillus species [33]. In India, A. flavus was isolated in more than 80% of AFRS cases according to diverse authors [25, 44–46]. A. flavus was also isolated from 50% of patients diagnosed with AFRS in the Middle East [47].

As noted above, epidemiological studies are few and far between regarding AFRS. Attempts at carrying out global and national studies are challenging as the climate and socioeconomic data may not correlate with the microregions where AFRS may exist within a county. This is evident from the AlQahtani et al. [29] study that found no correlation between climate and AFRS even though there is a strong sense of a correlation between warm, high humidity regions and AFRS amongst clinicians and researchers. The epidemiology of AFRS will continue to be a relevant topic of study as climate change affects various regions of the world.

1.5. Potential Effects of Climate Change on AFRS Epidemiology

As fungi are ubiquitous in nature, there is a considerable risk of personal exposure—a risk that can be higher depending on the environment. While most fungi are not pathogenic, some fungal species are known to cause disease while some others are opportunists, and the adverse health effects associated with fungal exposure have become an area of public concern. Exposure can occur through different routes including direct skin contact, ingestion, or inhalation of fungal components such as spores, filamentous hyphae, or microscopic fragments. These fungal components contain antigens that can elicit an immune response when encountered. Climate change has effects on vapor pressure, carbon dioxide concentrations, and barometric pressure resulting in increased atmospheric heat and precipitation, which increases pollen production. This has resulted in an increase of over 20% in both annual pollen counts and the duration of the Spring pollen season [48]. Climate change has also caused pollen to migrate northward [49]. This has resulted in an approximate 30% increase in the prevalence of AR worldwide [50]. In addition, animal studies show that the pollen produced under elevated atmospheric carbon dioxide levels can elicit a more potent allergic response [51]. Climate change has profound effects on air pollution by promoting dust storms, increasing emissions and promoting wildfires [52]. These events increase air pollution as assessed by particulate matter (PM2.5). Animal models of PM2.5 exposure show increased type 1 and 2 inflammatory mediators in the nasal tissues and lavage aspirates and decreased molecular markers of barrier function [53]. Recent human observational studies have shown the effect of PM2.5 exposure on the increased prevalence of CRS [54].

Our knowledge of the role of climate change in the epidemiology of AFRS is evolving [55, 56]. Fungal species are now surviving in warmer environments and negatively affecting both human and plant health. Increased humidity and weather extremes due to climate factors promote mold growth and are promoting growth of novel species of fungus [57]. Fungi with known geographic distributions are enlarging their distributions [58]. Fungal species have emerged to cause significant outbreaks that appear related to climate change. Research in this area will be critical and may also improve our overall understanding of the pathophysiology of AFRS [59].

2. Associated and Overlapping Conditions

Several other medical conditions are thought to be related to AFRS. In this section, we describe the literature and work supporting these potentially associated conditions, which can aid in our future investigation into AFRS pathophysiology.

2.1. Fungal Sensitivity With Asthma

Asthma with fungal sensitization tends to be more severe than nonsensitized asthma [60]. Due to the concept of the “unified airway,” a better grasp of the pathophysiology of asthma development due to fungal sensitivity is highly relevant to our investigation of AFRS. Understanding the role of fungi, especially lower airway fungal infection (airway mycosis) and hypersensitivity to fungi, is essential to understanding the pathogenesis of severe asthma and related conditions such as allergic bronchopulmonary mycosis (ABPM). ABPM is also termed allergic bronchopulmonary aspergillosis (ABPA) when the sensitization is to an Aspergillus species. A related entity, severe asthma with fungal sensitization (SAFS), is defined as severe asthma with fungal sensitization in the absence of ABPM [61, 62]. Clinically, SAFS does not present with the mucoid impactions or central bronchiectasis that are often present in patients with ABPM, and serum IgE levels are lower in SAFS than ABPM [62].

ABPM is defined variously [63, 64], but perhaps the most widely used definition includes indices of lung and airway damage in the context of asthma with very high IgE levels together with fungal sensitization [62]. Regardless, the published definitions of SAFS and ABPM are limited as they fail to capture the most severe asthma patients with underlying airway mycosis, most of whom do not show evidence of fungal sensitization using standard methods [7, 65]. This diagnostic challenge is reminiscent of the issues that arise with our current standard AFRS diagnostic criteria. A more clinically useful classification scheme might include the term Airway Mycosis Related Allergic Airway Disease (AMRAAD) that involves culture of respiratory secretions for fungi from those with asthma [7]. Regardless of how defined, ABPM is in many ways the lower airway equivalent of upper airway AFRS as both represent the extreme expression of allergic/eosinophilic inflammation in their respective locations, involving substantial tissue damage and remodeling, high eosinophil and IgE levels, and tenacious impacted mucus containing abundant fungi [66, 67].

ABPA is a distinct entity involving greater lung damage as compared with SAFS. ABPA predominantly occurs in patients with asthma or cystic fibrosis, often accompanied by cough with production of dark mucus plugs. Diagnosing ABPA requires establishing sensitivity to Aspergillus antigens by skin test reactivity and/or direct measurement of circulating specific IgE or IgG to Aspergillus, in the presence of precipitation of IgG antibodies or specific IgG antibodies to Aspergillus. ABPA should be considered analogous to AFRS with mucoid impaction akin to ABPA occurring in the paranasal sinuses accompanied by pansinusitis, nasal plugs and polyps; surprisingly, however, ABPA and AFRS rarely present in the same patient simultaneously. The key pathogenetic mechanisms of ABPA are not well understood but are thought to originate from interactions between fungi and the airway mucosa. Fungi are unable to be fully cleared from the airway mucosal surface and establish residence, resulting in both type 2 inflammation (with resultant eosinophilia and elevated IgE mediated by IL-4, IL-5, and IL-13) and non-type 2 inflammation (with neutrophil recruitment mediated by IL-1, IL-6, and IL-17). The primary treatment strategies are therefore reducing inflammation and fungal burden. Systemic glucocorticoids may be used in the treatment of ABPA but their use must be balanced against the risks of prolonged steroid therapy. Antifungal agents such as itraconazole and voriconazole and newer azoles reduce the antigenic stimulus in ABPA and may therefore modulate disease activity in patients. The use of monoclonal antibodies against IgE (omalizumab), IL-5 signaling, or the IL-4-receptor-alpha has been used in several case reports and series with resultant reduction in symptoms, exacerbations, and corticosteroid dosing [68]. While these data are promising and have been summarized in meta analyses [69] and real-world studies [70], these findings need to be confirmed in prospective, randomized, placebo-controlled trials.

Microbiologically, severe allergic asthma and CRSwNP are both characterized by the overwhelming growth of diverse fungi from respiratory secretions, including many molds and frequently yeasts such as Candida albicans [71]. Experimentally, most if not all fungi isolated from the human airway are capable of inducing asthma-like disease in mice, suggesting that most fungi isolated from the human airway are potentially pathogenic [72, 73]. In lieu of performing airway cultures, immunodiagnosis is often preferred. Studies of CRSwNP including AFRS have shown that T cell-based immunodiagnostic approaches are far more sensitive as compared with IgE-based methods and confirm that in most patients, airway mycosis is associated with both CRSwNP and severe asthma [7]. Unfortunately, such methods are not commercially available. Ultimately, the semantic distinctions between SAFS, ABPM, and AMRAAD might be irrelevant except that they might indicate distinct genetically defined immunodeficiencies that lead to airway mycosis. Limited literature now supports the treatment of severe asthma with antifungals [74]. Currently available antifungals have many drawbacks, but future agents are showing potential improvements in efficacy with reduced side effects as compared with existing agents [75]. This is an interesting potential divergence from the current management recommendations for AFRS (see Section 3).

2.2. Invasive Fungal Sinusitis

Recently, limited literature has suggested that there is a risk of progression from AFRS, a noninvasive form of fungal sinusitis, to invasive forms of fungal sinus disease. Invasive fungal sinusitis (IFS) is an aggressive disease originating in the paranasal sinuses; there is significant risk of intracranial and orbital involvement with up to 80% mortality [76]. Immunocompromised patients are at risk for invasive forms of fungal sinusitis. However, only a small percentage of immunocompromised patients will ultimately develop IFS, and host risk factors for developing the disease remain unknown. While fungal sinusitis is most common in a noninvasive form, the possibility that fungal sinusitis could be a spectrum of disease has been raised [77]. The possibility of progression in mildly immunocompromised patients is highly concerning. However, it has been reported in both fungal ball and AFRS patients, and is most commonly seen with Aspergillus species [77].

The mechanism of fungal invasion or progression from a noninvasive state is unclear. Very little is understood regarding the contribution of the host environment or deficiencies in the mucosal barrier to the risk of invasion. Other than a general immunocompromised state leading to a risk of IFS development, there are limited data regarding IFS pathophysiology. Work in other fungal infections has identified that specific matrix metalloproteinases (MMPs) may play a role in the local host response, and MMPs may degrade specific tight junction proteins [78]. A recent study at Washington University in St Louis compared IFS (n = 8) and similarly immunosuppressed control patients without IFS (n = 8). Bulk RNA sequencing revealed differences in expression amongst these patient cohorts in seven immune related genes including MMP-3 and MMP-12, both involved in chemokine processing and the innate local immune response to fungus [79]. These specific MMPs have also been noted to be secreted in response to fungus in other areas of research [78].

Preliminary data also suggest that IFS patients have disrupted nasal epithelium of specific tight junction proteins [79]. Interestingly, prior work has shown that epithelial proteins are altered in AFRS when compared with control patients. These alterations include an increase in “leaky” mucosal integrity protein expression and a decrease in tight junction proteins. This results in overall higher permeability of AFRS sinonasal epithelium [80].

There may be a “two-hit” hypothesis for IFS development. It is possible that fungal exposure, in addition to immune suppression, leads to progression of disease from noninvasive to invasive forms of fungal sinusitis. For example, some immunosuppressive medications target tight junction proteins, such as claudins [81], and there is evidence that secreted MMPs, in response to fungal infection, can cause degradation of tight junction proteins to allow for immune cell migration [82]. A deeper understanding of AFRS pathophysiology will aid in our investigation of all forms of fungal sinusitis, as the relationship may be more overlapping than previously thought.

2.3. Immunodeficiency

Immunodeficiency is known to play a role in rhinosinusitis; however, the contribution of immunodeficiency to AFRS is unclear. Rhinosinusitis is very common in patients with antibody deficiency disorders, estimated to affect 63–96% of patients with CVID [83]. In a meta-analysis of 1068 patients, 23% of patients with chronic rhinosinusitis not responsive to medical therapy and sinus surgery for at least 1 year had some form of Ig deficiency [84]. The finding of an underlying antibody deficiency disorder in patients with refractory rhinosinusitis has ranged from 0.5 to 10.4% for CVID, 7 to 69% for SAD, and 1 to 6.2% for SIgAD [83]. The most common causes of infectious rhinosinusitis in these patients consist of bacterial and viral pathogens, unlike IFS which occurs in patients with diabetes, hematologic malignancy and neutropenia.

Long-term treatment of rhinosinusitis in patients with antibody deficiency includes topical nasal therapy with nasal steroids and nasal saline rinses, as needed or prophylactic antibiotics, Ig replacement therapy, and treatment of the underlying immune defect. Ig replacement therapy is recommended for patients with chronic rhinosinusitis and underlying CVID [83]. AFRS appears to primarily affect immunocompetent individuals; however, invasive forms of fungal sinusitis, possibly progressed from AFRS, may become more prevalent and worrisome due to changes in climate and fungal growth. This will make the study of AFRS in the setting of immunodeficiency critical in the future.

3. Treatment Recommendations

3.1. Medication and Biologics

In contrast to classic CRS, the foundation of AFRS treatment is surgery. The vast majority of clinical studies in the AFRS literature indicate that medical therapy alone is ineffective in alleviating symptoms and that surgical intervention, alone or in combination with medical therapy, leads to improved clinical outcomes [85]. Adjuvant medical therapy plays a critical role in the successful treatment of AFRS with the prior evaluation of agents such as oral and topical steroids, oral and topical antifungals, and allergen immunotherapy (AIT) [86].

Steroids, including systemic and topical, reduce the inflammatory response, which in turn causes polyp regression and decreased sinomucosal edema [87]. Most efficacy studies have used steroids for perioperative optimization and postoperatively to decrease disease recurrence [88–90].

Few studies have evaluated topical steroids in a dedicated AFRS population [91–93]. Nested analyses of AFRS patients that have been included in other CRS/CRSwNP studies have shown that topical steroids are beneficial in AFRS [90]. However, there are only a few studies evaluating the role of antifungals in CRS that included AFRS patients [1] and a few case series that have reported the benefits of systemic antifungal therapies in patients with AFRS [94–96]. A Cochrane systematic review examining topical and oral antifungals in patients with AFRS was unable to make a recommendation regarding these medications due to low quality evidence [97].

Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP; unfortunately, these clinical trials did not include AFRS patients [98–100]. However, AFRS patients have a similar immunologic profile with other CRSwNP subgroups, suggesting that biologics may be a viable option for AFRS patients following FESS.

3.2. Functional Endoscopic Sinus Surgery

Since the earliest descriptions of AFRS, surgical intervention has been considered critical to disease management [101]. Although aggressive surgery with removal of diseased mucosa was initially advocated [101], this soon transitioned to a more conservative approach as AFRS was understood to be an immunologic - rather than infectious - entity [102]. Current surgical approaches for AFRS are typically endoscopic, involving creation of wide sinus ostial openings and removal of all visible eosinophilic mucin. Goals of surgery for AFRS include: 1) symptom improvement, 2) sinus aeration, 3) removal of eosinophilic mucin (and thus, removal of the immunologic stimulus for ongoing inflammation), 4) increasing access for topical medical therapies, and 5) supporting the diagnosis of AFRS through tissue pathology evaluation.

Of the five Bent and Kuhn criteria [24], three are identifiable on clinical evaluation: type I IgE-mediated hypersensitivity, nasal polyposis, and characteristic CT findings. Two criteria are identified on histopathology: eosinophilic mucin without fungal invasion and positive fungal stain. The histopathologic components of the Bent and Kuhn AFRS criteria are supported by tissue specimens sent at surgery, often delaying formal diagnosis.

As AFRS progresses, collections of mucin in the sinuses and at the sinus ostial openings often cause bony erosion and expansion [15, 39]. This may inherently create widened sinus ostia, enabling removal of mucin through standard endoscopic sinus surgery techniques. At times, however, extended approaches or adjunctive procedures may be considered to facilitate sinus ostial patency, removal of mucin, and access for maintenance topical medical therapies [103–107]. However, open craniofacial surgical approaches are rarely necessary for AFRS.

An active controversy in the surgical management of AFRS relates to potential operations on the contralateral, non-diseased side when patients initially present with unilateral disease. Interestingly, Bent and Kuhn’s initial 1994 description of AFRS note a predominance of unilateral disease [108]. In more recent series, the unilateral predominance remains in younger children [36, 109]; however, older children and adults with AFRS present with unilateral versus bilateral disease in nearly equivalent proportions [109–111]. It has been reported that patients initially presenting with unilateral AFRS may eventually develop contralateral or bilateral disease recurrence in up to 25–27% of patients [112]. This has led some authors to advocate for initial bilateral endoscopic sinus surgery in AFRS patients who initially present with unilateral disease [112]. Not surprisingly, considering surgical risks and healthcare costs, operating on non-diseased sinuses remains an area of active discussion.

Outcomes of endoscopic sinus surgery are generally favorable, and there are rare reports of improved surgical outcomes for AFRS patients compared with other CRS subtypes [113]. More commonly, however, AFRS has been associated with a propensity toward recurrence and need for revision surgery [20, 114, 115]. A 2020 systematic review and meta-analysis of 34,220 CRSwNP patients (mean follow-up of 3 years) noted an overall surgical revision rate of 18.6%, but this rose to 28.7% for AFRS [20]. In a single-center study, it was reported that women with AFRS had significantly greater improvement in SNOT-22 and endoscopy scores postoperatively than men [4]. The potential for surgical recidivism with AFRS supports the notion that surgery should not be viewed as a cure for this disease, but rather surgery is a part of the overall treatment paradigm to facilitate symptom improvement and maximize the effect of medical therapy for AFRS.

3.3. Allergen Immunotherapy

Due to fungal sensitization in all patients, AIT has been investigated as a treatment option for AFRS. Results are variable and there are several challenges to this work. Investigation into fungal diversity in respiratory disease has primarily focused on patients with asthma [116–120] with limited data reported in CRS [121].

The evidence for the use of AIT for fungal sensitivity is variable. This may be largely due to the variable quality of fungal immunotherapy reagents (i.e., extracts). Irregular quality and the limited breadth of available fungal extracts impact the clinical evaluation of fungal sensitization across human disease [122]. The manufacturing of fungal extracts is limited to known fungi with available, suitable culture media. The profound diversity of strains within a species (e.g., Aspergillus fumigatus has >200 strains) results in non-standardized cultures between manufacturers. A “mold mix” reagent has limited individual species content thus reducing potency plus the protease content of molds can degrade other allergens when mixed in solution. Those selected for diagnostic skin testing and in AIT further vary across individual practices. Despite these limitations, fungal AIT studies in patients with AR with or without asthma and fungal sensitization using standardized extracts of the major allergen of Alternaria alternata, Alt a1, demonstrate reductions in seasonal symptoms, medication use, bronchial reactivity to fungal challenge, and skin prick test size [122, 123]. The utility of testing for fungal sensitization and treatment with fungal AIT in allergic respiratory diseases is substantiated from these data.

Limited data support the use of AIT in AFRS [124–128]. No placebo-controlled studies have been performed. In limited case series, no safety concerns were identified with fungal AIT in AFRS, and the available data support possible clinical benefit despite the lack of rigorous study designs. Additionally, all studies included AIT to all documented sensitizations, fungal and nonfungal, for a given patient. We currently lack data that any clinical benefit observed is directly the result of the use of fungal antigens in AIT. Placebo-controlled clinical trials with standardized fungal extract concentrations are needed to evaluate the clinical benefit of fungal AIT in AFRS.

4. Pathophysiology of AFRS and translational work

Several related translational research topics were discussed. These topics include mucosal and epithelial dysregulation as well as the role of fungal exposure in these interactions. The design of improved in vitro and animal models was also discussed to further our understanding of the role of fungus on the unified airway.

4.1. Mucosal Immunity

AFRS appears to result from a sustained type 2 mucosal inflammatory response, in which local antibody-secreting cells (ASCs) produce IgE that binds to mast cells, basophils, and epithelial cells to drive pathogenic cytokine production, although the origins of these mucosal IgE ASCs and the IgE itself remain unclear. A standard model of allergic sensitization would involve IgE ASC generation in a germinal center of a draining secondary lymphoid organ, such as those of Waldeyer’s ring, after antigen presentation to a T lymphocyte. An alternative hypothesis posits that B cells encountering fungal antigens within nasal-associated lymphoid tissue or tertiary lymphoid structures undergo extrafollicular differentiation into IgE ASCs locally—an idea supported by findings such as epsilon switch circles, elevated markers of activation on ASCs, and naive-like IgE ASCs isolated from AFRS polyps [129].

Future work should focus on confirming the ontogeny of IgE ASCs, confirming observations of transcriptional differences between pathogen IgE ASCs and protective non-IgE ASCs, identifying the antibody specificity of all IgE ASCs, and investigating whether AFRS NP IgE ASCs are capable of long-term survival or migration to secondary lymphoid organs or bone marrow.

4.2. Epithelial and Nasal Airway Cell Barrier Function in AFRS

Epithelial and nasal airway barrier dysfunction in AFRS can be studied using in vitro models. Cultured airway epithelial cells on permeable supports provide useful models to study the impact of AFRS and other diseases on cell function, including barrier function. One way to optimize sample utility is to take nasal cell isolates either from curettage or polyp dissection and initially propagate them in a basal state using rho kinase inhibitors and irradiated fibroblasts (so called “conditionally reprograming conditions” (CRC)) [130]. The CRC method increases the expansion capacity of the cells and also generates basal cells that can be independently analyzed for growth/repair and differentiation potential as well as electrophysiological and solute barrier function. The resultant basal cells can subsequently be cultured at an air–liquid interface (ALI) in specialized medium which results in a differentiated monolayer that reflects either normal or polyp airway epithelia, depending on the source tissue.

Epithelial barrier function is regulated by the apical junctional complex, which includes tight junctions and adherens junctions [131]. There are two major classes of tight junctions with distinct molecular composition, bicellular and tricellular junctions [132]. Generally, bicellular junctions regulate paracellular ion permeability and tricellular junctions regulate paracellular flux of small molecules. Ion permeability is measured electrophysiologically using transepithelial resistance and paracellular flux is typically measured using differently sized fluorescent tracers.

Knockout cell models have been used to define molecular components that regulate different paracellular permeability [133]. Tight junctions are primarily composed of transmembrane proteins in the claudin family that control flux by forming paracellular ion and water channels [134]. There are two dozen claudins; cells fine tune barrier function through differential claudin expression. Different claudins intermix within tight junction strands to form subdomains with different permeability characteristics [135,136]. Notably, inflammation is an important driver of increased paracellular permeability through changes in tight junction architecture and composition. Upregulation of pore forming claudin-2 by cytokines such as TNF-α has been shown to integrate into tight junction strands and replace barrier forming claudin-4, increasing paracellular permeability by a model known as claudin switching [137]. This has been observed to occur in epithelial cells isolated from people with AFRS, which are enriched for claudin-2 [80]. AFRS cells are also deficient in junctional adhesion molecule A (JAM-A), which regulates the solute flux pathway. Work investigating the manipulation of the altered cell barriers in AFRS is ongoing.

4.3. Fungal–Epithelial Interactions

It is now clear that epithelial immune and inflammatory responses are important in the pathogenesis of AFRS. There are three key roles of the sinonasal epithelium in AFRS: 1) Epithelial cells respond to pathogens by producing a host of antimicrobial (in this case, antifungal) products that are effectors of innate immunity; 2) Epithelial cells play an important, if not central, role in defining the “endotype” of the adaptive immune response that will occur (i.e., Type 1, 2, or 17 responses); and 3) The viscid “allergic mucin” that is produced in copious quantities in AFRS may contain large quantities of crosslinked fibrin mesh derived by unregulated extravascular and intraluminal coagulation that is a consequence of the loss of epithelial cell expression of tissue plasminogen activator, an important fibrinolytic protein that regulates extravascular coagulation. Taken together, it can be stated that the sinonasal epithelium is not only a target of inflammation promoted by conidia and hyphae; it is also centrally involved in the host response to this ubiquitous organism. The fungal–epithelial interactions are critical to the development of AFRS, and work on this topic is critical for a complete understanding of AFRS pathophysiology.

4.4. Eicosanoid Dysregulation in AFRS

Recently, dysregulated prostaglandin receptor synthesis has been hypothesized as a driver in AFRS. In recent work, epithelial cells from healthy controls and AFRS patients were expanded in ALI for 14 days and mRNA was subjected to bulk RNA-seq analysis [138]. Nineteen differentially expressed genes between AFRS and healthy samples were identified. Overall gene expression in 11 of the differentially expressed genes was low. TXN was the only gene highly expressed in all AFRS and healthy samples, and MIR6723 was highly expressed by two healthy samples but otherwise remained low. FAM43A, PTGER2, and FOLR1 were genes with the lowest adjusted p value; however, PTGER2 expression was the most consistent between samples within each group, suggesting dysregulation of the gene in AFRS.

The PTGER2 gene encodes for prostaglandin E receptor 2 (EP2), one of four G-protein-coupled membrane receptors that mediate the activity of prostaglandin E2 (PGE2) [139]. In addition, dysregulation of PGE2 receptors has been previously characterized in CRSwNP [140]. Specifically, downregulation of EP2 was reported in AERD [141]. Using immunocytochemistry, perinuclear localization of EP2 was found in both healthy and AFRS tissues. Taken together, these results suggest dysregulated prostaglandin receptor synthesis in AFRS, another potential target for future drug development. Interestingly, while EP2 is generally considered pro-inflammatory, it has a protective, broncho-dilatory effect on the lower airway [142]. Perhaps the increased expression of EP2 in the lower airway is responsible for the low incidence of comorbid asthma in AFRS. Further investigation is needed to understand the clinical implications of eicosanoid dysregulation in AFRS.

4.5. Role of Antimicrobial Peptides in the Pathophysiology of AFRS

Antimicrobial peptides (AMPs) are integral components of the innate immune system, playing a crucial role in defending against microbial threats. Three main families of AMPs—defensins, cathelicidins, and histatins—exhibit distinct mechanisms of action. Defensins act by forming pores in microbial membranes, disrupting their integrity. Cathelicidins, such as LL-37, possess broad-spectrum antimicrobial activity and can modulate immune responses. Histatins, primarily found in saliva, contribute to antifungal defense by disrupting the fungal cell membrane.

Several studies have explored the involvement of AMPs in the pathophysiology of CRS [143, 144]. Various studies indicate altered AMP expression in CRS, suggesting a potential association between AMP dysregulation and the pathophysiology of these sinus disorders. In CRSwNP, b-Defensin was found to be downregulated in sinonasal mucosa compared with healthy controls and in vitro IL-4 and IL-13 could decrease its expression levels. For LL-37, CAMP expression was upregulated in CRSwNP versus CRSsNP. In vitro studies showed that stimulation with fungal allergens induced mRNA and protein levels of LL-37 [145, 146]. These studies suggest dysregulation of AMPs may contribute to CRS pathophysiology, but specific understanding about whether this dysregulation of AMP is the cause or effect of CRS remains unclear.

Histatins, in particular, have drawn attention in the context of AFRS. A study by Tyler et al. [147] reported significant downregulation of histatin expression in AFRS compared with nonfungal CRSwNP. Recent data from UT Houston further confirms minimal histatin protein levels in AFRS sinus mucosa, correlating with decreased antifungal activity in secretions from AFRS patients [148]. Additionally, representatives of the Defensin (DEFA1) and Cathelicidin (CAMP) families also exhibited significant downregulation in AFRS compared with nonfungal CRSwNP [149].

Further investigation into the immune response in AFRS revealed a significant decrease in IL-17 and IL-22-producing T cells in AFRS sinus mucosa. The examination of T cell differentiation mechanisms identified dysfunctional IL-6/STAT3 signaling in AFRS patients, contributing to the reduced presence of IL-17 and IL-22-producing T cells in the sinus mucosa. This suggests that AFRS may involve a dysfunction in T cell differentiation, leading to a lack of AMP production and the accumulation of fungi laden mucin in diseased sinus mucosa. Notably, these observations unveil a potential therapeutic avenue: despite the overall downregulation of AMPs, epithelial cells from AFRS patients demonstrated the ability to produce AMPs when stimulated with IL-22. This indicates a potential strategy for AFRS treatment-boosting AMP production through targeted IL-22 stimulation. Figure 2 shows a representation of active translational research areas in AFRS.

FIGURE 2.

Active areas of translational research.

5. Ongoing and Future Research Needs

This meeting highlighted several future research needs regarding AFRS, which are described below. Plans to investigate these areas are also outlined where applicable.

5.1. Improvement and Clarification of Diagnostic Criteria

As highlighted in “Diagnosis of AFRS,” there are several limitations and controversies surrounding diagnostic criteria for AFRS. A consensus on these criteria is critical for both 1) improved treatment recommendations for potentially misclassified patients, and 2) improved generalizability of research outcomes by including patients in research studies with limitations of strict inclusion criteria.

5.2. Severity and Prognostication

An improved understanding of prognostication for AFRS patients would allow for counseling, appropriate follow-up and potential cost-effective AFRS management. Patients with various diseases and conditions can exhibit a broad spectrum of illness severity, defined by symptoms, comorbidities, and diagnostic results. Prognostic stratification aims to identify characteristics in a patient’s initial state that correlate with future target events [150].

There are four steps to developing a prognostication scale: [151]

Define an appropriate population:

Collect data from a methodologically sound, appropriate population, preferably an inception cohort with baseline conditions determined at “zero-time” (the start of the observation period).

Choose a target event:

Express stratification results as rates or percentages indicating whether the target event occurred in specified cohort groups.

Create partitions:

Develop nonoverlapping and mutually exclusive categories (partitions) for variables, typically ranging from 2 to 10, to represent a variable’s array of expressions.

Define univariate categories:

Express each predictor variable in univariate categories, considering single or compound features. Single variables rely on elements from one type of data, while compound variables involve multiple types of data.

5.2.1. Statistical Methods

While an ideal prognosis analysis would involve a “natural history” population without interventions, modern clinical realities necessitate studying the clinical course of the entire cohort, assuming no effect from interventional maneuvers. The “nil hypothesis,” states that none of the interventional maneuvers have affected the clinical course and allows the investigator to proceed with the analysis of prognosis. Conjunctive consolidation, a multivariable technique, is ideal for prognostic stratification [152–156]. It does not assume linear relationships among variables, instead combining independent variables into composite variables. This intuitive technique results in prognostic groups recognizable to clinicians, as demonstrated in various clinical medicine examples [153, 157, 158].

5.2.2. Potential Study Design

Prognostic stratification involves identifying the population, defining the target event, identifying predictor variables, and arranging variables. Conjunctive consolidation is a straightforward, intuitive multivariable technique for creating unique prognostic strata. For AFRS, a potential study design could include the use clinical information regarding AFRS patients with a target event of “escalation of care” such as the need for revision surgery, repeated oral steroids after an initial surgery, or initiation of biologics following an initial complete surgical resection.

5.3. Clinical Trials

Despite significant clinical interest in AFRS from multiple medical and surgical specialties, there is a paucity of recent clinical trials studying treatments for this pathology. The AFRS population has been specifically excluded in several recent trials studying biologic therapies for CRSwNP. This was the case in the LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 studies where “fungal rhinosinusitis” was a key exclusion criterion [98]. These studies, assessing dupilumab in adults with severe CRSwNP, led to the eventual regulatory approval of dupilumab for the treatment of CRSwNP. While there are clear differences between AFRS and CRSwNP that may justify this exclusion, it makes evidence-based management of the AFRS population challenging.

A search of ClinicalTrials.gov illustrates the limited number of current clinical trials in AFRS with only one active clinical trial. The Dupilumab in Allergic Fungal Rhinosinusitis (LIBERTY-AFRS-AI) study recently completed enrollment. This study evaluated the efficacy of dupilumab in a multinational cohort of patients with AFRS. The initial primary outcome planned for the study, the need for rescue therapy with systemic corticosteroids or surgery, was adjusted to change in sinus opacification with a reduction in planned enrollment [159]. The LIBERTY-AFRS-AI study required participants to meet all five Bent and Kuhn criteria for AFRS for enrollment, likely a key element of rigorous clinical trials in AFRS. While histologic evidence of AFRS in a study involving surgical intervention is straightforward, collection of eosinophilic mucin outside of a surgical setting or confirmation of the presence of this during prior surgery can pose significant logistical challenges and must be considered in future studies of AFRS.

6. Summary

AFRS topic	Key points
Presentation of disease [1]	• Younger age at presentation compared with other subtypes of CRSwNP [3–5] • High association with environmental atopy [10] • A lower-than-expected association with asthma [10] • Bony sinus expansion • Unilateral disease • Higher recurrence rates than other subtypes of CRSwNP [20] • Significant impact on olfaction [22]
Diagnosis of AFRS	• Bent and Kuhn criteria often used [24]; there are limitations in sensitivity and specificity: • Nasal polyps may be absent in treated AFRS patients • Eosinophilic mucin lacks specificity, as it is also found in AERD • Positive fungal culture can occur in healthy controls, and is nonspecific [27]
Epidemiology of AFRS	• Limited data; geographic, socioeconomic, and racial disparities may exist • Approximately 6–7% of CRS can be attributed to AFRS [28, 29]
Climate change	• Increased temperatures and changing climates affect both allergens and fungal growth, fungi with known geographic distributions are expanding [57,58]
Associated conditions with AFRS	• The relationship of AFRS and various forms of asthma with fungal sensitivity is under investigation [66, 67] • There is a potential overlap with pathophysiology of invasive fungal sinusitis; there is a possible spectrum of fungal sinusitis [77]
AFRS treatment	• Functional endoscopic sinus surgery is recommended • Oral and topical steroids are often used to decrease polyps and inflammation [90] • Insufficient data to support antifungal use [97] • Data for biologics use is limited for AFRS [98, 100] • Limited support for allergy immunotherapy in AFRS; data are variable [124, 128]
Ongoing bench-to-bedside research regarding AFRS pathophysiology (Figure 2)	• Mucosal immunity, fungal–epithelial interactions and the effects on barrier integrity are under investigation [80, 129, 160] • Work on antimicrobial peptide effects on the immune system is currently underway as a potential treatment option [147] • Dysregulated prostaglandin receptor synthesis may occur in AFRS; this is another potential target for AFRS treatment [138,141]
Future research needs	• Improved accuracy of diagnostic criteria • Severity and prognostication to improve counseling and treatment decisions • Clinical trials evaluating biologics in AFRS patients are ongoing • Improved animal or in vitro models for studying AFRS