Allergic Fungal Rhinosinusitis in Europe: Literature Review and Own Experience Free

Chronic rhinosinusitis, according to the definition of the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS 2020), is nasal congestion or nasal discharge (anterior/posterior) associated with facial pain and/or olfactory disorders [1]. It can be primary or secondary. Primary rhinosinusitis includes localized or diffuse Th2 or non-Th2 rhinosinusitis. Regardless of the extent, allergic fungal rhinosinusitis (AFRS) is classified as primary Th2-dependent chronic inflammation.

According to the Bent and Khun criteria [2], the so-called major criteria should be met, i.e., the presence of polyps in the nasal cavity, fungi on staining, eosinophilic mucin without fungal invasion into the sinus tissue, a characteristic CT scan picture with soft tissue differential densities, and type I hypersensitivity to fungal allergens. Minor criteria, on the other hand, include the presence of eosinophil-rich allergic mucin (visual or histopathological), positive fungal stain, no immunodeficiency or diabetes. Eosinophilic fungal rhinosinusitis also meets these criteria, except for the presence of specific IgE antibodies directed against fungal allergens.

Fungal rhinosinusitis (FRS) is the inflammation of the nasal cavity and the sinuses, taking an invasive or non-invasive form – the invasive rhinosinusitis can be acute invasive (AIFRS) or fulminant (FIFRS) as well as chronic invasive (CIFRS) and chronic granulomatous (CGFRS); the non-invasive form is represented by saprophytic fungal infections, fungus balls, and AFRS [3, 4].

AFRS accounts for 6–9% of fungal rhinosinusitis and most commonly affects the ethmoid sinuses (71–92%), maxillary sinuses (7–76%), sphenoid sinuses (58–86%), and frontal sinuses (29–65%) [5‒9]. AFRS is observed among patients living in arid and tropical regions of the world. In northern India, it affects 110 individuals per 100,000 inhabitants during wheat-thrashing season (March or April) [10], whereas in Israel, it is 500 per 100,000 [11]. It is a condition common in southern North America, southern Asia, the Middle East, and Sudan. The pathomechanism of the disease is based on mucosal hypersensitivity to fungal antigens including Bipolaris, Curvularia, Alternaria, Aspergillus, and Fusarium [12‒16].

The aim of the authors was to reveal how often AFRS occurs among immunocompetent CRS patients living in Europe, what factors may favour its development, and how to treat it most effectively. The available literature has been reviewed, and own experiences have been presented.

The systematic search was performed in accordance with the PRISMA 2020 checklist [17]. Three investigators (A.K., D.G., and M.K.) independently conducted a comprehensive literature review using the PubMed and ScienceDirect electronic databases. The databases were searched between July 1, 2022, and September 30, 2022. The following keyword was used: allergic fungal rhinosinusitis. The time criterion was used in the search, i.e., papers published from 2002 to 2022 were reviewed. Neither informed consent nor ethics approval was required as this study was a systemic review of published papers. The studies were screened for inclusion using the following criteria: (1) AFRS diagnosed based on the Bent and Khun criteria; (2) AFRS diagnosed in European countries; (3) written in English; (4) human studies; (5) case report. The criteria for exclusion included (1) not all of the Bent and Khun criteria for the diagnosis of AFRS fulfilled; (2) AFRS diagnosed in non-European patients; (3) not written in English; (4) no case report.

Records from different databases were exported to EndNote 20. Two reviewers (M.K. and A.K.) independently screened all titles and abstracts. When a disagreement occurred, the relevant articles were discussed between the reviewers until consensus was reached. All the studies that did not meet the inclusion criteria were excluded. Figure 1 presents the process of literature search and screening.

The literature search revealed 2,356 references, of which 121 references were initially removed by a primary screening process, which involved identifying and excluding duplicates from searches. The remaining 2,235 references underwent a secondary screening process and assessment. Following the review of abstracts and summaries, 277 publications regarding AFRS were selected for further screening. 242 papers discussed AFRS diagnosed among non-European populations. 35 publications from Europe were selected for a full-text review. From these, 7 were deemed eligible for inclusion. 35 papers were identified as appropriate for the review. Twelve of these were not written in English, and one report was not retrieved. Further, 5 review articles were excluded as they did not mention any AFRS cases. The full-text reviews revealed that in ten of these articles, AFRS cases mentioned did not meet the Bent and Khun diagnostic criteria (i.e., no type I hypersensitivity to fungi was documented, and the data about fungi were not always detectable). After excluding these studies, the final search identified 7 papers that included AFRS cases diagnosed using the Bent and Khun criteria. The risk of bias for all studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [18].

All 7 papers were published in English between 2003 and 2019. In total, 92 cases were presented. Of all the described cases, the majority were men (52 subjects). The mean age of men was 37.88 (SD 12.52) and that of women was 45.71 (SD 8.19). Table 1 contains articles in which the authors present cases of patients diagnosed with AFRS. After a detailed analysis of 92 described patients, some discrepancies were found in the “purity” of qualifications, which the authors of the study particularly cared about. 4 cases presented by Corradini [19] were atopic with positive tests for inhalant allergens, including mould spores. However, specific IgE for fungi cultured from nasal washes was negative (despite high total IgE). The patient presented by Cavanna [20] was atopic, with a history of early childhood asthma and Curvularia lunata found in the sinuses, which was confirmed by genetic testing. However, no specific antibodies against fungal antigens were found. The clinical picture suggested FRS, the more so that permanent improvement was obtained after endoscopic sinus surgery and antifungal treatment. Oretti [21] presented a patient with polysensitization, hyphae Aspergillus fumigatus in the sinuses but without conclusive confirmation of body immunization by specific IgE. In this case, permanent improvement was also achieved after Draf IIA and ethmoidectomy. Thus, finally, 86 cases of AFRS were reported in Europe over 20 years, confirmed by specific IgE for the present fungus. In the analysed literature, allergic bronchopulmonary aspergillosis was present in 66 patients. Bronchial asthma was diagnosed in 65 patients, and inhalant allergy was often present. Bronchiectasis occurred in 12 cases. The most common allergy confirmed by prick testing was allergy to A. fumigatus (in 73 cases). Only two studies assessed the biodiversity of fungi in air samples obtained from the patients’ homes. The most predominant species was Aspergillus niger. Unfortunately, no more data on the living or working conditions of the described patients were provided.

In 13 cases, the involved sinuses were operated endoscopically; in one case, Draf IIA procedure was applied (the approach was used to access the frontal sinus). After the surgical treatment, there was no recurrence of the disease in 6 patients, and significant improvement was achieved in 3 patients. Eight patients were treated with oral and topical steroids after surgery. In the treatment of AFRS, antibiotic therapy (2 cases), antifungal treatment (2 cases), antihistamine treatment (1 case), and nasal rinsing with saline (2 cases) were used as the only treatment. 19 patients were treated with systemic oral steroids only. Full recovery was achieved in 3 cases, significant improvement in 14 cases, and no improvement in 5 cases.

In 2019, a 51-year-old man was admitted to the Department of Laryngology and Laryngological Oncology in Katowice-Ochojec due to profuse dripping of purulent secretion down the back of the throat, headache, and olfactory disorders. The patient reported bouts of shortness of breath, especially after exertion and temperature change. He used salbutamol on an ad hoc basis. Lung imaging showed no abnormalities. His job involved dismantling old car upholstery.

The patient was operated on in another centre in 2015, 2016, and 2018 due to the inflammation of the left sphenoid sinus. During the last operation, the histopathological examination of the sinus contents revealed the presence of eosinophilic secretion and A. fumigatus mycelium. A. fumigatus-specific IgE was >100 UI, and total IgE was −5,276 UI. Skin prick tests to inhalant allergens showed atopy to grass, mugwort, mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae), and A. fumigatus. Despite positive tests, the patient did not report any worsening of symptoms during the grass and mugwort pollen season or exposure to mite allergen. The endoscopic examination of the nasal cavity showed profuse discharge of purulent contents from the left sphenoid sinus. Computed tomography showed complete shadowing of the left sphenoid sinus (Fig. 2.). AFRS was diagnosed. The patient was qualified for endoscopic surgery. The procedure involved widening of the sinus ostium, from which brown masses and abundant mucopurulent contents were removed. The sinus was rinsed using the HydroCleanse Sinus Wash Delivery System (Medtronic). In the bacteriological examination, Klebsiella oxytoca was obtained, no fungi were grown, and the histopathological examination revealed hyphae (mycelial hyphae). After the operation, a short course of antibiotic was prescribed according to the antibiogram and intranasal steroid – mometasone at a dose of 2 × 200 μg.

After 6 months, the patient presented with headache and expectoration of purulent secretion. The endoscopic examination revealed purulent discharge from the operated sinus with polyps. Methylprednisolone was introduced at a dose of 16 mg/24 h with a dose reduction over 4 weeks. The local condition improved, and the total IgE decreased to 3,067 UI. It was recommended to rinse the nasal cavity once a day using a set for sinus irrigation with fluticasone 400 μg. After another 6 months, total IgE was 1,890 UI. Topical treatment was maintained as before. In May 2021, the total IgE was 791.90 IU, and the patient reported the presence of viscous secretions after coughing in the morning. The endoscopic examination revealed a trace of purulent secretions in the crusts at the ostium of the left sphenoid sinus. The patient did not use inhaled drugs. Sinus irrigation with 1.0 budesonide every 2 days and 2 × 2 doses of mometasone were recommended. In May 2022, the patient was in good condition, without coughing, shortness of breath, or secretions dripping down the back of the throat. The endoscopic examination revealed no abnormalities. Total IgE was 372.70 UI, and specific IgE of A. fumigatus was 52.70 UI. The patient changed his job. He remains under medical supervision (Fig. 3).

In March 2018, a 39-year-old patient was admitted to the Department of Laryngology and Laryngological Oncology due to dripping of purulent secretion and restriction of nasal patency on the left side. She reported bouts of shortness of breath during her stay at the swimming pool and in damp rooms. She worked as a dental hygienist. Computed tomography of the paranasal sinuses showed opacity of the maxillary sinus, ethmoid cells, and sphenoid sinus on the left side (Fig. 4.). The Lund-Mackay score was 7 points. The endoscopic examination of the nasal cavity revealed profuse mucopurulent discharge from the left sphenoid sinus and polyps. In spirometry, the FEV1 value was 102%. Prick tests were performed, showing allergy to A. fumigatus. A. fumigatus-specific IgE was 5.40 UI. The patient was qualified for endoscopic surgery, and left anthroethmosphenoidectomy was performed. Enterobacter cloacae was present in the bacteriological examination, hyphae and eosinophilic secretion in the histopathological examination. After the operation, inhalation steroid therapy with formoterol was recommended, as well as sinus rinsing with budesonide (2 × 1.0 g) and fluticasone aerosol (2 × 200 μg). After 6 months, the local condition improved. The endoscopic examination revealed wide, unobstructed sinus ostia, no pyorrhoea, and a decrease in specific IgE to the value of 3.69 UI. The patient inhaled drugs only before entering damp rooms and before exercise. The results of the spirometry test were normal. The patient remains under ENT control.

An earlier publication [4] described a patient operated on in our centre due to inflammatory lesions in the left sphenoid sinus, who had dead mycelium in the histopathological examination of the sinus contents and a positive reaction to the Alternaria and Penicillium allergen in the prick tests. This patient had no recurrence for 12 months after endoscopic surgery. The postoperative course was different than in the case of the afore-mentioned female patient, and possibly positive mould spore tests and the presence of mycelium in the sinus were not related.

The conducted literature review suggests a rare occurrence of AFRS in Europe compared to other regions of the globe, which is probably related to a different kind of “exosome” in which we live. It seems important to look for sources of exposure that may contribute to the development of the disease. In the case of the patients described by the authors of the study, it was professional contact with old damp fabrics or frequent stays in damp rooms. Despite the rare diagnosis of ARFS, we should all use the more strict criteria for diagnosis and standardized treatment methods. Perhaps such a small number of cases results from the lack of unequivocal confirmation of the disease with the presence of specific IgE antibodies, which was one of the accepted inclusion criteria. The presence of specific antibodies against the antigen of the present fungus is a criterion that distinguishes AFRS from another eosinophilic CRSwNP endotype. The example of our male patient shows that the correct diagnosis was made quite late and, as a result, the effective treatment was implemented only after four surgeries. Based on the literature review, it can be concluded that AFRS often coexists with allergic bronchopulmonary aspergillosis, which underlines the systemic nature of the disease.

According to EPOS 2020 [1], all the cases meeting the Bent and Khun criteria [2] in the absence of specific IgE antibodies are included in AFRS. However, it seems that the presence of specific IgE indicates a systemic nature of the disease, in contrast to local eosinophilia or type I allergy as in the case of staphylococcal superantigens or local allergic rhinitis [22]. Immediate hypersensitivity (type I) is a consequence of the activation of CD4+ helper lymphocytes (Th2 CD4+) and follicular helper lymphocytes (Tfh) secreting interleukin 4 (IL-4) in response to protein antigens or chemical molecules associated with proteins. Two cytokines produced by Th2 CD4+ IL-4 lymphocytes and interleukin 13 (IL-13) stimulate B lymphocytes to produce IgE by plasma cells. Antibody class switching to IgE takes place mainly in the lymphoid organs, where Tfh lymphocytes play an auxiliary role. Th2 cells also produce interleukin 5 (IL-5), which promotes eosinophil-mediated inflammation. IgE antibodies bind with high affinity to receptors on mast cells. After binding to a specific allergen, they cause their degranulation and release of granule content, synthesis and release of lipid mediators and cytokines. The cytokines stimulate the influx of neutrophils and eosinophils, which are involved in the development of the late phase of inflammation. The inflammation may affect the mucous membranes of the respiratory, digestive, and skin systems. In the case of AFRS patients, a defect in the Th17 response should be considered, which is of key importance in the response to bacterial and fungal infections, especially those affecting the epithelial barrier.

In the described cases, the disease affected the sinuses and bronchi in the form of atopic asthma. With the improvement of the local condition, dyspnoea, coughing fits, and wheezing in the chest subsided. The patients with normal spirometric values discontinued inhaled medications. The female patient continues to use inhaled bronchodilators in wet rooms (swimming pool). The authors suggest the need for early treatment with a systemic steroid, followed by a locally acting one in the form of irrigation. In the case of this patient, the IgE values were relatively low, and the disease lasted for a short time, so it was decided to implement only intranasal treatment. Repeated, multiple surgeries do not bring the expected effect because they do not treat the ongoing local and systemic inflammation. The example of our patient shows that it took a long time before the correct diagnosis was made and effective treatment was implemented. Opening of the sinus ostia and mechanical removal of the sinus contents, anti-inflammatory treatment with a systemic steroid, regular rinsing of the sinuses with the addition of a steroid, removal of a potential source of infection should be adopted as the standard treatment regimen in the case of AFRS.

The authors of the study also analysed the treatment of AFRS proposed in the non-European literature, where endoscopic treatment of the affected sinuses was most often used, followed by oral steroid therapy starting with 40 mg prednisone with a dose reduction over a month [23, 24], and continued by using steroid solutions in the form of low-volume, high-pressure sinus rinsing (budesonide 1.0 mg) as well as locally acting aerosol at a dose of 200 μg per day. Extremely different methods of treatment can be found in the literature. However, functional endoscopic sinus surgery remains the basic and first stage of treatment in most AFRS cases [23, 24]. According to EPOS 2020 [1], postoperative systemic corticosteroids improve short-term outcomes in AFRS and are likely to reduce long-term recurrence. Nasal and oral steroid therapy, oral and topical antifungal drugs (itraconazole, fluconazole), rinsing the nose with saline solution, immunotherapy, antihistamines, and antibiotic therapy are also used in the treatment process [25‒27]. While using intranasal steroid, nebulized intranasal steroid is better than simple nasal steroid sprays. There is some evidence that oral antifungals may reduce inflammation and recurrence in AFRS; however, a controlled study is required. Limited data exist to support the use of topical antifungal therapy. Immunotherapy to both fungal and non-fungal antigens in atopic individuals with AFRS is also mentioned in EPOS 2020 as likely to improve symptoms and reduces revision surgery; however, there is a lack of placebo-controlled randomized trials in AFRS [1]. Changes in tomography, mycelium, and eosinophilic infiltrates may not have primary fungal aetiology. Secondary chronic rhinosinusitis or fungal superinfection of primary Th2-dependent CRS should be considered.

Adoption of all the criteria of diagnosis suggested by Bent and Khun seems appropriate, especially in the era of personalized biological treatment. The presence of specific IgE antibodies and inflammatory cytokines characteristic of the first immune mechanism suggests a systemic nature of the disease and makes it possible to introduce additional treatment, such as specific immunotherapy or biological treatment [28‒31]. Unfortunately, there are no data on the effectiveness of specific immunotherapy, but treatment with anti-IgE monoclonal antibodies or blockers of the alpha subunit of the IL-4 or anti-IL-5 receptor gives hope. Biological therapy plays an increasingly important role in AFRS, and the effects of its use are at least promising [29, 32].

Based on the literature review, it was found that the occurrence of AFRS confirmed by specific IgE antibodies in Europe is rare, which may be the result of insufficient diagnostics. Due to the systemic nature of the disease, the authors of the study suggest specifying diagnostic criteria, which will facilitate the correct diagnosis and accelerate the initiation of appropriate, personalized treatment.

Ethical approval was waived by the Local Ethics Committee of Medical University of Silesia. Patients signed informed consent regarding publishing their data and photographs.

The authors have no conflicts of interest to declare.

This article did not receive any funding.

M.K.: study design, visualization, methodology, data curation, and review preparation. G.S-M.: study design, formal analysis, validation, original draft preparation, and supervision. A.K. and D.G.: methodology and data curation. J.G.: validation and supervision.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Edited by: D.Y. Wang, Singapore.