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Fungal rhinosinusitis (literature review)

20 февраля 2020

Fungal rhinosinusitis (literature review)

Lucia Gariuc1*

1Chair of otorhinolaryngology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova.

Corresponding author:

Gariuc Lucia, PhD student

Chair of otorhinolaryngology

Nicolae Testemitanu State University of Medicine and Pharmacy

165, Stefan cel Mare si Sfant ave., Chisinau, Republic of Moldova, MD-2004

e-mail: lucia_gariuc@outlook.com 

Short title: Fungal rhinosinusitis

What is not known yet, about the topic

Due to the lack of standard criteria for diagnosis and the potential invasiveness of fungal rhinosinusitis, especially in patients at risk, it is essential to have a correct and rapid diagnosis in order to initiate treatment as soon as possible for a favorable prognosis.

Research hypothesis

Exposure of a narrative synthesis of contemporary literature and ample presentation of non-invasive and invasive forms of fungal rhinosinusitis.

Article’s added novelty on this scientific topic

The article presents a summary of contemporary international studies on the epidemiology, etiology, pathophysiology, clinical picture, diagnosis, differentiated diagnosis, complications, treatment and prognosis of non-invasive and invasive forms of fungal rhinosinusitis.

ABSTRACT

Introduction. FRS remains a controversial disease, with unclear pathophysiology, incomplete knowledge of epidemiology and medical mycology. Further research is needed to elucidate the exact etiological and pathogenetic role of fungal species in CRS, improving the diagnosis and treatment of FRS to determine a better prognosis.

Material and methods. From the PubMed and Scopus (Elsevier) databases, articles published during the years 2000-2017, were selected according to the keywords: fungal rhinosinusitis, fungus ball, allergic fungal rhinosinusitis, acute invasive fungal rhinosinusitis, chronic invasive fungal rhinosinusitis, granulomatous invasive fungal rhinosinusitis. Information on the epidemiology, etiology, pathophysiology, clinical picture, diagnosis, differentiated diagnosis, complications, treatment and prognosis of non-invasive and invasive forms of fungal rhinosinusitis was selected and processed.

Results. After processing the information from the PubMed and Scopus (Elsevier) databases, 575 articles on FRS were found according to the search criteria. The final bibliography contains 52 relevant sources, which were considered representative for the materials published on the topic of this synthesis article.

Conclusions. Non-invasive FRSs include saprophytic fungal infections, fungus ball, and FRS caused by eosinophils. IFRS requires emergency diagnosis and early treatment due to the reserved vital and functional prognosis.

Keywords: fungal rhinosinusitis, fungus ball, allergic fungal rhinosinusitis, acute invasive fungal rhinosinusitis, chronic invasive fungal rhinosinusitis, granulomatous invasive fungal rhinosinusitis.

INTRODUCTION

Fungal rhinosinusitis (FRS) is one of the most challenging conditions for otolaryngologists, primarily in terms of diagnosis and treatment [1, 2]. Due to the lack of standard criteria for diagnosis and the potential invasiveness of FRS, especially in patients at risk, a correct and rapid diagnosis is essential in order to initiate treatment as quickly as possible for a favorable prognosis. The only way to make a reliable diagnosis is to perform the detailed clinical examination and take the biopsy samples [3, 4, 5].

Despite the recognition for over two centuries of FRS as a serious entity and due to the results of all the studies carried out in recent years, the condition is still a controversial disease, with unclear pathophysiology, incomplete knowledge about epidemiology and medical mycology [3, 6]. Further research is needed to elucidate the exact etiological and pathogenetic role of fungal species in chronic rhinosinusitis (CRS), to improve the diagnosis and treatment of FRS to determine a better prognosis [1, 7, 8].

Fungi are increasingly involved as an important pathogen in the etiology of CRS; they may play a minor role, as part of a more complex interaction between multiple factors and, vice versa, they may be the main factor in some forms of CRS, however, fungi are not a universal etiological factor [5, 9]. However, the incidence and prevalence of various forms of FRS have not been accurately documented in prospective studies. Assessment of the exact pathophysiological mechanism is crucial in determining whether changes in CRS treatment are needed and, if so, how to address them [1, 6]. In order to establish appropriate and effective therapeutic strategies and minimize side effects, it is necessary to elucidate the pathophysiological mechanisms by which fungi initiate or perpetuate the inflammation, the nature of fungal interactions with the mucosal surface (for example, as part of a biofilm that represents an important mechanism for microorganism survival or as a non-specific invader of disturbed epithelial barriers), the optimal methods of drug delivery [1, 3, 10].

In the context of rapid development and improvement of diagnostic and treatment technologies, the purpose of the article is to present a synthesis of the latest data on epidemiology, etiology, pathophysiology, clinical picture, diagnosis, differentiated diagnosis, complications, treatment and prognosis of non-invasive and invasive forms of FRS.

MATERIAL AND METHODS

In order to achieve the objective set, the initial search of the scientific literature, identified by Google search engine, PubMed and Scopus (Elsevier) databases, was carried out. The criteria for the selection of articles included non-invasive and invasive forms of fungal rhinosinusitis using the following keywords: "fungal rhinosinusitis", "fungus ball", "allergic fungal rhinosinusitis", "acute invasive fungal rhinosinusitis", "chronic invasive fungal rhinosinusitis", and "granulomatous invasive fungal rhinosinusitis".

For the advanced selection of bibliographic sources, the following filters were applied: full-text articles, articles in English, articles published between 2000 and 2016. After a preliminary analysis of the titles, original articles, editorials, narrative synthesis, systematic and meta-analysis articles containing relevant information and contemporary concepts on the etiopathogenesis, diagnosis, and treatment of various forms of FRS were selected. In addition, a search was performed on the lists of bibliographic references of the sources identified in order to highlight relevant additional publications, which were not found during the initial database search.

The information from the publications included in the bibliography was collected, classified, evaluated and synthesized, highlighting the main features of the contemporary vision on epidemiology, etiology, pathophysiology, clinical picture, diagnosis, differentiated diagnosis, complications, treatment and prognosis of non-invasive and invasive FRS forms.

In order to minimize the risk of systematic errors (bias) in the study, a thorough search in the databases was performed to identify the maximum number of publications relevant to the study purpose. Only studies that met the validity criteria were evaluated. Reliable criteria have been used to exclude the articles from the study. Both the researches pointing out positive results and the researches that do not highlight the benefit of the intervention has been analyzed.

If necessary, to clarify some notions were consulted additional sources of information. Duplicate publications, articles that did not meet the purpose of the paper and which were not accessible for full view, were excluded from the list of publications generated by the search engine.

RESULTS

After processing the information identified by the Google Search engine and from the PubMed and Scopus (Elsevier) databases, according to the search criteria, were found 575 articles addressing the topic of FRS. After the primary analysis of the titles, 74 articles were qualified possibly relevant for the given synthesis. After the repeated review of the sources, 52 publications were finally selected relevant to the purpose. The final bibliography comprised 52 articles considered representative for the materials published on the topic of the synthesis article.

The publications which did not reflect the topic addressed, although were selected by the search program, as well as the articles that were not accessible for free viewing through the HINARI database (Health Internet Work Access to Research Initiative) or available in the medical science library of Nicolae Testemitanu State University of Medicine and Pharmacy, were subsequently excluded from the list.

Fungal rhinosinusitis is divided into two categories based on histopathological findings – non-invasive and invasive ones. The term "invasiveness" refers to the invasion of the sinus mucosa and bone, the spread of infection in the adjacent structures and tissues. Non-invasive FRSs are subdivided into saprophytic fungal infections, fungus ball and FRS caused by eosinophils (allergic FRS, eosinophilic mucin RS and eosinophilic FRS), and invasive FRS (IFRS) includes three subtypes – acute IFRS, chronic IFRS, and granulomatous IFRS [7, 11, 12].

Local colonization with saprophytic fungi refers to the asymptomatic infestation of rhinosinus mucosal crusts with fungi, frequently in patients who have previously undergone sinus surgery. The possibility of further growth may lead to the formation of fungus ball. However, most patients with local colonization with fungi have clinical consequences very rarely. They are usually asymptomatic, have a benign evolution and treatment is not necessary [3, 7, 13].

Fungus ball is a relatively less frequent manifestation of FRS, being localized, non-invasive, nonaggressive or little aggressive or extramucosal. According to recent recommendations of some scientists (Thompson G. et al., 2012; Lop-Gros J. et al., 2016), the use of the old and unspecific terms of "aspergillosis", "aspergilloma" and "mycetoma" is not appropriate [13, 14].

Epidemiology. Fungus ball occurs in normal immunocompetent persons, usually at the age of 60-70 years, although in some retrospective studies the age ranged within 14-87 years. There is a considerable and constant female predilection of approximately 57-64%, with a ratio of 1.5-1.9:1 [3, 15, 16].

In general, the disease is unilateral, only one sinus being affected (up to 90-99% of cases) [12, 17]. The most common localization is the maxillary sinus (78-94%), followed by the sphenoid sinus (4-15%). The involvement of ethmoid sinuses (1-15%) is frequently adjacent to the maxillary sinus [14, 17], and the involvement of frontal sinuses is much rarer, but the reason of the involvement is still unexplained [17, 18].

According to Bosi G. et al. (2012), fungus ball accounts for 3.7% of all inflammatory CRS cases requiring surgery [15].

Etiology. The most commonly involved pathogen (in European countries) is Aspergillus (in 90-96% of cases), mainly Aspergillus fumigatus, less commonly Aspergillus flavus, Aspergillus niger and Aspergillus nidulans. The Mucorales species rank second. Other species of fungi are rarely found: Cephalosporium, Candida albicans, Scedosporium apiospermum, Cladosporium [1, 12, 15, 17].

The pathophysiology of sinus fungus ball remains unknown. The disease develops under 2 conditions: the penetration of fungal hyphae and spores into a paranasal sinus and the creation of a medium contributing to the growth of fungi [15, 19, 20].

There are 3 possible theories of fungus ball development: aerogenous, odontogenic and mixed [15, 19, 20]. It has been suggested that immune disorders and / or factors affecting the nasal mucus may be more important in FRS pathophysiology than nasal anatomical variations with obstruction of the ostiomeatal complex [21, 22, 23, 24]. There is growing evidence that, along with infection, inflammatory immune responses to fungi play a major role in the etiology and pathophysiology of CRS [25].

The clinical picture in patients with fungus ball is nonspecific, frequently identical with bacterial CRS resistant to antibiotic treatment. The unilateral symptomatology should attract the clinician`s attention, namely: a sensation of chronic pressure or facial pain that involves one of the paranasal sinuses, these being complemented by possible associated symptoms (mucopurulent or purulent anterio-posterior rhinorrhea, crusts in nasal fossae, cacosmia or dysosmia) [1, 12, 14, 15] Occasionally patients may have unusual symptoms – epistaxis, visual disorders, seizures, fever, cough and proptosis. In the case of sphenoid localization of fungus ball, headache and facial pain are common [1, 14, 15]. Symptoms are usually long lasting, may be present for months or even years, and fungus ball may be occasionally detected. About 18% of patients may be asymptomatic and 10% have nasal polyps (NP) [17, 26, 27].

Nasal endoscopic examination is nonspecific in most cases. Sinusoscopy (in the case of maxillary localization) can highlight the characteristic feature of "fungus ball" and allows collecting the material for fungal and histopathological analysis [1].

The classical radiological examination can identify focal hyperdense areas, simulating a foreign body, which in fact represents calcium phosphate deposits agglomerated in the areas of mycelial necrosis. Their unilateral localization is evocative [1].

Computed tomography (CT) imaging is the most reliable diagnostic imaging method, although the specific diagnosis of FRS requires microscopic confirmation. In the case of CT examination, some signs are evocative for the fungal etiology (but without being pathognomonic) or, rather, their association: the presence of a "metallic tone" image at the intrasinus level with a foreign body feature; the existence of multiple calcifications or microcalcifications on sinus opacity; heterogeneous content, unilaterally or, more rarely, in several sinuses; lack of osteolysis areas, possibly only bone erosion, probably caused by prolonged mechanical compression, exerted by fungus ball on bone walls, and chronic non-granulomatous inflammation of the mucosa [12, 14, 15, 26].

Magnetic resonance imaging (MRI) is much less useful in cases of FRS, but it is indicated in complicated forms, with areas of osteolysis and extension in adjacent tissues (invasive FRS). Sinus content appears on MRI as a hypointense signal or even absent signal at T1 and T2 (pseudotumoral image), due to high protein density and dehydration of these caseous masses, with increased concentrations of ferromagnetic elements [12, 26].

The medical history, clinical examination, endoscopic examination and imaging examination present valuable information only for the suspicion of fungus ball, the definitive diagnosis is based on the macroscopic evaluation, biopsy and histopathological examination of surgical parts [1, 15, 28].

Fungus ball, from an anatomopathological point of view, is an extramucosal accumulation of dense conglomerations of degenerating fungal hyphae, pressed as a layer or sphere into the sinus cavity. The hyphae branch at an angle of 45º and measure 3-6 micrometers in diameter, and the sporulated structures reach up to 30 micrometers [12, 26]. The lack of fungal invasion in the sinus mucosa, blood vessels or bone, the absence of allergic mucin in sinuses and the lack of granulomatous reaction [1, 14, 18] are important for the positive diagnosis of fungus ball.

The direct mycological examination involves the examination on the microscope slide of the caseous mass taken from the sinus and microscopic visualization of the mycelial filaments and positive results in 62-94% of cases [1, 12, 14, 18, 26]. Mycological cultures are less important in the case of sinus fungus ball, because of the fungal growth in only 23-50% of the cultures and the false-positive results by accidental contamination, but also because of the ubiquitous saprophytic spores without pathological significance in healthy persons [1, 15, 17, 29].

Complications are occasionally observed in untreated fungus ball of the paranasal sinuses. Recurrent bacterial RS is the most common [17].

The differentiated diagnosis of fungus ball is made with invasive FRS (IFRS), bacterial CRS, rhinoscleroma, benign sinus lesions (mucosal cyst, antrochoanal polyp, mucocele, hematoma, inflammatory pseudotumor), benign sinus tumors (sinonasal papilloma, fibro-osseous lesion, salivary gland tumors, mesenchymal tumors – fibroma, lipoma, myxoma etc.), malignant sinus tumors (carcinoma, adenocarcinoma, lymphoma) [28].

Treatment. The purpose of the treatment of patients with fungus ball is surgical removal of the fungal hyphae mass with the restoration of drainage and ventilation of the affected sinus. In most cases, the condition is managed by endoscopic techniques [12, 15, 30], and open surgery (Caldwell-Luc), whether associated or not associated with endoscopic treatment, is required in a small number of cases [15, 17, 28]. Both techniques – endoscopic and open surgery, have similar results, but endoscopic sinus surgery is considered the "gold standard", less invasive method and first-line surgery, with a success rate of 97% and a negligible complication rate [15, 28, 30].

Both intraoperatively and postoperatively, it is essential to perform sinus irrigation with saline solution, which increases the mucociliary clearence, facilitates the elimination of mucoid secretions and the removal of any fungal residues. Intrasinus cortisone instillations may also be used intraoperatively, and systemic or local antifungal treatment is rarely required [17, 31].

The prognosis in patients with fungus ball treated surgically (wide opening of the affected sinus and complete removal of fungal hyphae) is very good [32]. The recovery rates are 98-100% [18]. In the case of rigorous surgery, fungus ball recurrences are an exception – the general recurrence rates reported in the literature range from 0% to 10% of cases [32].

Thus, fungus ball of the paranasal sinuses has a distinctive clinicopathological presentation. The disease occurs more frequently in elderly patients, with a mean age of 64 years, and has a female predominance. Classically, it involves a single paranasal sinus in more than 90% of cases, most commonly the maxillary sinus, and associated bone destruction may be present. Characteristic imaging findings and histopathological examination confirm the diagnosis. Calcification and / or erosion of the inner sinus wall on CT scan are considered the most specific and have a strongly suggestive role for a correct diagnosis. At surgery, there is usually a cheesy, friable, green, brown, black or yellow mass. The lesion is easily separated from the underlying mucosa. There is a characteristic histopathological image – luminal aggregation of fungal hyphae. Endoscopic sinus surgery is the basic treatment with excellent results and limited morbidity that does not require local or systemic antifungal treatment.

Allergic fungal rhinosinusitis (AFRS) is a distinct and frequent form of FRS with NP formation, an immunologically mediated non-invasive fungal inflammation, a chronic, hypertrophic and refractory sinus disease, with a marked recurrence tendency. The disease is characterized by the accumulation of allergic fungal mucin in the nasal sinuses, type 1 hypersensitivity, characteristic histological image and a predilection for mucocele formation and bone erosion [1, 33, 34, 35].

Epidemiology. AFRS is increasingly common in different geographical regions, especially in hot and humid climate. AFRS affects adolescents and young adults between the ages of 20 and 42, with the mean age of diagnosis of 21.9 years. Patients are generally from vulnerable socio-economic groups, usually immunocompetent and with a history of atopy, although not all have a history of allergic rhinitis (AR) or asthma [36, 37, 38].

The actual incidence and prevalence of AFRS is unknown. The overall incidence of the disease is estimated in 5-12% of all cases of hypertrophic sinus disorders that require surgery. AFRS, diagnosed according to the Bent and Kuhn criteria, has geographical variations and affects 4-25%, and in North India even up to 51%, of all CRS cases requiring surgery [38, 39, 40]. Asthma is associated in 33-100% of patients with AFRS, in over 27% – hypersensitivity to aspirin, in 60-100% – a history of AR, and 70-90%s – signs of atopy [35, 39, 41] .

Etiology. The condition is considered an allergic reaction to fungi. The causative fungi are usually from the Dematiaceous family – one of the many specific groups of fungi, recognized for its potential pathogen. Among them, Bipolaris spicifera is the most common species. Among other types of fungi are Aspergillus, Alternaria, Curvularia, Exserohilum, Drechslera, Helminthosporium and Fusarium [13, 39, 40, 41].

The pathophysiology of AFRS remains unknown and controversial. Allergy mediated by IgE (type I hypersensitivity) and possibly mediated by IgG – immune complexes (type III hypersensitivity), according to the Gell and Coombs classification, with the subsequent onset of an intense inflammatory response with eosinophils and tissue edema is considered a physiopathologically important factor in the development of AFRS. Tissue edema and other risk factors (septal anatomical changes or hypertrophy of the conchae with the obstruction of the sinus ostium) favor stasis of sinus secretions, which creates an ideal anaerobic environment for the further proliferation of fungi with the increased degree of antigenic exposure and the possibility of triggering allergic reactions. At one point, the cycle becomes self-perpetuating and results in the process product: allergic mucin – the material that fills the sinuses involved in patients with AFRS. The lesion may extend to the involvement of other sinuses, causing bone expansion and erosion [13, 35, 37].

The AFRS diagnosis begins with a detailed history. There are some clinical aspects that present a warning sign for the clinician: patient`s age (usually young people, with a mean age of 22 years), immunocompetent, with a long-term clinical picture of CRS [1, 33, 37, 39]. On physical examination, NPs are a universal endoscopic finding, but in more severe cases diplopia, ptosis and telecanthus can be identified [34, 37, 40].

Nasal crusts develop in sinus cavities having a semi-solid, thick and viscous consistency, yellow-green, white-brown, gray, brown or black colour, a peanut butter consistency due to bacterial superinfection or fungal material. It consists of fungi and mucin (a glycoprotein-based secretion, rich in carbohydrates) – eosinophilic mucus or allergic fungal mucin. Eosinophils are the predominant and consistent cellular component of eosinophilic mucus [38, 41, 42].

The histopathological examination is the most important part of AFRS diagnosis. Histological evaluation of the biopsy or surgical specimen reveals a triad: eosinophilia, Charcot-Leyden crystals and extramucosal branched non-invasive fungal hyphae. The presence of fungi in mucin, but not in the tissues of patients with AFRS, differentiates AFRS from IFRS [37, 40, 43]. The fungal cultures of the eosinophilic mucin may have some evidence to support the diagnosis and treatment of AFRS, but must be interpreted with caution. Histological examination of the allergic mucin remains the most reliable indicator of AFRS [37].

The CT images frequently show a dense, heterogeneous, asymmetrical material that fills and extends one or more paranasal sinuses. There are areas of heterogeneous intensity of the signal in the affected sinuses, a sign called "double density". In more severe cases, due to erosion of the adjacent bones and extension of sinuses, the disease extends into the adjacent tissues, including the spaces occupied by vital organs – brain, orbit and large vessels. Depending on the study, the frequency of bone erosion ranges from 19% to 98% [37, 38, 40]. The characteristic features of MRI are the central hypointense areas or the lack of signal in T1/T2, with the increase of the peripheral signal T1 and T2 [1, 35, 40].

The most commonly used diagnostic criteria for AFRS were proposed by Bent and Kuhn in 1994. In order to make a positive diagnosis, patients must meet all 5 major criteria. Minor criteria only serve to support the diagnosis, to describe each patient individually [21, 34, 38].

The major diagnostic criteria for AFRS are: a) eosinophilic mucin without fungal invasion; b) positive fungal staining of sinus content, without fungal invasion in sinus tissue; c) NP with an incidence ranging from 75% to 100% of cases; d) characteristic imaging signs reflecting the structure of the excrescences developed in sinuses and e) type I hypersensitivity to fungi (history, skin tests, or serological tests) [24, 39, 43].

The other 6 criteria are minor: 1) history of asthma; 2) unilateral predominance; 3) imaging evidence of bone erosion; 4) positive rhinosinus fungal culture; 5) presence of Charcot-Leyden crystals in samples taken during surgery; and 6) serum eosinophilia [1, 35, 39].

Differential diagnosis. The main problem of the diagnosis is the differentiation of AFRS from other fungal diseases of the paranasal sinuses: local colonization with saprophytic fungi, fungus ball, and eosinophilic mucin RS, different forms of IFRS etc. (Table 1) [1, 37, 42].

The optimal treatment of patients with AFRS is still unclear to date and there is no successful long-term treatment. The management of AFRS requires the removal of secretions for antigen elimination and restoration of normal sinus drainage (surgical treatment) and recurrence control (drug treatment). Combinations of surgical and medical methods (corticosteroids, antifungal drugs and immunotherapy) are used to manage the complications with symptoms relief. The purpose of the surgery is to completely eliminate local secretions, allergic mucin and fungal residues, to perform the extraction of NP, marsupialization of the involved sinuses by preserving and maintaining the integrity of the underlying mucosa and access for post-operative treatment with the subsequent long-term prevention of recurrence either by immunomodulation (immunotherapy and/or corticosteroids) or fungistatic antimicrobial remedies. Endoscopic sinus surgery is required for most cases and is an important component of AFRS management [24, 38, 39].

The accepted preoperative medical regimen includes the initiation of systemic corticosteroid therapy (0.5-1.0 mg/kg/day of prednisone) approximately a week prior to surgery to reduce intranasal inflammation and NP volume. Corticosteroids are the most effective agents in the prevention of relapses, and in selected cases are used as a first-line treatment. In addition, antibiotics are administered preoperatively as a result of common post-obstructive concomitant bacterial RS [33, 37].

The post-operative care begins immediately after surgery by saline nasal irrigation. Systemic corticosteroids, initiated before surgery, are continued during the postoperative period. Corticosteroids, administered systemically or in the form of nasal sprays, are the most effective agents in preventing recurrences and selecting cases for first-line treatment. Prednisolone, administered orally, beginning with 0.4-0.6 mg/kg/day post-operatively is recommended with a gradual reduction by 0.1 mg/kg/day every 4 days to 0.2 mg/kg/day. After maintaining the mucosa normal for 4 months, the dose is reduced to 0.1 mg/kg/day for another two months. Intranasal local corticosteroids (budesonide) are accepted as standard treatment in long-term postoperative medical management [24, 34, 35, 38].

Non-steroidal treatment is attractive and rational, but with minimal evidence of efficacy, and includes the use of leukotriene receptor antagonists or leukotriene synthesis inhibitors (montelukast), selective anti-IgE monoclonal antibodies (omalizumab), immunotherapy with specific fungal antigens systemic antifungal preparations (itraconazole – 200 mg twice daily orally, between 3 weeks and 6 months postoperatively, ketoconazole, fluconazole) and steroid-impregnated antibiotic gels [24, 38, 39, 40].

Immunotherapy with specific fungal antigens may be considered as an additional treatment option for treating concomitant allergic disease in patients with AFRS [40]. Immunotherapy reduces crust formation, NP development, the need for systemic corticosteroids and the rate of repeated surgery [35].

Surgery, both alone and in combination with other medical treatments, leads to improved outcomes, but the recurrence rate of NP and eosinophilic mucus is extremely high. Conservative medical treatment, without surgery, is not effective in the long term [24, 33, 34].

A better understanding of AFRS has led to some changes in the management concept of this condition. The surgical treatment has shifted from radical interventions to more conservative procedures with tissue preservation, based almost entirely on endoscopic techniques. Medical therapy has shifted from systemic antifungal treatment to various forms of local and immunomodulatory treatment. Currently, endoscopic surgery combined with anti-inflammatory treatment is considered the gold standard [37, 39, 40].

Complications. In addition to the potential complications of rhinosinus surgery (risk of orbital and/or intracranial penetration), there is an additional risk of damage to exposed structures (dura mater and orbit), as the disease is often limited to these structures, without invading them [42]. The extension of AFRS beyond the limits of the paranasal sinuses occurs in orbit, the anterior, middle and posterior cranial fossae [37, 44].

Orbital involvement without loss of vision has been found in 14.6% of patients and results, more frequently, in proptosis (6.1%) and telecanthus (7.3%). Vision loss (3.7%) is reversible with immediate surgical treatment of the underlying condition [37].

Evolution and prognosis. AFRS is a non-invasive, resistant and immunologically mediated fungal inflammation, with a marked tendency to recur. Surgery for AFRS without postoperative medical treatment is associated with recurrence rates of up to 100%. Global rates of early (months) or late (years) recurrence vary from 10% to 100% with varying degrees of severity [35, 37, 40].

FRSs determined by eosinophils represent a heterogeneous group of entities, of which AFRS, eosinophilic mucin RS and eosinophilic FRS are distinct sub-categories. These conditions are related and poorly differentiated syndromes, and all refer to CRS (lasting >12 weeks), accompanied by opacification of sinuses with allergic mucin or a dense and thickened mucus, ranging from light brown to brown or black [13].

The reason for this sub classification is accounted for the fact that eosinophilic inflammation is an important feature in the pathogenesis of CRS, even though multiple causal factors, namely – allergic and non-allergic ones, contribute to it. A strong clinical and pathological association of eosinophilia with asthma is another important observation. In contrast, the pathological processes, considered most likely in CRS without eosinophilic inflammation, are the changes that affect the local or systemic (innate or acquired) immunity, mucociliary clearance, or sinus ventilation [25].

Eosinophilic mucin RS was described by Ferguson in 2000 as a systemic disorder with immunological control disorder, associated with upper and lower airway eosinophilia and lack of fungi in eosinophilic mucin [6, 7, 45]. Unlike AFRS, in which about 40% of patients have asthma, in eosinophilic mucin RS more than 90% of patients have asthma. Eosinophilic mucin RS develops bilaterally, whereas AFRS may be unilateral. There is no evidence of Aspergillus infection in these patients, but eosinophilic mucus is similar to that seen in AFRS. Eosinophilic mucin RS is similar to AFRS but develops according to other mechanisms. AFRS represents an allergic response to fungi in predisposed persons, and eosinophilic mucin RS is caused by a systemic disorder of immunological control. Ferguson found significant clinical and immunological differences between AFRS and eosinophilic mucin RS [46]. Four mechanisms have been proposed for the pathogenesis of eosinophilic mucin RS: AFRS, non-allergic eosinophilic FRS, superantigen inducing eosinophilic RS and eosinophilic RS exacerbated by aspirin [3, 6, 7, 45].

Therefore, eosinophilic mucin RS is a uniform bilateral disorder, which occurs more frequently in older people, combined with a significantly higher frequency of asthma, an increased incidence of aspirin sensitivity, and frequently an IgG1 deficiency. Total IgE levels are increased in patients with both entities but are significantly higher in AFRS. IgG1 deficiency is common in eosinophilic mucin RS and is rarely reported in AFRS. Type I hypersensitivity (higher IgE levels), Charcot-Leyden crystals, bone erosion and heterogeneous opacity with sinus expansion on CT scans are significantly associated with AFRS, and asthma is significantly associated with eosinophilic mucin RS [6, 7, 45].

Eosinophilic FRS. Contrary to the prevailing view that fungi are responsible for CRS in only a selected group of patients with distinct pathophysiology, Ponikau et al. demonstrated in 1999 the presence of fungi in the nasal mucus in 96% and found type I hypersensitivity in <25% of patients with CRS. Scientists have found in the mucus fungi together with eosinophils and eosinophil degradation products. Often, eosinophils detected in mucus were in clusters with several Charcot-Leyden crystals, but mostly in the form of cellular and crystal residues. Typical radiological features for AFRS may be present, but they are not mandatory, nasal polyposis is not mandatory either [3]. The scientists renamed "allergic mucin" into "eosinophilic mucin" and coined the term "eosinophilic FRS" [6, 7, 36].

Ponikau et al. (1999), further developed the hypothesis, demonstrating that fungi cause eosinophilic inflammation with a high level of major basic protein in mucus, in the absence of type I hypersensitivity reaction in CRS patients. Major basic protein damages the nasal epithelium of the lumen and allows secondary bacterial infections to affect the epithelium. The concept of non-atopic eosinophilia to fungi is also supported by studies, which have shown that mononuclear cells in the peripheral blood of CRS patients show exaggerated humoral and cellular responses after exposure to frequent airborne fungi species, in particular to Alternaria species. Such reactions lack in healthy subjects in the control group. The aberrant inflammatory and immune response in ubiquitous fungi may explain chronic eosinophilic inflammation in CRS patients [6, 7, 36].

Unlike AFRS, which is an IgE-dependent disease, eosinophilic FRS is a non-IgE-dependent disease [3]. Thus, in AFRS there is an allergic (eosinophilic) mucin with many eosinophils and the presence of non-invasive fungi with increased levels of specific fungal IgE. Patients with eosinophilic FRS and eosinophilic mucin RS do not have specific IgE and differ by the presence (eosinophilic FRS) or absence (eosinophilic mucin RS) of the microscopically visualized fungi in eosinophilic mucin.

Eosinophilic mucin disorders can be broadly divided into 2 categories – non-fungal and fungal ones. The non-fungal group includes eosinophilic mucin RS, and the fungal group includes AFRS and eosinophilic FRS with the presence of fungal hyphae [3, 6].

AFRS, eosinophilic mucin RS and eosinophilic FRS could be different manifestations of the same pathological process, with considerable overlap of clinical features, imaging and immunological parameters and the possibility of transition from one form to another in the same patient [3, 6, 7, 45 ].

Invasive fungal rhinosinusitis is a group of disorders with three subtypes (acute IFRS, chronic IFRS, and granulomatous IFRS), which requires urgent diagnosis and early treatment due to the reserved vital and functional prognosis. This condition occurs in immunocompromised patients, patients with neutropenia, immunosuppressive therapy, hematologic disease, malignancies, organ and bone marrow transplantation, advanced HIV infection, diabetes mellitus, protein malnutrition, and corticodependent patients. Much less often (but cases are reported), IFRS can occur in immunocompetent persons. Thus, most patients with IFRS already have poor physical development, due to previous illnesses or treatment-related diseases, and the prognosis is reserved and mortality is high. In addition, these factors present difficulties in the diagnosis and treatment of IFRS, which can progress rapidly with significant disorders. Therefore, the diagnosis of IFRS should be established as soon as possible for the initiation of aggressive surgical and systemic antifungal treatment [1, 13, 47, 48].

The species Aspergillus and Mucormycosis are the most common organisms in IFRS. Most (about 80%) invasive fungal infections are caused by Aspergillus fumigatus. Aspergillus flavus is the second most common pathogen species (approximately 15-20%), Aspergillus niger and Aspergillus terreus occur to a lesser extent [1, 48].

The diagnosis of IFRS entails the following diagnostic criteria: (1) RS confirmed by imaging examination; (2) histopathological evidence of fungal invasion of the mucosa, submucosa, blood vessels or bones of the paranasal sinuses; and (3) necrotic tissue with minimal infiltration of inflammatory cells [1, 4, 47, 48].

The clinical suspicion of IFRS, based only on the clinical picture, is difficult to formulate, although the fungal etiology should be considered in cases of chronic purulent rhinosinusitis in two or more prolonged antibiotic treatments [1, 47].

The otorhinolaryngologic clinical examination can provide important diagnostic information in patients with risk factors for IFRS. The most common sign is ischemic nasal mucosa with pale and edematous areas, which bleeds very little and is painful when performing various invasive maneuvers. Black eschars usually occur in the last stages of the disease due to vascular thrombosis and tissue necrosis and are considered almost pathognomonic for IFRS. In the case of orbital involvement, limitation of the movements of the eyeballs is detected, as well as ptosis or loss of vision. The invasive potential of the disease can lead to the involvement of skin, hard and soft palate or intracranial extension, which must exclude the diagnosis of bacterial infection [1].

Imaging techniques offer significant diagnostic help, especially computerized tomography (CT). Although many aspects of CT are suggestive of IFRS, none of them has been established as pathognomonic. Some studies have reported that adipose tissue infiltration may be periantral and "may represent the earliest imagistic evidence of invasive fungal disease". Other authors have found that thickening of the sinus mucosa with unilateral nasal inflammation in patients at risk may be early predictors of IFRS [1].

Magnetic resonance imaging (MRI) should be performed in patients with suspected intracranial extension of IFRS, this method being more sensitive to identifying intracranial or orbital lesions [1].

The histopathological examination is essential and it is the one that can diagnose the disease with certainty, finding necrosis, inflammation and mycelial filaments [1].

Treatment of acute or chronic IFRS consists of the reversal of immunosuppression, adequate systemic antifungal treatment and prompt aggressive surgical debridement of the affected tissues [48].

Acute invasive fungal rhinosinusitis is, in general, a rare condition, but the most dangerous form of FRS and the most common form of IFRS, with up to 4 weeks of rapid progression, endangers life and requires immediate medical care. Patients with AIFR previously had survival rates of 20-75%, correlating with the management of the underlying condition. Recent studies have highlighted that along with the improvement of diagnosis, treatment and prophylaxis (active surveillance of the at-risk population, reversal of neutropenia and other causes of immunosuppression, reversal of diabetic ketoacidosis, prompt aggressive surgical debridement and systemic antifungal chemotherapy), survival rates improved and mortality reduced from 50-80% to about 18% [12, 48, 49].

Etiology and pathogenesis. The disease occurs quite rarely – in up to 4% of patients with bone marrow transplantation – especially affecting severely immunocompromised patients. People diagnosed with leukemia, acquired immunodeficiency syndrome, aplastic anemia, uncontrolled diabetes mellitus or hemochromatosis are the most vulnerable. Patients with organ or bone marrow transplants, anticancer chemotherapy and long-term corticosteroid use are also vulnerable [42, 50, 51].

The infection is often attributed to fungal invasion, which previously colonized sinuses, or inhaled fungal spores. The Aspergillus or Zygomycetes fungi are the most common causative agents, triggering the condition which has a sudden and extremely aggressive evolution. Fungi develop and progress rapidly by invading arterial blood vessels. Tissue necrosis, secondary to blood flow obstruction, leads to tissue infarction which is pale, gray or black. Fungi spread and invade the adjacent areas (hard palate, orbit, cavernous sinus, cranial nerves, skull base, carotid artery, and brain) through the bone tissue of sinuses. The disease can spread quickly (hours or days) and can endanger life if it is not timely diagnosed or treated [12, 47, 50, 51].

Clinical picture. The first symptoms can mimic bacterial CRS and include fever, nasal congestion, facial pain, epistaxis, and headache. Thereafter, patients may experience a "latent" phase, in which pain may transiently disappear with the rapid onset of severe signs and symptoms. Late symptoms include a sensation of facial numbness or numbness of the palate, ptosis, vision disorders, facial edema, toothache, central neurological symptoms, and even death. The disease, especially in the case of intracranial extension, can be fatal with short-term mortality rates of 30-83% of patients, and in the case of untreated disease – a mortality rate of 97-100% [12, 49, 50].

The most common predisposing factor to acute IFRS is neutropenia, especially less than 1000 neutrophils per µL of blood, which significantly reduces the inflammatory response and the body's ability to fight infection [50, 52].

Acute IFRS is best visualized by nasal endoscopy and usually affects the nasal septum, conchae and paranasal sinuses. There are necrotic ulcers of the nasal septum (eschars), as the blood vessels are affected their tissue becomes necrotized [12, 42, 50].

The CT imaging should be rapidly used in acute IFRS diagnosis. The main features suggestive for this condition include nasal edema, mucoperiosteal thickening of sinuses, bone erosion, orbital invasion, edema of the facial soft tissue, and infiltration of the periantral or retroantral soft tissues. Although these findings are not pathognomonic for acute IFRS, severe unilateral thickening of the nasal mucosa and soft tissue, including the conchae, septum, and lower nasal part are the most common findings on CT scans. Bone damage can be easily seen on CT images with an intracranial and intraorbital spread of inflammation, a highly suggestive picture for acute IFRS, but often found late. There is a predilection for unilateral involvement of the ethmoid and sphenoid sinuses [4, 12, 50].

MRI is another useful imaging technique for the detection of acute IFRS. The method is more sensitive, compared to CT, in the early screening and diagnosis of acute IFRS, it is superior in the evaluation of the intracranial and intra-orbital spread of the disease [4, 12, 50].

However, the "gold standard" of acute IFRS diagnosis is histopathological examination, which, however, is time-consuming and may delay the diagnosis and treatment. Histopathological examination reveals fungal hyphae in sinus mucosa, submucosa, blood vessels or bones and soft tissue invasion [4].

Diagnosis. The diagnostic criteria proposed for acute IFRS include: (1) thickening of the mucosa or air-fluid levels corresponding to sinusitis on imaging scans and (2) histopathological evidence of fungal hyphae in mucosa, submucosa, blood vessels or sinus bones [50].

Physical examination and nasal endoscopy are essential for the determination of signs of considerable edema, pallor, ischemia or necrosis of the nasal mucosa and paranasal sinuses. Imaging along with the physical examination and biopsy endoscopy are crucial for diagnosing the condition [2, 4].

Given the high mortality rate and non-specific early symptoms, acute IFRS should be suspected in any patient who has symptoms of CRS and a history of immune system dysfunction or poorly controlled diabetes mellitus [49].

Acute IFRS treatment consists of (1) prompt aggressive surgical debridement of the affected tissues, representing the "gold standard"; (2) reversal of immunosuppression, and (3) adequate systemic antifungal treatment (amphotericin B – intravenously, 0.25-1.0 mg/kg/day up to a total dose of 2-4 g for 6-8 weeks) [4, 46, 50]. After exclusion of Mucormycoses species, voriconazole – an effective remedy for the treatment of Aspergillus and Dematiaceous species, (6 mg/kg in 2 doses and then 4 mg/kg every 12 hours) is administered intravenously [13].

If acute IFRS is refractory or the patient has intolerance to amphotericin B, isavuconazole (Cresemba) is the alternative treatment – a newly approved, clinically safe and effective antifungal agent. The drug has distinct advantages over amphotericin B and posaconazole, as it is not associated with nephrotoxicity, has excellent absorption and bioavailability, and is well tolerated [49].

Antifungal preparations may be administered orally and intravenously, depending on the severity of infection, the causative agent, the ongoing immunosuppressive treatment or the underlying disorder [50].

Given the speed of acute IFRS evolution, treatment should be prompt. It consists of a combination of surgical therapies and aggressive antifungal medication, to restore patient`s immunity. Repeated surgery is often required, just to be able to completely clean the area and stop the disease development. The combination of surgical and antifungal treatment has a recovery rate of 30-80% and a mortality rate of 10-40%. The lowest rate of healing is associated with the intracranial extension of the lesion [13, 42, 46, 50].

Increasing the absolute number of neutrophils in patients with quantitative neutropenia is an important step in the treatment of acute IFRS [50].

The prognosis is extremely poor if the host immune response does not improve. Patients on immunosuppressive therapy should probably discontinue the treatment [50].

Chronic invasive fungal rhinosinusitis, unlike acute IFRS, is much rarer, evolving over 12 weeks and presenting a much slower destructive process. The insidious progression occurs over several months to years, when fungal organisms invade the mucosa, submucosa, blood vessels and bone walls of the paranasal sinuses. The extension to the vascular network or adjacent structures and inflammatory reactions are very rare. The most affected are the ethmoid bone or sphenoid sinuses, but other sinuses can also be affected as easily [12, 48, 50].

The disease develops for up to three months, being frequently triggered by the species of fungi Mucor, Rhizopus, Aspergillus, Bipolaris and Candida [12, 13, 50].

Patients who have a history of CRS, are usually immunocompetent, but patients with diabetes mellitus or immunocompromised are sensitive. Symptoms may include pain of the paranasal sinuses, sero-haemorrhagic nasal secretion, epistaxis, NP and fever. In the case of lesion extension, the patients can complain of periorbital edema, ptosis, vision disorders up to blindness, paralysis of the cranial nerves and involvement of the soft tissues. The erosion of the cribriform plate can result in chronic headache, seizures, focal neurological deficits. Invasion of the pterygopalatine fossa, infratemporal fossa, and skull base may manifest through cranial neuropathy [12, 42, 50].

Intranasal examination reveals nasal congestion and polypoid mucosa. Masses of soft tissue can be identified. Non-contrast CT shows soft tissue hyperattenuation in one or more paranasal sinuses, which can mimic a malignant tumor or masses by destroying sinus walls and extending beyond its limits. On MRI images the signal intensity decreases on T1 images and the signal intensity decreases significantly on T2 images. Shiny mottled changes or irregular bone destruction can also be found in the paranasal sinuses. Sclerotic changes in the bone walls of the affected sinuses can also be noted, which represent a chronic sinus lesion [12].

The invasion of adjacent structures – orbit, cavernous sinus and anterior cranial fossa, can lead to epidural abscess, abscess or parenchymal encephalitis, meningitis, cavernous sinus thrombosis, osteomyelitis, mycotic aneurysm, stroke and hematogenous dissemination [12].

As in the case of acute IFRS, the recovery of the immune balance is essential, by surgical exenteration of the affected tissues and developed formations and the administration of the systemic antifungal treatment [12, 51]. Therapy should be as aggressive as for acute IFRS due to high mortality and morbidity rates [12].

Granulomatous invasive fungal rhinosinusitis, also known as primary paranasal granuloma or indolent FRS, is found in patients with an easily identifiable immune deficiency. Moreover, the incidence of this disease is prevalent in Sudan, India, Pakistan and Saudi Arabia. Granulomatous IFRS is usually caused by Aspergillus Flavus. The evolution may last from a few months to a few years, and the symptoms include chronic migraines and gradual edema of the face, until vision can be affected [12, 13, 42, 50].

Patients are generally immunocompetent. Symptoms include ptosis or a mass extended in the nose, orbit, or paranasal sinuses. The name of the disease comes from a particular feature used in the diagnosis – the development of some non-caseous inflammatory granulomatous infiltrations with giant cells and hyphae (inflammatory nodular lesions). The evolution is chronic and indolent with an eventual extension beyond the walls of the paranasal sinuses – in orbit and / or intracranially [12, 42, 50].

Imaging findings are rare and similar to those of chronic IFRS. The condition is often detected only when the patient presents with a mass growing in the area of the cheek, orbit, nose or paranasal sinuses. The microscopic analysis shows specific granulomatous formations and the presence of Aspergillus flavus fungi. Treatment includes surgery (debridement) and antifungal remedies [13, 42, 50]. Treatment with itraconazole 8-10 mg/kg/day decreases the high postoperative relapse rate [42].

Table 1. Differential diagnosis of different forms of fungal rhinosinusitis.

Parameter

Fungus ball

Allergic fungal rhinosinusitis

Invasive fungal rhinosinusitis

Epidemiology

A localized and low frequency disease which affects normal immunocompetent persons aged 60-70 years.

A common disease in geographic regions with hot and humid climate which affects immuno-competent young people with a history of atopy, aged 20-42 years.

A rare disease which affects immunocompromised patients and patients with poorly controlled diabetes mellitus.

Incidence

3.7% of all chronic inflammatory rhinosinusitis cases requiring surgery.

4-25% of all chronic inflammatory rhinosinusitis cases requiring surgery.

0.5-4% of patients with bone marrow transplantation.

Etiology

Aspergillus fumigatus.

Bipolaris spicifera.

Aspergillus fumigatus and Aspergillus flavus.

Localization

Unilateral location, affecting just one sinus (most commonly the maxillary sinus).

Multiple paranasal sinuses are affected, bilateral involvement.

There is a predilection for unilateral involvement of ethmoid and sphenoid sinuses.

Invasiveness

Non-invasive, extramucosal.

Non-invasive, extramucosal.

Tissue fungal invasion with extension into adjacent areas.

Pathophysiology

Aerogenous, odontogenic and mixed theories

Immunologically mediated: allergy mediated by IgE (type I hypersensitivity) and IgG (type III hypersensitivity).

Severe immunocompromised patients with neutropenia.

Clinical picture

Nonspecific, long-lasting, frequently identical with chronic bacterial rhinosinusitis refractory to antibiotic treatment.

Nonspecific, long-lasting, frequently identical with chronic bacterial rhinosinusitis refractory to antibiotic treatment.

The first symptoms can mimic chronic bacterial rhinosinusitis, severe signs and symptoms occur subsequently.

Endoscopic assessment

Cheesy, friable, green, brown, black or yellow mass, easily separable from the underlying mucosa ("fungus ball").

Nasal polyps, nasal crusts, semi-solid, thick, viscous yellowish-green, white-brown, gray, brown or black consistency, peanut butter consistency (eosinophilic mucus).

Significant edema, pallor, ischemia or necrosis of the nasal mucosa and paranasal sinuses.

CT

Unilaterally partial or total heterogeneous hyperdense sinus opacity with microcalcifications or metallic appearance, lack of osteolysis areas, bone erosion.

Areas of heterogeneous intensity ("double density" sign) and erosion of adjacent bones with the disease extension in adjacent tissues in more severe cases.

Mucoperiosteal thickening of the sinus mucosa with unilateral nasal inflammation, nasal edema, bone erosion and destruction with intracranial and intraorbital invasion.

MRI

Hypointense or absent signal on T1 and T2 (pseudotumor image).

Hypointense signal or no signal in the central areas with increased peripheral signal on T1 and T2.

Hypointense signal on T1 images and significantly reduced signal on T2 images, invasion of adjacent structures.

Histopathological examination

Extramucosal accumulation of dense conglomerates of degenerated fungal hyphae, without histological evidence of fungal invasion of the mucosa, blood vessels or bone.

Eosinophilic mucin containing eosinophils, Charcot-Leyden crystals and non-invasive branched extramucosal fungal hyphae.

Necrosis, inflammation and fungal hyphae in sinus mucosa, submucosa, blood vessels or bones and soft tissue invasion.

Evolution

Slow, benign and oligosymptomatic.

Treatment-resistant, frequent recurrences.

Rapid, high mortality rate in acute invasive fungal rhinosinusitis, chronic and indolent with eventual extension in chronic invasive fungal rhinosinusitis and granulomatous invasive fungal rhinosinusitis.

Complications

Occasionally recurrent bacterial rhinosinusitis.

Extrasinus complications with invasion of the orbit and cranial fossae.

Extrasinus complications with orbital and intracranial extension.

Treatment

Complete (endoscopic or surgical) extraction of fungal concretions, sinus irrigation with saline solutions.

Complete (endoscopical or surgical) removal of allergic mucin and nasal polyps, recurrence management (treatment with corticosteroids, antifungal medication and immunotherapy).

Prompt aggressive surgical debridement of affected tissues, reversal of immunosuppression and appropriate systemic antifungal treatment.

Prognosis

Very good, with a recovery rate of 98-100% and low recurrence rate.

Good with frequent recurrences.

Extremely weak if the host immune response does not improve.

CONCLUSIONS

FRS is an important clinical issue with various manifestations, which should be considered in all immunocompromised patients and patients with CRS. It can be non-invasive or invasive, with five main subtypes.

Fungus ball occurs in a single sinus, most commonly in the maxillary sinus, and the affected individuals are not usually atopic. The sinuses contain hyper-attenuated material and there may be some evidence of a chronic rhinosinus disease or smooth bone erosion. Surgical removal is the method of choice, the disease recurrence being unusual.

AFRS is a condition of young atopic individuals. There is usually pansinusitis with expansion and thinning of the affected sinuses. The sinus content is hyper-attenuated and is characterized by an increased intensity of T1 signal and reduced intensity of T2 signal on MRI images. Surgical removal and antiallergic treatment are the main management methods, without the need for systemic or local antifungal toxic treatment.

Acute IFRS affects immunocompromised patients and patients with poorly controlled diabetes mellitus. Orbital and intracranial invasion is common, and mortality is high, except for early detection and aggressive treatment. The imaging features are subtle in the early stages and require attention to detect the early signs of invasion.

Chronic IFRS and chronic granulomatous IFRS are characterized by a prolonged clinical evolution with a slow progression of the disease. The imaging features may mimic aggressive neoplastic lesions. Orbital and cranial invasion is the common feature of these chronic sinus disorders.

Declaration of conflicting interests

Nothing to declare.

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