Noninvasive fungal rhinosinusitis: a case series

Introduction: Fungal rhinosinusitis (FRS) remains a rare disease. The noninvasive forms are hard to diagnose. The management protocols remain controversial. We aim to describe the clinical, radiological and pathological features of noninvasive FRS and present our management protocol and follow-up results. Patients and methods: This descriptive study was conducted in the ear-nose-throat department of the university hospital, Taher Sfar in Mahdia, Tunisia. All patients who responded to the definition of noninvasive FRS (fungal balls and allergic fungal sinusitis) were included. The study was conducted over a three year period (May 2017 – April 2021). Results: Eleven patients were included in this study: four cases of fungal balls and seven cases of allergic fungal sinusitis. Patients presented with symptoms of chronic recurrent rhinosinusitis with no response to conventional treatments. Computed tomodensitometry scan showed opacification of the paranasal sinuses in all patients. Other signs were heterogeneous opacities, local calcifications and thinning of the bony walls of the sinuses. Histopathological findings were inflammatory polyps in all cases of allergic FRS with the presence of fungal hyphae in 42.8% of the cases. All patients underwent surgery after a median delay of 12 [6–24] months of the symptom’s onset. The used procedures were endoscopic middle meatal antrostomy for all patients, ethmoidectomy (81.8%) and sphenoidotomy (36.4%). None received systemic antifungals or corticosteroids with a favorable outcome in all cases. Conclusion: Symptoms of noninvasive FRS are nonspecific. The scan images contribute to the diagnosis, but the perioperative findings and the histopathological results remain crucial. The management is mainly surgical.


Introduction
Fungal rhinosinusitis (FRS) consists of a group of heterogeneous affections 1 . At one time FRS was considered a rare disease but its incidence seems to be increasing all over the world 2 . The diagnosis is particularly difficult. On one hand, the clinical presentation is non-specific and sometimes misleading. On the other hand, fungal colonization of the sinuses is very common making it hard to be certain of its implication in the genesis of the pathology 3,4 . The most used classification is based on histopathological evidence of tissue invasion by fungi. It divides FRS into invasive and noninvasive forms. The invasive FRS includes acute invasive, granulomatous invasive FRS, and chronic invasive FRS. The noninvasive FRS includes fungal colonization, fungal ball, and allergic fungal sinusitis 5 . The aim of this study is to describe the clinical, radiological and pathological features of noninvasive FRS in our ear-nose-throat (ENT) department and present our management protocol and follow-up results.

Patients and methods
This descriptive study was conducted in the ENT department of the university hospital, Taher Sfar in Mahdia. All patients who responded to the definition of noninvasive fungal rhinosinusitis (fungal balls and allergic fungal sinusitis) according to the 2009 consensus were included 5 . The study was conducted over a three-year period between May 2017 and May 2021.
The patients' medical records were consulted and data including demographic characteristics, clinical examination findings, computed tomodensitometry scan results, cytopathology findings and management details were collected.
Computed tomodensitometry scan images were obtained using a General Electric BrightSpeed Elite 16 slice CT scanner. Coronal and sagittal views were reformatted with a 1.25 mm slice thickness.
Magnetic resonance imaging was not available in our hospital, so, it was only realized for patients who could afford to pay for it in the private sector.
Statistical analysis was carried out with Statistical Package for Social Sciences (SPSS) Statistics, version 23, (IBM Corp., Armonk, NY. Released 2015). The results were expressed as numerical values (percentages) for categorical variables, medians [interquartile range] for continuous variables when Kolmogorov-Smirnov p-value was inferior to 0.05 and means ± standard deviation when Kolmogorov-Smirnov p-value was superior to 0.05. Univariate analysis was performed using the chi-square tests. Co-variates retained in the final model were the ones significant at the level of 5%.

Results
Eleven patients were included in this study, four cases of fungal balls and seven cases of allergic fungal sinusitis ( Table 1). The median age was 33 [25-42] years with a sex ratio of 0.83. Two patients were diabetics and one patient had asthma.
None of the patients reported a history of dental infection or endodontic procedure.
None of the patients presented with fever. Anterior rhinoscopy was performed for all patients. Polyps were found in six cases (54.5%). The presence of mucopurulent drainage was noted in four patients (36.4%). A septal deviation was found in four cases (36.4%).
MRI of the facial mass was performed in four patients. In all cases, it showed T2 hypointense (signal void) images suggestive of the mycotic origin ( Figure 2).
Histopathological findings were inflammatory polyps in all cases of allergic FRS with the presence of fungal hyphae in 45.8% of the cases. For fungal balls, masses of aspergillosis mycelia along with inflammatory cells were found in 75% of the cases ( Table 1).
All patients underwent surgery after a median delay of 12 [6-24] months of the symptom's onset. The used procedures were endoscopic middle meatal antrostomy for all patients (100%), ethmoidectomy for nine patients (81.8%), sphenoidotomy for four patients (36,4%), septoplasty for three patients (27.3%) and turbinoplasty for one patient (9.1%). Details of the surgical procedures and perioperative findings are presented in Table 1, Figure 3 and Figure 4. None of the patients received systemic antifungal treatment. All were prescribed a local treatment with nasal saline topical. The seven patients diagnosed with allergic FRS received nasal steroid sprays (63.6%). After a median follow-up delay of three [1][2][3][4][5][6][7][8][9][10][11][12] months, all patients had a favorable outcome, and no recurrence was reported during this period. However, in the case of allergic FRS, the recovery seemed to take more time, and symptoms seemed to persist a little longer than the fungal ball cases.

Amendments from Version 1
Some information was initially ambigus and some details were added to clarify it.
Lund -Mckay CT assessment was added to the radiological data (Table 1).
New references were added to enrich the manuscript based on the reviewers' advice.
Any further responses from the reviewers can be found at the end of the article     None of the symptoms such as nasal obstruction, rhinorrhoea, anosmia and epistaxis, was associated with either of the forms (fungal balls or allergic fungal sinusitis) with respective p-values of 1, 1, 0.2 and 1.

Discussion
Although sinusitis is very common, fungal sinusitis remains rare, but the prevalence seems to be rising all over the world, Aspergillus sp. being the most implicated fungal agent 6 .
The fungi's implication in rhinosinusitis has been widely discussed and many diagnostic criteria have been proposed in order to identify the different forms. The most used classification is the one dividing FRS into invasive and noninvasive sinusitis based on histopathological findings. On one hand, the invasive forms include acute invasive FRS, granulomatous invasive FRS, and chronic invasive FRS. On the other hand, noninvasive forms include saprophytic fungal infestation, fungal ball, and fungus related-eosinophilic FRS, mainly allergic FRS 5 . In this study, we only focused on noninvasive FRS presenting as fungal balls or allergic fungal sinusitis. This pathology, as found in our results, mainly occurs among young adults 7 .
In line with our findings, individuals with allergic FRS or fungal balls are reported to present with the typical symptoms of chronic rhinosinusitis, including nasal congestion, facial pain when pressuring the sinuses, and nasal discharge 1 . The symptoms are chronic (> three months), recurrent and resistant to conventional treatments usually prescribed for chronic rhinosinusitis 6 . These two forms, despite their common clinical presentation, have different physiopathology. In the case of fungal balls, the fungi colonizing the sinus mucosa produce a dense conglomeration of hyphae within the maxillary sinus or, less frequently, in the sphenoid sinus 8 . In the case of allergic FRS, a profound Th2 lymphocyte response associated with eosinophilic mucin within the sinus was noted 8 . Many studies suggest that fungi may have an effect on sinus mucosa in susceptible individuals. The absence of convincing immunological data and the controversial role of antifungal agents make it hard to conclude the real role of fungi in the genesis of allergic FRS 3 . Some suggest that the mechanism is similar to allergic bronchopulmonary aspergillosis, fungal antigens induce a type I hypersensitivity reaction with the production of IgE, IgA and IgG 6 .
According to the recent classification of Chronic Rhinosinusitis, the fungal ball is most often related to an endodontic history. For the 4 cases of fungal ball in our series, there was no history of dental infection nor procedure 9 . All patients were referred to a dentist for a specialized dental examination and eventual treatment of a dental cause to reduce the risk of recurrence.
Anterior rhinoscopy findings reported in the literature are congruent with our findings, mainly congestive mucosa, mucopurulent discharge and polyps especially in the case of allergic FRS 10 .
The computed tomodensitometry scan images contribute to the diagnosis. In the case of fungal balls, the affection mostly concerns the maxillary sinus. The most reported features were calcifications within the maxillary sinus followed by complete opacification, partial opacification with an irregular surface and bony sclerosis or bone thickening 11 . These signs remain nonspecific and could be seen in sinusitis of other origins or neoplasms. The MRI is more performant, the fungal ball is hypointense on T1-weighted and T2-weighted images.
In the case of allergic FR, scan images typically show bilateral pansinusitis. The opacification of the sinuses is explained by the hyperattenuated mucin. In many cases, as noted for our patients, expansion and thinning of sinus walls were reported.
T1-weighted MRI images may show mixed signal intensities. T2-weighted images are mostly hypointense but may show flow voids 1 .
Histopathological findings are the main diagnostic criterion. It is the only element to confirm the noninvasive form of the disease. The other findings reported were copious mucin, abundant eosinophils, Charcot-Leyden crystals, with rare noninvasive fungal hyphae in case of allergic FRS. Tightly packed fungal hyphae without allergic mucin are the characteristic feature of fungal balls 12 .
The results of fungal cultures were not presented in our study.
In the literature, Aspergillus fumigatus is the most incriminated fungal species in the genesis of fungal balls, but the fungal cultures were negative in 65% of cases. In allergic FRS, the use of type I hypersensitivity testing is a fundamental diagnosis criterion. This test is unfortunately unavailable in our settings. Fungal cultures are not useful since studies have shown a difference between the fungal species cultured and fungal-specific sensitivities revealed by the allergy testing 1 .
The diagnosis of fungal balls is easily confirmed when there is radiological evidence of sinus opacification with or without radiographic heterogeneity, a mucopurulent or necrotic material in the sinus and a histological aspect associating a dense conglomeration of hyphae and inflammation of the mucosa without invasion 5 .
The diagnosis of allergic FRS is less evident, based on the association of many criteria; type I hypersensitivity to fungi, nasal polyposis, fungi on staining, eosinophilic mucin without fungal invasion into sinus tissue, and characteristic radiological findings on CT scanning 6 . The determination of serum IgE level could be an additional element in the diagnosis 13 . But, this biomarker was not available in our laboratory.
The management of noninvasive FRS is mainly surgical. Surgical opening of the natural sinus ostium with the evacuation of fungal debris is the treatment of choice in the case of fungal balls. An inferior meatal window combined with the middle meatal antrostomy could reduce the risk of leaving residual debris 13 . After the removal of fungal hyphae, no additional treatment is necessary according to most recommendations 1,6 .
The management of allergic FRS is less consensual. Surgical management was adopted by most series to remove polyps, open sinus ostia, and clear the eosinophilic fungal mucin.
Many medical therapies were tried in the management of allergic FRS. Oral corticosteroid therapy over a period of 2 to 6 months, with close monitoring of side effects and topical steroids were the most used medications with a reported improvement of the symptoms and reduction of recurrences 13 . Oral antifungals such as voriconazole and itraconazole and topical antifungal agents have been proposed by some authors, especially, in immunocompromised patients in order to prevent invasive forms of FRS. However, these therapies remain unsupported by solid data 6,14 . Leukotriene antagonists and immunotherapy have also been used with no evidence of a better outcome 1,15 . Our management protocol was based on endoscopic surgery with postoperative topical steroids with a favorable outcome.
This study is, to our knowledge, the first to report cases of noninvasive FRS in Tunisia. This disease, once rare, is reported more and more. Our management protocol seems to have good results, but we conducted a single-center study with a limited number of cases. On the other hand, the follow-up period was limited, and recurrences may occur in the future.
Multicenter studies with a longer follow-up could refine the results and help draw better conclusions.

Conclusion
Noninvasive FRS is to be evoked when a patient presents with symptoms of chronic recurrent rhinosinusitis with no response to conventional treatments. Scan images could help steer toward the diagnosis, but the perioperative findings and the histopathological results remain crucial. Surgical treatment is the milestone in the management of FRS.

Consent
Written informed consent for publication of their clinical details and clinical images was obtained from the patients.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.

Open Peer Review
only realized for patients who could afford to pay for it in the private sector. We added this sentence to the manuscript.
Concerning the evaluation of CT findings in cases studied, I would prefer Lund -Mckay scores for the accurate evaluation of the severity of sinusitis numerically rather than a descriptive one.
secondary CRS and is most often related to an endodontic history (more than 80% of cases). For the 4 fungal balls of the series, there is no information regarding the dental history, the specialized dental examination, the dentascan. The treatment of dental causes should be combined with surgical treatment to reduce the risk of recurrence. "Contemporary Classification of Chronic Rhinosinusitis Beyond Polyps vs No Polyps: A Review" 1 . Jessica W Grayson, Claire Hopkins, Eri Mori, Brent Senior, Richard J Harvey.
An inferior meatal window combined with the middle meatal antrostomy for the treatment of fungal balls would reduce the risk of leaving residual debris (EPOS2020) 2 Yes