Post-COVID-19 acute invasive fungal rhinosinusitis: a systematic radiological approach in the light of clinico-surgical characteristics

Background The objective is to describe the radiological imaging findings of post-COVID-19 acute invasive fungal rhinosinusitis (AIFRS), being familiar with the wide variety of imaging spectrum, thus raising the suspicion for early diagnosis. Methods: In this retrospective study, we reviewed the imaging findings in 54 patients with proven post-COVID-19 AIFRS who underwent endoscopic/surgical debridement from April 2020 to September 2021. Most of these patients presented with facial or orbital swelling or facial pain. Medical records with a special emphasis on radiological imaging (50 NCCT of the paranasal sinuses and 17 MRIs of the orbit) were reviewed regarding the degree of mucosal disease of sinuses, nasal cavity, and nasopharynx, extra sinus soft tissue infiltration, especially orbital and cerebral extension (parenchymal, cavernous sinus, vascular or neuro-invasion). Results We reported findings in 54 patients with post-COVID-19 AIFRS, of whom 30 were men and 24 were women with a mean age of 48.06. Unexpectedly, infiltration of pterygopalatine fossa was found to precede mucosal opacification of sinuses nasal cavity and affection of nasopharynx. Out of 54 patients, 49 showed inflammatory changes involving pterygopalatine fossa, 29.6% of patients showed infiltration of orbital tissues, 22 patients suffered from a fungal invasion of the cavernous sinus and 3 patients had carotid artery involvement. Conclusions Imaging findings of AIFRS significantly vary from subtle mucosal thickening of paranasal sinuses, up to orbital and intracranial extension with vascular thrombosis and neuroinvasion. The hallmark inflammatory tissue infiltration into the pterygopalatine fossa and facial soft tissue may precede mucosal disease.


Background
Since breaking at the end of 2019, the COVID-19 pandemic continues to be a challenge on a global scale. While efforts are being maintained to understand the pathophysiology and treatment of COVID-19 aiming to contain the disease, many other health problems were brought to the surface on top of COVID-19. Some of these disorders may affect patients during active COVID-19 infection in the recovery period was variable sequelae. One of the most devastating diseases that were brought back to action in the COVID-19 era is acute invasive fungal rhino-sinusitis (AIFRS) [1].
The coincidence of diabetes mellitus, unintended consequences of high-dose steroid administration, possible immune effects of COVID-19 virus and possibly the use of contaminated industrial oxygen may all have a predisposing contribution to this new organism [2].
In AIFRS, the middle turbinate has always been thought to be the epicentre of infection in most cases from where it tends to spread to the rest of the nasal cavity and sinuses. Mucor has angioinvasive properties that enable it to rapidly progress through tissue borders beyond the limits respected in the immunocompetent status. Spreading along neurovascular bundles appears to be the highway for this pathogen, resulting in extensive tissue necrosis with consequent high mortality of 50-80% and high morbidity in those who survive [3].
The fundamental to successful management is early and aggressive medical and surgical treatment. Systemic antifungals should be administered and correction of underlying comorbidities. Surgical debridement is used for removing all necrotic tissue [4].
A biopsy is essential to confirm the diagnosis. However, the microbiological diagnostic pathway for AIFRS is special, since tissue grinding can lead to negative results because of the destruction of the hyphae, causing unsuccessful culture growth; therefore, it is important to inform the laboratory early about the suspicion of AIFRS to adapt the diagnostic technique. Recent developments tend to favour molecular diagnostic assays in order to accelerate the diagnosis [5].
The use of radiological investigations is indispensable to the initial diagnosis and guidance of management. Computed tomography (CT) is the workhorse for imaging the paranasal sinuses. MRI is used to evaluate the orbit, perineural spread along the trigeminal nerve, cavernous sinus involvement and cerebral extension [1]. We need more details on the common radiological findings of AIFRS described before. Imaging findings are variable. Sever sinonasal mucosal thickening with signs of inflammatory involvement just outside the paranasal sinuses and features of potential complications raise suspicion of the diagnosis. Mild sinonasal mucosal thickening is not specific to the diagnosis of the disease [6].
A systematic reporting approach with a structured checklist is helpful to not miss critical findings in the radiological report [1,7].
The aim of this study is to describe radiological imaging findings of AIFRS in COVID-19 patients, being familiar with different radiologic characteristics, and raise the suspicion for early diagnosis.

Patients
This retrospective study was conducted in our University Hospital in the period between April 2020 and November 2021. Medical records of 54 confirmed COVID-19 patients with pathologically proved acute invasive fungal sinusitis were reviewed with a special emphasis on radiographic imaging. Demographic data and medical history of other comorbidities complete clinical examination including nasal endoscopy, and laboratory and histopathological findings were collected.

Ethics approval
This study was approved by the local ethics committee.

Image acquisition
(a) Non-contrast computed tomography (NCCT) paranasal sinus protocol performed using a multislice CT Aquilion One, Toshiba Medical Systems, Otawara, Japan: The scan was obtained in the axial plane from above the frontal sinuses through the hard palate; slice thickness of 1 mm with no spacing, and field of view (FOV) 170-190 mm.

Image reconstruction
Reconstructions were performed using a bone algorithm (section thickness of 0.5 mm with 0.5-mm spacing). Multiplanar reformations were also completed in the coronal and sagittal plane using post-processing: The reconstructed images were transferred to the workstation (Vitrea Fx, Vital Images, USA). (b) MR imaging of the orbit was performed using a 1.5 T MR scanner (Signa16 channel, Excite, GE Healthcare, Milwaukee, WI, USA).

Statistical analysis
Analysis of the data was performed; number, mean ± standard deviation (SD), and frequency (percent) for categorical data were calculated. Chi-square test (with exact p value) is used to describe categorical data distribution. P < 0.05 was considered a significant level.
The correlation of findings was tested using Pearson test. All statistical analyses were analysed using IBM SPSS software package version 25.0 (Armonk, NY: I BM Corp).

Results
The demographic and clinical variables of the 54 patients included in the study were analysed. The age ranged from 12 to 73 years with the mean age of 48.06 ± 16.5 years, being 55.6% male and 44.4% female ( Table 1). As expected, the most common predisposing conditions were diabetes mellitus. The second common comorbidity is hypertension in 27 patients ( Table 2). Clinical presentation is variable but often dramatic, with the rapid development of unilateral facial pain, tingling, numbness in the malar areas (92.6%), extension into the orbit resulting in proptosis, deterioration in vision or even visual loss (70.4%), facial skin infarction, and ulceration in 46.3%. Cerebral extension resulted in disturbed conscious level in 6 patients (11.1%) ( Table 1).
Surgical debridement was done for 52/54 patients; 37.2% of patients had external debridement, 37% had endoscopic debridement, and 24.1% had combined open and endoscopic debridement, two patients passed away before surgery (Table 1). All patients who underwent surgical treatments had sinonasal tissue infarction. The aim of the surgery was to excise the necrotic tissue till healthy tissue with fresh bleeding is encountered. Beyond endoscopic debridement, maxillectomy was done in 5 patients and orbital exenteration in 13 patients (24.1%). Systemic antifungal was prescribed for 50 patients on diagnosis and was continued in the post-operative period. Mucor species was the most isolated fungal pathogens (77.8%) followed by Aspergillus fumigatus (22.2%) ( Table 1). The overall mortality in the study group was 40.7% (Table 1).
Mucosal opacification degree of the frontal, maxillary, sphenoidal, anterior ethmoidal, posterior ethmoidal, anterior nasal cavity, posterior nasal cavity and nasopharynx was reported (Fig. 1). The degree of opacity had relatively poor sensitivity and specificity as predictors for AIFS. In particular, 61% of the patients with subtle/insignificant mucosal thickening in the nasal cavity or nasopharynx, while 100% of patients showed sinonasal soft tissue infarction at endoscopy/surgery (Fig. 2). Unilateral predominance existed. Bilateral AIFR was present in one case with a strong predilection of the disease on the left side.

Discussion
AIFRS is a severe and life-threatening condition. In this study, a systematic reporting approach is used by both the reading otolaryngologist and the reading radiologist to understand the clinical-radiological relevance of findings. Patients had a wide range of imaging characteristics. It varied from subtle mucosal thickening of sinuses up to cerebral extension. In our patients, sinonasal soft tissue necrosis was detected in 54/54 patients, inflammatory soft tissue changes extending from the sinuses into the facial subcutaneous tissue (25/54) as well as into the infratemporal and in 49/54 patients into the temporal fossa. Orbital (16/54 patients) and cerebral involvement (22/54 patients) were frequent in our study leading to neurological complications and bony destruction in 22/54 cases; cranial nerve involvement was not uncommon (14 patients).
The degree of mucosal opacification of sinuses and nasal cavity and nasopharynx had relatively poor sensitivity and specificity. Extrasinus soft tissue involvement correlated most strongly with involvement in the pterygopalatine fossa. The correlation between mucosal opacification and infiltrations was very weak. Unilateral predominance existed. Bilateral AIFR was present in one case with a strong predilection of the disease on the left side. Nasal Septal ulceration was reported in 31.5% only. We found unenhanced mucosal areas at the middle turbinate (black turbinate) as well as in the ethmoidal sinuses in 10 patients, The CT findings presented hypodense opacification of the sinuses, unlike chronic fungal infections where the sinuses are hyperdense due to the build-up of mineralrich fungal waste products. The cross-sectional imaging features of AIFRS associated with COVID-19 infections do not differ from those reported in the literature for AIFRS associated with other risk factors [8]. This is in concordant with the study of Middlebrooks et al. [1,7].
The black turbinate sign described by Baumgartner et al. [9] refers to a lack of contrast enhancement of invaded mucosa due to occlusion of small vessels. The sign could also be called the black mucosa sign.
Middlebrooks et al. [7] recently proposed a simple and robust diagnostic model to serve as an easily applicable screening tool for at-risk patients with 23 variables that allow for three levels of involvement: (1) nasal cavity, paranasal sinuses, (2) rhino-orbital disease, rhino-orbitocerebral. MRI contrast administration allows delineation of subtle areas of invasion, recognition of necrosis, and thrombosis of structures such as the cavernous sinus [1,10,11].
In the current study, we obtain the mean age of 48.06 ± 16.5 years younger than that recorded by Shintani in the USA [13]. The mean age was 58.0 ± 2.2 years, with nearly the same sex predilection of 55.9% male (55.6% male, 44.4 female).
The most common presenting symptoms of patients with AIFRS were unilateral facial pain, tingling, and numbness in the malar areas 92.6% in concordance with Turner et al. [14] who recorded facial swelling (64.5%), fever (62.9%), and nasal congestion (52.2%. Extension into the orbit results in proptosis, deterioration in vision or even visual loss (70.4%), facial skin infarction, and ulceration in 46.3%. In addition, Yin et al. [15] described that unilateral facial swelling, pain, or erythema were the most common presentations, involvement of the orbit or pterygopalatine fossa on imaging, and mucosal necrosis is seen on endoscopy. As expected, the most commonly associated predisposing conditions were diabetes mellitus in concordance with the study of Malleshappa et al. [16] found that 78.4% patients were diabetic in concordance with the study of Wandell et al. [17] aggressive infection occurring in immunocompromised patients.
Mucor species (77.8%) was the most commonly isolated fungal pathogens followed by Aspergillus fumigatus (22.2%). As Raab et al. [6] pointed out, Mucorales is not the only fungi, which can infect the sinuses, Aspergillus spp. can also lead to invasive fungal sinusitis.
The aim of surgery is to excise the necrotic tissue thus maxillectomy is done in 5 patients and orbital exenteration in 13/54 patients. Systemic antifungal was described for 50 patients. This is discordant with Turner et al. [14], who described external debridement for 37.2%, endoscopic debridement in 37% and combined open and endoscopic debridement for 24.1% and Malleshappa et al. [16] who recorded partial/total maxillectomy (29.4%), orbital exenteration (7.8%) and craniotomy (2%), while Allensworth et al. [18] found that ten patients underwent maxillectomy, six with orbital exenteration. In concordance with a study done by Yin et al. [15], most patients were treated with a combination of intravenous antifungal medication and surgery. Two patients passed away before surgery.
Despite improvements in medical and surgical therapy, survival remains limited. The overall mortality in the AIFR was 40.7% in concordance with the study of Turner et al. [14] who stated an overall survival rate equalled 49.7% and Allensworth et al. [18] recorded (68%) survived which was nearly the same mentioned in the study of Malleshappa et al. [16] that gave a survival rate of 68.2% overall.
Strength of the study, up to our knowledge and the published data, is that it had a large sample and our patients were a good representative of the medical problem. Second, multidisciplinary reporting expanded the scope of data analysis. AIFRS in COVID-19 patients is a matter of urgency; consequently, this study had some limitations. First, it was a single institutional study. Second, patient selectivity bias was possible due to rapid disease progression and poor prognosis. Third, the lack of a comparator control group limited our findings. Finally, the availability of long-term clinical outcomes was modest. The international longitudinal study is necessary for future studies.

Conclusions
The radiological signs of AIFRS in COVID-19 patients largely vary. Inflammatory involvement outside the paranasal sinuses into facial or orbital soft tissue is the hallmark. The suspected diagnosis should be directly given to the referring physician and the medical microbiological laboratory to direct diagnostic pathways and treatment.

Acknowledgements
Special thanks to our colleagues and seniors in the hospital for their help.

Author contributions
ES analysed and interpreted the patient data, performed the statistical analysis of results, and was a major contributor in writing the manuscript. RS was the contributor in writing the manuscript and data interpretation. MA was the contributor in writing the manuscript. KE collected the data, analysed and interpreted the patient data, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Funding
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate This study was approved by the ethics committee of Tanta University Hospital. Ethics committee reference numbers is (34341/12/20). The patients provided written informed consent written informed consent in the patients' native language.

Consent for publication
The patients provided written informed consent in the patients' native language. All patients included in this research gave informed written consent to publish the data contained within this study. All participants enrolled in the study provided informed written consent to participate.

Competing interests
Authors declare no competing interests.