key: cord-0788739-o1d4113c authors: Patel, Dhrumil Deveshkumar; Adke, Shrishail; Badhe, Padma V.; Lamture, Swastika; Marfatia, Hetal; Mhatre, Pauras title: COVID-19 associated rhino-orbito-cerebral mucormycosis: imaging spectrum and clinico-radiological correlation- a single Centre experience date: 2021-11-06 journal: Clin Imaging DOI: 10.1016/j.clinimag.2021.10.014 sha: 2ded56231b68f6adea30ee305a1fbfab165f7b04 doc_id: 788739 cord_uid: o1d4113c PURPOSE: The study aims to depict the radiological features of Cov-ROCM, depict the common routes of spread to orbits and intracranial compartment and look for an association of the risk factors with radiological severity of the disease. METHODS: 96 patients who had COVID-19 infection in the past 3 months and were diagnosed with ROCM underwent CECT PNS examinations which were assessed by two experienced radiologists. They were divided into three groups based on the intraorbital and intracranial involvement and were correlated with various risk factors. RESULTS: The incidence of bony erosions which was the commonest finding (75%) was double in Cov-ROCM than the ROCM cases of pre COVID era (33–40%). The most common route of spread to orbit was through angioinvasion(52%) with intact orbital walls; and intracranial extension was via erosion of the cribriform plate(52%). Sphenoid sinus involvement is strongly associated with intracranial and intraorbital involvement.(p-value = .0004). History of longer ICU stays and being on mechanical ventilation as a part of COVID management is associated with aggressive disease pattern(p-value = .002). Similarly, poor glycaemic control signified by raised HbA1c levels showed statistically significant correlation with severe Cov-ROCM(intraorbital/intracranial extension) (p-value = .040). CONCLUSION: Amidst the COVID pandemic, it is pertinent to look at bony erosions in case of any sinusitis, especially bony maxillary walls and the turbinates. The intraorbital compartment must be viewed thoroughly even in the absence of bony erosions due to the angioinvasive nature of these fungi. Aggressive follow-up for patients with ICU stays for COVID and for glycaemic control would help reduce the morbidity. The start of the second wave of the COVID epidemic in India saw a substantial rise in the cases of Rhino-Orbito-Cerebral mucormycosis (ROCM) which conventionally used to occur in patients of immunosuppressed individuals and Diabetic ketoacidosis. (1) These cases of ROCM were seen within 3 months of COVID-19 infection with the mean interval between COVID infection and development of ROCM being 10 days. (2) The risk factors predisposing to this newer entity, the COVID-associated ROCM (Cov-ROCM) were found to be diabetes mellitus irrespective of ketoacidotic state and administration of corticosteroid and broad-spectrum antibiotics as a part of the management of COVID infection. Computed Tomography (CT) scan of paranasal sinuses is usually the initial modality of imaging to depict the regions involved. (6) Hence our primary objective is to depict the radiological features and routes of spread in Cov-ROCM to orbit and intracranial cavity. Another objective is to look for an association between the risk factors and radiologically severe Cov-ROCM. This single centre cross-sectional study was approved by the Institutional Review Board, willing to give informed consent, with age less than 18 years, or on immunosuppressant drugs for indications other than COVID-19 infection-related were excluded from the study. Patients demographic data underlying comorbidities, all history pertaining to COVID-19 infection and HbA1c level were collected. Reports of the KOH mount or culture growth specific for Mucormycosis using necrosed tissue samples were recorded. A plain and contrast-enhanced CT examination of the paranasal sinuses was performed. The area covered was from the vertex of the skull up to the hyoid bone. Brain and Orbit were covered to look for any intraorbital/intracranial extension, as the disease is angioinvasiveness and can affect sites distant from the affected paranasal sinuses. MDCT machine Philips Brilliance CT 64 channel-DS was used. All scans were reviewed by two Head and Neck Radiology specialists separately (one with experience of 20 years and another 4 years), who were blinded to previous images and clinical information. In cases of inter-reader discrepancies, a consensus was reached through discussion. Imaging findings of nasal cavity, paranasal sinuses, bones and routes of spread were corroborated with the FESS(Functional Endoscopic Sinus Surgery) findings. Also, in case of subtle/ indeterminate findings in the orbit and intracranial cavity, MRI brain/orbits were used to confirm them. Each scan was evaluated for soft tissue involvement/irregular mucosal thickening of the nasal cavity and the paranasal sinuses. The presence of hyperdense contents (HU>60) which are relatively specific for the presence of fungal elements after ruling out the possibility of haemorrhage was noted. A focal area of discontinuity was labelled as bony erosions. Involvement of the subcutaneous tissue/fat stranding was looked for in specific areas, namely premaxillary and preseptal regions. Regional extensions/fat stranding were noted in the suprahyoid neck space especially the retroantral fat pad. Intraorbital extension of the soft tissue/fat stranding was evaluated in the extraconal and intraconal compartments with particular attention to extraocular muscles and involvement of the orbital apex. Abnormal enhancement of the optic nerve or fat stranding around the optic nerve was considered to be optic neuritis. Intracranial complications noted were pachymeningeal and leptomeningeal involvement, cavernous sinus thrombosis, internal carotid artery thrombosis, infarct, hematoma, or intraparenchymal abscess. The exact routes of spread of the disease to the orbits and the intracranial cavity were recorded. In cases where there was no bony erosion or direct abnormal soft tissue extension into the intraorbital and intracranial compartments, the spread of the disease was classified as J o u r n a l P r e -p r o o f being via angioinvasion. In case of multiple routes of spread, the one with the bulk of soft tissue was considered. Aggressive Cov-ROCM in the study was labelled whenever there was involvement of the intraorbital or intracranial compartments. Patients were divided into 3 groups based on the areas of involvement. Group A included patients with involvement limited to nasal cavity and paranasal sinuses, Group B consisted of patients with extension into intraorbital disease only and Group C involved patients with intracranial extension. Data coding and entry were done in Microsoft Excel spread sheets. Descriptive and inferential statistical analysis was done by using SPSS version 21 (Statistical Package for Social Sciences) software. The raw data was compiled, classified, presented in a tabulated manner to bring out important details. Descriptive statistics like frequency, proportion, Mean, Standard deviation were used. One-way ANOVA, Kruskal Wallis Test, Independent t-test were used as inferential statistics. P less than 0.05 was considered statistically significant. All patients who were eligible to participate in the study as per inclusion and exclusion criteria were included in study using the purposive sampling method. We observed that it was a male predominant disease with men being affected 3 times than women. Diabetes mellitus turned out to be the most common risk factor amongst these patients with mean HbA1c levels of 8.68%. Some form of steroid administration as a part of COVID-related management was noted in more than 80 percent of patients. The average CT severity score of the COVID infection fell into the moderate category (mean=10.66). (Table 1 ) The most common sinuses to be involved were the maxillary and ethmoid sinuses. There was a statistically significant association between involvement of the sphenoid sinus and Table 3 ) On comparison of the patient with aggressive Cov-ROCM with those without Bony erosions were found in 79% of the patients with maxillary sinus wall involvement being the commonest. (Table 3) . Amongst suprahyoid neck spaces, Retroantral fat pad was the most commonly involved (51%) while Pterygopalatine fossa ( Figure 2d ) and Masticator space involvement was seen in 26 and 17 patients respectively. The orbital disease was seen in about 60% of the study population (n= 57) with intraconal involvement in 21 of them. Optic neuritis was seen in about 38.5% of the patients with orbital involvement. (Figure 3 a,b ,c,d)( Table 3) Common intracranial extensions were seen in the form of cavernous sinus thrombosis (n=7) and pachymeningeal enhancement (n=8). (Figure 4c ,d) Cerebral abscesses were seen in five patients. (Table 3) . The routes of spread to the orbit and intracranial spread are shown in Poor glycaemic control (higher HbA1c levels) showed a statistically significant correlation with a more invasive form of ROC mucormycosis. (p-value=.04/ Kruskal-Willis test) ( Table 4) A statistically significant association between the average number of days of ICU stay and intracranial involvement (p = 0.002/ t-test) was seen. An average of 1.2 days for Group A & B together compared to 3.7 days in Group C. Also, while 6 patients from Groups B & C were on mechanical ventilation, none had a similar history in group A. (Table 4) As seen in Table 4 , there is no statistically significant correlation in the average CT severity score (p=0.670/ Chi-square test), or association of the number of patients with steroid intake (p-value=.320/ Chi-square test) for each group. Similarly, no significant association was seen when comparing the modes of oxygen delivery (namely, nasal prongs, face mask, Non rebreather mask ventilation, and mechanical ventilation ) across the 3 groups(p = 0.150/ Chisquare test). (Table 4 ) The study revealed that bony erosions were seen in 75% of the patients of Cov-ROCM; with those of maxillary wall being the commonest. However, as per DelGaudio et al., Gupta K. et al and Jacob Therekattu et al., the ROCM cases found in the pre-COVID era had bony erosions in only 33-40% of them. (7) (8) (9) . This is a distinct aggressive finding of COVIDassociated ROCM as compared to those in the pre-COVID era. Moreover, they can be easily detected even on plain CT scans. Some of the characteristic erosions noted were in the nasal septum, hard palate, and alveolar process of the maxilla (which can present as loosening of teeth). Since sphenoid sinus forms a part of the base of the skull and the orbital apex, its involvement predisposed to intra-orbital and intracranial extension. Superficial cellulitis is another early finding to diagnose ROCM, as the involvement of the superficially located subcutaneous fat is not common in non-fungal sinusitis. About 35% of the patients in the study showed features of superficial cellulitis, with the commonest being premaxillary fat stranding/soft tissue replacement. (n=27) (Figure 2b) The lethality of the ROCM is due to its invasiveness to involve critical surrounding areas, the orbit and the cranial cavity. The knowledge of pathways of spread to these areas would help the surgeon in targeting specific areas to prevent further spread or at least check its normalcy before completing the procedure. Moreover, a systematic approach with a checklist will greatly enhance the value of the preoperative imaging report for referring surgeons. CT diabetics amongst Cov-ROCM cases. (2, 3, 15) In addition to the fact that our study population had 71% diabetics amongst them, we found that those with poor glycaemic control was associated with more invasive disease. (p-value=.040).In other words, severe DM did predispose to intraorbital or intracranial extension. In the pre-COVID era, Yang et al. had shown that the SARS coronavirus had a propensity to cause Islet cell damage which would predispose individuals to develop DM or worsen glycaemic control in known cases. (16) Additionally, the question of COVID itself being an independent risk factor has arisen. While we did not compare the ROCM cases with and without a history of COVID, we were able to show that radiological COVID severity depicted with the help of CT severity score was not associated with severity of Cov-ROCM. However, it is to be noted that since the average CT severity score of all the patients with Cov-ROCM in this study was in the moderate category, it can be concluded that COVID infection may predispose to ROCM. Also, Cov-ROCM was seen to be male dominant disease likely due to the fact that the diabetes was primarily male predominant. (Table 1 ) COVID-19 data of our city showed that 54% of the COVID patients were male which does not support the male preponderance in Cov-ROCM. (17) We found that higher ICU stay predisposed to Cov-ROCM with intracranial extension (Group C); as those with intracranial extension staying in the ICU as many as 3 times than those without (p-value=.046). Also shown is that amongst patients without a history of being on mechanical ventilation, none showed intraorbital/intracranial extension. Hence, an early aggressive approach in those patients with a history of ICU stay and being on mechanical ventilation would help control the spread of the disease and reduce the overall morbidity. Since our study was a cross-sectional study, the course of the disease and its outcomes were not assessed. Our study includes CT examination of the patients, since it is the initial imaging modality of choice with easy availability and superiority in diagnosing bony erosions. MRI was not included in our study due to resource constraints and patient cooperation. The efficacy of CT vs MRI needs to be investigated to analyse the feasibility and practicality of one modality over the other. In conclusion, Cov-ROCM can be tackled by using approaches of primary prevention, early diagnosis and targeted approach. Primary prevention in form of glycaemic control and close follow-up of patients with a history of mechanical ventilation. Early diagnosis can be enabled by the characteristic radiological findings in Cov -ROCM, these include bony erosion, hyperdense content within the sinuses and superficial cellulitis. These findings can raise the suspicion of Cov -ROCM on plain CT scans too. Moreover, due to the angioinvasiveness of the fungi, extension to the intraorbital compartment must be assessed irrespective of evidence of direct extension. 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