1. Background and Importance
The Coronavirus disease 2019 (COVID-19) devastatingly swept the world and has become a pandemic. By the fifth wave of COVID-19 (delta variant) in Iran, a great surge of post-COVID-19 mucormycosis is being referred to, and its high mortality has become a grave consequence [1, 2]. Currently, the triad of COVID-19, corticosteroid therapy, and uncontrolled diabetes mellitus (DM) are considered predisposing for mucormycosis [3].
The clinical system for staging rhino-orbital cerebral mucormycosis (ROCM) has been designed based on anatomical progression and severity and consists of four stages. The fourth stage includes the involvement of the central nervous system (CNS) [4]. A multi-centric study in India showed that, of the 2669 patients with post-COVID-19 ROCM, 21.4% (573) were at stage 4. In the CNS, cavernous sinus was most commonly involved (53%), followed by internal carotid artery (ICA) stenosis/occlusion (18%), temporal lobe abscess (12%), frontal lobe abscess (2.8%), skull base osteomyelitis (7.1%) [5], cerebral infarct [6, 7] and pachymeningitis [8], with a high mortality rate (59.1%) [9].
Our report aims to discuss clinical features, contributing factors, and outcomes of two diabetic patients with COVID-19 associated with ROCM. A multidisciplinary team consisting of an infectious disease specialist, otorhinolaryngologist, ophthalmologist, and neurosurgeons with timely aggressive debridement could provide patient survival. 

2. Case Presentation
Case 1
A 50-year-old man was admitted for the second time to the hospital with complaints of recurrent right ocular pain and swelling accompanied by acute visual loss (light perception). On examination, he had severe proptosis, ptosis, and ophthalmoplegia. Right-sided facial nerve palsy (House-Brackmann facial nerve grade 4) and V2-V3 severe hypoesthesia were detected. The treatments he had received during primary admission for COVID-19 were O2 with mask, interferon, dexamethasone, and remdesivir (200 mg on day 1 followed by 100 mg on days 2–5, in single daily infusions). He had been discharged with metformin and hydrochlorothiazide for type 2 DM and hypertension; on the fourth-day post-discharge, he was admitted. 
Investigation revealed leukocytosis (21000 per mm3), lymphopenia (11%), and moderate rise in C-reactive protein (CRP) (41 mg/L), while erythrocyte sedimentation rate (ESR) was 45 mm/h. Serum glucose was 388 mg/dL, and HbA1C was 10.8%, with no clinical evidence of ketoacidosis. A spiral chest computed tomography (CT) scan revealed bilateral patchy ground-glass opacities and consolidation, suggesting COVID-19 pneumonia (Figure 1A). 

Endoscopic sinus biopsy and debridement were performed. Multiple different staining (Figure 2 parts A-C)of invaded tissues showed the spores, hyphae (broad, aseptate or pauci-septate, wide-angled with branching at 90°) with angioinvasion, in association with tissue damage and acute suppurative inflammation, confirming mucormycosis. 

During his stay, he was treated with IV liposomal-amphotericin B (L-AmB) (CAS No. 1397-89-3) (AmBisome-Gilead Co., USA) (5 mg/kg, daily for 6 weeks), oral posaconazole (5 mL every 6 hours for 2 weeks), and additional IV caspofungin (70 mg/stat and 50 mg/d) for 2 weeks. 
Definitive debridement consisted of maxillectomy, ethmoidectomy, sphenoidectomy, right-sided turbinectomy, and infratemporal fossa lesion resection and orbital apex decompression, which was done two days later. On repeat ophthalmological consult, right orbital exenteration was performed. 
Later, he became drowsy and agitated with a decreased Glasgow coma scale (GCS) 13. A second contrast-enhanced magnetic resonance imaging (MRI) revealed a right frontal abscess, enlarged skull base lesions, midline shift, and frontal horn collapse (Figure 1B). He became a candidate for transcranial surgery. Right frontotemporal incision and pterional craniotomy were performed for debridement and resection of necrotic tissue and frontal lobe abscess. Then the orbital roof was debrided in an extradural manner. After entering the orbit, all necrotic tissues were removed, and the cavity was irrigated with H2O2 solution and packed with povidone-iodine (PVP-I) mesh. The patient had an uneventful postoperative course, and medical treatment was continued with IV infusion of L-AmB and oral suspension of posaconazole. At the 6-month follow-up, the patient was in good condition, and the fungal culture was negative for mucormycosis (Figure 1C, 1D). 

Case 2
A 44-year-old male with known poorly controlled type I- DM since 4 years ago receiving insulin was infected with COVID-19 40 days prior to referral to our hospital. He had received IV-antiviral and dexamethasone as treatment in the primary center. He was admitted with a complaint of pain and swelling of the left eye and face, followed by acute visual loss. On physical examination, he had severe proptosis of the left eye, ptosis, conjunctival chemosis, ophthalmoplegia, left periorbital and maxillary tenderness, left facial palsy (House-Brackmann facial nerve grade 4), and V1-V2-V3 hypoesthesia. Laboratory data revealed leukocytosis, lymphopenia (7.5%), elevated CRP (161 mg/L), and ESR (73 mm/h). His serum glucose was 304 mg/dL, and his HbA1C was 11.4%. Chest CT scan showed bilateral peripheral patchy ground glass opacities in favor of COVID-19 and pneumonia (Figure 3A). 

A Spiral CT scan of paranasal sinuses (PNS) without contrast revealed left maxillary, ethmoid, and sphenoid sinuses opacification with bony erosion. An endoscopic endonasal evaluation was in favor of mucormycosis, and biopsies were obtained.
According to clinical and imaging findings, L-AmB was begun intravenously, and 6 times retrobulbar injections were performed, along with the administration of IV posaconazole. Definitive endoscopic sinus debridement was repeated twice within 3 weeks, along with turbinectomy, removal of the medial wall of the maxillary sinus, and left orbital exenteration.
During the hospital stay, he developed headaches and drowsiness with a GCS of 14. A second contrast-enhanced MRI revealed cavernous sinus thrombosis, cellulitis, and abscess formation spreading within the skull base (Figure 3B). Craniotomy was planned for anterior skull base debridement and abscess drainage. A bicoronal incision in the supine position anterior wall of the frontal sinus was removed on the left side, as well as the necrotic mucocele within the sinus, and thorough debridement was performed. The floor of the sinus cavity was removed associated with ethmoidectomy to expose the cribriform plate. Then the orbital necrotic tissue was debrided, maxillary sinus was unroofed, and total debridement and curettage of the maxillary sinus were performed. The resultant cavity was irrigated with H2O2 solution and packed with PVP-I mesh, and the patient was put on intravenous L-AmB ; after discharge, he was continued on oral suspension of posaconazole. At a 6-month follow-up after discharge, the patient was symptom-free without abnormal radiological findings (Figure 3C, 3D).

3. Discussion
The increasing incidence of ROCM in the setting of COVID-19 was a matter of immediate concern in India, Iran, and elsewhere. CNS involvement has been documented in 37% of the cases of post-COVID-19 ROCM [9]. Although most cases with post-COVID-19 stage 4-ROCM have been reported from India [5, 7, 8], reports from Egypt [10], USA [6], Turkey [11], and Iran [12] are on the surge.
The multidisciplinary ROCM care team must know the warning symptoms and signs of CNS involvement. V1 and V2 trigeminal hypoesthesia, ptosis, and features of the third, fourth, and sixth nerve palsy indicate cavernous sinus involvement. Bilaterality of these signs associated with contralateral orbital edema indicates cavernous sinus thrombosis. Hemiparesis, altered consciousness, and focal seizures indicate brain invasion and infarction [4]. Our cases with stage 4c (involvement beyond the cavernous sinus/skull base, ICA occlusion, and frontal sinus or lobe abscess) imply the involvement of the PNS, orbits, and CNS. 
The concomitant use of steroids (>3 weeks), monoclonal antibodies such as tocilizumab, and broad-spectrum antibiotics for the management of COVID-19 can increase the chances of new-onset fungal infection [13]. According to the published literature, 76% of the patients with COVID-19-associated ROCM gave a history of prolonged high-dose systemic corticosteroids [14]. Both of our patients had a history of prolonged IV dexamethasone without tocilizumab and or azithromycin.
Other major risk factors for mucormycosis include uncontrolled DM, hematological or solid organ malignancies, chronic kidney or liver disease, immunological disorders, prior history of chronic sinusitis, iron overload, deferoxamine therapy and trauma [1], and use of mechanical ventilation or supplemental oxygen >3 weeks. Both of our patients had a history of poor-controlled DM. Nevertheless, DM may be induced de novo by COVID-19 infection; hence it might not only be a risk factor for a severe form of COVID-19 disease but also that infection could induce new-onset diabetes. Potential β-cell damage caused by the virus leading to insulin deficiency has been proposed by some studies [15]. Prophylactic oral posaconazole could be considered high-risk COVID-19 patients for ROCM [4].
In terms of therapeutic interventions, patients with CNS involvement alone seem to cope better than when PNS debridement and orbital exenteration are included in their management, which had been done for our patients [5]. In addition, the standard antifungal drug used in the studies was L-AmB, with or without posaconazole, as in our patients who received both drugs [6, 7, 8, 12].
PVP-I is considered to have the broadest spectrum of antimicrobial action compared with other common antiseptics, showing efficacy against bacteria, fungi, protozoa, and several viruses. PVP-I exposure damages the cell wall in fungi, such as Candida and Mucor species [16]. Previous studies have suggested that 0.5% PVP-I drop or irrigation solution or soaked mesh pieces packed in each nostril before and after operation in patients with PNS mucormycosis and COVID-19 is safe and protective, while betadine mouth gargle should be given to prevent ROCM in high-risk patients [4, 17]. Therefore, the intracranial abscess cavity was washed, and the nasal cavity was packed with PVP-I mesh. Using betadine 0.5% is safe and cost-effective in the deadly conditions of COVID-19 and may reduce the viral and fungal load in the PNS cavity perioperatively. 

Because anterior ethmoidal air cells and frontal sinuses are not easily available during classic endonasal endoscopic approaches, the fronto-ethmoidal approach may be recommended as a solution for cases with extensive anterior skull base involvements. 
Mortality in patients with ROCM with CNS involvement has been reported to be significantly higher (59.1%) compared with those without signs of progression to the CNS (24.3%) [9]. Nevertheless, both of our patients were alive after 6 months of follow-up. 

Study Limitations    
 The approval of the predisposing effect of COVID-19 associated with corticosteroid therapy or DM for ROCM needs a sufficient number of cases for statistical evaluation which makes it a limitation of our study.

4. Conclusion
Clinicians should be aware that ROCM may be a complication of COVID-19 in high-risk patients. Therefore, control of the patient’s underlying systemic condition, upper airway hygiene for mucormycosis, educating physicians about the early diagnosis, and prompt treatment with antifungals along with aggressive resection of cerebral abscess and necrotic tissues are the mainstays of management for ROCM. 

Ethical Considerations
Compliance with ethical guidelines
 We obtained written informed consent from the patient, as recommended by the Ethical Review Board of Tehran University of Medical. 

Funding
 This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions
Conception and design: Hooshang Saberi; Data collection: Pedram Sdaghat, Ehsan Jaberansary, Nazi Derakhshanrad, Asghar Hajipour, Pouyan Aminishakib; Data analysis and interpretation: Nazi Derakhshanrad; Drafting the article: Hooshang Saberi, Nazi Derakhshanrad; Critically revising the article: Hooshang Saberi and Asghar Hajipour; Reviewing the submitted manuscript and final version approval: All authors.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgements
 The authors appreciate Marjan Sohrabi, Farzad Pakdel, Azin Tabari, and Ahmadreza Hojjati Marvast.



References

1. Jose A, Singh S, Roychoudhury A, Kholakiya Y, Arya S, Roychoudhury S. Current understanding in the pathophysiology of SARS-CoV-2-associated rhino-orbito-cerebral mucormycosis: A comprehensive review. Journal of Maxillofacial and Oral Surgery. 2021; 20(3):373-80. [DOI:10.1007/s12663-021-01604-2] [PMID] [PMCID]
2. Bari MS, Hossain MJ, Akhter S, Emran TB. Delta variant and black fungal invasion: A bidirectional assault might worsen the massive second/third stream of covid-19 outbreak in South-Asia. Ethics, Medicine and Public Health. 2021; 19:100722. [DOI:10.1016/j.jemep.2021.100722] [PMID] [PMCID]
3. Solanki B, Chouhan M, Shakrawal N. Mucor alert: Triad of covid-19, corticosteroids therapy and uncontrolled glycemic index. Indian Journal of Otolaryngology and Head & Neck Surgery. 2021; 74:3075–7. [DOI:10.1007/s12070-021-02801-8] [PMID] [PMCID]
4. Honavar SG. Code mucor: Guidelines for the diagnosis, staging and management of rhino-orbito cerebral mucormycosis in the setting of covid-19. Indian Journal of Ophthalmology. 2021; 69(6):1361-5. [DOI:10.4103/ijo.IJO_1165_21] [PMID] [PMCID]
5. Sen M, Honavar SG, Bansal R, Sengupta S, Rao R, Kim U, et al. Epidemiology, clinical profile, management, and outcome of covid-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India-collaborative OPAI-IJO study on mucormycosis in covid-19 (COSMIC), report 1. Indian Journal of Ophthalmology. 2021; 69(7):1670-92. [DOI:10.4103/ijo.IJO_1565_21] [PMID] [PMCID]
6. Dallalzadeh LO, Ozzello DJ, Liu CY, Kikkawa DO, Korn BS. Secondary infection with rhino-orbital cerebral mucormycosis associated with covid-19. Orbit. 2022; 41(5):616-9. [DOI:10.1080/01676830.2021.1903044] [PMID]
7. Revannavar SM, PS S, Samaga L, VK V. Covid-19 triggering mucormycosis in a susceptible patient: A new phenomenon in the developing world? BMJ Case Reports. 2021; 14(4):e241663. [DOI:10.1136/bcr-2021-241663] [PMID] [PMCID]

8. Sen M, Lahane S, Lahane TP, Parekh R, Honavar SG. Mucor in a viral land: A tale of two pathogens. Indian Journal of Ophthalmology. 2021; 69(2):244-52. [DOI:10.4103/ijo.IJO_3774_20] [PMID] [PMCID]
9. Hoenigl M, Seidel D, Carvalho A, Rudramurthy SM, Arastehfar A, Gangneux JP, et al. The emergence of covid-19 associated mucormycosis: Analysis of cases from 18 countries. The Lancet Microbe. 2021; 3(7):e543-52. [DOI:10.1016/S2666-5247(21)00237-8] [PMID] [PMCID]
10. Fouad YA, Abdelaziz TT, Askoura A, Saleh MI, Mahmoud MS, Ashour DM, et al. Spike in rhino-orbital-cerebral mucormycosis cases presenting to a tertiary care center during the covid-19 pandemic. Frontiers in Medicine. 2021; 8:645270. [DOI:10.3389/fmed.2021.645270] [PMID] [PMCID]
11. Bayram N, Ozsaygılı C, Sav H, Tekin Y, Gundogan M, Pangal E, et al. Susceptibility of severe covid-19 patients to rhino-orbital mucormycosis fungal infection in different clinical manifestations. Japanese Journal of Ophthalmology. 2021; 65(4):515-25. [DOI:10.1007/s10384-021-00845-5] [PMID] [PMCID]
12. Veisi A, Bagheri A, Eshaghi M, Rikhtehgar MH, Rezaei Kanavi M, Farjad R. Rhino-orbital mucormycosis during steroid therapy in covid-19 patients: A case report. European Journal of Ophthalmology. 2022; 32(4):NP11-6. [DOI:10.1177/11206721211009450] [PMID] [PMCID]
13. Mehta S, Pandey A. Rhino-orbital mucormycosis associated with covid-19. Cureus. 2020; 12(9):e10726. [DOI:10.7759/cureus.10726] [PMID] [PMCID]
14. Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in covid-19: A systematic review of cases reported worldwide and in India. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2021; 15(4):102146. [DOI:10.1016/j.dsx.2021.05.019] [PMID] [PMCID]
15. Bornstein SR, Rubino F, Khunti K, Mingrone G, Hopkins D, Birkenfeld AL, et al. Practical recommendations for the management of diabetes in patients with covid-19. The lancet Diabetes & Endocrinology. 2020; 8(6):546-50. [DOI:10.1016/S2213-8587(20)30152-2] [PMID]
16. Ashour MM, Abdelaziz TT, Ashour DM, Askoura A, Saleh MI, Mahmoud MS. Imaging spectrum of acute invasive fungal rhino-orbital-cerebral sinusitis in covid-19 patients: A case series and a review of literature. Journal of Neuroradiology. 2021; 48(5):319-24. [DOI:10.1016/j.neurad.2021.05.007] [PMID] [PMCID]
17. Khan MM, Parab SR. 0.5% povidone iodine irrigation in otorhinolaryngology surgical practice during covid 19 pandemic. American Journal of Otolaryngology. 2020; 41(6):102687. [DOI:10.1016/j.amjoto.2020.102687] [PMID] [PMCID]