Title Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respiratory Distress Syndrome

Acute invasive fungal rhinosinusitis is a rare, although highly morbid, infection primarily affecting immunosuppressed individuals. The same population is at particularly high risk of complications and mortality in the setting of SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome. The authors present a case of acute invasive fungal rhino-orbital mucormycosis in a patient with COVID-19 and discuss the prevalence, diagnosis, and treatment of fungal coinfections in COVID-19. Prompt recognition, initiation of therapy, and consideration of the challenges of rapidly evolving COVID-19 therapy guidelines are important for improving patient survival. Acute invasive fungal rhinosinusitis (AIFRS) is a rare, lifethreatening infection with a high risk of mortality. It commonly affects immunocompromised individuals, including those with hematological malignancy, diabetes mellitus, and organ transplantation. The global pandemic of coronavirus disease 2019 (COVID-19) has infected >18 million people internationally and over 4 million in the United States alone. Caused by coronavirus-2 (SARS-CoV-2), the disease may progress to acute respiratory distress syndrome (ARDS), a condition that increases the susceptibility of pulmonary fungal coinfections. The authors present a case of invasive fungal rhinosinusitis with orbital involvement in a patient with COVID-19 and discuss the prevalence of fungal coinfection with COVID-19, as well as the diagnostic and management challenges faced in critically ill patients. This case report, including the collection and evaluation of protected patient health information, was performed in compliance with the provisions of the United States of America Health Insurance Portability and Accountability Act of 1996 and adhered to the World Medical Association’s ethical principles for medical research involving human subjects outlined in the Declaration of Helsinki as amended in 2013. CASE PRESENTATION A 60-year-old man with a history of poorly controlled insulin-dependent diabetes, asthma, hypertension, hyperlipidemia, and recent travel to Mexico presented to an outside emergency department with dyspnea and hypoxia. Testing negative for SARS-CoV-2, he was discharged home with a diagnosis of bronchitis and treated with antibiotics and home oxygen. One week later, he represented with worsening symptoms. Although serum glucose was mildly elevated (105–143 mg/ dl), he had marked hyperglycemia (600 mg/dl) the night before. After testing positive for SARS-CoV2, he was transferred to the University of California, San Francisco for a higher level of care for COVID-19 and the associated ARDS. On arrival, because of increasing oxygen demand, he was intubated in the intensive care unit and started on remdesivir. The following day, the patient was found to have prominence of the right eye. Computed tomography angiography of the brain, orbits, and neck revealed right globe proptosis with asymmetric retrobulbar fat stranding and extensive opacification of right maxillary, ethmoid, and frontal sinuses. There was also partial opacification of the right sphenoid sinus and erosions of the lamina papyracea (Fig. 1). The clinical and radiographic findings were highly suspicious for acute invasive fungal rhinosinusitis with orbital involvement. Hemoglobin A1c was found to be 14.0%. Intranasal tissue culture and biopsy was performed via bedside nasal endoscopy on hospital day 2. Frozen sections were not performed due to prolonged decontamination requirements for the cryotome in the setting of known COVID-19 infection; thus, the tissues were formalin fixed before processing. The patient was started on intravenous vancomycin and cefepime, antifungal coverage with liposomal amphotericin B, and strict glucose management. On hospital day 4, histopathology demonstrated mucormycosis with angioinvasion, and therefore, caspofungin was added to the medical regimen (Fig. 2). Fungal cultures ultimately grew Rhizopus species. The patient’s respiratory status was tenuous, requiring prone positioning 16+ hours daily to maintain oxygenation on 100% FiO 2 and thus precluded MRI evaluation or surgical management. The ophthalmology service was consulted on hospital day 5, once histopathology confirmed invasive fungal infection. On bedside ophthalmologic examination, the right eye had mild proptosis with erythema and edema of the eyelids and conjunctival chemosis. The right pupil was fixed and mid-dilated due to an old third nerve palsy, while the left was pharmacologically constricted by his sedative medications, limiting assessment for a relative afferent pupillary defect. The patient was unable to participate with vision or motility testing due to intubation before ophthalmic examination. The remainder of the examination including dilated fundus examination was unremarkable. The patient was treated with a series of 3 daily retrobulbar injections of liposomal amphotericin B (3.5 mg/dl; off-label usage) to the right orbit. Concurrently, the patient was also started on a 10-day course of dexamethasone 6 mg daily and a single dose of convalescent plasma as a treatment for COVID-19. Unfortunately, the dexamethasone led to hyperglycemia that was difficult to manage despite aggressive insulin usage. On hospital day 10, the patient had improved respiratory status, allowing endoscopic surgical debridement by otolaryngology. COVID-19 infection control precautions included the use of powered air purifying respirators and the exclusion of trainees from operative management to minimize the risk of exposure to medical staff. He was subsequently transitioned from liposomal amphotericin B to posaconazole due to acute kidney injury. His health status continued to decline despite ongoing treatment,