Prevention and Treatment of COVID-19-Associated Mucormycosis

The present article will describe the unique factors present in COVID-19 patients that predispose these individuals to develop mucormycosis with emphasis placed on the prevention and treatment of COVID-19-associated mucormycosis (CAM). Viral specific factors, pre-existing diabetes mellitus, and COVID-19 treatments combine to facilitate the development of mucormycosis. There appears to be a gross overutilization of steroid and antibiotic therapy among COVID-19 patients. Appropriate stewardship of antibiotic and steroid therapy in conjunction with tight glucose control may prevent the development of CAM and facilitate effective treatment with pharmacologic and surgical therapy. Appropriate treatment for CAM has been extrapolated from traditional mucormycosis therapies, and high-level, empiric evidence regarding the efficacy of CAM-specific treatments does not exist. Cellular impacts of COVID-19, poor diabetic management, and overuse of antibiotics and corticosteroids likely combine and increase the risk of mucormycosis in COVID-19 patients. Minimizing these risk factors should curb the development of CAM and facilitate the treatment of CAM. Current treatment of CAM has been borrowed from traditional mucormycosis therapy. Future prospective studies are needed to begin developing CAM-specific treatment regimens.


Introduction
Mucormycosis is a rare, rapidly invasive, fungal infection caused by fungi in the order Mucorales that occurs primarily in immunocompromised individuals [1]. Rhizopus oryzae is the most common culprit responsible for mucormycosis [2]. The first confirmed report of COVID-19-associated mucormycosis (CAM) occurred in May 2020, and over 2000 additional cases of CAM have been identified since that time, representing a geographically disproportionate rise in mucormycosis during the COVID-19 pandemic with the majority of documented cases occurring in India [3, 4••, 5, 6]. Pre-existing comorbidities, viral specific effects, and COVID-associated treatments combine to facilitate the development of CAM. Mucormycosis can occur during or after COVID infection, and although the median duration between COVID infection and development of mucormycosis is between 13 and 18 days [4 ••, 7], invasive mucor was noted as early as 2 days and as late as 90 days after COVID diagnosis [8]. Other fungal species, including Aspergillus, have produced acute invasive fungal sinusitis in COVID patients,however, mucor has been found to be the causative agent over 90% of the time [9]. While significant disagreement [3] exists in the literature, CAM may represent a more deadly form of mucormycosis with mortality rates around 50%, while previous mortality rates reported for mucormycosis are closer to 33% [4••, 8, 10]. Mucormycosis is suspected following direct examination revealing pallor, eschar, or insensate mucosa and confirmed with fungal culture and tissue biopsy demonstrating invasive fungal organisms. Newer diagnostic options such as in situ hybridization and polymerase chain reaction are infrequently utilized alternatives that have the potential to improve the speed and accuracy of diagnosis in the future [11•, 12]. Effective treatment of mucormycosis involves a high degree of suspicion, prompt diagnosis, mitigation of exacerbating factors, and early initiation of antifungal therapy and surgical debridement (Table 1). Due to the poor outcomes associated with CAM even with prompt treatment, a strong emphasis should be placed on prevention of this devastating disease among COVID patients. This review will focus on the prevention and treatment of novel CAM.

Treatment Prevention
A number of modifiable and non-modifiable risk factors combine in COVID patients that appear to facilitate the development of mucormycosis. Non-modifiable factors include COVID-19 viral specific effects, such as impaired ciliary clearance [23], hepcidin activation via viral mimicry leading to increased free iron to fuel fungal proliferation [24], free radical mediated endotheliitis [25], and upregulation of receptors like GRP78 and fungal ligand spore coating homolog protein that facilitates fungal angioinvasion [26].
Modifiable risks can be broken down into pre-existing factors, namely diabetes, and treatment-related factors including steroid and antibiotic use. Prior to the COVID-19 endemic, 40% of mucor patients were diabetic [1], while 77% of patients with CAM have pre-existing diabetes. Elevated blood sugar results in glycosylation of transferrin and ferritin, thereby decreasing iron binding and increasing free iron [27]. Abundant free iron stimulates mucor proliferation, and the acidotic environment present in diabetic ketoacidosis facilitates the germination of fungal spores [27]. Corticosteroids impair phagocytic clearance of fungi and increase blood sugar promoting development of mucormycosis [28]. Only critically ill COVID patients with ARDS, high oxygen requirements, or those receiving mechanical ventilation have been shown to benefit from corticosteroids (RECOVERY). In practice, however, a large proportion of non-critically ill COVID patients have received steroids, and these courses are often at higher doses and for longer durations than recommended even for critically ill COVID patients [29].
Antibiotic therapy suppresses normal, healthy bacterial flora leaving the host more vulnerable to invasion by fungus. Approximately 75% of COVID patients receive antibiotic courses despite estimates that bacterial co-infection with COVID-19 occurs in only 8.6% of patients, revealing a substantial overuse of antibiotics in this patient population [30,31].
While viral specific effects of COVID-19 that predispose patients to the development of CAM may be difficult to combat, there should be close attention to tight glucose control, reservation of steroid therapy for critically ill COVID patients, and good stewardship of antibiotics to prevent the development of CAM. Similarly, for patients who have developed CAM, it is of the utmost importance to address the above modifiable risk factors to optimize the patient's immune function and create the least hospitable environment possible for the Mucorales fungus.

Therapy
In an effort to avoid re-inventing the wheel, treatment for CAM has been extrapolated from the management of traditional mucormycosis. Currently, high-level, empiric evidence regarding the efficacy of CAM-specific treatments does not exist. Available CAM-specific literature consists of observational case reports, case series, and systematic reviews encompassing a myriad of complex treatment regimens with variable dosages, durations, and combinations of pharmacologic and surgical therapies. The extreme heterogeneity of existing data makes it exceedingly difficult to create meaningful comparisons between treatment regimens for CAM. The following treatment section will summarize the therapies that have been utilized in the management of CAM; however, it is important to note that findings specific to the treatment of CAM are based exclusively on Level V and VI evidence at this time. [32]. This drug serves as a broad-spectrum antifungal with a low incidence of clinical resistance among Mucorales strains [33]. AmB comes in a deoxycholate formulation, as well as lipidic formulations, including AmB lipid complex (ABLC) and liposomal AmB (L-AmB). The lipidic formulations tend to be preferred due to their lower risk of nephrotoxicity, increased central nervous system penetration, and decreased side effects like headache, fever, hypotension, dyspepsia, and pain at the injection site [34][35][36]. Of the lipidic options, L-AmB has been shown to induce less toxicity and produce fewer side effects than ABLC [37][38][39]. Due to the potential nephrotoxic effects of AmB, other antifungal options should be considered for patients with severe kidney disease. During AmB therapy, monitoring of hepatic and renal function, careful electrolyte repletion, and adequate hydration are important to recognize and address potential toxicities [35]. Dosing of L-AmB for CAM has ranged from 3 to 10 mg/kg/day [40]. Five to 10 mg/kg/day was recommended in the 2019 Global Guideline for the Diagnosis and Management of Mucormycosis [32],however, a randomized controlled trial evaluating treatment of pulmonary mucormycosis found 3 mg/kg/day dosing to be equally efficacious [41]. Ultimately, the patient's clinical response and tolerance of the drug should guide dosing. AmB has been previously administered via nebulized solution for topical therapy [42] and has been injected intrathecally with success in mucormycosis patients, though available data is sparse [43,44]. Intravenous AmB treatment should be continued until clinical improvement is noted, usually sometime between 2 and 4 weeks, before the patient is transitioned to step-down therapy with oral antifungals [45]. A lack of clinical response, progression of disease, or drug intolerance may necessitate earlier transition from AmB to an alternative antifungal. Of note, certain rarer Mucorales strains have not been shown to be sensitive to amphotericin B, including Cunninghamella and Apophysomyces [46].

Pharmacologic treatment Amphotericin B Intravenous amphotericin B (AmB) serves as the first-line medical therapy for treatment of mucormycosis and is the most commonly used treatment for CAM
Posaconazole Posaconazole is an azole antifungal utilized as a step-down therapy, a salvage therapy following initial treatment with AmB, a first-line therapy in patients who cannot take AmB, or as a mucormycosis prophylactic in at-risk patients [45, 47, 48••]. Posaconazole is the second most commonly used drug for the treatment of CAM after AmB [40]. Despite its use for prophylaxis in immunocompromised patients, mucormycosis has been shown to develop in patients taking posaconazole, which has led providers to primarily use this drug as a second-line treatment [49,50]. Intravenous dosing is 300 mg BID on the first day followed by 300 mg QD, and oral dosing is 200 mg QID followed by 400 mg BID after stabilization of disease [45]. Therapeutic drug monitoring is recommended, a number of drug interactions exist, and side effects include hepatotoxicity, QTc prolongation, nausea, vomiting, diarrhea. and headache [45].
Isavuconazole Isavuconazole is an extended-spectrum azole with similar indications as posaconazole for the treatment of CAM [48••]. Although acting via the same mechanism as posaconazole, isavuconazole offers the advantage of a unique formulation that decreases nephrotoxicity and side effects, including hepatotoxicity and QT prolongation, in comparison to other azoles [51]. Additionally, mortality rates in mucormycosis patients treated with first-line isavuconazole therapy have been shown to be equivalent to mortality rates in patients treated with AmB, making this oral medication an excellent alternative for patients who cannot tolerate or do not respond to amphotericin B [52]. Intravenous and oral dosing is 372 mg TID for 2 days, followed by 372 mg ""QD [45]. Therapeutic drug monitoring is not required for isavuconazole [45]. [53,54]. A study by Reed et al. [55] evaluating 41 patients with rhino-orbital-cerebral mucormycosis found that patients treated with combined amphotericin B and caspofungin therapy had improved survival that was most pronounced in patients with cerebral involvement [55]. Side effects of echinocandins tend to be much milder than those associated with AmB and the azole medications,however, patients can experience fever, rash, edema, nausea, vomiting, diarrhea, bronchospasm, dyspnea, and hypotension [56]. Side effects can often be managed by simply reducing the rate of infusion [57]. [58,59]. IFN-gamma is active against the broadest range of fungal organisms [60], and although clinical data is limited, IFN-gamma in combination with nivolumab successfully treated mucormycosis refractory to standard therapies [61], and this drug combination has been used successfully in a CAM patient.

Cytokines Cytokines including interferon gamma (IFN-gamma), granulocyte colony-stimulating factor (GCS-F), and granulocyte-monocyte colony-stimulating factor (GM-CSF) have been utilized in an attempt to bolster the host immune response against mucormycosis. In vitro work has shown both CM-CSF and IFN-gamma may boost the natural immune response against certain Mucorales strains
Surgical debridement Mucormycosis is an angioinvasive process leading to infarction and necrosis of involved tissues. Effective treatment requires surgical debridement to remove devitalized tissue harboring the fungus that cannot be penetrated by systemic antifungal therapy. The combination of antifungal therapy and surgical debridement has been shown to improve survival compared with antifungal therapy alone in CAM patients [62,63]. An endoscopic endonasal approach provides excellent access and visualization for thorough debridement in the majority of cases; however, when facing frank orbital invasion, exenteration can be considered [10,64]. Recent evidence suggests that patients with orbital involvement who undergo less invasive treatments, such as retrobulbar amphotericin B injections, may achieve equivalent rates of survival compared to patients who undergo orbital exenteration [65]. Successful debridement usually requires multiple trips to the operating room with targeted biopsies to guide further debridement to ensure clear margins [66].
Hyperbaric oxygen Hyperbaric oxygen therapy (HBOT) has been shown to inhibit fungal growth, enhance tissue healing and angiogenesis, and correct lactic acidosis, which promotes the efficacy of amphotericin B [67,68]. Limited evidence from small case series suggests that the addition of HBOT to standard antifungal and surgical therapy may improve survival in mucormycosis patients, especially for diabetic patients [69][70][71]. HBOT used as adjunctive therapy with antifungal and surgical treatment has been successfully utilized in a kidney transplant patient with CAM [72].

Conclusion
Cellular impacts of the COVID-19 virus, uncontrolled diabetes mellitus, overutilization of corticosteroids, and poor stewardship of antibiotics combine in COVID-19 patients to increase their risk of developing mucormycosis. Addressing these modifiable risk factors is crucial for both prevention and successful treatment of CAM. Existing treatment strategies for CAM have been borrowed from traditional mucormycosis therapy. Literature specifically addressing the treatment of CAM is sparse and largely observational. Additionally, the vast heterogeneity among the described treatment regimens utilized for CAM makes meaningful comparisons between specific therapies challenging. Future prospective studies are needed to begin developing evidence-based, CAM-specific treatment regimens.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest
The authors declare that they have no conflict of interest.

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