COVID-19 and mucormycosis superinfection: Exploring the missing pathophysiological links

The coronavirus disease 2019 continues to unearth new facets that portend grave clinical implications. In recent times, there has been mounting fervor regarding coronavirus disease 2019 and mucormycosis superinfection. While the correlation between the two is conspicuous, the underlying pathophysiological mechanisms that render a patient with coronavirus disease 2019 susceptible to mucormycosis, or vice versa, are still elusive.

The coronavirus disease 2019 continues to unearth new facets that portend grave clinical implications. In recent times, there has been mounting fervor regarding coronavirus disease 2019 and mucormycosis superinfection. While the correlation between the two is conspicuous, the underlying pathophysiological mechanisms that render a patient with coronavirus disease 2019 susceptible to mucormycosis, or vice versa, are still elusive.

Introduction
From its detrimental effects on various organs such as the liver to its potential long-term neurological effects, coronavirus-2019 (COVID-19) has continued to ravage healthcare systems across the world [1,2]. With the advent and distribution of vaccinations worldwide, at a historic pace, the world is slowly paving the way for a return to normalcy. However, the pandemic continues to reveal new challenges. One of these is superinfection with mucormycosis, an opportunistic fungal infection. Pre-pandemic, its prevalence has been primarily observed in immunocompromised patients, such as those with uncontrolled diabetes mellitus, neutropenia, hematological malignancies, and similar conditions [1]. Herein, we chronicle the relationship between COVID-19 and mucormycosis, collating the available sparse literature and positing future directions.
Untreated, the "black fungus" mucormycosis is rapidly fatal. Mucormycosis is caused by various fungi species from the Mucorales order [3]. As Mucorales spores exist widely in nature, it is possible for them to be present in the nasal mucosa of healthy people as a commensal organism [4]. If the patient develops a state of immunosuppression, however, this is when it may germinate pathologically within the paranasal sinuses and spread to nearby structures such as the orbit and, even worse, intracranially [5]. In Europe most cases have been identified with Rhizopus spp. (34 %), Mucor spp. (19 %), and Lichtheimia spp. (19 %) [3]. Its etiology, however, varies based on geography. For example, many cases in Australia were non-Rhizopus species infecting immunocompetent patients through trauma, yet these were limited to local infections. On the other hand, necrotizing fasciitis due to infection from intramuscular injections have been reported in India, and these cases were due to much rarer species of the Mucorales order.
The global incidence of mucormycosis has risen over the past few decades, yet these rising statistics have been virtually restricted to developing countries like India. In the United States and Europe, the prevalence is 0.01-0.02 per 100,000 population [3]. Meanwhile, India sees a prevalence of 14 per 100,000. In adults, the mortality rate ranges from 20 % to 100 % due to comorbidities, site of infection, treatment availability, and other factors such as quality healthcare systems. In children, the rate is 33.3 %. Historically, the rarity of mucormycosis has been the major obstacle in research [3]. This has prevented large studies and clinical trials that would typically elucidate information on its epidemiology, diagnosis, and treatment. It is treated with amphotericin-B, a last-line antifungal reserved for serious, systemic fungal infections. The only new antifungal drug with activity against Mucorales is isavuconazole; however, it offers little benefit over amphotericin-B and is replete with severe side effects.

Pathophysiology
COVID-19 has been shown to enter the cell via the ACE2 and TMPRSS-2 receptors. While ACE2-R is a ubiquitous receptor in the body, it has higher rates of expression in respiratory, renal, and gastrointestinal epithelium. TMPRSS-2 receptors are similar: they are present on many epithelia but especially on that of respiratory and gastrointestinal [1,2]. It has a propensity for attacking lymphocytes by binding to ACE2 receptors on these cells, inducing lymphopenia, reducing CD4 + and CD8 + T-cell counts and consequently reducing immunity levels. This damage is compounded with the raised interleukin levels (IL-2, IL-6, IL-7, interferon gamma inducible factor, granulocyte colony stimulating factor), effectively achieving a state of cytokine storm [4,6]. This causes atrophy of lymphoid tissue, weakening the defense system reserve pool, and preventing future production and proliferation of protective lymphocytes.
Furthermore, there is lactic acidosis, which destroys type II alveolar cells-the regenerative lung cells-leading to a plethora of respiratory difficulties that exacerbate acid-base levels. Eventually, this causes hypoxemia and hypoperfusion. Therefore, tissues depend on anaerobic metabolism that worsens the already present acidic conditions. Coupled with the urgent need to treat the cytokine storm via immunosuppressive steroids, all of this promotes an optimal environment for the fungus to thrive [7]. Finally, two other conditions fuel Mucorales growth in the infected body: raised ferritin levels due to increased hemolysis (iron is toxic to phagocytes) and a raised body temperature (they are thermotolerant organisms) [8]. The fungus receives its nutrition from ACE-2 mediated damage to pancreatic beta cells that results in and elevated plasma glucose levels [9,10]. In fact, this explains why mucormycosis is more prevalent in those with diabetes: it thrives when there is an abundance of sugar. In a study in Mexico reviewing mucormycosis cases, diabetes was an underlying comorbidity in up to 72 % of patients [3]. As mucormycosis invades blood vessels via endothelial damage, the insulin resistance and raised glucose levels result in proliferation of the fungus and progressive weakening of an already shattered immune system. These catastrophic consequences can only mean the eventual deterioration of the patient. While Mucorales can be a commensal organism in immunocompetent patients, the severe cases of COVID-19 infection are often immunocompromised and are hospitalised for longer, with some even requiring long-term mechanical ventilation. This ventilation further makes them susceptible to infections like mucormycosis.

Literature review
We perused the PubMed, MEDLINE, and SCOPUS databases using the medical subject headings (MeSH) "Coronavirus disease 2019", "COVID-19" AND "Mucormycosis." Articles in languages other than English were excluded. Case reports, case series, correspondence articles, and editorials were included in the present review. A total of 12 cases were retrieved, comprising 11 males and 1 female. The mean age of onset was 48±17 years. Notably, the mortality rate hovered at a soaring 33.3 %, further invoking the notion of early intervention in afflicted patients. These outcomes are depicted in Table 1.
The studies in the infection in the context of COVID-19. The key takeaway is clear: mortality and morbidity are very high. COVID-19 complications have been a major focus and thus repeatedly described in numerous published studies since its initial outbreak; the potential havoc that a COVID-19 infection can wreak on the immune system thus lends a helping hand to the opportunistic Mucormycosis-causing bugs.

Conclusion
As there is currently no standard protocol that is being implemented to treat Mucormycosis in COVID-19 patients, there is undoubtedly an overwhelming need to formulate one. Moreover, the results of the current study have ramifications beyond a COVID-19 and Mucormycosis superinfection. While COVID-19 has been shown to produce an immunosuppressed state on its own, the need for a standard protocol is further necessitated when considering COVID-19 patients with concurrent immunosuppressive conditions, as they are even more susceptible to Mucormycosis and its deleterious effects and often fatal outcome. The optimal strategy would be to find an equilibrium between a testament regimen that does not overly suppress the immune system while also resolving the ongoing cytokines storm characteristic of severe COVID-19.
Given these evolving challenges, it is imperative that large scale trials are designed-not just to discern the interplay between COVID-19 and Mucormycosis, but also other immunosuppressive states that can portend significant morbidity and mortality.

Limitations
The article has some limitations. For instance, having a prior diagnosis of diabetes mellitus is a well-established predisposing factor for developing a mucormycosis infection. The causality between COVID-19 and mucormycosis cannot be reliably drawn. Nevertheless, there is a conspicuous correlation between the two that cannot be discounted. Finally, while Mucormycosis infection can be seen worldwide, it has a higher prevalence in the more underdeveloped regions of the world. Thus, published cases are much more likely to come from these regions.

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Author statement TA, WN, TK: conceived the idea, designed the study, and drafted the manuscript.
MAK, AA, MA: conducted literature search and created the illustrations.
AA, AA, KTM, SS: revised the manuscript critically and refined the illustrations.
TA and WN: revised the final version of the manuscript critically and gave the final approval.

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Declaration of competing interest
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