COVID-19 Associated Mucormycosis: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Dilip Kumar Shanmugam.

Mucormycosis has become increasingly associated with COVID-19, leading to the use of the term “COVID-19 associated mucormycosis (CAM)”. Treatment of CAM is challenging due to factors such as resistance to many antifungals and underlying co-morbidities. India is particularly at risk for this disease due to the large number of patients with COVID-19 carrying comorbidities that predispose them to the development of mucormycosis. Additionally, mucormycosis treatment is complicated due to the atypical symptoms and delayed presentation after the resolution of COVID-19. 

  • mucormycosis
  • COVID-19
  • fungal infection

1. Introduction

Mucormycosis is a life-threatening invasive fungal infection (IFI), which, although once considered rare, has become increasingly prevalent in patients affected by SARS-CoV-2 [1]. The fungi responsible for mucormycosis belong to the order Mucorales and include genera such as Rhizopus, Rhizomucor, Mucor, Lichtheimia, Cunninghamella and Saksenaea. These fungi are commonly present in the environment. Although they are well recognized to cause opportunistic infections in immunocompromised patients, 19% of mucormycosis has been reported in immunocompetent patients [2,3][2][3]. A main reason behind recent mucormycosis infections is COVID-19 [4].

2. Mechanisms of Pathogenesis

Mucormycosis invasion occurs through glucose-regulated proteins (GRPs), which are molecular chaperones of the Hsp70 family (70 KDa Heat Shock Proteins) [18][5]. Although these are present in the endoplasmic reticulum (ER) under normal circumstances, ER stress conditions such as DKA, and the associated changes in tissue microenvironment (glucose, iron and ketone bodies), result in overexpression of GRPs in different compartments and the cell surfaces [8][6]. GRP78 is an essential receptor for adhesion and invasion of fungal hyphae and the resultant injury of endothelial cells [19,20][7][8]. The interaction with fungi is mediated by the fungal ligand spore-coating homolog protein (CotH) in Rhizopus, commonly CotH3 for ROCM. In pulmonary mucormycosis, invasion and infection are facilitated by fungal CotH7 with integrin-β1 (with heterodimer formation with integrin-α3) [20][8], which enables the superficial entry into the nasal epithelium. Further invasion involves attachment to the collagen IV and laminin in the extracellular matrix of the basement membrane of the endothelial cells [16][9]. Mucoricin, a ricin-like toxin produced by the fungi, may also aid this invasion and virulence [21,22][10][11]. Apart from adhesion, endocytosis is also responsible for causing damage to the host cells. Platelet-derived growth factor receptor (PDGFR) is involved in endocytosis and angioinvasion, which results in the dissemination of the infection and necrosis [23][12]. The mechanisms are discussed further along with risk factors to highlight the role of each element in causing disease.

3. Association of COVID-19 with Risk Factors of Mucormycosis and Their Role in Infection

The probability of acquiring mucormycosis is associated with various risk factors, of which the most important ones are DM (with or without ketoacidosis) and conditions causing immunocompromised status [27][13]. The primary risk factor affecting a population may also vary with geographical location. For example, in countries such as India, Iran and Mexico, the major pre-existing risk factor is DM, while primarily hematological malignancies are the main risk factor in Europe [5][14]. The predisposing condition may also determine the type of mucormycosis caused. Hematological malignancies and neutropenia are commonly associated with pulmonary mucormycosis, while DM is often related to rhinomaxillary and rhinocerebral disease [5,17,28][14][15][16]. Cutaneous mucormycosis is often associated with trauma or burns [5,9][14][17]. COVID-19, with or without immunosuppressive therapies, may act via various pathways to have a synergistic effect in creating an environment favorable for the development of CAM. Therefore, severe COVID-19 is considered a risk factor for mucormycosis. This section analyses CAM based on the link between COVID-19 and the various risk factors for mucormycosis. Additionally, the synergistic roles of these risk factors are explored.

3.1. Diabetes Mellitus and Diabetic Ketoacidosis

One of mucormycosis’s primary and most common risk factors is uncontrolled DM (especially with ketoacidosis). DM increases the severity of SARS-CoV-2 and the risk of mucormycosis [9][17], especially RCM. Mucormycosis seen in diabetic patients has clinical manifestations, including cranial nerve palsy, diplopia, mid-facial pain, proptosis, periorbital oedema, apex orbital syndrome, and palatal ulcers [7][18]. COVID-19 is responsible for an acute cortisol stress response, which may raise serum cortisol levels and hyperglycemia in both persons with and without DM [29][19]. Diabetes may be pre-existing or associated with COVID-19 infection (corticosteroid therapy for COVID-19 or other infectious diseases predisposes patients to mucormycosis) [27][13]. Diabetes or a hyperglycemic state is often associated with an inflammatory condition responsible for constant recruitment and activation of immune cells, which further exacerbates the inflammatory phenotype by increased secretion of proinflammatory cytokines. In these circumstances, antiviral immunity activation in response to SARS-CoV-2 infection also intensifies inflammation, which increases the chances of mucormycosis and other secondary infections [27][13]. DM promotes the growth and proliferation of fungal pathogens by affecting the immune system, affecting phagocytosis, chemotactic activity and transendothelial migration of neutrophils [30][20]. The virus affects angiotensin-converting enzyme 2 (ACE2) producing cells (including beta cells of the pancreas), leading to the decreased breakdown of angiotensin II. This causes insulin resistance and upregulation of the sodium and hydrogen exchanger (NHE). NHE can increase damage to the pancreas due to its role in insulin release [31][21]. NHE affects Na+ and Ca2+ transport, which leads to hypoxia [32][22]. This, along with COVID-19 associated cell lysis, leads to increased lactate levels, insulin resistance and endothelial damage. COVID-19 also causes lactic acidosis (accumulation of lactic acid), which further increases the activity of the NHE pump and increases the blood glucose level by gluconeogenesis. This also increases the serum iron concentration, which acts as a nutrition source for the growth of fungi [30][20]. Fungi of Mucorales are present generally in the environment [33][23]. They are opportunistic pathogens because normal human serum (at physiological pH range) can provide nutritional immunity against fungal invasion due to the iron-binding properties of transferrin and ferritin. This prevents fungi from getting access to iron for its functions [34][24]. However, COVID-19 may also cause diabetic ketoacidosis. Under the acidic conditions of diabetic ketoacidosis (DKA) (pH 4), this iron-binding ability reduces due to glycosylation of iron sequestering proteins, and so iron is no longer bound and utilized by the fungus for its disease pathogenesis [35][25]. Further, the favorable environment for fungal growth (high glucose levels, acidic conditions, ketone bodies such as β-hydroxy butyrate [BHB] and resultant free iron) created by DKA is responsible for increased expression of glucose-regulator protein 78 (GRP-78) on the surface of endothelium cells [8][6]. This interaction traps the inhaled spores in the nasal cavity, causing ROCM [20][8]. It is also involved in the entry of the SARS-CoV-2 and has been proposed as a potential drug target for targeting the virus [36,37][26][27]. As a result, invasion and injury of endothelial cells by Rhizopus is increased and tissue necrosis is observed [38][28]. DKA also causes immunosuppression by affecting T-lymphocyte induction, interferon-gamma and phagocytosis [8][6]. Additionally, administration of steroids in COVID 19 patients with pre-existing diabetes can affect phagocytosis by White Blood Cells and the destruction of pathogens by macrophages at various stages, making them more susceptible to Mucorales infections [38][28].

3.2. Immunosuppression

Prolonged administration of corticosteroid therapy or immunomodulatory drugs to patients with COVID-19 and pre-existing comorbidities can increase their risk of developing CAM. It was found that immunocompromised patients who crossed a threshold of 600 mg of prednisone (cumulative dose) or 2–7 g methyl prednisone (preceding month alone) are at higher risk of mucormycosis infection. In a study conducted by Patel et al. 2021, it was found that for the majority of the patients, the cumulative glucocorticoid dose administered vastly exceeded the recommended dosage. However, shorter courses of corticosteroid treatment of even 5–14 days have been found to predispose diabetic patients to mucormycosis [38,39][28][29]. Additionally, dexamethasone, a WHO-recommended corticosteroid treatment for severe or critically ill patients with COVID-19, has been associated with higher susceptibility to IFIs. These immunomodulatory and corticosteroid treatments and COVID-19 may affect phagocytosis and other immune responses [27][13]. Although steroid treatment in DM patients increases the risk of them developing CAM, the literature supports that patients without DM have also developed CAM after steroid use. Therefore, it is recommended that steroid therapy be avoided, especially in patients who exhibit mild COVID-19 [40][30]. It has been hypothesized that COVID-19-mediated ACE2 dysregulation creates a cascade that results in an environment suitable for fungal growth through its effects on the pancreas, lungs, colon, ileum, esophagus, cardiovascular and cardiovascular tissues [30][20]. ACE2 is ubiquitous on the lymphocyte surface and is likely involved in lymphocyte damage in COVID-19 infection [41][31]. COVID-19 is believed to cause immunosuppression due to lymphocyte damage by apoptosis due to the cytokine storm (which involves elevated levels of various proinflammatory cytokines such as several interleukins and TNF-α) and the resultant lymphoid tissue atrophy [30,42][20][32]. This cytokine storm also results in lactic acidosis, which has a detrimental effect on the proliferation of lymphocytes [43][33]. Together, these factors cause a reduction in lymphocytes (lymphocytopenia) [31][21]. SARS-CoV-2 infection lowers the levels of CD4 and CD8 T-cells. It also affects the responses of lymphocytes Th1 and Th2 (T helper type 1 and 2 cells) [44][34]. As a result, COVID-19 patients with acute respiratory distress syndrome (ARDS) exhibit immune system alteration and increased susceptibility to IFIs such as mucormycosis. Given the potential impact on the immune system, COVID-19 treatment with immunomodulatory drugs, such as IL-6 inhibitors, should be reserved for selected patients according to existing guidelines [40][30]. COVID-19 is also associated with a reduction in phagocytosis, thrombosis and endothelialitis [38][28]. Endothelial adhesion and penetration are crucial for mucormycosis entry and infection. The increased IL-6 levels in response to COVID-19 and acidosis also result in ferritin production, leading to intracellular iron accumulation, which damages the tissue. This tissue damage is responsible for releasing iron into the bloodstream, enabling fungus growth [45][35].

3.3. Nosocomial Sources

Mucormycosis may also be associated with nosocomial sources, especially during prolonged hospitalization [46][36]. Non-sterile equipment in hospitals is the main disseminator of infections among immunocompromised patients. Such equipment includes unsterilized/non-sterile bandages, nitroglycerin patches, ostomy bags, hospital linens, adhesive tape, wooden tongue depressors and even consumables such as probiotics, pre-packaged food and allopurinol tablets [5,47,48][14][37][38]. Medical apparatus and devices inserted into the body can allow direct access of fungal pathogens to infect the body. This includes intravascular devices such as IV catheters, lancets for insulin measurement, tubes inserted into the body, intubation, injections, and dental and surgical procedures [49][39]. A similar mode of infection is seen in intravenous drug abusers [38][28]. Prolonged ICU treatment can also increase the risk of mucormycosis, especially in patients under mechanical ventilation [50][40]. Environmental factors such as fungal pathogens in the air, water or surfaces in a hospital may also be responsible for hospital-associated mucormycosis. One such instance is the presence of oxygen humidifiers in hospitals which can spread potentially contaminated water, resulting in the significant spread of the disease [1]. Additionally, problematic plumbing and ventilation can augment the spread of infection among patients and lead to a community outbreak [5][14]. In the case of a heart transplant patient who did not demonstrate any of the usual risk factors associated with CAM, it was suggested that COVID-19 was responsible for lymphocytopenia and the resultant immunosuppression, which led to fungal infection [9][17]. The extent of respiratory pathology or pulmonary damage has been correlated with the nature of the risk of contracting CAM [51][41]. Intubation or mechanical (invasive) ventilation in the intensive care unit (ICU) for COVID-19 patients with ARDS for prolonged periods is a commonly observed risk factor for acquiring mucormycosis [52][42].

3.4. Other Factors

In general, treatment for COVID-19 with various antibiotics and immunosuppressive therapies such as monoclonal antibodies and steroids can cause dysbiosis of the human microbiome and damage epithelial linings, which aids the development of IFIs. One such treatment for COVID-19 is zinc, since it is known to have antiviral effects [53][43]. However, extensive use of zinc is significantly associated with occurrence of CAM since it promotes the growth of pathogenic fungi, without much benefit in treating COVID-19 [54,55][44][45]. Protracted treatment with antifungals for pre-existing fungal infections and a history of IFIs also increase the patient’s chances of being infected by Mucorales fungi [27][13]. Additionally, the renal tropism of the COVID-19 virus may also be responsible for kidney injury. Deferoxamine, administered to treat renal failure, is involved in iron sequestration by the Mucorales fungi, leading to mucormycosis [27][13]. In addition to all these aspects, in some cases, mucormycosis was observed even in COVID-19 patients without underlying predisposing factors, suggesting that the infection was responsible for creating a microenvironment favorable for the fungal population [56][46].

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