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 Table of Contents  
MAJOR REVIEW
Year : 2021  |  Volume : 33  |  Issue : 3  |  Page : 254-259

Rhino-orbito-cerebral mucormycosis in COVID 19 patients: Understanding the pathophysiology


Dr. Rajendra Prasad Centre for Ophthalmic Sciences; Oculoplasty and Orbital Tumor Services, All India Institute of Medical Sciences, New Delhi, India

Date of Submission28-Jun-2021
Date of Decision30-Jun-2021
Date of Acceptance01-Jul-2021
Date of Web Publication08-Dec-2021

Correspondence Address:
Dr. Sahil Agrawal
Oculoplasty and Orbital Tumor Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_152_21

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  Abstract 


The pandemic caused by severe acute respiratory syndrome coronavirus 2 has had health implications of unprecedented magnitude. The second wave of the pandemic hit India with a tremendous rise in the number of patients requiring care not only for the viral inflammatory disease but also for secondary infections. Nearly 6–7 new patients of rhino-orbito-cerebral mucormycosis with active or resolved COVID-19 infection are reporting daily at a tertiary institute in Northern India. This another battle against an epidemic of mucormycosis, within an already established ongoing war of COVID-19 pandemic has aroused a need to understand the causal factors and implement effective prevention and control programs. The authors performed a thorough literature review in PubMed to understand the correlation between the two diseases. This review summarizes the plausible risk factors, and environmental determinants of mucormycosis in COVID-19, that are of particular importance to public health professionals.

Keywords: Black fungus, COVID-19, mucormycosis, ROCM


How to cite this article:
Das D, Bajaj MS, Modaboyina S, Agrawal S. Rhino-orbito-cerebral mucormycosis in COVID 19 patients: Understanding the pathophysiology. Kerala J Ophthalmol 2021;33:254-9

How to cite this URL:
Das D, Bajaj MS, Modaboyina S, Agrawal S. Rhino-orbito-cerebral mucormycosis in COVID 19 patients: Understanding the pathophysiology. Kerala J Ophthalmol [serial online] 2021 [cited 2022 Jan 21];33:254-9. Available from: http://www.kjophthal.com/text.asp?2021/33/3/254/331928




  Introduction Top


As the second ripple of the COVID-19 pandemic touched India, the nation documented a record number of new COVID-19 cases in the 1st week of May 2021. Amid this chaos, a new epidemic of rhino-orbito-cerebral mucormycosis or popularly called “the black fungus,” emerged. Nearly 6–7 new patients of rhino-orbito-cerebral mucormycosis with active or resolved COVID-19 infection are reporting each day at a tertiary eye care institute in Northern India. Even though the second wave of the pandemic has started showing a gradual reduction, alarmingly, the number of mucormycosis cases is increasing daily. Therefore, there is a need to understand the pathophysiology behind the development of mucormycosis infection among these patients.


  Methodology Top


To understand disease pathogenesis, the authors conducted a two-step literature review. The first search was performed in PubMed using the keywords “Mucormycosis,” “pathogenesis,” “rhino-orbito-cerebral mucormycosis” and “Rhizopus.” The search was limited to the last 3 decades (1990–2020). Studies, reviews, systemic reviews, meta-analysis, and case reports with significant data were included. The authors noted that the major risk factors for the development of Mucormycosis were found to be diabetes, immunocompromised state, solid organ transplant, and hematopoietic stem cell transplantation.

The authors then conducted a second stage literature review, using the keywords “immune response,” “COVID 19,” “Diabetes,” “Rhino-orbito-cerebral mucormycosis,” “invasive fungal disease,” “novel coronavirus 2019,” “SARS COV 2,” “solid organ transplant,” “stem cell transplantation.” The search was limited to December 2019 to May 2021. Studies, reviews, systemic reviews, meta-analysis, and case reports with significant data were included.


  Results Top


After, performing the literature review, the authors were able to formulate certain patient-related factors, few virulence factors of certain species of the fungus and some sources of infection which could attribute to the development of the disease.


  Patient-Related Factors Top


Mucormycosis is one of the most rapidly progressive invasive fungal infections affecting human beings. Although the fungi can be found everywhere in nature; it rarely affects normal individuals.[1],[2] The disease most commonly is seen in diabetics, immunocompromised hosts, patients with leukemia, lymphoma, multiple myeloma, multiple blood transfusion, septicemia, hepatitis, cirrhosis, renal failure, and patients on chemotherapy or steroids. In the past, diabetes was considered to the most common associated systemic illness; however, due to the progress in knowledge pertaining to the treatment, presently immunocompromised state secondary to chemotherapy has become the commoner systemic association in European and North American developed countries.[3],[4] In developing nations such as India, the prevalent association still remains diabetes.[5] Rhino-orbito-cerebral mucormycosis is the most common form of mucormycosis and seen particularly in cases of uncontrolled diabetes mellitus[6] [Figure 1].
Figure 1: Plausible risk factors creating a conducive ideal environment for mucor growth

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Diabetes in COVID-19

Diabetes being a chronic inflammatory disease process hinders the normal response of the body to a pathogen. Hyperglycemia leads to oxidative stress and causes tissue inflammation by upregulating the production of pro-inflammatory cytokines, and adhesion molecules.[7] Inadequately controlled high blood sugars have also been linked to abnormal lymphocyte proliferative response to stimuli, unusual monocyte/macrophage reaction, and impaired neutrophil response.[8],[9] Patients with COVID-19 infection may have preexisting diabetes or latent diabetes mellitus, making them susceptible to the disease.[10] However, contrary to the popular belief that an individual acquires diabetes following high doses of steroids, the statement may not be completely correct. A COVID-19 patient can develop diabetes by any or combination of the following ways:

Pancreatic beta-cell damage by a direct viral invasion of the islets

Angiotensin-converting enzyme (ACE) 2 receptors are present in the lungs and are known to be associated with the cellular entry of COVID-19.[11] Studies have shown that both the exocrine glands and beta cells of the pancreas express a larger number of ACE 2 receptors than the lungs. In a retrospective study of 121 COVID 19 patients, elevated serum amylase and lipase levels were noted primarily in severe COVID 19 patients indicating damage to the pancreas.[12],[13] Another study by Yang et al. revealed patients with COVID 19 infection developing acute diabetes after acquiring the viral disease.[14] Therefore, the virus can directly invade the pancreas and lead to the acute onset of diabetes [Figure 2].
Figure 2: Pancreatic beta-cell damage by a direct viral invasion of the islets

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Other than the ACE 2 receptor, transmembrane protease serine (TMPRRSS) 2, a protease enzyme, also partakes in the cellular entry of the virus. Studies involving human lungs with camostat mesylate, a TMPRRSS blocker has shown decreased severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) infection.[15] The same TMPRRSS receptor has also been found in gastrointestinal tissues, namely the stomach, pancreas, liver, and intestine. COVID-19 infection can cause hyperglycemia by acting directly on these receptors located in pancreatic tissues.[15],[16],[17]

Insulin resistance from severe inflammation

COVID-19 infection is associated with high levels of inflammatory mediators, procalcitonin, ferritin, interleukin-6 (IL-6), and C-reactive protein being the more common ones.[18],[19],[20] Accumulation of innate immune cells complexes in tissues results in the release of inflammatory mediators such as IL-6 and transforming growth factor-α.[21] These inflammatory mediators can themselves lead to damage of beta cells of the pancreas by converging on various signaling molecules as JUN kinase, inhibitor kappa B kinase β, and nuclear factor-κB and even directly stop the action of insulin by phosphorylating insulin receptor substrates 1 and 2[21],[22] [Figure 3].
Figure 3: Insulin resistance from severe inflammation

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Glucocorticoids

As mentioned earlier, during COVID-19 infection, the human body undergoes a sudden surge in inflammatory mediators. The virus after entering the respiratory epithelial cells invokes a sudden production of cytokines in large quantity along with a weak interferon response. Membrane-bound immune receptors mediate the pro-inflammatory response of T-Helper 1 cells, CD 14+ CD16+ monocytes. Macrophages and neutrophils reach the respiratory epithelial cells and the inflammatory event follows.[23] The surge often termed as cytokine storm, requires immediate control, for which glucocorticoids are used routinely.[23],[24] Glucocorticoids in the form of methylprednisolone as well as dexamethasone have been proven to reduce the risk of death in severe COVID-19 cases.[25],[26],[27] However, a high dose of glucocorticoids themselves can lead to diabetes by causing varying degrees of beta-cell dysfunction, insulin resistance, and insulin release. Yasuda et al. have demonstrated the reduction of binding affinity of insulin due to the use of hydrocortisone, prednisone, and dexamethasone.[28] In vitro studies of glucocorticoids on the beta-cell function of cultured rat insulin-secreting insulinoma, has revealed an impaired insulin release following glucocorticoid usage.[29]

Phosphoenyl pyruvate carboxykinase (PEPCK) is known to regulate glyceroneogenesis in the liver and adipose tissues. However, in the presence of glucocorticoids, the PEPCK gene is suppressed leading to inhibition of glyceroneogenesis. This results in an increase of fatty acids in the blood which interferes with glucose uptake and insulin resistance.[30]

Multiple studies are there which has documented steroid-induced hyperglycemia in hospitalized patients with or without preexisting diabetes.[31],[32],[33] Xiao et al. have reported 34.7% cases developing steroid-induced diabetes in patients who received steroids in SARS in 2004.[34] We have also come across several patients developing steroid-induced diabetes for which both oral hypoglycemics and insulin was needed to control hyperglycemia.

Impaired defense mechanisms against mucor

Mucormycosis is commonly found in patients with impaired function of phagocytes.

The complement system is an integral component of humoral immunity. They help in the opsonization and phagocytosis of macrophages via macrophages and neutrophils. Diabetes is known to be associated with reduction of Complement factor 4 (C4) leading to impaired action of the polymorphonuclear dysfunction and reduced cytokine response.[35],[36]

Hyperglycemia also blocks glucose-6-phosphate dehydrogenase and increases apoptosis of polymorphonuclear leukocytes.[36] In tissues that do not depend on insulin for glucose transport, a hyperglycemic environment leads to raised glucose levels within the cell. These tissues utilize nicotinamide adenine dinucleotide phosphate (NADPH) for the metabolism of the excess glucose causing depleted levels of NADPH making the tissues prone to oxidative stress.[36]

Neutrophils play an important role in the inhibition of fungal proliferation. In chronic diabetes and diabetic ketoacidosis, where there is low pH, phagocytes become dysfunctional, leading to impaired chemotaxis and defective intracellular killing of hyphae.[37]

Iron availability

Mucor requires iron for its cell growth and development.[38] In SARS CoV 2 infection the iron metabolism is greatly affected. In the initial stages, the innate immune system takes control of the iron metabolism and restricts iron absorption by raising the hepcidin levels. Consequently, the serum iron levels decrease.[39]

However, once diabetic ketoacidosis sets in, there is an increase in free iron levels in serum. The acidotic environment disrupts the binding of transferrin to free iron by proton mediated pathway.[40]

Zinc is a micronutrient which is responsible for maintaining tissue barrier such as the respiratory epithelium. In addition to its barrier function, it also participates in redox reaction and is an essential component for working the immune system. It is believed to reduce the progression of COVID 19 infection.[41] Zinc has been therefore overtly used in the management of COVID 19. Zinc and Iron are known to compete for metabolic processes due to their relatively similar physico-chemical properties, therefore a sudden rise in Zinc levels can lead to increased iron availability.[42]

Rhizopus oryzae expresses gene encoding high-affinity iron permease (FTR-1), which produces redundant surface reductases involved in free iron assimilation by reductive pathway. Heme also acts as a source of iron for Rhizopus, expressing heme oxygenase enzymes. This probably explains the angio-invasive nature of organisms for obtaining iron from host hemoglobin. Rhizoferin, a siderophore secreted by Rhizopus, also supplies iron through a receptor-mediated pathway[40] [Figure 4].
Figure 4: Iron uptake in mucorales

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Role of glucose regulated protein 78

Glucose regulated protein 78 (GRP78) is a cellular protein belonging to the HSP70 protein family that is mainly present in the endoplasmic reticulum. Its main function is involved in protein folding and assembly, acting as a chaperone protein. However, in a variety of cells, it is translocated to the cell surface, where it acts as a receptor for Mucorales, helping in penetration and damage to endothelial cells.[43] GRP78 is overexpressed in cases where serum glucose and iron are elevated, like diabetic ketoacidosis.


  Virulence Factors Top


Cunninghamella species have been identified to have more than twice the mortality rates compared with Rhizopus species. Inherently greater resistance to antifungal agents and polymorphonuclear leucocyte-mediated hyphal damage likely contributes to poorer outcomes. Rhizopus secrete certain enzymes like aspartic proteinase, which helps in increased cell lysis, and have an active ketone reductase system, which helps in active proliferation in ketoacidosis states.[44]


  Source of Mucor Infection Top


Hospital

The exact transmission of mucormycosis still remains a mystery. The popularly accepted notion is that the fungi inoculate the nasal mucosa, after which it spreads to the nasal sinuses and the orbit, eventually advancing to the cranial cavity.

Hospital at times serves as a possible source of infection. In the 1970s an outbreak of mucormycosis cases was noted in multiple hospitals of America, where eventually elasticized bandages were found to be contaminated with Rhizopus. The manufacturer implemented necessary hygienic guidelines which lead to a decrease in the number of cases.[45],[46] Osteotomy bags were responsible for a cluster of 2 cases of mucormycosis in 2005. The gum used in the bags were made from the sap of a tree, which was recognized as the source of the fungus.[47] Similarly, osteotomy bags have been found to spread the infection in a premature infant and in an adult with renal insufficiency.[48],[49] Wooden tongue depressors were responsible for mucormycosis infection in 4 premature infants while being used as a splint for intravenous cannulation site.[50] Intravenous and intraarterial catheters, urinary bladder catheters and even thoracic drains have also been noted to act as a source of mucormycosis infection.[51],[52],[53] Adhesive tapes, adhesive urine bag, temperature probe, skin patch for testing hypersensitivity all have been implicated in cutaneous mucormycosis cases.[54],[55],[56],[57] Bed linens, insulin infusion pumps, prosthetic valves, and nasal packings have also been described as the source in many cases.[58]

Environment

Other than Hospitals, the disease has been also found to occur near construction sites. Cluster cases of pulmonary mucormycosis have been documented in the literature.[59],[60]

Possible preventive measures from developing Mucor

The majority risk for developing mucor are patients with diabetes, COVID-19 infection and steroid use. Stringent protocols should be followed by hospitals and institutions starting steroids in COVID-19 patients, especially those with preexisting diabetes. Strict glycemic control should be maintained with oral hypoglycemic agents and insulin injections. As the number of patients is rising due to pandemics, paramount importance should be given to following infection control protocols at the hospital level. Timely identification of nosocomial outbreaks and pseudo-outbreaks is critical in curbing the disease and starting antifungals to reduce mortality and morbidity associated with the disease.

Voriconazole has been used as a prophylactic antifungal in stem cell recipients, but there was the incidence of breakthrough mucormycosis. This was probably due to an increase in virulence of fungus following exposure to voriconazole. In patients with prolonged neutropenia, organ transplant, graft versus host disease, or history of mucor, Posaconazole can have been proven to be beneficial as a prophylactic drug. However, care should be taken by monitoring serum levels to identify adequate absorption and compliance since low levels have an increased risk of breakthrough mucormycosis. Isavuconazole has also shown its efficacy as a prophylactic drug in cases of hematologic malignancies.[61] Patients with high-risk features should be advised to maintain healthy living practices and avoid activities leading to trauma or exposure to fungal spores.


  Conclusions Top


Mucormycosis in COVID 19 is a life-threatening condition. Although clinical reports are abundant and the clinical manifestations of mucormycosis have been extensively described, the pathogenetic basis of the disease is only recently becoming clearer. The development of the disease revolves around the hyperglycemic state of the patients. Patients with neutropenia, diabetic ketoacidosis, and those on deferoxamine therapy are at increased risk of developing mucormycosis. The angioinvasion and pathology in various organs, in the at-risk host, is a result of the virulence factors involved in the host-pathogen interaction.

A better and clearer understanding of the predisposing conditions and host defenses, thereby their correction and augmentation, respectively, with counteracting the virulence of mucor, will furnish promisable outcomes with resultant reduction of morbidity and mortality.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
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