Kerala Journal of Ophthalmology

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

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


Deepsekhar Das, Mandeep Singh Bajaj, Sujeeth Modaboyina, Sahil Agrawal 
 Dr. Rajendra Prasad Centre for Ophthalmic Sciences; Oculoplasty and Orbital Tumor Services, All India Institute of Medical Sciences, New Delhi, India

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

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.



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;33:254-259


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 19 ];33:254-259
Available from: http://www.kjophthal.com/text.asp?2021/33/3/254/331928


Full Text



 Introduction



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



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



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



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}

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}

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}

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}

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



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



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



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.

References

1Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SC, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: An initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 2019;19:e405-21.
2Prabhu RM, Patel R. Mucormycosis and entomophthoramycosis: A review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 2004;10 Suppl 1:31-47.
3Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al. Zygomycosis in Europe: Analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect 2011;17:1859-67.
4Kontoyiannis DP, Yang H, Song J, Kelkar SS, Yang X, Azie N, et al. Prevalence, clinical and economic burden of mucormycosis-related hospitalizations in the United States: A retrospective study. BMC Infect Dis 2016;16:730.
5Chakrabarti A, Singh R. Mucormycosis in India: Unique features. Mycoses 2014;57 Suppl 3:85-90.
6Prakash H, Ghosh AK, Rudramurthy SM, Singh P, Xess I, Savio J, et al. A prospective multicenter study on mucormycosis in India: Epidemiology, diagnosis, and treatment. Med Mycol 2019;57:395-402.
7Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract 2020;162:108142.
8Moutschen MP, Scheen AJ, Lefebvre PJ. Impaired immune responses in diabetes mellitus: Analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections. Diabete Metab 1992;18:187-201.
9Iacobellis G. COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Res Clin Pract 2020;162:108125.
10John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: The perfect storm for mucormycosis. J Fungi (Basel) 2021;7:298.
11Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, et al. Effects of angiotensin II receptor blockers and ACE (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: A single-center retrospective study. Hypertension 2020;76:51-8.
12Liu F, Long X, Zhang B, Zhang W, Chen X, Zhang Z. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection. Clin Gastroenterol Hepatol 2020;18:2128-30.e2.
13Huang I, Lim MA, Pranata R. Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression. Diabetes Metab Syndr 2020;14:395-403.
14Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47:193-9.
15Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.
16Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014;88:1293-307.
17Drucker DJ. Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications. Endocr Rev 2020;41:41(3):bnaa011.
18Lazzaroni MG, Piantoni S, Masneri S, Garrafa E, Martini G, Tincani A, et al. Coagulation dysfunction in COVID-19: The interplay between inflammation, viral infection and the coagulation system. Blood Rev 2021;46:100745.
19Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
20Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-43.
21Odegaard JI, Chawla A. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb Perspect Med 2012;2:a007724.
22Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801.
23Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol 2021;93:250-6.
24Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect 2020;80:607-13.
25Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect 2020;53:436-43.
26RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384:693-704.
27Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: Results from a randomised controlled clinical trial. Eur Respir J 2020;56:2002808..
28Yasuda K, Hines E 3rd, Kitabchi AE. Hypercortisolism and insulin resistance: Comparative effects of prednisone, hydrocortisone, and dexamethasone on insulin binding of human erythrocytes. J Clin Endocrinol Metab 1982;55:910-5.
29Linssen MM, van Raalte DH, Toonen EJ, Alkema W, van der Zon GC, Dokter WH, et al. Prednisolone-induced beta cell dysfunction is associated with impaired endoplasmic reticulum homeostasis in INS-1E cells. Cell Signal 2011;23:1708-15.
30Hwang JL, Weiss RE. Steroid-induced diabetes: A clinical and molecular approach to understanding and treatment. Diabetes Metab Res Rev 2014;30:96-102.
31Spanakis EK, Shah N, Malhotra K, Kemmerer T, Yeh HC, Golden SH. Insulin requirements in non-critically ill hospitalized patients with diabetes and steroid-induced hyperglycemia. Hosp Pract (1995) 2014;42:23-30.
32Healy SJ, Nagaraja HN, Alwan D, Dungan KM. Prevalence, predictors, and outcomes of steroid-induced hyperglycemia in hospitalized patients with hematologic malignancies. Endocrine 2017;56:90-7.
33Donihi AC, Raval D, Saul M, Korytkowski MT, DeVita MA. Prevalence and predictors of corticosteroid-related hyperglycemia in hospitalized patients. Endocr Pract 2006;12:358-62.
34Xiao JZ, Ma L, Gao J, Yang ZJ, Xing XY, Zhao HC, et al. Glucocorticoid-induced diabetes in severe acute respiratory syndrome: The impact of high dosage and duration of methylprednisolone therapy. Zhonghua Nei Ke Za Zhi 2004;43:179-82.
35Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol 2010;6:94-101.
36Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol 1999;26:259-65.
37Chinn RY, Diamond RD. Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: Relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. Infect Immun 1982;38:1123-9.
38Stanford FA, Voigt K. Iron assimilation during emerging infections caused by opportunistic fungi with emphasis on mucorales and the development of antifungal resistance. Genes (Basel) 2020;11(11):1296.
39Taneri PE, Gómez-Ochoa SA, Llanaj E, Raguindin PF, Rojas LZ, Roa-Díaz ZM, et al. Anemia and iron metabolism in COVID-19: A systematic review and meta-analysis. Eur J Epidemiol 2020;35:763-73.
40Ibrahim AS, Spellberg B, Edwards J Jr. Iron acquisition: A novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis 2008;21:620-5.
41Wessels I, Rolles B, Rink L. The potential impact of zinc supplementation on COVID-19 pathogenesis. Front Immunol 2020;11:1712.
42Kondaiah P, Yaduvanshi PS, Sharp PA, Pullakhandam R. Iron and zinc homeostasis and interactions: Does enteric zinc excretion cross-talk with intestinal iron absorption? Nutrients 2019;11:1885.
43Liu M, Spellberg B, Phan QT, Fu Y, Fu Y, Lee AS, et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest 2010;120:1914-24.
44Lewis RE, Pongas GN, Albert N, Ben-Ami R, Walsh TJ, Kontoyiannis DP. Activity of deferasirox in mucorales: Influences of species and exogenous iron. Antimicrob Agents Chemother 2011;55:411-3.
45Rammaert B, Lanternier F, Zahar JR, Dannaoui E, Bougnoux ME, Lecuit M, et al. Healthcare-associated mucormycosis. Clin Infect Dis 2012;54 Suppl 1:S44-54.
46Gartenberg G, Bottone EJ, Keusch GT, Weitzman I. Hospital-acquired mucormycosis (Rhizopus rhizopodiformis) of skin and subcutaneous tissue: Epidemiology, mycology and treatment. N Engl J Med 1978;299:1115-8.
47LeMaile-Williams M, Burwell LA, Salisbury D, Noble-Wang J, Arduino M, Lott T, et al. Outbreak of cutaneous Rhizopus arrhizus infection associated with karaya ostomy bags. Clin Infect Dis 2006;43:e83-8.
48White CB, Barcia PJ, Bass JW. Neonatal zygomycotic necrotizing cellulitis. Pediatrics 1986;78:100-2.
49Mullens JE, Leers WD, Smith GW. Phycomycosis involving the intestine and anterior abdominal wall: A case report. Ann Surg 1970;171:303-8.
50Mitchell SJ, Gray J, Morgan ME, Hocking MD, Durbin GM. Nosocomial infection with Rhizopus microsporus in preterm infants: Association with wooden tongue depressors. Lancet 1996;17:441-3.
51Pérez de la Espejo MP, Barrero Candau R, Chinchón Espino D, Campoy Martínez P. Bladder mucormycosis. Report of one case. Arch Esp Urol 2004;57:67-9.
52Abter EI, Lutwick SM, Chapnick EK, Chittivelu S, Lutwick LI, Sabado M, et al. Mucormycosis of a median sternotomy wound. Cardiovasc Surg 1994;2:474-7.
53Amin SB, Ryan RM, Metlay LA, Watson WJ. Absidia corymbifera infections in neonates. Clin Infect Dis 1998;26:990-2.
54Dickinson M, Kalayanamit T, Yang CA, Pomper GJ, Franco-Webb C, Rodman D. Cutaneous zygomycosis (mucormycosis) complicating endotracheal intubation: Diagnosis and successful treatment. Chest 1998;114:340-2.
55Grim PF 3rd, Demello D, Keenan WJ. Disseminated zygomycosis in a newborn. Pediatr Infect Dis 1984;3:61-3.
56du Plessis PJ, Wentzel LF, Delport SD, van Damme E. Zygomycotic necrotizing cellulitis in a premature infant. Dermatology 1997;195:179-81.
57Blair JE, Fredrikson LJ, Pockaj BA, Lucaire CS. Locally invasive cutaneous Apophysomyces elegans infection acquired from snapdragon patch test. Mayo Clin Proc 2002;77:717-20.
58Lanternier F, Lortholary O. Zygomycosis and diabetes mellitus. Clin Microbiol Infect 2009;15 Suppl 5:21-5.
59Rickerts V, Böhme A, Viertel A, Behrendt G, Jacobi V, Tintelnot K, et al. Cluster of pulmonary infections caused by Cunninghamella bertholletiae in immunocompromised patients. Clin Infect Dis 2000;31:910-3.
60Krasinski K, Holzman RS, Hanna B, Greco MA, Graff M, Bhogal M. Nosocomial fungal infection during hospital renovation. Infect Control 1985;6:278-82.
61Fontana L, Perlin DS, Zhao Y, Noble BN, Lewis JS, Strasfeld L, et al. Isavuconazole prophylaxis in patients with hematologic malignancies and hematopoietic cell transplant recipients. Clin Infect Dis 2020;70:723-30.