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Review Articles

Immunopathology of COVID-19 and its implications in the development of rhino-orbital-cerebral mucormycosis: a major review

Tarjani Vivek Davea Ophthalmic Plastic Surgery Service, LV Prasad Eye Institute, Hyderabad, IndiaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-2751-1391View further author information
ORCID Icon,
Akshay Gopinathan Nairb Aditya Jyot Eye Hospital, Mumbai, India;c Advanced Eye hospital and Institute, Navi Mumbai, IndiaORCID Iconhttps://orcid.org/0000-0002-7872-977XView further author information
ORCID Icon,
Joveeta Josephd Jhaveri Microbiology Centre, Kallam Anji Reddy Campus, LV Prasad Eye Institute, Hyderabad, IndiaORCID Iconhttps://orcid.org/0000-0002-8421-1977View further author information
ORCID Icon &
Suzanne K Freitage Ophthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USAView further author information
Pages 670-679 | Received 27 Dec 2021, Accepted 01 Jul 2022, Published online: 20 Jul 2022

ABSTRACT

Purpose

To present a literature review on various immunopathologic dysfunctions following COVID-19 infection and their potential implications in development of rhino-orbital-cerebral mucormycosis (ROCM).

Methods

A literature search was performed via Google Scholar and PubMed with subsequent review of the accompanying references. Analogies were drawn between the immune and physiologic deviations caused by COVID-19 and the tendency of the same to predispose to ROCM.

Results

Sixty-two articles were reviewed. SARS-CoV-2 virus infection leads to disruption of epithelial integrity in the respiratory passages, which may be a potential entry point for the ubiquitous Mucorales to become invasive. COVID-19 related GRP78 protein upregulation may aid in spore germination and hyphal invasion by Mucorales. COVID-19 causes interference in macrophage functioning by direct infection, a tendency for hyperglycemia, and creation of neutrophil extracellular traps. This affects innate immunity against Mucorales. Thrombocytopenia and reduction in the number of natural killer (NK) cells and infected dendritic cells is seen in COVID-19. This reduces the host immune response to pathogenic invasion by Mucorales. Cytokines released in COVID-19 cause mitochondrial dysfunction and accumulation of reactive oxygen species, which cause oxidative damage to the leucocytes. Hyperferritinemia also occurs in COVID-19 resulting in suppression of the hematopoietic proliferation of B- and T-lymphocytes.

Conclusions

COVID-19 has a role in the occurrence of ROCM due to its effects at the entry point of the fungus in the respiratory mucosa, effects of the innate immune system, creation of an environment of iron overload, propagation of hyperglycemia, and effects on the adaptive immune system.

Introduction

Rhino-orbital-cerebral mucormycosis (ROCM) is a grave fungal infection produced by opportunistic fungi belonging to the order Mucorales.Citation1,Citation2 ROCM can progress rapidly and is known to have a very high risk of morbidity and mortality.Citation3,Citation4 Mucorales commonly establish disease in patients who are immunocompromised especially those with uncontrolled diabetes and diabetic ketoacidosis (DKA).Citation5 The Mucorale spores are ubiquitous in the environment and can aggregate on and infect the nasal and sinus mucosa. Contiguous spread of infection may occur to the orbit, brain, cavernous sinus, pterygopalatine fossa and infratemporal fossa. Disease establishment occurs once filamentous growth is initiated. The filamentous fungal hyphae produce angio-invasion, vascular thrombosis, and resultant tissue necrosis.Citation6 The clinical hallmark is a necrotic lesion, the eschar, that can be visualized in the nasal or oral cavity.Citation6

The global pandemic of coronavirus disease 2019 (COVID-19) has affected over 187 million individuals internationally.Citation7 There is accumulating evidence demonstrating that COVID-19 infection increases the overall risk of developing secondary fungal infections including COVID associated mucormycosis (CAM) either during or following recovery from COVID-19.Citation8–13 COVID-19 dysregulates the host immune system and physiologic mechanisms at multiple levels, predisposing COVID-19 patients to CAM. The current efficacy of amphotericin B (liposomal form) and isuvaconazole, which are used in the treatment of ROCM, is about 60–70%.Citation14 At present, the incidence of ROCM following COVID-19 is increasing around the world. This poses an urgent need to understand the immunopathologies in the development of CAM and explore novel treatment strategies. The current review aims at summarizing the various immunopathologies and their implications in development of CAM.

Method of literature review

A literature review was conducted via Google Scholar and PubMed followed by a review of the references procured. The words and combinations used for the review included: Mucorales, mucormycosis pathogenesis, mucor pathology, diabetes and mucor, mucormycosis, and diabetic ketoacidosis, innate immunity in COVID-19, adaptive immunity in COVID-19. Non-English language literature was excluded from the search. Abstracts and relevant papers were reviewed in detail. Analogies were drawn between the immune and physiologic deviation caused by COVID-19 and the tendency of the same to predispose to ROCM. This review divides the effect of COVID-19 on development of ROCM in the following broad categories: (1) Effects at the entry point in the respiratory mucosa, (2) Effects on the innate immune system, (3) Role of iron overload, (4) Role of hyperglycemia, (5) Effects on the adaptive immune system.

Results

Effects at the entry point in the respiratory mucosa

Effect of COVID-19 on respiratory epithelium

Brosnahan et al. published a review on COVID-19 and its effect on the respiratory system. They described that SARS-CoV-2 virus infection can lead to damage to the function and structure of the respiratory mucosal cells from the nasal cavity to the alveoli.Citation15 It has been shown that SARS-CoV-2 virus enters human cells via its spike protein (S) by its interaction with the angiotensin converting enzyme 2 (ACE2) receptor.Citation16,Citation17 Koparal et al. studied the mucociliary clearance in the nasal mucosa of COVID-19 patients and concluded that when compared to healthy controls, the time required for nasal mucociliary clearance was prolonged in COVID-19 patients.Citation18 Chilvers et al. reported that human coronavirus disrupts the respiratory ciliated epithelium, thus impairing mucociliary clearance.Citation19

Respiratory epithelium in CAM

The respiratory epithelial cells act as the first innate immunity barrier to the entry of Mucorales into the body. Bouchara et al. studied the attachment of the spores of Rhizopus to extracellular matrix components in the respiratory epithelium.Citation20 They concluded that the recognition of laminin or type IV collagen of the exposed basement membrane by the spores of Mucorales may participate in their adherence to basement membranes. Once adherent, the spores may germinate into hyphal structures and lead to invasive disease.

Correlation of respiratory epithelial damage in COVID-19 and CAM

In a healthy host, the respiratory lining is intact, and this prevents fungal spores from germinating into hyphal structures. However, when the physical barrier of the respiratory mucosa is breached in a predisposed host, the fungal spores can form hyphae and become invasive. Since SARS-CoV-2 virus infection leads to disruption of epithelial integrity in the respiratory passages, this may be a potential entry point for the ubiquitous Mucorales to become invasive.

GRP78 upregulation following COVID-19

COVID-19 virus binds to the host ACE2 receptor via the SARS-CoV-2 spike (S) glycoprotein.Citation21–23 Viral glycoproteins are capable of inducing endoplasmic reticulum (ER) stress within the cells.Citation24,Citation25 Excess ER stress causes upregulation of (glucose-regulated protein) GRP78. When compared to a control group, a significantly higher expression of the GRP78 receptor was reported in the COVID-19 infection group by Sabirili et al. and Koseler et al.Citation26,Citation27

Role of GRP78 in CAM

Liu et al. conducted an animal study wherein they studied the exact interaction of GRP78 in the occurrence of mucormycosis. They demonstrated that GRP78 was a novel host receptor that facilitated Mucorales to invade and damage the human endothelial cells.Citation27 Alqarihi et al. conducted a mouse study to elucidate the role of GRP78 and integrins in host cell invasion due to mucormycosis.Citation28 They noted that the susceptibility of the host cells to the Mucorales was due to the interaction between the host upregulated GRP78 and the fungal cell surface protein CotH3. This upregulation was further propagated by concurrent diabetic ketoacidosis (DKA). It has been demonstrated that elevated concentrations of glucose and iron, consistent with those noted during DKA, enhance surface GRP78 expression and therefore cause damage to endothelial cells by Mucorales in a receptor-dependent manner.Citation29

Correlation of GRP78 upregulation in COVID-19 and CAM

GRP78 is a multifunctional protein which is activated after endoplasmic reticulum (ER) stress in the cells. COVID-19 infection is known to increase ER stress and thus upregulate GRP78 levels. GRP78 levels also elevate in DKA. For both the SARS-CoV-2 virus and Mucorales, GRP78 is known as a host cell receptor. Thus, COVID-19 related GRP78 upregulation may aid in spore germination and hyphal invasion by Mucorales.

Effects of the innate immune system

Effect of COVID-19 on macrophage function

Macrophages are the first line of defence in innate immunity against infections. Macrophages are capable of engulfing, degrading, and presenting pathogenic antigens, thus helping in localization of infection. This particular step also helps in priming the adaptive immune response. Feng et al.Citation30 reported the effect of coronaviruses on hematopoietic cells, showing that coronaviruses can infect macrophages and interfere in their normal functioning. Coronavirus-infected macrophages express high levels of CD86, CD80, and major histocompatibility complex I (MHC I). However, they do not express major histocompatibility complex II (MHC II). This imbalance limits the antigen presenting ability of macrophages to helper T-cells.Citation31,Citation32

Role of macrophage dysfunction in CAM

Macrophages, in their role in innate immunity, act as antigen-presenting cells. Larval zebrafish and mouse models have shown that depletion of macrophages increases susceptibility to mucormycosis.Citation33 López-Muñoz et al.Citation34 studied the effect of mucormycosis on macrophages. In a zebrafish model, they demonstrated that mucormycosis by itself causes macrophage apoptosis, thus rendering macrophages unable to demonstrate innate immune function against the fungus.Citation34 Additionally, Waldorf et al. reported that in cortisone-treated mice, macrophages are unable to kill Rhizopus oryzae spores. Also, in this immunosuppressed environment, macrophages fail to inhibit spore germination. This leads to the germination of spores and formation of invasive hyphal filaments.Citation35

Correlation of macrophage dysfunction in COVID-19 and CAM

COVID-19 causes interference in macrophage functioning by direct infection. This reduces macrophage phagocytic function and antigen presenting capacity. This effect is compounded by apoptosis of macrophages induced by Mucorales. Furthermore, in those cases who have severe COVID-19 who develop the resultant immunosuppression, failure to inhibit Mucorales spore germination may lead to active infection with the hyphal structures.

Effect of COVID-19 on neutrophil function

During infections, the first innate leukocytes that are activated are the neutrophils.Citation36 The main function of neutrophils is the removal of pathogens and debris, which is achieved by phagocytosis.Citation37 A well-regulated innate immune process recruiting macrophages and neutrophils is an early protective action against viral infections. Hyperglycemia, either due to steroid treatment or to insulin resistance, that develops following COVID-19 infection deactivates neutrophils. An additional immunologic role of neutrophils includes the release of the unique neutrophil extracellular traps (NETs). NETs are DNA fragments in association with granular antimicrobial proteins. Through reactive oxygen species (ROS)-independent mechanisms, NETs result in immediate entrapment of the viruses and render them inactive.Citation38 They also help trigger cytokine production to restrict virus replication.Citation36 At times, in severe COVID-19 associated cytokine storm, there is an overproduction of NETs. This leads to lung tissue damage by NETosis which involves microthrombosis and tissue necrosis.Citation39–41

Role of neutrophils in CAM

Neutrophils express their fungicidal activity by the production of neutrophil cationic peptide and neutrophil superoxide anion.Citation42 They express this fungicidal activity by damaging the fungal hyphae.Citation43,Citation44 Hyperglycemia, which is one of the primary risk factors for the occurrence of mucormycosis, leads to neutrophil deactivation. This may lead to the fungal spores germinating into hyphal structures and thus giving rise to an invasive infection.

Correlation of neutrophil dysfunction in COVID-19 and CAM

Hyperglycaemia is known to be a common predisposing factor for the development of COVID-19 as well as CAM.Citation45 While there is an increase in neutrophil count in the more severe stages of COVID-19 infection, there is also an associated production of NETs. Increased NET formation may result in tissue damage due to inflammatory reactions that destroy the surrounding tissues and favor microthrombosis. The resultant necrosis may allow the ubiquitous Mucorales spores to cross healthy epithelial barriers. Also, hyperglycemia and ketoacidosis result in dysfunctional neutrophils and hence a decrease in the body’s ability to fight invasion by Mucorales.Citation33

Effects of COVID-19 on platelets, dendritic cells, and natural killer (NK) cells

Platelets are one of the key cells in the innate immune response. While their primary role is in hemostasis, another important role is in the immune response against pathogens, by inhibiting their dissemination through the circulation, which could increase the severity of infection.Citation46 Platelets help in fighting microbes by producing antimicrobial peptides such as platelet factor 4.Citation47 Typical hematologic features of COVID-19 include thrombocytopenia, lymphopenia, and neutrophilia.Citation48 NK cells modulate the immune response that is mounted when a pathogen is encountered. There is a reduction in the number of NK cells and blunting of the effector functions of NK cells in COVID-19.Citation46 This results in a decrease in the clearance of infected and activated cells and also results in an unabated elevation of toxic inflammatory markers.Citation46 Previous literature has clearly shown that SARS-CoV can cause infection of the dendritic cells (DC). This can lead to an upregulation of inflammatory chemokines following a very poor antiviral cytokine expression.Citation49,Citation50 Dendritic cells play a prime role in specific T-cell responses, cytokine production, and antigen presentation.Citation49 In patients with COVID-19, a loss of DC function could lead to delayed response of the immune system.

Role of dendritic cells, platelets, and NK cells in CAM

In vitro studies have demonstrated that platelets possess the capacity to adhere to Mucorales spores. Once adherent, they undergo activation and release granules that can inhibit germination of spores and formation of hyphae.Citation47 Platelets also possess the ability to produce fungal hyphal damage.Citation51 The presence of hyphal forms of Mucorales can lead to dendritic cell mediated upregulation of T-helper cells. The T-helper cells can reduce the invasiveness of Mucorales.Citation42 However, Rhizopus hyphae can also lead to decreased secretion of interferons by NK cells. One can thus conclude that that NK cell activity can get immunosuppressed by Mucorales hyphae.Citation5253Citation53,

Correlation of dendritic cells, platelets, and NK dysfunction in COVID-19 and CAM

Platelets reduce the hematologic dissemination of pathogens, NK cells, and assist in the clearance of the infected host cells. Dendritic cells help in priming the T-cell specific immune response against invading pathogens. Thrombocytopenia, a reduction in the number of NK cells, and infected dendritic cells are seen in cases of COVID-19 infection. Thus, there is a reduction in the immune mediated activity against Mucorales.

Adaptive immunity in COVID-19 infection

Systemic hyperferritinemia may be present in severe COVID-19 disease.Citation54 Ferritin is a known inflammatory biomarker.Citation55,Citation56 Mitochondria are one of the prime targets of iron-mediated oxidative stress in cells. Appropriate functioning of mictochondria relies on the uptake of iron for biogenesis of iron-sulfur clusters, synthesis of heme, and for its storage in mitochondrial ferritin.Citation57 Increased intraocular oxidative stress is linked to reactive oxygen species (ROS), which emanate from the mitochondria.Citation58,Citation59 Cytokines such as IL-6 and TNF (tumor necrosis factor)-alpha impede ATP production following mitochondrial oxidative phosphorylation. These cytokines are found in abundance in COVID-19 serum. This leads to mitochondrial ROS production in the cell.Citation60,Citation61 ROS in turn cause an increase in mitochondrial membrane permeability and alter mitochondrial metabolism, resulting in apoptosis. Therefore, cellular stress and death occurs due to disruption of mitochondrial iron metabolism or cellular iron levels.Citation62–66 Chougnet et al. conducted a study evaluating the effect of mitochondrial dysfunction on the action of dendritic cells.Citation67 They concluded that the cross-presenting capacity of DCs is severely affected by different components associated with mitochondrial dysfunction such as increased ROS production, reduced membrane potential, and reduced ATP synthesis. This reduces the capacity of the DC in priming the adaptive immune system against invading pathogens.Citation68

Role of adaptive immunity in CAM

Macrophage dysfunction following oxidative stress and ROS release due to the mitochondrial system being overwhelmed result in failure of the innate immunity mechanism against Mucorales.Citation69–71 An in vitro study showed that Mucorales hyphae can induce a prominent DC release of IL-23. IL-23 is known to upregulate Th-17 responses. Morikawa et al. published a study on the role of serum ferritin in hematopoiesis and the immune system.Citation72 They concluded that ferritin has an inhibitory effect on proliferation of human hematopoietic progenitor cells and also on proliferation of T lymphocytes. They also reported that human B lymphocyte differentiation and maturation is directly suppressed by ferritin. As both B lymphocytes (as a part of innate immunity) and T lymphocytes (as a part of adaptive immunity) play a role in the defence against ROCM, high serum ferritin causes reduction in the overall functioning of the immune system.

Correlation of adaptive immunity in COVID-19 and CAM

Cytokines released in COVID-19 infection cause mitochondrial dysfunction and accumulation of ROS, resulting in poor functioning of macrophages and DCs. Ferritin is released as an inflammatory mediator during COVID-19 infection. The resultant hyperferritinemia results in suppression of the hematopoietic proliferation of B and T lymphocytes. This affects both innate and adaptive immunity which are defence mechanisms against Mucorales.

Hyperglycemia, insulin resistance, and diabetic ketoacidosis in COVID-19 infection

Newer understanding suggests that COVID-19 infection is intricately related to insulin resistance (IR) and diabetes mellitus (DM).Citation73,Citation74 DM and the degree of hyperglycemia cause an increase in the COVID-19 severity and mortality.Citation75–77 Further, patients with COVID-19 infection can develop de-novo DM or acute complications of a pre-existing DM, including hyperosmolarity and diabetic ketoacidosis (DKA).Citation78–81 Virally induced inflammation and immune dysfunction increase insulin resistance via several mechanisms.Citation82 Focal pancreatitis has also been shown in patients who died due to COVID-19.Citation83 Virus-induced interferon (IFN) activity increases muscle insulin resistance, causing hyperinsulinemia to maintain a euglycemic state.Citation84,Citation85 Investigations confirm that expression of ACE2 occurs in the pancreas physiologically.Citation86 It is known that ACE2 is the cellular receptor necessary for both SARS-CoV and SARS-CoV-2 infection.Citation86 Thus, SARS-CoV-2 may lead to direct injury to islet cells by binding to ACE2 in the pancreas. This can lead to impaired glycemic control in patients with COVID-19.Citation85 Acute worsening of pancreatic beta cell function can precipitate DKA.Citation86

Role of hyperglycemia, diabetes mellitus, and diabetic ketoacidosis in CAM

Hyperglycemia has been reported as the commonest predisposing factor for the development of mucormycosis.Citation87,Citation88 Hyperglycemia and DKA both reduce effective phagocytic cell functions.Citation42,Citation89 A significantly lower chemotaxis has been found in neutrophils of patients with DM type 1 and 2 than in those of controls.Citation90,Citation91 Neutrophils of diabetic patients and those with DKA have shown a lower phagocytic capacity compared to the neutrophils of controls.Citation55,Citation92 It was also noted that there was an inverse relationship between HbA1c levels and phagocytotic rate.Citation93 DKA also has a role in increasing the amount of available free iron to Mucorales as discussed subsequently.

Correlation of hyperglycemia, diabetes mellitus, and diabetic ketoacidosis in COVID-19 and CAM

Hyperglycemia is a common risk factor for the development COVID-19 as well as mucormycosis.Citation87,Citation88 COVID-19 infection can lead to insulin resistance due to virus-related immune dysfunction and a direct effect on pancreatic islet cells, resulting in hyperglycemia and DKA. Both of these conditions interfere with neutrophil and macrophage function which are central to innate immunity against Mucorales.

Occurrence and consequences of iron overload in COVID-19 infection

COVID-19 causes increased ferritin synthesis via proinflammatory cytokines such as TNF-α, interleukin 6 (IL-6), and IL-lβ.Citation94 Increases in ferritin subsequently cause increased serum iron levels that result in abnormal phagocytic function in iron-overloaded patients.Citation94 It has been shown that iron-overload causes decreased bactericidal activity of neutrophils and decreased chemotactic responsiveness.Citation93 Exogenous iron is taken up by macrophages. Excessive uptake of iron can cause damage to the macrophage lysosomes, which can result in cytotoxicity. Macrophages have been shown to take up exogenous iron leading to lysosomal iron accumulation that may be cytotoxic to macrophages.Citation93 It is also known that excess iron-containing porphyrins and proteins impede the presentation of antigens to macrophages by major histocompatibility complex (MHC) Class II-restricted T-cells.Citation95 This interferes with the antigen presenting capacity of macrophages to the helper T-cells.

Role of iron overload and hyperglycemia in ROCM pathogenesis

As discussed, COVID-19 infection leads to increased serum transferrin, ferritin, and iron levels. This iron overload affects the phagocytic activity of neutrophils and macrophages and also interferes in the antigen presenting capacity of macrophages, thus causing a hit to the immune mechanisms along both innate and adaptive immunity pathways. It is now known that patients where serum levels of iron are very high, are highly susceptible to mucormycosis.Citation96 Ibrahim et al. published a review on the significance of acquisition of iron by Mucorales in the pathomechanism of mucormycosis.Citation52 They described pathways of high-affinity iron permeases via which Mucorales absorb iron. Iron is a prerequisite element for cellular growth and cellular development, and is associated with many vital Mucorales processes. Thus, any pathway or milieu that increases iron availability contributes to the increased virulence of Mucorales.Citation97 This is further corroborated by the observation that patients on iron chealators such as deferoxamine are at an increased risk of developing extensive ROCM.Citation98,Citation99 Hyperglycemia and DKA create a unique metabolic milieu that predisposes to increased available iron to Mucorales. Proteins such as ferritin and transferrin can get excessively glycosylated due to hyperglycemia, thus diminishing their iron affinity.Citation4 It has been shown that the iron-binding capacity of serum transferrin is affected by the existing pH.Citation100 In acidotic pH conditions such as DKA, the iron-binding capacity of transferrin decreases drastically, leading to increased available free iron for Mucorales metabolism.Citation100,Citation101

Correlation in COVID-19 infection and ROCM

Iron is a crucial element required by Mucorales for metabolism. Infection with COVID-19 causes release of ferritin as an inflammatory marker. Via induction of insulin resistance, COVID-19 infection can lead to de-novo DM or further aggravation of the pre-existing disease.Citation73–76 DM and resultant ketoacidosis decrease the iron binding affinity of serum transferrin, resulting in raised free iron levels. All of the above mechanisms allow for increased availability of iron to Mucorales and increase its virulence.

Conclusions

This review highlights the role of pre-existing diseases such as diabetes mellitus, the use of immunosuppressive therapy, and systemic immune alterations resulting from COVID-19 infection that may lead to rhino-orbital-cerebral mucormycosis (Supplement Table S1). SARS-CoV-2 virus infection causes respiratory epithelial breakdown as well as a compromised immune response to infection. In individuals with compromised immune systems, recruitment, and efficacy of macrophages and neutrophils is limited. Additionally, platelet-mediated control over the hematologic dissemination of pathogens, NK cell-mediated clearance of infected host cells, and dendritic cell-mediated priming of the T-cell specific immune response against invading pathogens are disturbed by the SARS-CoV-2 virus. Cytokines released in COVID-19 infection cause mitochondrial dysfunction and accumulation of ROS, resulting in poor functioning of macrophages and dendritic cells affecting the adaptive immunity arm that fights infection. Additionally, systemic hyperferritinemia, which is commonly seen in COVID-19 patients, results in suppression of B- and T-lymphocytes. This affects both innate and adaptive immune mechanisms against Mucorales. New onset transient hyperglycemia associated with COVID-19 or pre-existing diabetes mellitus with poor control and diabetic ketoacidosis in patients with COVID-19 result in sub-optimal functioning of macrophages and neutrophils, again predisposing to mucormycosis. Increased availability of free iron in COVID-19 provides a milieu that increases the virulence of Mucorales. Hence, COVID-19 and mucormycosis share several host risk factors. The innate and adaptive immunity derangements following COVID-19 infection result in an environment that may cause a predisposed patient to develop rhino-orbital-cerebral mucormycosis.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.

References

  • Gamaletsou MN, Sipsas NV, Roilides E. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep. 2012;14(4):423–434. doi:10.1007/s11908-012-0272-6.
  • Chakrabarti A, Das A, Sharma A, Panda N, Das S, Gupta KL, et al. Ten Years’ experience in zygomycosis at a tertiary care centre in India. J Infect. 2001;42(4):261–266. doi:10.1053/jinf.2001.0831.
  • Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis. Pathophysiology, presentation and management. Clin Microbiol Rev. 2005;18(3):556–569. doi:10.1128/CMR.18.3.556-569.2005.
  • Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycete in human disease. Clin Microbiol Rev. 2000;13(2):236–301. doi:10.1128/CMR.13.2.236.
  • International Diabetes Federation. 2020. https://idf.org/our-network/regionsmembers/south-eastasia/members/94-india.html. Accessed February 28, 2021
  • Sugar AM. Agents of mucormycosis and related species. In: Mandell G, Bennett J, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier; 2005:2979.
  • Ibrahim AS, Je E, Sg F. Zygomycosis. In: Dismukes W, Pappas P, Sobel J, eds. Clinical Mycology. New York, NY: Oxford University Press; 2003:241–251.
  • Zhou P, Liu Z, Chen Y, Xiao Y, Huang X, Fan XG. Bacterial and fungal infections in COVID-19 patients: a matter of concern. Infect Control Hosp Epidemiol. 2020;41(9):1124–1125. doi:10.1017/ice.2020.156.
  • Chen X, Liao B, Cheng L, Peng X, Xu X, Li Y, et al. The microbial coinfection in COVID-19. Appl Microbiol Biotechnol. 2020;104(18):7777–7785. doi:10.1007/s00253-020-10814-6.
  • White PL, Dhillon R, Hughes H, Wise MP, Backx M. COVID-19 and fungal infection: the need for a strategic approach. Lancet Microbe. 2020;1(5):e196. doi:10.1016/S2666-5247(20)30127-0.
  • Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus. 2020;12:e10726.
  • Waizel-Haiat S, Guerrero-Paz JA, Sanchez-Hurtado L, Calleja-Alarcon S, Romero-Gutierrez L. A case of fatal rhino-orbital Mucormycosis associated with new onset diabetic ketoacidosis and COVID-19. Cureus. 2021;13(2):e13163. doi:10.7759/cureus.13163.
  • Sen M, Lahane S, Lahane TP, Parekh R, Honavar SG. Mucor in a viral land: a tale of two pathogens. Indian J Ophthalmol. 2021;69(2):244–252. doi:10.4103/ijo.IJO_3774_20.
  • Natesan SK, Chandrasekar PH. Isavuconazole for the treatment of invasive aspergillosis and mucormycosis: current evidence, safety, efficacy, and clinical recommendations. Infect Drug Resist. 2016;9:291–300. doi:10.2147/IDR.S102207.
  • Brosnahan SB, Jonkman AH, Kugler MC, Munger JS, Kaufman DA. COVID-19 and respiratory system disorders: current knowledge, future clinical and translational research questions. Arterioscler Thromb Vasc Biol. 2020;40(11):2586–2597. doi:10.1161/ATVBAHA.120.314515.
  • Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181(4):894–904. doi:10.1016/j.cell.2020.03.045.
  • Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Life Sci. 2020;63(3):457–460. doi:10.1007/s11427-020-1637-5.
  • Koparal M, Kurt E, Altuntas EE, Dogan F. Assessment of mucociliary clearance as an indicator of nasal function in patients with COVID-19: a cross-sectional study. Eur Arch Otorhinolaryngol. 2020;13:1–6.
  • Chilvers MA, McKean M, Rutman A, Myint BS, Silverman M, O’-Callaghan C. The effects of coronavirus on human nasal ciliated respiratory epithelium. Eur Respir J. 2001;18(6):965–970. doi:10.1183/09031936.01.00093001.
  • Bouchara JP, Oumeziane NA, Lissitzky JC, Larcher G, Tronchin G, Chabasse D. Attachment of spores of the human pathogenic fungus Rhizopus oryzae to extracellular matrix components. Eur J Cell Biol. 1996;70:76–83.
  • Huang Y, Yang C, Xu XF, Xu W, Liu SW. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020;3:1–9.
  • Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020;11(1):1620. doi:10.1038/s41467-020-15562-9.
  • Shang J, Ye G, Shi K. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581(7807):221–224. doi:10.1038/s41586-020-2179-y.
  • Versteeg GA, Ps VDN, Bredenbeek PJ, Spaan WJM. The coronavirus spike protein induces endoplasmic reticulum stress and upregulation of intracellular chemokine mRNA concentrations. J Virol. 2007;81(20):10981–10990. doi:10.1128/JVI.01033-07.
  • Chu H, Chan CM, Zhang X, Wang Y, Yuan S, Zhou J, et al. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells. J Biol Chem. 2018;293(30):11709–11726. doi:10.1074/jbc.RA118.001897.
  • Sabirli R, Koseler A, Goren T, Turkcuer I, Kurt O. High GRP78 levels in Covid-19 infection: a case-control study. Life Sci. 2021;265:118781. doi:10.1016/j.lfs.2020.118781.
  • Köseler A, Sabirli R, Gören T, Türkçüer İ, Kurt Ö. Endoplasmic reticulum stress markers in SARS-COV-2 infection and pneumonia: case-control study. In Vivo. 2020;34(3 suppl):1645–1650. doi:10.21873/invivo.11956.
  • Liu 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(6):1914–1924. doi:10.1172/JCI42164.
  • Alqarihi A, Gebremariam T, Gu Y, Swidergall M, Alkhazraji S, Soliman SSM, et al. GRP78 and integrins play different roles in host cell invasion during mucormycosis. MBio. 2020;2(11):01087–20.
  • Feng Z, Diao B, Wang R, Wang G, Wang C, Tan Y, et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv; 2020.
  • Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):1–13. doi:10.1038/s41586-020-2286-9.
  • Dirk BS, Pawlak EN, Johnson AL, Van Nynatten LR, Jacob RA, Heit B, et al. HIV-1 Nef sequesters MHC-I intracellularly by targeting early stages of endocytosis and recycling. Sci Rep. 2016;6(1):37021. doi:10.1038/srep37021.
  • Dirk BS, Heit B, Dikeakos JD. Visualizing interactions between HIV-1 nef and host cellular proteins using ground-state depletion microscopy. AIDS Res Hum Retroviruses. 2015;31(7):671–672. doi:10.1089/aid.2014.0333.
  • Ghuman H, Voelz K. Innate and adaptive immunity to mucorales. J Fungi (Basel). 2017;3(3):48. doi:10.3390/jof3030048.
  • López-Muñoz A, Nicolás FE, García-Moreno D, Pérez-Oliva AB, Navarro-Mendoza MI, Hernández-Oñate MA, et al. An adult zebrafish model reveals that Mucormycosis induces apoptosis of infected macrophages. Sci Rep. 2018;8(1):12802. doi:10.1038/s41598-018-30754-6.
  • Waldorf AR, Levitz SM, Diamond RD. In vivo broncho alveolar macrophage defense against Rhizopus oryzae and Aspergillus fumigatus. J Infect Dis. 1984;150:752–760.
  • Lamichhane PP, Samarasinghe AE. The role of innate leukocytes during influenza virus infection. J Immunol Res. 2019;12:8028725.
  • Rosales C. Neutrophils at the crossroads of innate and adaptive immunity. J Leukoc Biol. 2020;108(1):377–396. doi:10.1002/JLB.4MIR0220-574RR.
  • Barr FD, Ochsenbauer C, Wira CR, Rodriguez-Garcia M. Neutrophil extracellular traps prevent HIV infection in the female genital tract. Mucosal Immunol. 2018;11(5):1420–1428. doi:10.1038/s41385-018-0045-0.
  • Ruan Q, Yang K, Wang W, Jiang L, Song J. Correction to: clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(6):1294–1297. doi:10.1007/s00134-020-06028-z.
  • Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep. 2016;6(1):25359. doi:10.1038/srep25359.
  • Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–287. doi:10.1038/nm.4294.
  • Coutinho HD, Lôbo KM, Bezerra DA, Lôbo I. Peptides and proteins with antimicrobial activity. Indian J Pharmacol. 2008;40(1):3–9. doi:10.4103/0253-7613.40481.
  • Chamilos G, Lewis RE, Lamaris G, Walsh TJ, Kontoyiannis DP. Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through toll-like receptor 2 induction but display relative resistance to oxidative damage. Antimicrob Agents Chemother. 2008;52(2):722–724. doi:10.1128/AAC.01136-07.
  • Chinn 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(3):1123–1129. doi:10.1128/iai.38.3.1123-1129.1982.
  • Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, et al. Multicenter epidemiologic study of coronavirus disease–associated Mucormycosis, India. Emerg Infect Dis. 2021 Jun 4;27(9):2349–2359. doi:10.3201/eid2709.210934. Epub ahead of print. PMID: 34087089.
  • Watson CN, Kerrigan SW, Cox D, Henderson IR, Watson SP, Arman M. Human platelet activation by Escherichia coli: roles for FcγRIIA and integrin αIIbβ3. Platelets. 2016;27(6):535–540. doi:10.3109/09537104.2016.1148129.
  • van Eeden C, Khan L, Osman MS, Cohen Tervaert JW. Natural killer cell dysfunction and its role in COVID-19. Int J Mol Sci. 2020;21(17):6351. doi:10.3390/ijms21176351.
  • Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834–847. doi:10.1002/ajh.25829.
  • Rao VUS, Arakeri G, Subash A, Rao J, Jadhav S, Suhail Sayeed M, et al. COVID-19: loss of bridging between innate and adaptive immunity? Med Hypotheses. 2020;144:109861. doi:10.1016/j.mehy.2020.109861.
  • Law HK, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W, et al. Chemokine up-regulation in SARS-coronavirus–infected, monocyte-derived human dendritic cells. Blood. 2005;106(7):2366–2374. doi:10.1182/blood-2004-10-4166.
  • Perkhofer S, Kainzner B, Kehrel BE, Dierich MP, Nussbaumer W, Lass-Flörl C. Potential antifungal effects of human platelets against zygomycetes in vitro. J Infect Dis. 2009;200(7):1176–1179. doi:10.1086/605607.
  • Ibrahim AS, Spellberg B, Edwards J Jr. Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis. 2008;21(6):620–625. doi:10.1097/QCO.0b013e3283165fd1.
  • Voelz K, Gratacap RL, Wheeler RT. A zebrafish larval model reveals early tissue-specific innate immune responses to Mucor circinelloides. Dis Model Mech. 2015;8(11):1375–1388. doi:10.1242/dmm.019992.
  • Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi:10.1016/S0140-6736(20)30183-5.
  • Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748–773. doi:10.1039/C3MT00347G.
  • Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401–409. doi:10.1093/intimm/dxx031.
  • Rouault TA. Mitochondrial iron overload: causes and consequences. Curr Opin Genet Dev. 2016;38:31–37. doi:10.1016/j.gde.2016.02.004.
  • Starkov AA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann NY Acad Sci. 2008;1147(1):37–52. doi:10.1196/annals.1427.015.
  • Herst PM, Rowe MR, Carson GM, Berridge MV. Functional mitochondria in health and disease. Front Endocrinol (Lausanne). 2017;8:296. doi:10.3389/fendo.2017.00296.
  • Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13(2):148–159. doi:10.1038/cmi.2015.95.
  • Naik E, Dixit VM. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med. 2011;208(3):417–420. doi:10.1084/jem.20110367.
  • Jouihan HA, Cobine PA, Cooksey RC, Hoagland EA, Boudina S, Abel ED. Iron-Mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Mol Med. 2008;14(3–4):98–108. doi:10.2119/2007-00114.Jouihan.
  • Aguirre JD, Culotta VC. Battles with iron: manganese in oxidative stress protection. J Biol Chem. 2012;287(17):13541–13548. doi:10.1074/jbc.R111.312181.
  • Park D, Han CZ, Elliott MR, Kinchen JM, Trampont PC, Das S, et al. Continued clearance of apoptotic cells critically depends on the phagocyte UCP2 protein. Nature. 2011;477(7363):220–224. doi:10.1038/nature10340.
  • Janssen E, Tabeta K, Barnes MJ, Rutschmann S, McBride S, Bahjat KS, et al. Efficient T cell activation via a Toll-Interleukin 1 Receptor-independent pathway. Immunity. 2006;24(6):787–799. doi:10.1016/j.immuni.2006.03.024.
  • Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol. 2007;292(2):C670–686. doi:10.1152/ajpcell.00213.2006.
  • Chougnet CA, Thacker RI, Shehata HM, Hennies CM, Lehn MA, Lages CS, et al. Loss of phagocytic and antigen cross-presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. J Immunol. 2015;195(6):2624–2632. doi:10.4049/jimmunol.1501006.
  • LeBlanc DM, Barousse MM, Pl F Jr. Role for dendritic cells in immunoregulation during experimental vaginal candidiasis. Infect Immun. 2006;74(6):3213–3221. doi:10.1128/IAI.01824-05.
  • Eapen MS, Sharma P, Sohal SS. Mitochondrial dysfunction in macrophages: a key to defective bacterial phagocytosis in COPD. Eur Respir J. 2019;54(4):1901641. doi:10.1183/13993003.01641-2019.
  • Nicolás FE, Murcia L, Navarro E, Navarro-Mendoza MI, Pérez-Arques C, Garre V. Mucorales species and macrophages. J Fungi (Basel). 2020;6(2):94. doi:10.3390/jof6020094.
  • Roilides E, Antachopoulos C, Simitsopoulou M. Pathogenesis and host defence against Mucorales: the role of cytokines and interaction with antifungal drugs. Mycoses. 2014;57:40–47. doi:10.1111/myc.12236.
  • Morikawa K, Oseko F, Morikawa S. A role for ferritin in hematopoiesis and the immune system. Leuk Lymphoma. 1995;18(5–6):429–433. doi:10.3109/10428199509059641.
  • Govender N, Khaliq OP, Moodley J, and Naicker T. Insulin resistance in COVID-19 and diabetes. Prim Care Diabetes. 2021 Aug;15(4):629–634. doi:10.1016/j.pcd.2021.04.004.
  • Vallianou NG, Evangelopoulos A, Kounatidis D, Stratigou T, Christodoulatos GS, Karampela I, et al. Diabetes mellitus and SARS-CoV-2 infection: pathophysiologic mechanisms and implications in management. Curr Diabetes Rev. 2020;31.
  • Rubino F, Amiel SA, Zimmet P, Alberti G, Bornstein S, Eckel RH, et al. New-onset diabetes in Covid-19. N Engl J Med. 2020;383(8):789–790. doi:10.1056/NEJMc2018688.
  • Zhu L, She ZG, Cheng X, Qin JJ, Zhang XJ, Cai J, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 2020;31(6):1068–1077.e3. doi:10.1016/j.cmet.2020.04.021.
  • Holman N, Knighton P, Kar P, O’-Keefe J, Curley M, Weaver A, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(10):823–833. doi:10.1016/S2213-8587(20)30271-0.
  • Hollstein T, Schulte DM, Schulz J, Glück A, Ziegler AG, Bonifacio E, et al. Autoantibody-Negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report. Nat Metab. 2020;2(10):1021–1024. doi:10.1038/s42255-020-00281-8.
  • Chee YJ, Ng SJH, Yeoh E. Diabetic ketoacidosis precipitated by COVID-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin Pract. 2020;164:108166. doi:10.1016/j.diabres.2020.108166.
  • Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID-19 infection may cause ketosis and ketoacidosis. Diabetes Obes Metab. 2020;22(10):1935–1941. doi:10.1111/dom.14057.
  • Ren H, Yang Y, Wang F, Yan Y, Shi X, Dong K, et al. Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19. Cardiovasc Diabetol. 2020;19(1):58. doi:10.1186/s12933-020-01035-2.
  • Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989;84(1):205–213. doi:10.1172/JCI114142.
  • Eketunde AO, Mellacheruvu SP, Oreoluwa P. A review of postmortem findings in patients with COVID-19. Cureus. 2020;12:e9438.
  • Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-Converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586–590. doi:10.1007/s00134-020-05985-9.
  • Liu 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(9):2128–2130.e2. doi:10.1016/j.cgh.2020.04.040.
  • Reddy PK, Kuchay MS, Mehta Y, Mishra SK. Diabetic ketoacidosis precipitated by COVID-19: a report of two cases and review of literature. Diabetes Metab Syndr. 2020;14(5):1459–1462. doi:10.1016/j.dsx.2020.07.050.
  • Nair AG, Adulkar NG, D’-Cunha L, Rao PR, Bradoo RA, Bapaye MM, et al. Rhino-Orbital mucormycosis following COVID-19 in previously non-diabetic, immunocompetent patients. Orbit. 2021;40(6):499–504. doi:10.1080/01676830.2021.1960382.
  • Dave TV, Nair AG, Hegde R, Vithalani N, Desai S, Adulkar N, et al. Clinical presentations, management and outcomes of rhino-orbital-cerebral Mucormycosis (ROCM) following COVID-19: a multi-centric study. Ophthalmic Plast Reconstr Surg. 2021;37(5):488–495. doi:10.1097/IOP.0000000000002030.
  • Tater D, Tepaut B, Bercovici JP, Youinou P. Polymorphonuclear cell derangements in type I diabetes. Horm Metab Res. 1987;19(12):642–647. doi:10.1055/s-2007-1011899.
  • Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, et al. Impaired leucocyte functions in diabetic patients. Diabet Med. 1997;14(1):29–34. doi:10.1002/(SICI)1096-9136(199701)14:1<29:AID-DIA300>3.0.CO;2-V.
  • Marhoffer W, Stein M, Maeser E, Federlin K. Impairment of polymorphonuclear leukocyte function and metabolic control of diabetes. Diabetes Care. 1992;15(2):256–260. doi:10.2337/diacare.15.2.256.
  • Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance for human health. J Res Med Sci. 2014;19:164–174.
  • Van Asbeck BS, Marx JJ, Struyvenberg A, Verhoef J. Functional defects in phagocytic cells from patients with iron overload. J Infect. 1984;8(3):232–240. doi:10.1016/S0163-4453(84)93955-0.
  • Garner B, Li W, Roberg K, Brunk UT. On the cytoprotective role of ferritin in macrophages and its ability to enhance lysosomal stability. Free Radic Res. 1997;27(5):487–500. doi:10.3109/10715769709065788.
  • Carrasco-Marín E, Alvarez-Domínguez C, López-Mato P, Martínez-Palencia R, Leyva-Cobián F. Iron salts and iron-containing porphyrins block presentation of protein antigens by macrophages to MHC class II-restricted T cells. Cell Immunol. 1996;171(2):173–185. doi:10.1006/cimm.1996.0192.
  • Artis WM, Fountain JA, Delcher HK, Jones HE. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes. 1982;31(12):1109–1114. doi:10.2337/diacare.31.12.1109.
  • Husain S, Alexander BD, Munoz P, Avery RK, Houston S, Pruett T, et al. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis. 2003;37(2):221–229. doi:10.1086/375822.
  • Boelaert JR, Fenves AZ, Coburn JW. Registry on mucormycosis in dialysis patients. J Infect Dis. 1989;160(5):914. doi:10.1093/infdis/160.5.914.
  • Boelaert JR, Fenves AZ, Coburn JW. Mucormycosis among patients on dialysis. New Engl J Med. 1989;321:190–191.
  • Aasa R, Malmstroem BG, Saltman P. The specific binding of iron(iii) and copper(ii) to transferrin and conalbumin. Biochim Biophys Acta. 1963, September 24;75:203–222. doi:10.1016/0006-3002(63)90599-7.
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