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Fickweiler W, Park H, Park K, Mitzner MG, Chokshi T, Boumenna T, Gautier J, Zaitsu Y, Wu I-H, Cavallerano J, Aiello LP, Sun JK, King GL. Elevated Retinol Binding Protein 3 Concentrations Are Associated With Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy. Diabetes Care 2022;45(9):2159-2162.Abstract
OBJECTIVE: To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute. RESULTS: Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-β (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations. CONCLUSIONS: Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.
Moos WH, Faller DV, Glavas IP, Harpp DN, Kamperi N, Kanara I, Kodukula K, Mavrakis AN, Pernokas J, Pernokas M, Pinkert CA, Powers WR, Sampani K, Steliou K, Tamvakopoulos C, Vavvas DG, Zamboni RJ, Chen XH. Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury. Biochem Pharmacol 2022;203:115168.Abstract
Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
Gong Y, Tomita Y, Edin ML, Ren A, Ko M, Yang J, Bull E, Zeldin DC, Hellström A, Fu Z, Smith LEH. Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice. Metabolism 2022;134:155266.Abstract
INTRODUCTION: Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) leads to blindness. It has been widely reported that increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) diets reduce CNV. Of the three major pathways metabolizing ω-3 (and ω-6 LCPUFA), the cyclooxygenase and lipoxygenase pathways generally produce pro-angiogenic metabolites from ω-6 LCPUFA and anti-angiogenic ones from ω-3 LCPUFA. Howevehr, cytochrome P450 oxidase (CPY) 2C produces pro-angiogenic metabolites from both ω-6 and ω-3 LCPUFA. The effects of CYP2J2 products on ocular neovascularization are still unknown. Understanding how each metabolic pathway affects the protective effect of ω-3 LCPUFA on retinal neovascularization may lead to therapeutic interventions. OBJECTIVES: To investigate the effects of LCPUFA metabolites through CYP2J2 pathway and CYP2J2 regulation on CNV both in vivo and ex vivo. METHODS: The impact of CYP2J2 overexpression and inhibition on neovascularization in the laser-induced CNV mouse model was assessed. The plasma levels of CYP2J2 metabolites were measured by liquid chromatography and tandem mass spectroscopy. The choroidal explant sprouting assay was used to investigate the effects of CYP2J2 inhibition and specific LCPUFA CYP2J2 metabolites on angiogenesis ex vivo. RESULTS: CNV was exacerbated in Tie2-Cre CYP2J2-overexpressing mice and was associated with increased levels of plasma docosahexaenoic acids. Inhibiting CYP2J2 activity with flunarizine decreased CNV in both ω-6 and ω-3 LCPUFA-fed wild-type mice. In Tie2-Cre CYP2J2-overexpressing mice, flunarizine suppressed CNV by 33 % and 36 % in ω-6, ω-3 LCPUFA diets, respectively, and reduced plasma levels of CYP2J2 metabolites. The pro-angiogenic role of CYP2J2 was corroborated in the choroidal explant sprouting assay. Flunarizine attenuated ex vivo choroidal sprouting, and 19,20-EDP, a ω-3 LCPUFA CYP2J2 metabolite, increased sprouting. The combined inhibition of CYP2J2 with flunarizine and CYP2C8 with montelukast further enhanced CNV suppression via tumor necrosis factor-α suppression. CONCLUSIONS: CYP2J2 inhibition augmented the inhibitory effect of ω-3 LCPUFA on CNV. Flunarizine suppressed pathological choroidal angiogenesis, and co-treatment with montelukast inhibiting CYP2C8 further enhanced the effect. CYP2 inhibition might be a viable approach to suppress CNV in AMD.
Singhal S, Patel G, Singh RB, Goyal A, Avgush K, Koka J. Atezolizumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis and Takotsubo cardiomyopathy. BMJ Case Rep 2022;15(7)Abstract
Atezolizumab is a humanised monoclonal IgG1 antibody that is used in treating many solid malignancies. Endocrinopathies are known but a rare adverse event of these immunotherapeutic drugs. Autoimmune diabetes induced by atezolizumab has been rarely reported in the literature. We report the case of a woman in her eighth decade with no known history of diabetes who developed new-onset autoimmune diabetes and Takotsubo cardiomyopathy due to the adverse effects of atezolizumab therapy for hepatocellular carcinoma. We also review the characteristics and outcomes of cases previously reported in the literature.
Yousefi S, Pasquale LR, Boland MV, Johnson CA. Machine-identified Patterns of Visual Field Loss and An Association with Rapid Progression in the Ocular Hypertension Treatment Study. Ophthalmology 2022;Abstract
PURPOSE: To identify patterns of visual field (VF) loss based on unsupervised machine learning and to identify patterns that are associated with rapid progression. DESIGN: Cross-sectional and longitudinal study. PARTICIPANTS: A total of 2231 abnormal VFs from 205 eyes of 176 OHTS participants followed over approximately 16 years. METHODS: VFs were assessed by an unsupervised deep archetypal analysis algorithm as well as an OHTS certified VF reader to identify prevalent patterns of VF loss. Machine-identified patterns of glaucoma damage were compared against those patterns previously identified (expert-identified) in the OHTS in 2003. Based on the longitudinal VFs of each eye, VF loss patterns that were strongly associated with rapid glaucoma progression were identified. MAIN OUTCOME MEASURES: Machine-expert correspondence and type of patterns of VF loss associated with rapid progression. RESULTS: The average VF mean deviation (MD) at conversion to glaucoma was -2.7 dB (Standard Deviation (SD) = 2.4 dB) while the average MD of the eyes at the last visit was -5.2 dB (SD = 5.5 dB). Fifty out of 205 eyes had MD rate of -1 dB/year or worse and were considered rapid progressors. Eighteen machine-identified patterns of VF loss were compared with expert-identified patterns in which 13 patterns of VF loss were similar. The most prevalent expert-identified patterns included partial arcuate, paracentral, and nasal step defects, and the most prevalent machine-identified patterns included temporal wedge, partial arcuate, nasal step, and paracentral VF defects. One of the machine-identified patterns of VF loss predicted future rapid VF progression after adjustment for age, sex, and initial MD. CONCLUSIONS: An automated machine learning system can identify patterns of VF loss and could provide objective, and reproducible nomenclature for characterizing early signs of visual defects and rapid progression in patients with glaucoma.
Master CL, Bacal D, Grady MF, Hertle R, Shah AS, Strominger M, Whitecross S, Bradford GE, Lum F, Donahue SP. Vision and Concussion: Symptoms, Signs, Evaluation, and Treatment. Pediatrics 2022;Abstract
Visual symptoms are common after concussion in children and adolescents, making it essential for clinicians to understand how to screen, identify, and initiate clinical management of visual symptoms in pediatric patients after this common childhood injury. Although most children and adolescents with visual symptoms after concussion will recover on their own by 4 weeks, for a subset who do not have spontaneous recovery, referral to a specialist with experience in comprehensive concussion management (eg, sports medicine, neurology, neuropsychology, physiatry, ophthalmology, otorhinolaryngology) for additional assessment and treatment may be necessary. A vision-specific history and a thorough visual system examination are warranted, including an assessment of visual acuity, ocular alignment in all positions of gaze, smooth pursuit (visual tracking of a moving object), saccades (visual fixation shifting between stationary targets), vestibulo-ocular reflex (maintaining image focus during movement), near point of convergence (focusing with both eyes at near and accommodation (focusing with one eye at near because any of these functions may be disturbed after concussion. These deficits may contribute to difficulty with returning to both play and the learning setting at school, making the identification of these problems early after injury important for the clinician to provide relevant learning accommodations, such as larger font, preprinted notes, and temporary use of audio books. Early identification and appropriate management of visual symptoms, such as convergence insufficiency or accommodative insufficiency, may mitigate the negative effects of concussion on children and adolescents and their quality of life.
Bothun ED, Shainberg MJ, Christiansen SP, VanderVeen DK, Neely DE, Kruger SJ, Cotsonis G, Lambert SR, Lambert SR. Long-term strabismus outcomes after unilateral infantile cataract surgery in the Infant Aphakia Treatment Study. J AAPOS 2022;Abstract
PURPOSE: To characterize long-term strabismus outcomes in children in the Infant Aphakia Treatment Study (IATS). METHODS: This study was a secondary data analysis of long-term ocular alignment characteristics of children aged 10.5 years who had previously been enrolled in a randomized clinical trial evaluating aphakic management after unilateral cataract surgery between 1 and 6 months of age. RESULTS: In the IATS study, 96 of 109 children (88%) developed strabismus through age 10.5 years. Half of the 20 children who were orthophoric at distance through age 5 years maintained orthophoria at distance fixation at 10.5 years. Esotropia was the most common type of strabismus prior to age 5 years (56/109 [51%]), whereas exotropia (49/109 [45%]) was the most common type of strabismus at 10.5 years (esotropia, 21%; isolated hypertropia, 17%). Strabismus surgery had been performed on 52 children (48%), with 18 of these (35%) achieving microtropia <10Δ. Strabismus was equally prevalent in children randomized to contact lens care compared with those randomized to primary intraocular lens implantation (45/54 [83%] vs 45/55 [82%]; P = 0.8). Median visual acuity in the study eye was 0.56 logMAR (20/72) for children with orthotropia or microtropia <10Δ versus 1.30 logMAR (20/400) for strabismus ≥10Δ (P = 0.0003). CONCLUSIONS: Strabismus-in particular, exotropia-is common irrespective of aphakia management 10 years following infant monocular cataract surgery. The delayed emergence of exotropia with longer follow-up indicates a need for caution in managing early esotropia in these children. Children with better visual acuity at 10 years of age are more likely to have better ocular alignment.
Susarla G, Rizza AN, Li A, Han S, Khan R, Chan W, Lains I, Apivatthakakul A, Brustoski K, Khetan V, Raman R, Igo RP, Iyengar SK, Mathavan S, Sobrin L. Younger Age and Albuminuria are Associated with Proliferative Diabetic Retinopathy and Diabetic Macular Edema in the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study. Curr Eye Res 2022;47(10):1389-1396.Abstract
Purpose: The purpose of the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study is to identify non-genetic and genetic risk factors associated with diabetic retinopathy (DR). This report examines the non-genetic risk factors for DR in South Indian patients.Methods: Participants with South Indian ancestry and type 2 diabetes (T2D) were included from two sources: the Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study (SN-DREAMS) and prospective recruitment at Sankara Nethralaya affiliates. Fundus photography and optical coherence tomography (OCT) were obtained on participants. Fundus images were graded for DR severity and OCTs were graded for center-involved diabetic macular edema (ciDME). Multivariate analyses were performed using stepwise logistic regression to assess effects of the demographic and clinical factors on proliferative DR (PDR) and DME.Results: Among the 2941 participants with DR grading, participants with PDR were more likely to be younger [odds ratio (OR)=0.95], men (OR = 1.83), have a longer duration of diabetes (OR = 1.10), have a higher hemoglobin A1c (OR = 1.12), have albuminuria (OR = 5.83), have hypertension (OR = 1.69), have a higher HDL (OR = 1.02) and a lower total cholesterol (OR = 0.99) (all p < 0.05). Among the 483 participants with gradable OCT scans, participants who had ciDME were more likely to be younger (OR = 0.97), men (OR = 2.80), have a longer duration of diabetes (OR = 1.06), have lower triglycerides (OR = 0.99), and have albuminuria (OR = 3.12) (all p < 0.05).Conclusions: Younger age, male sex, longer duration of diabetes, higher HbA1c, and presence of albuminuria were identified as risk factors for PDR and DME in a South Indian population with T2D.
Bharti K, den Hollander AI, Lakkaraju A, Sinha D, Williams DS, Finnemann SC, Bowes-Rickman C, Malek G, D'Amore PA. Cell culture models to study retinal pigment epithelium-related pathogenesis in age-related macular degeneration. Exp Eye Res 2022;222:109170.Abstract
Age-related macular degeneration (AMD) is a disease that affects the macula - the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by the presence of lipid- and protein-rich extracellular deposits beneath the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative "dry" stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients' vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly betweendifferent models and culture conditions used in different labs, which would directly impact their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.
Singh RB, Yuksel E, Sinha S, Wang S, Taketani Y, Luznik Z, Yin J, Dohlman TH, Dana R. Prevalence of neurotrophic keratopathy in patients with chronic ocular graft-versus-host disease. Ocul Surf 2022;Abstract
PURPOSE: To determine the prevalence, clinical characteristics, and risk factors associated with neurotrophic keratopathy (NK) in patients with chronic ocular graft-versus-host disease (oGVHD). DESIGN: Retrospective cohort study. METHODS: We performed a chart review of patients diagnosed with chronic oGVHD between January 2015 and December 2018 at a single academic institution and recorded demographic data, systemic and ocular comorbidities, history of hematologic malignancy, transplant characteristics, oGVHD severity scores, and adnexal and ocular examination findings. We determined the prevalence of NK and clinical characteristics associated with NK in these patients. A multivariate logistic regression analysis was performed to determine the risk factors associated with NK in these patients. MAIN OUTCOME MEASURE: Prevalence of NK in chronic oGVHD. RESULTS: We identified 213 patients diagnosed with chronic oGVHD following hematopoietic stem cell or bone marrow transplantation from our electronic patient database, and the prevalence of NK was 14%. The mean age of oGVHD patients with NK was 62.6 ± 12.9 years; 48% were women, 19 had unilateral NK, and ten had bilateral NK. In the cohort, 56%, 20%, and 24% eyes of the patients had grades 1, 2, and 3 of NK, respectively. The mean time to diagnose NK after transplantation was 52.9 ± 45.4 months. oGVHD patients diagnosed with NK had a significantly higher NIH oGVHD severity score (p = 0.04) and a lower corneal sensation score (p = 0.0001) than those without NK. Our analyses showed a significantly higher CFS score (p = 0.01) and a trend toward lower Schirmer test scores (p = 0.16) and tear break-up times (p = 0.08) in oGVHD patients with NK. Additionally, we observed a significantly higher prevalence of persistent epithelial defect (p = 0.0001), corneal ulceration (p = 0.0001), and corneal perforation (p = 0.005) in oGVHD patients diagnosed with NK. A logistic regression analysis to determine factors associated with NK showed that a higher NIH oGVHD score (odds ratio [OR] = 2.03, p = 0.026) and history of cataract surgery (odds ratio [OR] = 5.03, p = 0.001) are significant risk factors for NK in oGVHD patients. CONCLUSIONS: The prevalence of NK in chronic oGVHD patients was 14% during the study period. Our analysis shows that oGVHD patients with a higher NIH oGVHD severity score and previous history of cataract surgery are at a higher risk of developing NK and may develop severe sequelae such as persistent epithelial defect or corneal ulceration.
Jacobs DS. Knowledge. Eye Contact Lens 2022;48(7):277.
Sepulveda-Falla D, Sanchez JS, Almeida MC, Boassa D, Acosta-Uribe J, Vila-Castelar C, Ramirez-Gomez L, Baena A, Aguillon D, Villalba-Moreno ND, Littau JL, Villegas A, Beach TG, White CL, Ellisman M, Krasemann S, Glatzel M, Johnson KA, Sperling RA, Reiman EM, Arboleda-Velasquez JF, Kosik KS, Lopera F, Quiroz YT. Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol 2022;144(3):589-601.Abstract
We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer's disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer's symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.
Saini C, Chen TC, Young LH, Vavvas DG, Vangel M, Papaliodis GN, Mukai S, Turalba AV, Rhee DJ, Wu DM, Eliott D, Miller JB, Song BJ, Shen LQ, Pasquale LR, Chodosh J. Restoration of Vision in Severe, Cicatricial, Ocular Surface Disease With the Boston Keratoprosthesis Type II. Am J Ophthalmol 2022;243:42-54.Abstract
PURPOSE: To assess clinical outcomes of patients with severe, cicatricial ocular surface disease (OSD) implanted with the currently marketed design of the Boston keratoprosthesis type II (BK2). DESIGN: Retrospective cohort study. METHODS: Records of consecutive patients undergoing BK2 implantation from June 2009 to March 2021 were assessed for postoperative visual acuity, postoperative complications, device replacement, and additional surgeries. RESULTS: Fifty-six eyes of 53 patients with a mean follow-up of 45.8 months (range, 0.2-134.7 months) were included. Stevens-Johnson syndrome/toxic epidermal necrolysis was the most common indication (49.1%), followed by mucous membrane pemphigoid (39.6%) and other OSD (11.3%). Visual acuity improved from logMAR 2.2 ± 0.5 preoperatively to 1.5 ± 1.2 at final follow-up. Of 56 eyes, 50 saw ≥20/200 at some point postoperatively. Of the eyes with a follow-up of more than 5 years, 50.0% retained a visual acuity of ≥20/200 at their final follow-up. The most common complications over the entire postoperative course (mean ∼4 years) were de novo or worsening glaucoma (41.1%), choroidal effusions (30.3%), retinal detachment (25.0%), and end-stage glaucoma (25.0%). In a univariate analysis, patients who experienced irreversible loss of ≥20/200 visual acuity were more likely to have been previously implanted with an older design of BK2, less likely to be on preoperative systemic immunosuppressive therapy, and less likely to have undergone concurrent glaucoma tube implantation, compared to patients who retained ≥20/200 acuity (P < .04 for all). CONCLUSIONS: Advances in device design and postoperative care have made implantation of BK2 a viable option for corneal blindness in the setting of severe cicatricial OSD.
Manley CE, Bennett CR, Merabet LB. Assessing Higher-Order Visual Processing in Cerebral Visual Impairment Using Naturalistic Virtual-Reality-Based Visual Search Tasks. Children (Basel) 2022;9(8)Abstract
Cerebral visual impairment (CVI) is a brain-based disorder associated with the maldevelopment of central visual pathways. Individuals with CVI often report difficulties with daily visual search tasks such as finding a favorite toy or familiar person in cluttered and crowded scenes. We developed two novel virtual reality (VR)-based visual search tasks combined with eye tracking to objectively assess higher order processing abilities in CVI. The first (virtual toybox) simulates a static object search, while the second (virtual hallway) represents a dynamic human search task. Participants were instructed to search for a preselected target while task demand was manipulated with respect to the presence of surrounding distractors. We found that CVI participants (when compared to age-matched controls) showed an overall impairment with visual search on both tasks and with respect to all gaze metrics. Furthermore, CVI participants showed a trend of worsening performance with increasing task demand. Finally, search performance was also impaired in CVI participants with normal/near normal visual acuity, suggesting that reduced stimulus visibility alone does not account for these observations. This novel approach may have important clinical utility in helping to assess environmental factors related to functional visual processing difficulties observed in CVI.
Dave TV, Nair AG, Joseph J, Freitag SK. Immunopathology of COVID-19 and its implications in the development of rhino-orbital-cerebral mucormycosis: a major review. Orbit 2022;41(6):670-679.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.

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