A case of COVID-19-associated mucormycosis due to Lichtheimia ramosa.

BACKGROUND: Mucormycosis is a life-threatening invasive fungal infection in immunocompromised and COVID-19 patients. CASE REPORT: Here, we report a fatal rhino-orbito-cerebral mucormycosis caused by Lichtheimia ramosa, in a 79-year-old diabetic female. She was initially admitted to the hospital for COVID-19 infection and received broad-spectrum antibiotics and corticosteroids. After 1 month, she was admitted again because of persistent headaches and decreased right eye movement when the computed tomography scan showed mucosal thickening and opacification of paranasal sinuses. Microbiological investigations, including culture and direct microscopy, and histopathological findings confirmed the diagnosis of proven mucormycosis. The isolated causal agent was identified as Lichtheimia ramosa by sequencing the entire ITS region of nuclear ribosomal DNA. Despite surgical debridement and administration of liposomal amphotericin B 5 mg/kg/day, the patient's level of consciousness suddenly deteriorated; she was intubated and mechanically ventilated in the ICU and died on the same day. CONCLUSION: To our knowledge, this is the first worldwide case of COVID-19-associated rhino-orbito-cerebral mucormycosis due to Lichtheimia ramosa.

Central Retinal Artery Occlusion in Rhino-Orbital-Cerebral Mucormycosis: An Inflammatory-Prothrombotic State.

PURPOSE: The aim was to evaluate patient profiles of rhino-orbital-cerebral mucormycosis (ROCM) cases with central retinal artery occlusion (CRAO) postcoronavirus disease 2019. DESIGN: A nonrandomized retrospective case-control study. METHODS: The ROCM cases presenting with CRAO were compared with a control ROCM group without CRAO at a tertiary care center. Demography, systemic status, clinical features, histopathology, imaging, and blood profile were assessed for any specific risk factors. RESULTS: A total of 12 patients were seen in the CRAO group and 16 in the non-CRAO group. The male-to-female ratio was 3:1 with a mean age of 49.5 years. In the CRAO group, 75% had diabetes mellitus with mean hemoglobin A1c of 9.03%, and 66.7% had received steroid treatment. All cases were histopathologically confirmed positive for mucor. There was a significant difference in mean D-dimer and serum ferritin between the 2 groups, with higher level in the CRAO group. All patients with CRAO had light perception-negative vision, with total ophthalmoplegia and proptosis seen in 66.7% of cases. Four patients had orbital apex involvement, 5 had cavernous sinus involvement, and 8 had intracranial involvement in the CRAO group. CONCLUSIONS: Inflammatory markers D-dimer and serum ferritin were significantly associated with CRAO, suggestive of hyperinflammatory and hypercoagulable state. A high index of suspicion should be maintained in cases with elevated markers and prophylactic anticoagulants can be started to prevent CRAO in a subset of patients.

Utility of itraconazole and terbinafine in mucormycosis: a proof-of-concept analysis.

An epidemic of mucormycosis followed the second wave of COVID 19 in the state of Uttar Pradesh, India in May 2021. This epidemic, however, had additional challenges to offer in the form of acute shortage of all forms of amphotericin B, posaconazole and isavuconazole. It was, therefore, planned to assess the trends in minimum inhibitory concentration (MIC) of antifungal agents, viz itraconazole and terbinafine, and provide a template for personalized therapy to see whether the results could be translated clinically. This is an observational, single-center study. Samples comprising nasal swab, nasal and paranasal sinus tissue, brain tissue, brain abscess and orbital content, derived from 322 patients from northern India with mucormycosis, of whom 215 were male and 107 were female, were used for analysis. Cultures were identified both by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and conventional methods of identification. Antifungal susceptibility was done for amphotericin B, posaconazole, isavuconazole, itraconazole and terbinafine as per Clinical Laboratory Standard Institute M38-A2. The outcome was identification of the species of mucormycosis and susceptibility to itraconazole and terbinafine besides other primary antifungal agents. Patients or the public were not involved in the design, or conduct, or reporting or in the dissemination plans of our research. Of 322 patients, 203 were culture-positive, of whom 173 were positive by both MALDI-TOF and conventional methods of identification. Final antifungal susceptibility testing was available for 150 patients. The most common Mucorales found to cause this epidemic was Rhizopus oryzae, followed by R. microsporus Amphotericin B, posaconazole and isavuconazole had low MIC values in 98.8% of all Mucorales identified. The MIC of itraconazole was species-dependent. 97.7% of Roryzae had MIC ≤2 µg/mL. However, only 36.5% of Rmicrosporus had MIC ≤2 µg/mL. For terbinafine, 85.2% of R. microsporus had MIC ≤2 µg/mL. We conclude that identification at the species level is required as antifungal susceptibilities seem to be species-dependent. Assessment of the efficacy of itraconazole and terbinafine warrants further studies with clinical assessment and therapeutic drug monitoring as they seem to be potential candidates especially when the primary agents are not available.

Mucormycosis of the Middle Ear and Neck Post COVID 19.

Mucormycosis is an opportunistic infection caused by fungi of order Mucorales and affect immunosuppressed patients. The cases of mucormycosis have surged during the COVID pandemic, especially in cases requiring steroids and mechanical ventilation. Here we present a case of a 40-year-old diabetic post COVID female patient. She presented with right earache, right facial paralysis (grade four) of two weeks duration and right sided neck swelling for ten days. Ultrasonography and computed tomography revealed multiple abscesses in the right side of the neck. Histopathological examination of tissue from the neck and middle ear confirmed the diagnosis of mucormycosis. This is a rare case of concurrent neck and middle ear mucormycosis in a post COVID patient. Keywords: Coronavirus; COVID 19; middle ear; mucormycosis; neck.

Serine/Threonine Phosphatase Calcineurin Orchestrates the Intrinsic Resistance to Micafungin in the Human-Pathogenic Fungus Mucor circinelloides.

Procedures such as solid-organ transplants and cancer treatments can leave many patients in an immunocompromised state. This leads to their increased susceptibility to opportunistic diseases such as fungal infections. Mucormycosis infections are continually emerging and pose a serious threat to immunocompromised patients. Recently there has been a sharp increase in mucormycosis cases as a secondary infection in patients battling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Mucorales fungi are notorious for presenting resistance to most antifungal drugs. The absence of effective means to treat these infections results in mortality rates approaching 100% in cases of disseminated infection. One of the most effective antifungal drug classes currently available is the echinocandins. Echinocandins seem to be efficacious in the treatment of many other fungal infections. Unfortunately, susceptibility testing has found that echinocandins have little to no effect on Mucorales fungi. In this study, we found that the model Mucorales Mucor circinelloides genome carries three copies of the genes encoding the echinocandin target protein ß-(1,3)-d-glucan synthase (fksA, fksB, and fksC). Interestingly, we found that exposing M. circinelloides to micafungin significantly increased the expression of the fksA and fksB genes, resulting in an increased accumulation of ß-(1,3)-d-glucan on the cell walls. However, this overexpression of the fks genes is not directly connected to the intrinsic resistance. Subsequent investigation discovered that the serine/threonine phosphatase calcineurin regulates the expression of fksA and fksB, and the deletion of calcineurin results in a decrease in expression of all three fks genes. Deletion of calcineurin also results in a lower minimum effective concentration (MEC) of micafungin. In addition, we found that duplication of the fks gene is also responsible for the intrinsic resistance, in which lack of either fksA or fksB led a lower MEC of micafungin. Together, these findings demonstrate that calcineurin and fks gene duplication contribute to the intrinsic resistance to micafungin we observe in M. circinelloides.

A Multiplex PCR and DNA-Sequencing Workflow on Serum for the Diagnosis and Species Identification for Invasive Aspergillosis and Mucormycosis.

There has been significant increase in the use of molecular tools for the diagnosis of invasive aspergillosis (IA) and mucormycosis. However, their range of detection may be too limited as species diversity and coinfections are increasing. Here, we aimed to evaluate a molecular workflow based on a new multiplex PCR assay detecting the whole Aspergillus genus and the Mucorales order followed by a species-specific PCR or a DNA-sequencing approach for IA and/or mucormycosis diagnosis and species identification on serum. Performances of the MycoGENIE Aspergillus spp./Mucorales spp. duplex PCR kit were analyzed on a broad range of fungal strains and on sera from high-risk patients prospectively over a 12-month period. The kit allowed the detection of nine Aspergillus species and 10 Mucorales (eight genera) strains assessed. No cross-reactions between the two targets were observed. Sera from 744 patients were prospectively analyzed, including 35 IA, 16 mucormycosis, and four coinfections. Sensitivity varies from 85.7% (18/21) in probable/proven IA to 28.6% (4/14) in COVID-19-associated pulmonary aspergillosis. PCR-positive samples corresponded to 21 A. fumigatus, one A. flavus, and one A. nidulans infections. All the disseminated mucormycosis were positive in serum (14/14), including the four Aspergillus coinfections, but sensitivity fell to 33.3% (2/6) in localized forms. DNA sequencing allowed Mucorales identification in serum in 15 patients. Remarkably, the most frequent species identified was Rhizomucor pusillus (eight cases), whereas it is barely found in fungal culture. This molecular workflow is a promising approach to improve IA and mucormycosis diagnosis and epidemiology.

Rhizopus microsporus as Causative Agent of Mucormycosis in COVID-19 Patient.

BACKGROUND: The pandemic of coronavirus disease (COVID-19) emerged as a fatal infection, especially in immunocompromised patients. Currently, this infection is managed with systemic corticosteroids. Co-infection of CO-VID-19 with opportunistic fungi is increasingly recognized. METHODS: We describe a case of rhino-cerebral mucormycosis 12 days following severe COVID-19 in a diabetic patient. RESULTS: He received 50 mg amphotericin B and surgical debridement. The patient's symptoms improved following medical and surgical intervention. CONCLUSIONS: Mucormycosis is an uncommon but serious infection that complicates the course of severe COVID-19. Subjects with diabetes mellitus and multiple risk factors may be at a higher risk for developing mucormycosis.

Myosin-II proteins are involved in the growth, morphogenesis, and virulence of the human pathogenic fungus Mucor circinelloides.

Mucormycosis is an emerging lethal invasive fungal infection. The infection caused by fungi belonging to the order Mucorales has been reported recently as one of the most common fungal infections among COVID-19 patients. The lack of understanding of pathogens, particularly at the molecular level, is one of the reasons for the difficulties in the management of the infection. Myosin is a diverse superfamily of actin-based motor proteins that have various cellular roles. Four families of myosin motors have been found in filamentous fungi, including myosin I, II, V, and fungus-specific chitin synthase with myosin motor domains. Our previous study on Mucor circinelloides, a common pathogen of mucormycosis, showed that the Myo5 protein (ID 51513) belonging to the myosin type V family had a critical impact on the growth and virulence of this fungus. In this study, to investigate the roles of myosin II proteins in M. circinelloides, silencing phenotypes and null mutants corresponding to myosin II encoding genes, designated mcmyo2A (ID 149958) and mcmyo2B (ID 136314), respectively, were generated. Those mutant strains featured a significantly reduced growth rate and impaired sporulation in comparison with the wild-type strain. Notably, the disruption of mcmyo2A led to an almost complete lack of sporulation. Both mutant strains displayed abnormally short, septate, and inflated hyphae with the presence of yeast-like cells and an unusual accumulation of pigment-filled vesicles. In vivo virulence assays of myosin-II mutant strains performed in the invertebrate model Galleria mellonella indicated that the mcmyo2A-knockout strain was avirulent, while the pathogenesis of the mcmyo2B null mutant was unaltered despite the low growth rate and impaired sporulation. The findings provide suggestions for critical contributions of the myosin II proteins to the polarity growth, septation, morphology, pigment transportation, and pathogenesis of M. circinelloides. The findings also implicate the myosin family as a potential target for future therapy to treat mucormycosis.

Mucormycosis: A hidden mystery of fungal infection, possible diagnosis, treatment and development of new therapeutic agents.

Mucormycosis is a fungal infection which got worsens with time if not diagnosed and treated. The current COVID-19 pandemic has association with fungal infection specifically with mucormycosis. Already immunocompromised patients are easy target for COVID-19 and mucormycosis as well. COVID-19 infection imparts in weak immune system so chances of infection is comparatively high in COVID-19 patients. Furthermore, diabetes, corticosteroid medicines, and a weakened immune system are the most prevalent risk factors for this infection as we discussed in case studies here. The steroid therapy for COVID-19 patients sometimes have negative impact on the patient health and this state encounters many infections including mucormycosis. There are treatments available but less promising and less effective. So, researchers are focusing on the promising agents against mucormycosis. It is reported that early treatment with liposomal amphotericin B (AmB), manogepix, echinocandins isavuconazole, posacanazole and other promising therapeutic agents have overcome the burden of mucormycosis. Lipid formulations of AmB have become the standard treatment for mucormycosis due to their greater safety and efficacy. In this review article, we have discussed case studies with the infection of mucormycosis in COVID-19 patients. Furthermore, we focused on anti-mucormycosis agents with mechanism of action of various therapeutics, including coverage of new antifungal agents being investigated as part of the urgent global response to control and combat this lethal infection, especially those with established risk factors.

The TLR-NF-kB axis contributes to the monocytic inflammatory response against a virulent strain of Lichtheimia corymbifera, a causative agent of invasive mucormycosis.

Invasive mucormycosis (IM) is a life-threatening infection caused by the fungal order Mucorales, its diagnosis is often delayed, and mortality rates range from 40-80% due to its rapid progression. Individuals suffering from hematological malignancies, diabetes mellitus, organ transplantations, and most recently COVID-19 are particularly susceptible to infection by Mucorales. Given the increase in the occurrence of these diseases, mucormycosis has emerged as one of the most common fungal infections in the last years. However, little is known about the host immune response to Mucorales. Therefore, we characterized the interaction among L. corymbifera-one of the most common causative agents of IM-and human monocytes, which are specialized phagocytes that play an instrumental role in the modulation of the inflammatory response against several pathogenic fungi. This study covered four relevant aspects of the host-pathogen interaction: i) The recognition of L. corymbifera by human monocytes. ii) The intracellular fate of L. corymbifera. iii) The inflammatory response by human monocytes against the most common causative agents of mucormycosis. iv) The main activated Pattern-Recognition Receptors (PRRs) inflammatory signaling cascades in response to L. corymbifera. Here, we demonstrate that L. corymbifera exhibits resistance to intracellular killing over 24 hours, does not germinate, and inflicts minimal damage to the host cell. Nonetheless, viable fungal spores of L. corymbifera induced early production of the pro-inflammatory cytokine IL-1ß, and late release of TNF-α and IL-6 by human monocytes. Moreover, we revealed that IL-1ß production predominantly depends on Toll-like receptors (TLRs) priming, especially via TLR4, while TNF-α is secreted via C-type lectin receptors (CTLs), and IL-6 is produced by synergistic activation of TLRs and CTLs. All these signaling pathways lead to the activation of NF-kB, a transcription factor that not only regulates the inflammatory response but also the apoptotic fate of monocytes during infection with L. corymbifera. Collectively, our findings provide new insights into the host-pathogen interactions, which may serve for future therapies to enhance the host inflammatory response to L. corymbifera.

Antifungal Effect of Nanoparticles against COVID-19 Linked Black Fungus: A Perspective on Biomedical Applications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that has caused a 'coronavirus disease 2019' (COVID-19) pandemic in multiple waves, which threatens human health and public safety. During this pandemic, some patients with COVID-19 acquired secondary infections, such as mucormycosis, also known as black fungus disease. Mucormycosis is a serious, acute, and deadly fungal infection caused by Mucorales-related fungal species, and it spreads rapidly. Hence, prompt diagnosis and treatment are necessary to avoid high mortality and morbidity rates. Major risk factors for this disease include uncontrolled diabetes mellitus and immunosuppression that can also facilitate increases in mucormycosis infections. The extensive use of steroids to prevent the worsening of COVID-19 can lead to black fungus infection. Generally, antifungal agents dedicated to medical applications must be biocompatible, non-toxic, easily soluble, efficient, and hypoallergenic. They should also provide long-term protection against fungal growth. COVID-19-related black fungus infection causes a severe increase in fatalities. Therefore, there is a strong need for the development of novel and efficient antimicrobial agents. Recently, nanoparticle-containing products available in the market have been used as antimicrobial agents to prevent bacterial growth, but little is known about their efficacy with respect to preventing fungal growth, especially black fungus. The present review focuses on the effect of various types of metal nanoparticles, specifically those containing silver, zinc oxide, gold, copper, titanium, magnetic, iron, and carbon, on the growth of various types of fungi. We particularly focused on how these nanoparticles can impact the growth of black fungus. We also discussed black fungus co-infection in the context of the global COVID-19 outbreak, and management and guidelines to help control COVID-19-associated black fungus infection. Finally, this review aimed to elucidate the relationship between COVID-19 and mucormycosis.

[COVID-19-associated mucormycosis in ophthalmological practice in the Volgograd region]. / COVID-19-assotsiirovannyi mukormikoz v oftal'mologicheskoi praktike Volgogradskogo regiona.

The problem of fungal infections in the era of COVID-19 has acquired special significance. This infection, directly or indirectly, through the use of glucocorticoids and antibiotics in its treatment, as well as poorer self-management of chronic diseases, has led to a wide spread of risk factors for fungal diseases among people who have had a novel coronavirus infection. The article presents two cases of COVID-19-associated mycosis, more related to mucormycosis, which were diagnosed by ophthalmologists in the Volgograd region. In the first case, the severe course of rhino-orbito-cerebral form of mucormycosis required a number of surgical interventions and prolonged treatment in the intensive care unit. In the second case, the patient asked for help without signs of aggravation of the general condition, but with irreversible local manifestations. In both cases, the eyeball was removed. Morphological examination revealed aseptal ribbon hyphae of different diameters, branching mainly at right angles, more typical for fungi of the Mucorales family. Due to the severe consequences of the disease, clinicians, including ophthalmologists, need to be especially alertness in patients with the described symptoms and risk factors in the post-COVID period.

Rhino-orbital mucormycosis in a patient with no susceptibility following P.vivax malaria infection-a case report.

BACKGROUND: Mucormycosis is a potentially lethal, angioinvasive fungal infection caused by the Mucoracea family comprising Mucor, Rhizopus, and Absidia species. It is commonly associated with uncontrolled diabetes mellitus, the use of corticosteroids, immunosuppressive drugs, and Covid-19 infection. The occurrence of mucormycosis in an immunocompetent patient is rare. Also, only a few case reports have been published where patients developed mucormycosis with associated malarial infection. CASE PRESENTATION: A young female presented with a 3-weeks history of painful swelling and outward protrusion of the right eye with complete loss of vision. She had a history of P.vivax malaria two weeks before her ocular symptoms. On ocular examination, there was proptosis and total ophthalmoplegia with loss of corneal sensations in the right eye. Hematological examination revealed normocytic normochromic anemia and thrombocytopenia. MRI was suggestive of right-sided pansinusitis and orbital cellulitis with right superior ophthalmic vein thrombosis and bulky cavernous sinus. Nasal biopsy was negative for fungal culture. An emergency surgical debridement of all the sinuses was done with right orbital exenteration. Histopathology confirmed the diagnosis of mucormycosis and the patient improved post-operatively on systemic antifungals. CONCLUSION: Such an association of mucormycosis with malaria infection is rarely reported in the literature and is hypothesized to be a result of immunosuppression caused by malaria. Also, emphasis is laid upon having a high index of suspicion for fungal infection in the setting of pansinusitis even if the risk factors are absent. We hereby report a case of rhino-orbital mucormycosis following P.vivax malaria in a 20-year-old female with anemia and thrombocytopenia.

Antibody Responses and CNS Pathophysiology of Mucormycosis in Chronic SARS Cov-2 Infection: Current Therapies Against Mucormycosis.

The incidence rate of opportunistic secondary infections through invasive fungi has been observed to be 14.5% to 27% in the SARS CoV pandemic during the year 2003. However, the incidence of SARS CoV-2 is accompanied by a substantial rise in secondary opportunistic infections like mucormycosis (black fungus), mainly in the immunocompromised individuals and diabetic patients taking steroids. Substantial rates of COVID-19 cases with mucormycosis were reported in India and other parts of the world. Previous research reports delineated the ability of Mucorales to invade the various tissues like lungs, brain, and sinus through the GRP78, and subsequently, this infection could invoke crusting, edema, and necrosis of the brain parenchyma, ptosis, proptosis, and vision loss due to intraorbital and intracranial complications. Similarities of these pathophysiological complications with already existing diseases are causing clinicians to face several challenges in order to diagnose and treat this disease effectively at the early stage. This minireview depicts the mucormycosis-induced immune and pathophysiological alterations in COVID-19 patients comorbid with diabetes and immunosuppression and also reported the various clinical manifestations, the therapeutic modalities, and the failures of anti-fungal vaccines. Therefore, the emerging mucormycosis in COVID-19 patients needs rapid investigation and selective optimization of the effective therapeutic modalities, including antifungal vaccines, to minimize the mortality rate.

The impact of mucormycosis (black fungus) on SARS-CoV-2-infected patients: at a glance.

The emergence of various diseases during the COVID-19 pandemic made health workers more attentive, and one of the new pathogens is the black fungus (mucormycosis). As a result, millions of lives have already been lost. As a result of the mutation, the virus is constantly changing its traits, including the rate of disease transmission, virulence, pathogenesis, and clinical signs. A recent analysis revealed that some COVID-19 patients were also coinfected with a fungal disease called mucormycosis (black fungus). India has already categorized the COVID-19 patient black fungus outbreak as an epidemic. Only a few reports are observed in other countries. The immune system is weakened by COVID-19 medication, rendering it more prone to illnesses like black fungus (mucormycosis). COVID-19, which is caused by a B.1.617 strain of the SARS-CoV-2 virus, has been circulating in India since April 2021. Mucormycosis is a rare fungal infection induced by exposure to a fungus called mucormycete. The most typically implicated genera are Mucor rhyzuprhizopusdia and Cunninghamella. Mucormycosis is also known as zygomycosis. The main causes of infection are soil, dumping sites, ancient building walls, and other sources of infection (reservoir words "mucormycosis" and "zygomycosis" are occasionally interchanged). Zygomycota, on the other hand, has been identified as polyphyletic and is not currently included in fungal classification systems; also, zygomycosis includes Entomophthorales, but mucormycosis does not. This current review will be focused on the etiology and virulence factors of COVID-19/mucormycosis coinfections in COVID-19-associated mucormycosis patients, as well as their prevalence, diagnosis, and treatment.

Intestinal mucormycosis in a patient with COVID-19: A case report.

The novel coronavirus disease (COVID-19) has spread to all the continents posing a serious threat to global health. It can present with myriad symptoms and complications including susceptibility to fungal co-infections. We hereby describe a case of mucormycosis in a 17 year old COVID-19 positive female with no known comorbidities presenting with abdominal pain and distention and ultimately developing intestinal perforation. Early identication of the symptoms is essential to make a correct and early diagnosis to prevent complications.

First report of rhino-orbital-cerebral mucormycosis after COVID-19 infection in Bulgaria.

Mucormycosis is a relatively rare infection but with a high mortality rate due to the difficult and time-consuming diagnostic and therapeutic process. The authors present the first case of rhino-orbital-cerebral mucormycosis, histologically and microbiologically proven, in a patient after COVID-19 infection in Bulgaria.

Rhino-orbital-cerebral mucormycosis: An epidemiological study from a tertiary care referral center in Western India.

Purpose: Rhino-orbital-cerebral mucormycosis (ROCM) is a rare opportunistic fungal infection with a fulminant course and an often fatal outcome. It can occur in immune-compromised patients such as those having uncontrolled diabetes, on long-term corticosteroid or immunosuppressive therapy, with COVID-19 infection, renal failure, AIDS, malignancy, or organ transplant. The aim of our study was to study the epidemiology of mucormycosis in COVID-19 patients and identify its risk factors. Methods: Ours was an epidemiological study wherein we gathered the demographic, clinical, histopathological, and radiological data of 458 patients of mucormycosis who presented to us between August 2020 and May 2021. Mucormycosis was defined through clinical and radiological findings or positive culture reports. Results: Out of all, 20.74% of patients did not have any past or concurrent history of COVID-19. The most common symptom of mucormycosis was orbital/facial pain (38.64%) and the most common sign was periocular/facial edema (50.74%). Mucormycosis involving the nose and sinuses (94.54%) was most common followed by rhino-orbital (45.41%) and brain involvement (10.04%). The most common risk factor for mucormycosis was diabetes [81.92%], followed by corticosteroid use [79.69%] and supplemental oxygen [48.90%]. Most of the patients received similar treatment with IV amphotericin B [88.64%] and local debridement [80.74%]. Conclusion: With the third wave of COVID-19 still lurking, a fatal fungal infection should be kept in mind in COVID-19 active as well as recovered patients, especially those who have co-morbid medical conditions such as uncontrolled diabetes and who are treated with large doses of corticosteroids.

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

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.

Immunoinformatic Design of a Multivalent Peptide Vaccine Against Mucormycosis: Targeting FTR1 Protein of Major Causative Fungi.

Mucormycosis is a potentially fatal illness that arises in immunocompromised people due to diabetic ketoacidosis, neutropenia, organ transplantation, and elevated serum levels of accessible iron. The sudden spread of mucormycosis in COVID-19 patients engendered massive concern worldwide. Comorbidities including diabetes, cancer, steroid-based medications, long-term ventilation, and increased ferritin serum concentration in COVID-19 patients trigger favorable fungi growth that in turn effectuate mucormycosis. The necessity of FTR1 gene-encoded ferrous permease for host iron acquisition by fungi has been found in different studies recently. Thus, targeting the transit component could be a potential solution. Unfortunately, no appropriate antifungal vaccine has been constructed as of yet. To date, mucormycosis has been treated with antiviral therapy and surgical treatment only. Thus, in this study, the FTR1 protein has been targeted to design a convenient and novel epitope-based vaccine with the help of immunoinformatics against four different virulent fungal species. Furthermore, the vaccine was constructed using 8 CTL, 2 HTL, and 1 LBL epitopes that were found to be highly antigenic, non-allergenic, non-toxic, and fully conserved among the fungi under consideration. The vaccine has very reassuring stability due to its high pI value of 9.97, conclusive of a basic range. The vaccine was then subjected to molecular docking, molecular dynamics, and immune simulation studies to confirm the biological environment's safety, efficacy, and stability. The vaccine constructs were found to be safe in addition to being effective. Finally, we used in-silico cloning to develop an effective strategy for vaccine mass production. The designed vaccine will be a potential therapeutic not only to control mucormycosis in COVID-19 patients but also be effective in general mucormycosis events. However, further in vitro, and in vivo testing is needed to confirm the vaccine's safety and efficacy in controlling fungal infections. If successful, this vaccine could provide a low-cost and effective method of preventing the spread of mucormycosis worldwide.