Disseminated Mucormycosis in a patient on long term immunosuppression: Severe fungal infections as multi-system disorders

Introduction: Mucormycosis is a rare, severe fungal infection with an incidence of 0.005 to 0.17 per million.1 but incidence has risen recently, particularly in the Asian subcontinent, due to use of immunosuppression for Covid19.2 Presentations can vary and are classified into: rhino-orbito-cerebral, pulmonary, cutaneous, disseminated, renal and gastrointestinal. Risk factors include diabetes, immunosuppression, iron overload, malnutrition, and prematurity.1,3 Although mucormycosis has an extremely high mortality rate and disseminated infection is usually fatal, treatment options exist if diagnosed early and surgical debridement may be curative. Objective(s): We present a case of mucormycois in a female patient in her 40s who was immunosuppressed with methotrexate for rheumatoid disease. This case is discussed to increase awareness of critical illness caused by opportunistic invasive fungal infections in immunosuppressed patients and promote timely identification and management. Method(s): We detail the clinical context and management of a patient with mucormycosis and discuss relevant literature. Result(s): A female patient in her 40s who had been experiencing upper respiratory tract symptoms for several weeks, including cough and brown sputum, was admitted with a presumptive diagnosis of methotrexate toxicity after a full blood count performed by the general practitioner demonstrated pancytopenia. Initially, National Early Warning System 2 score (NEWS2) was 2 but became intensely hypertensive during blood transfusion and then profoundly shocked with an escalating NEWS2. Broad-spectrum antibiotics and fluconazole were commenced for neutropenic sepsis and the patient was referred to critical care in multiple organ failure. Computerised tomography (CT) scan of the chest, abdomen and pelvis showed "left upper lobe consolidation, which with neutropenia might represent an angioinvasive aspergillosis". She had multiple areas of skin discolouration and desquamation. Haematology and Infectious Diseases opinions were sought, and a bone marrow biopsy was performed which showed severe toxic effects consistent with sepsis/life threatening infection. Progressive proptosis was noted, and CT scan of her head was requested. Sadly, she was never stable enough for CT transfer. Beta D Glucan and aspergillus antigen serology was negative. Broncho-alveolar lavage demonstrated Candida albicans and then, later, Rhizopus arrhizus was isolated and anti-fungal treatment changed to voriconazole and then amphotericin B. Upon reviewing the notes in light of the positive culture for Rhizopus, the patient had likely been exhibiting symptomatic Mucormycosis sinus infection for some time prior to this admission with disseminated infection. The patient's condition continued to deteriorate and she sadly died. Conclusion(s): * The Early Warning Score significantly underestimated how unwell the patient was upon arrival in ED, a systems-based assessment would have demonstrated that the patient had multiple system dysfunction and significant potential to deteriorate suddenly despite having stable observations * The methotrexate level has no clinical value in diagnosing or refuting a diagnosis of methotrexate toxicity * A full examination of the immunosuppressed patient including ENT is a necessity when searching for a source of infection * Invasive fungal infections can cause multi-system symptoms and atypical presentations * As a greater proportion of patients have received systemic immunosuppression for Covid-19, vigilance for more unusual pathogens, including Mucormycosis by clinicians is advised.

Mucormycosis Metabolic Network Modeling: A Constraint-Based Approach

Mucormycosis is an uncommon illness caused by the fungus Mucorales. India was concerned about mucormycosis and COVID-19 in 2020. To minimize morbidity and occurrence, prevent, and treat mucormycosis, analysis is required. Combining systems biology and bioinformatics-based mucormycosis research, this study simulates the Genome-scale metabolic model (GSSM) of a Rhizopus oryzae strain for the comprehension of the organism's metabolic mechanism. Several key metabolic pathways for a mucormycosis-causing fungus strain were identified in research publications and targeted for inclusion in a model of a metabolic network. Based on the Flux Balance Analysis (FBA) approach, an integrated model of these pathways at the scale of the genome's metabolism was developed and appropriate constraints were applied to the numerous reactions involved in Rhizopus oryzae's metabolism using the COBRA package in MATLAB. Hence, unique evidence of pharmacological targets and biomarkers that may function as diagnostic, early analytic, and therapeutic agents in mucormycosis was discovered. Our study investigates the role of key metabolites in the model by applying constraints and altering fluxes, which provides valuable candidates for drug development. . © 2023 IEEE.

Extra-Rhino Cerebral Manifestations of Mucormycosis in Head and Neck Region: An Insight.

Mucormycosis is a potentially life-threatening fungal infection with a high mortality rate. The difficulty and delay in diagnosis due to its rarity usually results in a poor prognosis. Most common site in head and neck region is the nose and paranasal sinuses. However there are other very unusual areas in head and neck region where mucormycosis is encountered. Knowledge of these unusual areas is must and can save a patient's life. To elaborate and highlight the unusual areas in head and neck region where mucormycosis can mimic other common diseases. This retrospective study was done from May 2010 to May 2019 over a period of 9 years. All histopathologically confirmed cases of Head and Neck mucormycosis were evaluated and data analyzed. Total 35 cases of head neck mucormycosis were encountered from May 2010 to May 2019 over a period of 9 years. Out of which 30 cases (85.72%) were of rhino-orbito-cerebral mucormycosis and 5 cases (14.28%) were EXTRA rhino-orbito-cerebral mucormycosis in head neck region. Mucormycosis at such unusual sites can cause diagnostic dilemma for the treating doctor. Clinical knowledge with anticipation is a must for success in treatment of mucormycosis in unusual places in head neck region especially when normal looking diseases does not respond to usual treatment.

Photodynamic inactivation of Rhizopus oryzae - in vitro study

During the COVID-19 pandemic, several complications arose in infected patients, one of them being mucormycosis, which is an extremely aggressive fungal disease with a high mortality rate, especially in patients with compromised immune systems. Most cases of mucormycosis are caused by the fungus Rhizopus oryzae, also known as black fungus, with 90% of cases affecting the rhinocerebral site. The treatment tools used are based on high doses of amphotericin B and posaconazole, associated with surgical resections when possible. However, even with aggressive antifungal treatment, the estimated attributable mortality rate is high [1]. In the absence of surgical debridement of the infected tissue, antifungal treatment alone is not curative. So there is a need for development of adjuvant treatments. Antimicrobial Photodynamic Therapy (aPDT) may constitute an auxiliary therapeutic option for mucormycosis [2]. Due to the lack of reports on the photodynamic inactivation of R. oryzae, we investigated different protocols Photodithazine (PDZ) as a photosensitizer. The response on the fungus growing rate under distinct treatment parameters as photosensitizer concentration, incubation time, and association with surfactant, will be presented for both white and black hyphal phases, and infective spore phase. Preliminary results show the potential use of photodynamic therapy for the inactivation and growth control of the R. oryzae.Copyright © 2023

Mucormycosis in patients with COVID-19 in Russia: the results of a prospective multi-center study.

We present the results of a prospective multicenter study of risk factors, etiology, clinical features, and treatment outcomes for mucormycosis in patients with COVID-19 (COVID-M) in the Russian Federation. The study included 60 adult patients with COVID-M. To analyze risk factors for COVID-M, we conducted a case-control study. The control group included 60 adult patients with COVID-19 without mucormycosis. To analyze the clinical manifestations of COVID-M, we created a control group of hematological patients with mucormycosis examined in 2011-2020. In patients with COVID-19, the risk of developing mucormycosis was significantly increased with diabetes mellitus (OR=49) and overweight (OR=4,75), as well as with the use of high (>=100 mg per day for prednisolone) doses of glucocorticosteroids (OR= 4,762), especially >=10 days (OR=25,4). The main localization of mucormycosis in patients with CO-VID-19 was the paranasal sinuses (95%) and the orbit (68%). Involvement of >=2 organs was identified in 70% of patients. The main causative agents of mucormycosis were Rhizopus arrhizus (43%) and unidentified mucormycetes (36%). 90-days overall survival of patients with mucormycosis and COVID-19 - 71%. The stay in the ICU (p=0,01), the use of mechanical ventilation (p=0,0481), the presence of CVC (p=0,049), CNS damage (p=0,016) and >= 2 organs (p=0,048) significantly worsened the prognosis of the disease. The best prognosis was in patients who received antifungal therapy (p=0,03875) and surgical treatment (p=0,046).Copyright © 2022 Authors. All rights reserved.

Mucormycosis in patients with COVID-19 in Russia: the results of a prospective multi-center study.

We present the results of a prospective multicenter study of risk factors, etiology, clinical features, and treatment outcomes for mucormycosis in patients with COVID-19 (COVID-M) in the Russian Federation. The study included 60 adult patients with COVID-M. To analyze risk factors for COVID-M, we conducted a case-control study. The control group included 60 adult patients with COVID-19 without mucormycosis. To analyze the clinical manifestations of COVID-M, we created a control group of hematological patients with mucormycosis examined in 2011-2020. In patients with COVID-19, the risk of developing mucormycosis was significantly increased with diabetes mellitus (OR=49) and overweight (OR=4,75), as well as with the use of high (>=100 mg per day for prednisolone) doses of glucocorticosteroids (OR= 4,762), especially >=10 days (OR=25,4). The main localization of mucormycosis in patients with CO-VID-19 was the paranasal sinuses (95%) and the orbit (68%). Involvement of >=2 organs was identified in 70% of patients. The main causative agents of mucormycosis were Rhizopus arrhizus (43%) and unidentified mucormycetes (36%). 90-days overall survival of patients with mucormycosis and COVID-19 - 71%. The stay in the ICU (p=0,01), the use of mechanical ventilation (p=0,0481), the presence of CVC (p=0,049), CNS damage (p=0,016) and >= 2 organs (p=0,048) significantly worsened the prognosis of the disease. The best prognosis was in patients who received antifungal therapy (p=0,03875) and surgical treatment (p=0,046).Copyright © 2022 Authors. All rights reserved.

Case series of invasive lung infections by Aspergillus species and zygomycosis among post COVID-19 and post-transplant individuals.

Airborne pathogens like Aspergillus bring the lungs in the frontline for defense. Pulmonary diseases caused by Aspergillus species are broadly classified as aspergilloma, chronic necrotizing pulmonary aspergillosis, invasive pulmonary aspergillosis (IPA), and bronchopulmonary aspergillosis. Intensive care unit (ICU) admission is required for a large number of patients associated with IPA. It is not yet known whether patients with coronavirus disease 2019 (COVID-19) are at a similar risk for IPA as for influenza. However, usage of steroids plays a leading role in COVID-19. The family Mucoraceae includes filamentous fungi of the order Mucorales, causing a rare opportunistic fungal infection known as mucormycosis. The most commonly reported clinical presentations of mucormycosis are rhinocerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and others. Here, we report a case series of invasive pulmonary infection by various fungi like Aspergillus niger, Aspergillus fumigatus, Rhizopus oryzae, and Mucor species. Specific diagnosis was made based on microscopy, histology, culture, lactophenol cotton blue (LPCB) mount, and chest radiography and computed tomography (CT). To conclude, opportunistic fungal infections like those due to Aspergillus species and mucormycosis are most commonly associated with hematological malignancies, neutropenia, transplant patients, and diabetes. Therefore, early diagnosis by direct microscopy, surgical interventions, and effective antifungal treatment form the ideal management for invasive fungal infections like aspergillosis and mucormycosis, instead of waiting for the culture reports.

Diverse Presentation of Mucormycosis: A Post COVID Catastrophe - A Case Series

The corona virus disease-19 (COVID-19) produced by SARS-CoV-2 has resulted in a wide spectrum of illness ranging from mild to life-threatening conditions thus enhancing the incidence of opportunistic infections among individuals harbouring comorbidities. Mucormycosis is a dreadful angio-invasive opportunistic infection produced by zygomycetes fungus in an immunocompromised host. The clinical manifestations of mucormycosis include rhino-orbital-cerebral (ROC), pulmonary, cutaneous, gastrointestinal, with ROC accounting for around 40% of cases. Diabetes, neutropenia, iron overload, cancer, and organ transplant are all major culprits. Both Aspergillus and Candida have been identified as the primary fungal pathogens causing co-infection in COVID-19 preyed individuals. The most predominant variety, Rhizopus Oryzae, is responsible for roughly 60% of mucormycosis infections in humans, as well as 90% of the Rhino-orbital-cerebral (ROCM) variant. Mucormycosis is the most widespread ailment in India. Until lately, India was declared to be the world's diabetes capital, with the second-largest number of people suffering from diabetes mellitus (DM). Diabetes has been recognised as the most common predictive marker for mucormycosis which explains the dramatic rise in Mucor cases in India lately particularly during second wave of COVID-19. The inflammatory onslaught caused by COVID 19 has debilitated patients' immune systems, making individuals vulnerable to mucormycosis outbreaks. The possible explanation that Mucorales spores appear to be expediting germination in people with COVID-19 is due to the perfect scenario of oxygen deprivation (hypoxia), hyperglycemia (steroid-induced), acidic form of media (metabolic acidosis, diabetic ketoacidosis), increased iron levels (elevated ferritin), and significantly reduced phagocytic activity of white blood cells (WBC) due to immunosuppression (SARS-CoV-2 or steroid mediated or associated comorbidities). Copyright © 2022 International Medical Sciences Academy. All rights reserved.

COVID-19-associated disseminated mucormycosis: An autopsy case report.

BACKGROUND: Reports of mucormycosis, an infectious disease that commonly affects immunocompromised individuals, have increased during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Disseminated mucormycosis associated with COVID-19 is rare but fatal and is characterized by an aggressive clinical course and delayed diagnosis. Our report documents a case of disseminated mucormycosis after COVID-19 infection. This is a rare pathological autopsy report on COVID-19-associated mucormycosis. CASE SUMMARY: A 58-year-old man was transferred to our hospital with severe COVID-19 pneumonia. During treatment for acute respiratory distress syndrome, he developed intra-abdominal bleeding that required a right hemicolectomy and ileostomy for hemostasis. The ileostoma and surgical wound developed necrosis followed by sepsis and multi-organ failure, which led to death. An autopsy revealed multiple thrombi associated with Rhizopus oryzae infection, which led to the necrosis of multiple infected organs. CONCLUSION: Early suspicion and diagnosis followed by treatment are keys to better outcomes of mucormycosis in patients with severe COVID-19.

Potential inhibitory activity of phytoconstituents against black fungus: In silico ADMET, molecular docking and MD simulation studies.

Mucormycosis or "black fungus" has been currently observed in India, as a secondary infection in COVID-19 infected patients in the post-COVID-stage. Fungus is an uncommon opportunistic infection that affects people who have a weak immune system. In this study, 158 antifungal phytochemicals were screened using molecular docking against glucoamylase enzyme of Rhizopus oryzae to identify potential inhibitors. The docking scores of the selected phytochemicals were compared with Isomaltotriose as a positive control. Most of the compounds showed lower binding energy values than Isomaltotriose (-6.4 kcal/mol). Computational studies also revealed the strongest binding affinity of the screened phytochemicals was Dioscin (-9.4 kcal/mol). Furthermore, the binding interactions of the top ten potential phytochemicals were elucidated and further analyzed. In-silico ADME and toxicity prediction were also evaluated using SwissADME and admetSAR online servers. Compounds Piscisoflavone C, 8-O-methylaverufin and Punicalagin exhibited positive results with the Lipinski filter and drug-likeness and showed mild to moderate of toxicity. Molecular dynamics (MD) simulation (at 300 K for 100 ns) was also employed to the docked ligand-target complex to explore the stability of ligand-target complex, improve docking results, and analyze the molecular mechanisms of protein-target interactions.

Post Covid-19 mixed fungal orbito-pansinusitis caused by Rhizopus Oryzae and Exophiala Jeanselmei-review and reports

We report a rare case of mixed fungal orbito-pansinusitis caused by Rhizopus oryzae and Exophiala jeanselmei in post-COVID-19 individuals. A 65-year-old patient was COVID-19-positive and treated as per the protocols. Following recovery after 3 weeks presents to the otorhinolaryngology outpatient department with complaints of nasal obstruction, stuffiness, pain over the maxilla, occasional fever spikes, and swelling over eyelids. He was diagnosed with a case of orbito-pansinusitis mucormycosis based on magnetic resonance imaging, nasal endoscopy, and microbiological findings. Intravenous (IV) fluconazole and amphotericin B were the conservative management initially followed by surgical debridement later. There was minimal residual deformity after patient recovery. Generally, secondary to immunosuppression or debilitating diseases leads to mucormycosis. The mode of entry for molds and spores of zygomycetes are through the respiratory tract through the nose and then reaches the sinuses, orbit, and intracranial structures. Hence, a good prognosis and to reduce morbidity by zygomycosis can be achieved by early clinical diagnosis, direct smears, and proper interventions. The diagnosis of fungal infections at the earliest is very important because the therapeutic management of fungal infection is quite challenging, especially in the case of R. oryzae and E. jeanselmei with immunocompromised state. The prophylactic drugs, steroids, and immunosuppressants for the treatment of COVID-19 should not be misused and must be used as per protocol and guidelines judiciously. © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Alternate Special Stains for the Detection of Mycotic Organisms in Oral Cyto-Smears-A Histomorphometric Study.

In the wake of the COVID-19 pandemic, fungal infections of the maxillofacial region have become prevalent, making their accurate diagnosis vital. Histopathological staining remains a simple, cost-effective technique for differentiation and diagnosis of the causative fungal organisms. The present study aims to evaluate the staining efficacy of Periodic Acid-Schiff (PAS), Alcian Blue, Safranin-O and Gomori's Methenamine Silver (GMS) on fungal smears. This research work also attempts to study the morphometric characteristics of Candida albicans, Aspergillus flavus, Rhizopus oryzae. Candida albicans, Aspergillus flavus and Rhizopus oryzae, 10 smears each, were stained using PAS, Alcian Blue, Safranin-O and GMS. The morphological characteristics and staining efficacy were examined, and semi-quantitative scoring was performed. Candida albicans, Aspergillus flavus and Rhizopus oryzae were stained for the first time with Safranin-O. The morphometric traits were then analyzed using an image analysis software. Safranin-O provided the most reliable staining efficacy amongst the stains and optimum morphological definition for all three organisms. Safranin-O was found to be superior to PAS and GMS, ensuring detection of even the most minute mycotic colonies. The hyphae of Aspergillus flavus to be the largest, and the spores and fruiting body of Rhizopus oryzae were found to be the largest amongst the three organisms compared. Early and accurate diagnosis of fungal infections can significantly reduce morbidity in orofacial fungal infections.

COVID-19-Associated Mucormycosis: An Opportunistic Fungal Infection. A Case Series and Review.

BACKGROUND: A surge in COVID-19-associated mucormycosis cases has been observed during the second wave of COVID-19 in summer of 2021. Most cases were reported from India. The Delta variant (B.1.617.2) was the most common variant circulating at that time. Mucormycosis is an opportunistic angioinvasive fungal infection with high morbidity and mortality. METHODS: We present 10 cases of COVID-19-associated rhino-orbital and rhino-orbital-cerebral mucormycosis managed in a secondary hospital in Oman. RESULTS: The median time for developing mucormycosis was two weeks after COVID-19 diagnosis. All patients were newly diagnosed or already known to have poorly controlled diabetes mellitus. Five patients received corticosteroid therapy for COVID-19. Three patients had severe COVID-19 and died of severe acute respiratory distress syndrome and septic shock. Another three patients died of advanced mucormycosis and cerebral involvement. Despite aggressive medical and surgical intervention, the mortality rate was 60% (6/10). CONCLUSION: Mucormycosis is an aggressive opportunistic infection with high morbidity and mortality that requires prompt recognition and urgent intervention. Uncontrolled blood sugar, the use of corticosteroids, and immune dysfunction due to COVID-19 are all important risk factors for development of mucormycosis. Worse outcomes are associated with poor glycemic control despite aggressive medical and surgical interventions.

Mucormycosis and COVID-19: A Dual Curse

Mucormycosis is a serious, but rare opportunistic, invasive and life-threatening fungal infection primarily caused by Rhizopus arrhizus with very high case fatality. Recently, its alarming rise in the number among COVID-19 patients mostly with uncontrolled diabetes and those who received excessive administration of steroids for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has raised interest among the scientific community to learn more about the said disease. The current review describes, its epidemiology, clinical presentation, risk factors, warning signs, diagnostic test and available preventive and treatment modalities for its effective management.

First Molecular Identification of Three Clinical Isolates of Fungi Causing Mucormycosis in Honduras.

Mucormycoses are rare but serious opportunistic fungal infections caused by filamentous organisms of the order Mucorales. Here we report the first molecular identification of Rhizopus oryzae (heterotypic synonym Rhizopus arrhizus), R. delemar, and Apophysomyces ossiformis as the etiological agents of three cases of severe mucormycosis in Honduras. Conventional microbiological cultures were carried out, and DNA was extracted from both clinical samples and axenic cultures. The ITS ribosomal region was amplified and sequenced. Molecular tools are suitable strategies for diagnosing and identifying Mucorales in tissues and cultures, especially in middle-income countries lacking routine diagnostic strategies.

Targeting mucormycosis polyprotein (RVT_1 region) through antifungal phytochemicals: An in-silico perspective

Mucormycosis has become a global issue due to its potential to infect and destroy organs, as well as its high fatality rate. Co-infecting with Covid 19 or when infecting after Covid 19, it becomes more lethal. Several antifungal medicines have been utilized to treat this illness, but they come with a slew of dangerous side effects. Hence, using various computational tools;the current study was attempted to determine several antifungal plant metabolites that can act as inhibitory agents of Rhizopus oryzae, which is responsible for 70% of mucormycosis cases. In total, 56 antifungal plant metabolites were evaluated against Rhizopus oryzae polyprotein (RVT_1 region). Four metabolites, i.e., emetine, jatrorrhizine, isoboldine, and 6-a-hydroxymedicarpin showed maximum binding affinity with the targeted polyprotein (RVT_1 region) according to the lowest global binding energy and binding energy. The fungal protein's critical binding sites and drug surface hotspots were uncovered. The best candidates were gone through an ADME (absorption, distribution, metabolism, and excretion) analysis to observe their drug profiles. According to the findings, none have any side effects that could interfere with their drug likeness efficiency as well as no significant toxic effects and allergenicity were found. The majority of the target classes for proposed drug candidates were enzyme groups (e.g., oxidoreductase, family a g protein-coupled receptor, enzyme, protease). Furthermore, emetine and jatrorrhizine have been proposed to have inhibitory potency against covid 19 in several studies. Hence, we strongly propose additional in vivo trials in order to experimentally validate our findings, based on the optimistic results.

COVID-19-associated-mucormycosis: possible role of free iron uptake and immunosuppression.

COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.

A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update.

BACKGROUND: COVID-19 disease may be associated with a wide range of bacterial and fungal infections. We report a patient with COVID-19 infection who developed rhino-facial mucormycosis during treatment with corticosteroids. CASE PRESENTATION: A 59-year-old non-diabetic male patient was admitted with a diagnosis of COVID-19 based on positive RT-PCR and CT of the lungs. Due to sever lung involvement, he was treated with methylprednisolone. The patient was re-admitted to hospital, due to nasal obstruction and left side facial and orbital swelling, several days after discharge. In sinus endoscopic surgery, debridement was performed and the specimens were sent to pathology and mycology laboratories. A nasal biopsy showed wide hyphae without septa. The sequenced PCR product revealed Rhizopus oryzae. Despite all medical and surgical treatment, the patient died. In addition, the characteristics of patients with COVID-19-associated mucormycosis were reviewed in 44 available literatures. In most studies, diabetes mellitus was the most common predisposing factor for mucormycosis. CONCLUSION: Our report highlights the need for assessing the presence of mucormycosis in patients with COVID-19 and also it shows that physicians should consider the potential for secondary invasive fungal infections in COVID-19 cases.