COVID-19 and Mucormycosis

In early December 2019, several cases of pneumonia of unknown etiology were reported from Wuhan, Hubei province, China. The disease resembles severe acute respiratory syndrome coronavirus (SARS CoV) of 2012 and was subsequently named SARS CoV-2 causing the 2019-novel coronavirus disease (COVID-19) by the World Health Organization (WHO). The first case of COVID-19 in India was reported on January 30, 2020. In the first wave, daily cases peaked in mid-September 2020 and began to drop by January 2021. However, a second wave beginning in March 2021 was experienced which was much larger than the first, with extreme shortages of hospital beds, oxygen cylinders, and other medicines including vaccines in parts of the country. In the second wave, an association of COVID-19 patients with mucormycosis further complicated the situation. COVID-19 associated mucormycosis (CAM) has been increasingly reported particularly among patients with uncontrolled diabetes. An increase in CAM cases could be probably due to immunosuppression caused by the use of steroids, other immunomodulators like tocilizumab. Rhino-orbitalcerebral mucormycosis is the most common presentation. The most common causative agent isolated is Rhizopus arrhizus. Simple KOH examination with broad, ribbon-like, aseptate hyphae that branch at right angles is diagnostic of mucormycosis. This can be further confirmed by culture examination. However, newer tests like MALDI-TOF for species identification are also being explored. The main treatment modality is surgical debridement, removing all the infected, dead, and necrotic tissue followed by simultaneous administration of antifungal antibiotics in the form of Amphotericin B. Liposomal amphotericin B is the drug of choice, however, if not available, amphotericin B deoxycholate, posaconazole, and isavuconazole can be given for the treatment of CAM. Prognosis and clinical improvement depend upon the stage of disease, the surgical management as well as the availability and administration of antifungal drugs. In media, mucormycosis is being projected as black fungus throughout this pandemic, though it is a misnomer and should not be used in the medical literature. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.

The battle against fungi: lessons in antifungal stewardship from COVID 19 times

The COVID-19 pandemic has highlighted the detrimental effect of secondary pathogens in patients with a primary viral insult. In addition to superinfections with bacterial pathogens, invasive fungal infections were increasingly reported. The diagnosis of pulmonary fungal infections has always been challenging; however, it became even more problematic in the setting of COVID-19, particularly regarding the interpretation of radiological findings and mycology test results in patients with these infections. Moreover, prolonged hospitalization in ICU, coupled with underlying host factors. such as preexisting immunosuppression, use of immunomodulatory agents, and pulmonary compromise, caused additional vulnerability to fungal infections in this patient population. In addition, the heavy workload, redeployment of untrained staff, and inconsistent supply of gloves, gowns, and masks during the COVID-19 outbreak made it harder for healthcare workers to strictly adhere to preventive measures for infection control. Taken together, these factors favored patient-to-patient spread of fungal infections, such as those caused by Candida auris, or environment-to-patient transmission, including nosocomial aspergillosis. As fungal infections were associated with increased morbidity and mortality, empirical treatment was overly used and abused in COVID-19-infected patients, potentially contributing to increased resistance in fungal pathogens. The aim of this paper was to focus on essential elements of antifungal stewardship in COVID-19 for three fungal infections, COVID-19-associated candidemia (CAC), -pulmonary aspergillosis (CAPA), and -mucormycosis (CAM).

Higher proinflammatory responses possibly contributing to suppressed cytotoxicity in patients with COVID-19 associated mucormycosis.

INTRODUCTION: COVID-19 Associated Mucormycosis (CAM), an opportunistic fungal infection, surged during the second wave of SARS Cov-2 pandemic. Since immune responses play an important role in controlling this infection in immunocompetent hosts, it is required to understand immune perturbations associated with this condition for devising immunotherapeutic strategies for its control. We conducted a study to determine different immune parameters altered in CAM cases as compared to COVID-19 patients without CAM. METHODOLOGY: Cytokine levels in serum samples of CAM cases (n = 29) and COVID-19 patients without CAM (n = 20) were determined using luminex assay. Flow cytometric assays were carried out in 20 CAM cases and 10 controls for determination of frequency of NK cells, DCs, phagocytes, T cells and their functionalities. The cytokine levels were analyzed for their association with each other as well as with T cell functionality. The immune parameters were also analyzed with respect to the known risk factors such as diabetes mellitus and steroid treatment. RESULTS: Significant reduction in frequencies of total and CD56 + CD16 + NK cells (cytotoxic subset) was noted in CAM cases. Degranulation responses indicative of cytotoxicity of T cell were significantly hampered in CAM cases as compared to the controls. Conversely, phagocytic functions showed no difference in CAM cases versus their controls except for migratory potential which was found to be enhanced in CAM cases. Levels of proinflammatory cytokines such as IFN-γ, IL-2, TNF-α, IL-17, IL-1ß, IL-18 and MCP-1 were significantly elevated in cases as compared to the control with IFN-γ and IL-18 levels correlating negatively with CD4 T cell cytotoxicity. Steroid administration was associated with higher frequency of CD56 + CD16- NK cells (cytokine producing subset) and higher MCP-1 levels. Whereas diabetic participants had higher phagocytic and chemotactic potential and had higher levels of IL-6, IL-17 and MCP-1. CONCLUSION: CAM cases differed from the controls in terms of higher titers of proinflammatory cytokines, reduced frequency of total and cytotoxic CD56 + CD16 + NK cell. They also had reduced T cell cytotoxicity correlating inversely with IFN-γ and IL-18 levels, possibly indicating induction of negative feedback mechanisms while diabetes mellitus or steroid administration did not affect the responses negatively.

Fungal Diseases and COVID-19

The physiological factors of COVID-19 infection and the environmental factors of treatment have predisposed a larger patient population to fungal infections. In this review, we provide an overview of the three most frequently documented fungal infections associated with COVID-19: aspergillosis, mucormycosis, and candidemia. For all three secondary infections, we review the literature making efforts to determine the incidence of infection, physiological or environmental causes of co-infection with COVID-19, and the mortality of infection both with and without COVID-19. These infections vary in their etiology in association with COVID-19 infection, in addition to their recommended treatments and mortality. Ultimately, we demonstrate the importance of early diagnosis of secondary infections and the proper identification of fungal pathogens for treatment purposes, while also highlighting research gaps in this new field. © 2023 Nova Science Publishers, Inc.

Effectiveness of facial palsy protocol among patient with mucormycosis following COVID-19: A case study.

A 41-year-old male with a history of diabetes mellitus presented with right facial palsy post COVID-19 Associated Mucormycosis. A 4-week physiotherapeutic intervention; ice therapy, Mime therapy, Facial Soft Tissue Manipulation, and Facial Proprioceptive Neuromuscular Stimulation, showed improvement in the symptoms of patient and scores of House- Brackman Facial Grading Scale.

COVID-19 associated multisystemic mucormycosis from India: a multicentric retrospective study on clinical profile, predisposing factors, cumulative mortality and factors affecting outcome.

PURPOSE: The clinical course of COVID-19 has been complicated by secondary infections, including bacterial and fungal infections. The rapid rise in the incidence of invasive mucormycosis in these patients is very much concerning. COVID-19-associated mucormycosis was detected in huge numbers during the second wave of the COVID-19 pandemic in India, with several predisposing factors indicated in its pathogenesis. This study aimed to evaluate the epidemiology, predisposing factor, cumulative mortality and factors affecting outcomes among the coronavirus disease COVID-19-associated mucormycosis (CAM). METHODS: A multicenter retrospective study across three tertiary health care centers in Southern part of India was conducted during April-June 2021. RESULTS: Among the 217 cases of CAM, mucormycosis affecting the nasal sinuses was the commonest, affecting 95 (44%) of the patients, orbital extension seen in 84 (38%), pulmonary (n = 25, 12%), gastrointestinal (n = 6, 3%), isolated cerebral (n = 2) and disseminated mucormycosis (n = 2). Diabetes mellitus, high-dose systemic steroids were the most common underlying disease among CAM patients. The mucormycosis-associated case-fatality at 6 weeks was 14%, cerebral or GI or disseminated mucormycosis had 9 times higher risk of death compared to other locations. Extensive surgical debridement along with sequential antifungal drug treatment improved the survival in mucormycosis patients. CONCLUSION: Judicious and appropriate management of the predisposing factor and factors affecting mortality associated with CAM with multi-disciplinary approach and timely surgical and medical management can be much helpful in achieving a successful outcome.

Evaluation of environmental Mucorales contamination in and around the residence of COVID-19-associated mucormycosis patients.

Introduction: Recently, India witnessed an unprecedented surge of coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) cases. In addition to patient management issues, environmental Mucorales contamination possibly contributed to the outbreak. A recent study evaluated environment contamination by Mucorales in the hospital setting. However, a considerable number of CAM patients were never admitted to a hospital before the development of the disease. The present study, therefore, planned to evaluate Mucorales contamination of patients' residences. Methods: The residential environment of 25 patients with CAM living in north India was surveyed. Air samples were collected from indoor and immediate outdoor vicinity of the patients' residence and cultured on Dichloran Rose-Bengal Chloramphenicol (DRBC) agar with benomyl for selective isolation of Mucorales. Surface swab samples were also collected from the air coolers fitted in those residences and cultured on DRBC agar. The isolates were identified by phenotypic and genotypic methods. Amplified fragment length polymorphism (AFLP) was employed to evaluate the genetic relatedness of the environmental and patients' clinical isolates. Results: The median spore count (mean ± SD, cfu/m3) of Mucorales in the air of patients' bedrooms was significantly higher than in the air in other rooms in those residences (3.55 versus 1.5, p = 0.003) or the air collected directly from the front of the air cooler (p < 0.0001). The Mucorales spore count in the environment did not correlate with either ventilation of the room or hygiene level of the patients' residences. Rhizopus arrhizus was isolated from the environment of all patients' residences (n = 25); other Mucorales species isolated were Cunninghamella bertholletiae (n = 14), Rhizopus microsporus (n = 6), Rhizopus delemar (n = 6), Syncephalastrum racemosum (n = 1), Lichtheimia corymbifera (n = 1), and Mucor racemosus (n = 1). Genetic relatedness was observed between 11 environmental isolates from the patients' bedrooms and respective clinical isolates from patients. Discussion: The study supported the view that the patients might have acquired Mucorales from the home environment during the post-COVID-19 convalescence period. Universal masking at home during patients' convalescence period and environmental decontamination could minimize exposure in those susceptible patients.

Are Unique Regional Factors the Missing Link in India's COVID-19-Associated Mucormycosis Crisis?

The exact cause of the disproportionate increase in COVID-19-associated mucormycosis (CAM) cases in India remains unknown. Most researchers consider the major cause of India's CAM epidemic to be the conjunction of the COVID-19 pandemic and associated corticosteroid treatment with the enormous number of Indians with diabetes mellitus (DM). However, excess CAM cases were not seen to the same extent in the Western world, where diabetes is prevalent and corticosteroids are also used extensively for COVID-19 treatment. Herein, we hypothesize that previously overlooked environmental factors specific to India were important contributors to the country's CAM epidemic. Specifically, we propose that the spread of fungal spores, mainly through fumes generated from the burning of Mucorales-rich biomass, like cow dung and crop stubble, caused extensive environmental exposure in the context of a large population of highly vulnerable patients with DM and COVID-19. Testing this hypothesis with epidemiologic studies, phylogenetic analyses, and strategic environmental sampling may have implications for preventing future epidemics.

Incidence, cumulative mortality and factors affecting the outcome of COVID-19-associated mucormycosis from Western India.

PURPOSE: To report the incidence, cumulative mortality, and factors influencing the outcomes from a large series of COVID-19-associated mucormycosis (CAM) from western India. METHODS: Consecutive patients with CAM between March 1 and May 10, 2021, with a minimum follow-up of 1 month were included. We recorded the presence of diabetes, use of steroids, and need for non-invasive ventilation (NIV) from the case files. The features of orbital involvement, treatment administered, and outcomes, i.e., death, orbital exenteration, or recovery were noted. Cumulative probability of adverse outcomes, defined as either death or exenteration, was reported using survival analysis. RESULTS: We treated 67 cases of CAM and found an incidence of 13.6 cases per 1,000 patients post-moderate to severe COVID-19. Uncontrolled diabetes (90%) with ketoacidosis (40%) and prior systemic steroids (84%) were the strongest predispositions. The onset of CAM was 15.1 ± 9.5 days (range: 6-42 days) after recovery from COVID-19. The cumulative probability of an adverse outcome was 38% (95% confidence intervals [CI] = 23.7-56.9%) on day 20. The patients who required NIV during COVID-19 were at seven times higher risk of experiencing an adverse outcome (hazard ratios [HR] = 6.92, 95% CI = 2.9-16.2) while those who received amphotericin- -B had a 61% lower risk (HR = 0.39, 95% CI = 0.16-0.97). CONCLUSION: The current outbreak of CAM was seen predominantly in uncontrolled diabetics, especially with ketoacidosis and steroid intake. The cumulative probability of death or orbital exenteration was 38% at day 20 of the infection and those who required NIV and did not receive amphotericin-B were at a high risk of these outcomes.

COVID-19 Associated Mucormycosis: A Systematic Review from Diagnostic Challenges to Management.

The coronavirus disease 2019 (COVID-19) outbreak has caused significant destruction, claiming over three million lives worldwide. Post SARS-COV-2 invasion, immunosuppression with hyperglycemia and elevated ferritin levels along with steroidal treatment creates a perfect storm for opportunistic infections. There is increasing evidence of mucormycosis co-infection in COVID-19 patients, during or post-treatment. A worse prognosis, a late diagnosis, and limited guidelines of screening and management of COVID-19 associated mucormycosis have made healthcare professionals fear an epidemic alongside a pandemic. This review geographically reports cases of COVID-19 associated mucormycosis (CAM), evaluates characteristics, clinical manifestations, and outcomes of mucormycosis in COVID-19 active or recovered patients. It further describes preventive strategies and recommendations for optimal management therapy that can be adopted worldwide to curtail an impending threat to the healthcare system.