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Risk Factors for Mucormycosis in COVID-19 Patients
Abstract  Identifying several cases of opportunistic infections such as mucormycosis in coronavirus disease 2019 (COVID-19) patients across the world has become a new health challenge in such patients. Since opportunistic infections can exacerbate COVID-19 patients' status, it's vital to identify their risk factors so that they may be prevented, diagnosed, and treated as soon as possible. Viral, fungal, environmental and host factors may be responsible for appearing this situation because long hospital stays and impaired host immune system function due to viral infection and excessive usage of glucocorticoids in managing COVID-19 patients are the main risk factors increasing the chance to get mucormycosis in COVID-19 patients. Moreover, educating health care workers and considering the association between mucormycosis of the paranasal sinuses and different strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the cause of COVID-19 can help prevent invasive fungal sinusitis in COVID-19 patients. Keywords: Mucormycosis, Risk factor, COVID-19   Background  COVID-19 pandemic caused by a novel coronavirus, SARS-CoV-2, emerged in late 2019 in Wuhan, China, and soon spread throughout the world (1). As different factors like age, gender, co-morbidities, education status, and viral load play role in COVID-19 severity, SARS-CoV-2-infected patients reveal a wide range of clinical features from asymptomatic infection or mild upper respiratory tract symptoms to multiple organ failure (MOF) and even death (2). In COVID-19 patients especially those who are critically ill, bacterial or fungal opportunistic co-infections with worse outcomes and higher mortality rates have been reported and evolved into a new concern (3). Mucormycosis is an invasive fungal infection commonly caused by Rhizopus and Rhizomucor genus belonging to the Mucorales order. Immunocompromised people have higher risks of getting Mucorales infection and in several reports, these infections have been diagnosed concurrently with COVID-19 infection (4-6). During the last 2-3 months several reports show a wide range of concurrently mucormycosis (Black fungus’ disease) with COVID-19 infection (7) and recently it has been postulated in Iran among COVID-19 patients. The occurrence of this mycose in Covid-19 patients in Iran has caused its widespread coverage in the social media and social concerns. Inhalation of spores or inoculation of wounds may result in Mucorales infection (8, 9). Because of vascular invasion and tissue infarction, this aggressive infection leads to death in 50% of infected people and leaves survivors with severe long-term consequences such as ocular traumas (8). Severe and irreversible consequences effects of opportunistic infections, as well as frequent reports of mucormycosis in COVID-19, emphasizes the need of identifying risk factors for mucormycosis in COVID-19 patients and its prevention, diagnosis, and therapeutic strategies. So, in this study, we reviewed host, environmental, and microbial risk factors to make preventative decisions about opportunistic co-infections in COVID-19 and reduce their complications. SARS-CoV-2 TRANSMISSION SARS-CoV-2 is a highly transmissible zoonotic novel coronavirus with the reproduction number of 3.28 (10). Humans were initially exposed to SARS-CoV-2 at Wuhan's Huanan seafood market and while the intermediate host of SARS-CoV-2 is unknown, bats are considered as natural reservoirs of SARS-CoV-2 due to the high sequence homology of their coronavirus strains with SARS-CoV-2 (11). As a result of the rapid spread of SARS-CoV-2 to over a hundred nations around the world, on March 11, 2020, its disease (COVID-19) was declared a pandemic by the world health organization (12). SARS-CoV-2 may transmit among humans and even from humans to animals in different ways. Notably close contact with respiratory droplets. and airborne transmission routes are the major ones (2, 13). As these transmission routes accelerate transmission from a small number of infected cases to many other people in indoor crowded spaces with poor ventilation, keeping social distancing and following health protocols are recommended (14). Other forms of transmission like fomite transmission and fecal-oral ways also have been reported in several studies and emphasize the importance of adhering to health rules (15, 16). Although 80% of COVID-19 patients are asymptomatic or have only mild upper respiratory symptoms, in 20% of cases pneumonia is followed by fever, cough, shortness of breath, nausea, and even acute respiratory distress syndrome (ARDS) as well as MOF (17). The rising incidence of fatal coinfections like mucormycosis in patients with COVID-19 is now becoming another challenge for health systems (3). MUCORMYCOSIS AND ITS CLINICAL FEATURES Human zygomycosis is caused by two Zygomycetes orders: Mucorales and Entomophthorales. Mucorales are divided into six families, each of which can cause cutaneous or deep infections known as mucormycosis in humans, particularly those who are immunocompromised (18). Oral, nasal, and cutaneous routes are possible forms of mucormycosis transmission and as it can’t spread between people or between people and animals it is not contagious (19). Inhaling fungal spores that are commonly found in soil, plants, and decaying fruits in the environment causes individuals to get lung/sinus mucormycosis. A skin infection also can arise after the fungus entry to the skin through a burn blister, or other types of skin injury (8, 9, 20). As fungus can spread through the bloodstream and invade other tissues, mucormycosis majorly characterized by vascular invasion, and is categorized into six groups of rhinocerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and rare presentations as a result of thrombosis and tissue infarction/necrosis of particular anatomic sites (21).  The most common form of mucormycosis is rhinocerebral involvement, which affects the sinuses, nose, eyes, and brain (22). The symptoms could be different due to the infected site but facial pain, headache, jaw pain, blurring of vision, double vision and cough, dyspnea, fever, blackened skin lesions on the nasal bridge or upper inside of the mouth, are common signs and symptoms of mucormycosis but a conclusive diagnosis requires histology examination and microbiological investigations (23). The major therapeutic techniques for slowing fungal invasion are antifungal medicines and rigorous surgical debridement of the infected region (24). Despite the use of various therapeutic approaches, the death rate for mucormycosis varies depending on the patient's underlying illnesses, stage of infection, fungus species, and affected anatomical location, but the overall mortality rate is reported to be 50% (25). Because of the high mortality rate, long-term consequences of aggressive therapeutic surgeries, and rising prevalence of mucormycosis in COVID-19 patients, assessing mucormycosis risk factors can help in improving more timely preventative, diagnostic, and therapeutic strategies for this time-sensitive opportunistic infection. HOST RISK FACTORS The following are key host risk factors that increase mucormycosis susceptibility in COVID-19 patients. Corticosteroid usage Glucocorticoids are often used to manage inflammatory and autoimmune diseases. They have also been demonstrated to enhance the survival rate in hypoxemic COVID-19 patients in the absence of specific and effective anti-COVID-19 medications. Due to the beneficial survival effects, inexpensiveness, and wide accessibility of glucocorticoids, they have been used with other interventions such as remdesivir, tocilizomab, and mechanical ventilatory support for managing COVID-19 patients (26). However, glucocorticoids suppress both the innate and adaptive immune systems and increase the risk of infections especially opportunistic ones by suppressing pro-inflammatory mediators, impairing immune cell migration, and phagocytic utility, and up-regulating anti-inflammatory factors (27). They also induce hyperglycemia by prompting insulin resistance that facilitates germination of Mucorales spores and worsens the infection. 76.3% of COVID-19 individuals diagnosed with mucormycosis had a history of corticosteroid usage (28), so there is a need to limit excessive administering and usage of glucocorticoids in COVID-19 patients. Immunocompromising states Owing to strong immune system functionality, healthy people appear to have a low chance of improving mucormycosis. Phagocytes of the innate immunity are the first line of defense when the spores enter the body and then the adaptive immune system supports limiting this invasive fungal infection (29). As in COVID-19 patients, there is a reduction in the cluster of differentiation CD4 positive and CD8 positive T cell levels and impaired innate immune responses secondary opportunistic fungal infections are common to be diagnosed (28). Pre-existing hereditary or acquired immunodeficiencies in COVID-19 patients also can elevate the risk of mucormycosis in them (30). Diabetes  Diabetes mellitus is a group of metabolic syndromes marked by persistent hyperglycemia caused by impaired insulin production, activity, or both (31, 32). Apart from the conventional consequences of diabetes like neuropathy or nephropathy, its effects on T cell response, inflammatory cytokines, neutrophil function, and humoral immune activity are associated with immunosuppression (33). Diabetes is one of the risk factors for COVID-19 severity which prolongs the hospitalization and recovery period and increases the probability of immunosuppressive medication for patients with moderate to severe forms of COVID-19 (34, 35). Due to these reasons, secondary infections have a significantly higher probability of developing in diabetic COVID-19 patients with or without diabetic ketoacidosis. Mucormycosis is observed to be more common in people with uncontrolled diabetes and hyperglycemic conditions. In a study reported by Dora E Corzo-León et al in 2017, 68% of patients with mucormycosis were diabetics (36). Malignancy Cancer is a genetic disorder that is eventually the outcome of environmental circumstances. Mutations in DNA, especially in proto-oncogenes or tumor suppressor genes’ regions can lead to uncontrolled proliferation of cells (37). Cancer cells can modulate the immunological responses with many strategies like spreading into the bone marrow and impairing white blood cell proliferation. Even cancer therapies such as chemotherapy, radiotherapy, and high-dose corticosteroids can potentially eliminate the immune response (38). Because neutrophils are important in the host defense against Mucorales, cancer or chemotherapy-induced neutropenic patients are more likely to develop mucormycosis (39). Furthermore, since the onset of severe forms of COVID-19, which are linked to long-term hospital stays and immuno-suppressive treatments, is more common in cancer patients focused susceptibility to clinical status is essential (2, 40). Malnutrition Malnutrition is defined as an imbalance between the required and received nutrients It can be classified as protein-energy malnutrition or micronutrient deficiency that increases susceptibility to a variety of infections and typically delays recovery (41). It has been reported that vitamin B12, folic acid deficiency (micronutrient deficiency), or severe protein-calorie malnutrition (protein-energy malnutrition) can negatively impact immune responses and can be associated with neutropenia(42). According to the study, mucormycosis, particularly the gastrointestinal variant, has been linked to severe malnutrition (43). High body mass index The body mass index (BMI) is the most widely used metric for determining anthropometric height/weight features in humans. It is calculated by dividing weight in kilograms by height in meters squared. By BMI index people are divided into underweight (BMI under18.5kg/m2), normal weight (BMI 18.5 to 25), overweight (BMI 25 to 30), or obese (BMI over 30) (44). Obesity is a low-grade inflammatory disease that has been associated with poor immunological function as well as a reduction in lung capacity. So obese patients are at increased risk of aggravating bacterial, viral, and fungal respiratory infections due to the chronic systematic inflammation and the higher risk of immune exhaustion (45). Also, obesity is a key risk factor for comorbidities linked with COVID-19 severity, such as diabetes, hypertension, and cardiovascular disease (46). According to research compared with non-obese COVID-19 patients, obese ones were at 2.26-fold odds of developing severe forms of infection (p=0.006) and 1.51-fold odds of increased mortality (p=0.006) (47).  Other host factors Renal diseases, older age, and secondary infections are other risk factors for mucormycosis because of impaired immune system function and there have been reports of fatal occurrences of systemic mucormycosis associated with acute or chronic renal failures (48), as shown in Figure 1. ENVIRONMENTAL RISK FACTORS                                                                                        Crowding Although mucormycosis is not contagious as crowding is a major route of the transmission of respiratory infections and COVID-19, it can indirectly increase the mucormycosis rate by increasing the proportion of infected people and individuals with severe respiratory infections and decreased lung capacity (2). Weather Climatic conditions play an important role in increasing the risk of many pathogenic infections. In mucormycosis, the relationship between temperature and humidity has been investigated and it is more common in summer and fall than in winter or spring. According to studies the most prevalent season for the incidence of mucormycosis was winter and they have been justified this discrepancy by explaining that the winter in their studied regions was like autumn in other Middle Eastern nations (49).  Lack of information of health workers Proper and sufficient training is a critical aspect in preventing and quick diagnosis and treatment of mucormycosis. Poor education about caring for people with skin wounds such as burns and skin lesions as well as poor information about the potency of dust, soil, and even water for infecting people with Mucorales can lead to unconscious transmission and worsening disease status (2). Shortage of anti-fungal drugs Amphotericin B is an antifungal medication that is used to treat serious, life-threatening mucormycosis. Shortage of antifungal drugs in India has been led to an exacerbation of mucormycosis progression in COVID-19 patients. On the other hand, also a shortage of anti-fungal medications can lead to increased commuting that is one of the risk factors of COVID-19 and secondary infections (50).  Lack of oxygen supply Countries are struggling to provide medical oxygen due to the increased transmissibility of novel SARS-CoV-2 variants, the increased number of newly infected patients, and the requirement for oxygenation and ventilation for managing hypoxic COVID-19 patients. As hypoxia in COVID-19 patients can worsen their condition and cause immune system impairment. Hypoxia, as well as hyperglycemia and immunosuppression, gives mucormycosis the chance to thrive, and in vitro analysis showed suppression of fungal growth in hyperbaric oxygen conditions (51). One of the important points about hyperbaric oxygen therapy is humidification because hyperbaric oxygenation without humidification can cause damage to the inner lining of the lungs. This humidification should be done with frequently changing sterilized water because the non-sterilized water is potentially a source of mucormycosis (52). Other environmental factors As shown in figure 1, poor ventilation, poverty, and low hygiene practice especially in hospitals can lead to an increased risk of developing mucormycosis infection as well as COVID-19. MICROBIAL RISK FACTORS Microbial factors associated with developing mucormycosis in COVID-19 patients can be divided into viral and fungal factors. Viral factors There is some evidence for the association between SARS-CoV-2 strains and mucormycosis development. COVID-19 prevalence and severity are linked to parameters such as transmissibility, viral load, and the development of novel strains of SARS-CoV-2 such as delta ans delta plus strain of COVID-19 partidularly from india. Also it has been reported that the using of steroids such as prednisolone, antibiotics and some traditional medicine as a self-medication could play role for increasing opportunistic mycoses during the COVID-19 epidemic in corona patients. Beside above factors, complex immune dysregulation in COVID-19 patients with severe respiratory failure vould prepared suitable condition for invasive mycosis like mucormycosis and aspergillosis.These factors can eventually be associated with impaired immune system function, long-term hospitalization, and raised risk of secondary infections such as mucormycosis (2). Fungal factors  Mucorales have many characteristics that allow them to avoid recognition by the host immune system. Different species of opportunistic fungi like Mucorales, aspergillus (Mucor, Rhizomucor, Rhizopus, Saksenaea, Cunninghamella, Apophysomyces, Absidia, Aspergillus fumigates, A. flavous, A. tereus) woeldwidly are atmosphere microflora and therefore these species could be contaminated COVID-19 patients during inhalation as etiologic agents of invasive mycoses. Rapid growth of all these species in human tissues and phospholipase B secretion also considered as important factor for pathogenesis of these species in COVID-19 patients. According to research, they develop resistance to host innate immune system activity by compromising phagocytic activity. They can also proliferate in harsh settings such as hypoxia, and this increased fungal load can lead to more infracted tissues and organs (53), as shown in Figure 1. Conclusions It can be concluded that as mucormycosis has a close linkage to diabetes, using from cortone and conditions that modulate the immune system, identifying COVID-19 patients with existing risk factors for mucormycosis and reducing corticosteroids administration in non-vital conditions can help prevent, fast diagnosis and treatment of this opportunistic infection. Providing anti-fungal and oxygen supply and re-informing medical staff and individuals about transmission routes of Mucorales, caring for skin wounds especially burns are environmental factors limiting the prevalence of this infection. Eventually finding the role of viral factors of SARS-CoV-2 and Mucorales immune-pathogenesis can help reduce the mortality rate of mucormycosis in COVID-19 patients. Conflict of interest No potential conflict of interest relevant to this article was reported. Funding This study was supported by Tabriz University of Medical Sciences (project number 66458).                          Figure1: Risk factors for mucormycosis in COVID-19 patients. ·           . 2018 Oct;61(10):764-769.  doi: 10.1111/myc.12802. Epub 2018 Jul 2. Rhinocerebral mucormycosis, risk factors and the type of oral manifestations in patients referred to a University Hospital in Tabriz, Iran 2007-2017 Saeed Nezafati 1, Abdolhassan Kazemi 2, Kasra Asgari 1, Amir Bahrami 3, Behrooz Naghili 4, Javad Yazdani 1 DOI: 10.1111/myc.12802 PMID: 29896908         Kazemi A. A case report of Cutaneous Mucormycosis. Mash-had Medical Journal. 1998. Vol. 3. P: 21-24.   Nashibi R, Afzalzadeh S, Mohammadi M J, Yari A R, Yousefi F. Epidemiology and Treatment Outcome of Mucormycosis in Khuzestan, Southwest of Iran, Arch Clin Infect Dis. 2017 ; 12(1):e37221. doi: 10.5812/archcid.37221.   Nikakhlagh, S., Saki, N., Rafiee, A., Mohammadi, M., Shahrokhi, M. 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Obesity is Associated with Poor Covid-19 Outcomes: A Systematic Review and Meta-Analysis. Horm Metab Res. 2021;53(2):85-93. doi:10.1055/a-1326-2125. [PubMed:33395706]. 48.       Gupta KL, Radotra BD, Sakhuja V, Banerjee AK, Chugh KS. Mucormycosis in patients with renal failure. Ren Fail. 1989;11(4):195-9. doi:10.3109/08860228909054931. [PubMed:2485482]. 49.       Bartzokas CA. Relationship between the metereological conditions and the air-borne fungal flora of the Athens metropolitan area. Mycopathologia. 1975;57(1):35-8. doi:10.1007/BF00431176. [PubMed:1207718]. 50.       Mathew BP, Nath M. Recent approaches to antifungal therapy for invasive mycoses. ChemMedChem. 2009;4(3):310-23. doi:10.1002/cmdc.200800353. [PubMed:19170067]. 51.       Ferguson BJ, Mitchell TG, Moon R, Camporesi EM, Farmer J. Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev Infect Dis. 1988;10(3):551-9. doi:10.1093/clinids/10.3.551. [PubMed:3393782]. 52.       Barbet JP, Chauveau M, Labbe S, Lockhart A. Breathing dry air causes acute epithelial damage and inflammation of the guinea pig trachea. J Appl Physiol (1985). 1988;64(5):1851-7. doi:10.1152/jappl.1988.64.5.1851. [PubMed:3391888]. 53.       Katragkou A, Walsh TJ, Roilides E. Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect. 2014;20 Suppl 6(s6):74-81. doi:10.1111/1469-0691.12466. [PubMed:24279587].  
  • 413
  • 17 Feb 2022
Topic Review
Rheumatoid Arthritis Gene Therapy
Rheumatoid arthritis (RA) is a systemic inflammatory joint disease affecting about 1% of the population worldwide. Current treatment approaches do not ensure a cure for every patient. Moreover, classical regimens are based on nontargeted systemic immune suppression and have significant side effects. Biological treatment has advanced considerably but efficacy and specificity issues remain. Gene therapy is one of the potential future directions for RA therapy, which is rapidly developing. Several gene therapy trials done so far have been of moderate success, but experimental and genetics studies have yielded novel targets. As a result, the arsenal of gene therapy tools keeps growing. Currently, both viral and nonviral delivery systems are used for RA therapy.
  • 574
  • 13 Jul 2021
Topic Review
Resveratrol in Bone Regeneration
The natural polyphenol Resveratrol (RSV) claims numerous positive effects on health due to the well documented biological effects demonstrating its potential as a disease-preventing agent and as adjuvant for treatment of a wide variety of chronic diseases. Since several studies, both in vitro and in vivo, have highlighted the protective bone aptitude of RSV both as promoter of osteoblasts’ proliferation and antagonist of osteoclasts’ differentiation, they could be interesting in view of applications in the field of dentistry and maxillofacial surgery.
  • 422
  • 14 Jul 2021
Topic Review
Resveratrol Effects on Atherosclerosis Progression
The beneficial effects of a Mediterranean diet are due to the numerous active compounds in the food and, particularly, the high concentration of compounds with synergistically acting antioxidant properties. Resveratrol, a stilbenoid nonflavonoid phenol, is an antioxidant that is naturally produced by numerous plants as a defensive agent in response to attacks from pathogens, such as bacteria and fungi. Resveratrol has several effects on human health, including on the lipid profile, where it primarily downregulates the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, reducing the synthesis of cholesterol. Resveratrol also increases the expression of low-density lipoprotein (LDL) receptors in the liver, contributing to the reduction in the LDL-cholesterol levels. 
  • 331
  • 31 May 2023
Topic Review
Resveratrol and TGF-β Signaling Pathway
Resveratrol (Res) is a well-known natural product that can exhibit important pharmacological activities such as antioxidant, anti-diabetes, anti-tumor, and anti-inflammatory. An evaluation of its therapeutic effects demonstrates that this naturally occurring bioactive compound can target different molecular pathways to exert its pharmacological actions. Transforming growth factor-beta (TGF-β) is an important molecular pathway that is capable of regulating different cellular mechanisms such as proliferation, migration, and angiogenesis. TGF-β has been reported to be involved in the development of disorders such as diabetes, cancer, inflammatory disorders, fibrosis, cardiovascular disorders, etc. 
  • 581
  • 06 Jul 2021
Topic Review
Reporting Thyroid Cytology
The Italian SIAPEC-AIT 2014 classification, the 2017 Bethesda System for Reporting Thyroid Cytology (TBSRTC), the 2016 UK Royal College of Pathologists (RCPath) thyroid reporting system, and the 2019 Japanese reporting system for thyroid aspiration cytology (JRSTAC2019) represent the most widely used reporting systems among clinicians and pathologists for the purpose of cytologically diagnosing, estimating the potential risk of malignancy (ROM), and defining the most appropriate treatment for a patient with a thyroid nodule. Although all the systems use overlapping diagnostic categories and morphologic criteria, they differ on the basis of the criteria for inclusion in the cytologic categories, which may, in turn, affect the ROM of a given category and the clinical management of the patient, particularly with regard to the “indeterminate” categories. 
  • 482
  • 17 Sep 2021
Topic Review
Renowned Indian Doctors to appreciate this Doctor's Day
Renowned Indian Doctors to appreciate this Doctor's Day
  • 9
  • 01 Jul 2024
Topic Review
Renal Rehabilitation
Chronic kidney disease (CKD) is a global health problem. In patients with CKD, exercise endurance is decreased, especially as renal dysfunction advances. This is due to the combined effects of protein-energy wasting, uremic acidosis, and inflammatory cachexia, which lead to sarcopenia and are aggravated by a sedentary lifestyle, resulting in a progressive downward spiral of deconditioning.
  • 204
  • 29 Jan 2024
Topic Review
Remission in Type 2 Diabetes
Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are the most effective interventions to induce weight loss and by extension remission in patients with diabetes.
  • 522
  • 02 Dec 2022
Topic Review
Relationship between Vitamin D and Insulin Resistance
Vitamin D seems to be involved in infections, autoimmune diseases, cardiometabolic diseases, and cancer development. The relationship between vitamin D and insulin resistance has been a topic of growing interest. Low 25-hydroxyvitamin D (25(OH)D) levels appear to be associated with most of the insulin resistance disorders described to date. In fact, vitamin D deficiency may be one of the factors accelerating the development of insulin resistance. Vitamin D deficiency is a common problem in the population and may be associated with the pathogenesis of diseases related to insulin resistance, such as obesity, diabetes, metabolic syndrome (MS) and polycystic ovary syndrome (PCOS). An important question is the identification of 25(OH)D levels capable of generating an effect on insulin resistance, glucose metabolism and to decrease the risk of developing insulin resistance related disorders.
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  • 08 Aug 2023
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