|Year : 2021 | Volume
| Issue : 3 | Page : 267-271
Mucormycosis “Black Fungus” new challenge associated with COVID 19
Falah Hasan Obayes Al-Khikani
Department of Medical Microbiology, College of Medicine, Babylon University, Babylon, Iraq
|Date of Submission||29-May-2021|
|Date of Acceptance||20-Jul-2021|
|Date of Web Publication||7-Sep-2021|
Falah Hasan Obayes Al-Khikani
Department of Medical Microbiology, College of Medicine, Babylon University, Babylon
Source of Support: None, Conflict of Interest: None
Corona virus-19 disease (COVID-19), caused by SARS-Cov-2. What was initially considered to be another worldwide flu epidemic mostly affecting the respiratory system has now emerged as a multi-organ disease, the most common extra-pulmonary involved organs include the blood vessels, eyes, heart, gastrointestinal tract, liver, skin, and kidneys. A growing number of case reports and series describe opportunistic fungal infections in COVID-19 patients. Co-morbidities such as diabetes mellitus, coupled with immune dysfunction and use of steroids, are hypothesized as the main causes. More recently, many cases of mucormycosis “black fungus” have been reported, particularly in Asian countries such as India. Mucormycosis is a rare angio-invasive illness caused by the fungi Mucorales, which is often seen in immunecompromised patients. Rhino-orbitocerebral, cutaneous, disseminated, gastrointestinal, and pulmonary forms of this unusual fungal infection exist. COVID-19 and Mucormycosis, Risks factors associated with Mucormycosis in COVID 19, Immune system response to mucormycosis, fungal pneumonias can resemble COVID-19, as well as prevention of these fungal will be discussed in this review.
Keywords: SARS-Cov-2 virus, COVID-19, Mucormycosis, black fungus, opportunistic infection
|How to cite this article:|
Al-Khikani FH. Mucormycosis “Black Fungus” new challenge associated with COVID 19. Biomed Biotechnol Res J 2021;5:267-71
| Introduction|| |
Some opportunistic fungal infections that may be life threatening such as mucormycosis, aspergilosis, and candidiasis are more susceptible to be developed in certain viral pathogens such as COVID-19 because the immune systems are focusing fighting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The evidence of these infections is mucormycosis appeared in India recently that affect who recovered from COVID-19.
Angioinvasion, tissue necrosis, and thrombosis are characteristics of rapid filamentous growth of an invasive fungal infection called mucormycosis with very high mortality rate more than 50% due to many reasons as the failure of the human immune system to successfully clear the infection, the aggressive nature of the infection, as well as the resistance or poor therapeutics currently employed.,,
Mucormycetes are several different types of fungi that have the ability to cause mucormycosis such as Saksenaea, Syncephalastrum species, Mucor species, Cunninghamella bertholletiae, Apophysomyces, Absidia, and Rhizomucor.
Certain prescription antifungal drugs are used for the management of the serious mucormycosis. These drugs may take through the mouth such as isavuconazole and posaconazole, whereas other drugs are given by vein as amphotericin B that widely used to treat invasive fungal infection,, and management of pulmonary mycotic diseases.
In extreme situations, surgery to remove infected or dead tissue may be recommended to prevent the fungus from spreading. This may include removing disfiguring sections of the nose or eyes, but it is critical to treat this life-threatening infection. The most prevalent infections are rhinocerebral and pulmonary. The rapid onset of tissue necrosis is a hallmark clinical indication of mucormycosis [Figure 1].
| Mucormycosis and COVID-19|| |
Mucormycosis is a fungal infection that affects the sinuses and lungs after inhaling fungal spores in the air. This infection has a low frequency in the past, with cases documented mostly in people with uncontrolled diabetes. However, numerous hospitals across the India recently are reporting an elevating in infections of COVID-19-associated mucormycosis (CAM).
Because the COVID-19 virus entered the pancreas and raised blood sugar levels, which encouraged fungal growth, CAM was also documented in individuals who had recently been diagnosed with diabetes. The virus may be able to penetrate and then destroy insulin-producing cells because the pancreas, which regulates blood sugar, is high in angiotensin-converting enzyme 2 (ACE2). The ACE2 protein (ACE2) is an enzyme involved in blood pressure regulation. It is thought to be the virus's “entry point” into the host. The journal nature describes, among other things, the story of a young 18-year-old student, infected by his parents, but asymptomatic, reached a few days later by extreme fatigue and a feeling of thirst. The diagnosis is made: it is Type 1 diabetes.
Mucormycosis is an uncommon, invasive, and fungal opportunistic infection that can be life threatening. It is caused by contact with mucor mold, which can be found in soil, air, and even human noses and mucus. It erodes facial structures as it progresses through the respiratory tract.
Patients die within days of contracting the disease, and in other cases, doctors have had to remove eyes and upper jaws to prevent the life-threatening infection from spreading. The treatment of mucormycosis necessitates the collaboration of eye surgeons, ENT specialists, general surgeons, and neurosurgeons.
Rhinocerebral mucormycosis (sinus and brain) symptoms include one-sided facial edema, lesion, congestion in the nose or sinuses fever, as well as black sores on the nasal bridge or upper interior of the mouth that swiftly worsen. Mucormycosis, in contrast with some other fungal infection,, cannot be transmitted from one person to another or between humans and animals.
Risks factors associated with Mucormycosis in COVID-19
Mucormycosis is more common in coronavirus patients who have a weaker immune system and diabetes. Mucormycosis, which is uncommon in India, has emerged as a new problem for COVID-19 patients on steroid therapy and those with diabetes. Strong steroids used to treat severe COVID-19 can reduce immunity and increase sugar levels, thereby helping the spread of “black fungus” and increasing its frequency.
Along with a large number of COVID-19 patients, India has millions who suffer from diabetes, which might also raise the risk of a black fungus infection. Many treatments used to treat COVID-19 decrease the body's immune system, which would typically defend the individual from a fungal infection. The fungus also has an easier time establishing itself in India due to the heat and humidity as well as other countries [Table 1].
Corticosteroid therapy, diabetes, organ transplant, persistent neutropenia, prolonged, skin trauma, burns, or surgical wounds, iron overload, malnourishment, and intravenous drug use are all risk factors for mucormycosis.
Immune system response to mucormycosis
Immunosuppressive therapy inhibits immunological phagocytic effector activities, increasing susceptibility to invasive mold infections significantly. The epithelial cells met at the early sites of infection, such as alveoli and skin epithelia, constitute the first line of defense against Mucorales.
Epithelial damage extends to the basement membrane in patients at risk of invasive mucormycosis, exposing extracellular matrix proteins. The basement membrane proteins laminin and Type IV collagen have been demonstrated to attach to Rhizopus oryzae resting spores. Mucorales spores germinate and penetrate host cells after adhering to basement membrane proteins. Mucorales sporangiospores enter a latent, resting phase during germination and expand in size as well as metabolic activity before beginning filamentous growth.
When it comes to mucormycosis, the neutrophil–Mucorales interaction is fascinating, especially because of the risk factor of neutropenia., Neutrophils are not readily recruited to resting Mucorales spores in the lungs of intranasal-infected mice under healthy immunological circumstances. Intranasal injection of enlarged Rhizopus spores, on the other hand, results in a significant increase in neutrophil recruitment as well as inflammation.
Resting spores are resistant to phagocytic in a healthy immunological person. Swollen spores and hyphae, on the other hand, are vulnerable to destruction by macrophages and neutrophils. The recruitment and efficacy of macrophage and neutrophil activity against mucormycetes are significantly reduced when immunological suppression is present. Mucorales come into contact with platelets after penetrating the endothelium lining. Platelets bind to both mucormycete spores and hyphae in vitro, suppressing germination and causing hyphal injury. Dendritic cells are activated and promote adaptive immunity only in response to Mucorales hyphae.
The role of platelets in the innate immune response to Mucorales is of particular interest because thrombosis is a characteristic of mucormycosis. Platelets attach to both Mucorales spores and hyphae in vitro, and platelet activation and granule release are induced. Platelet contact suppresses fungal germination, lowers hyphal growth, and causes hyphal damage in Rhizopus, Mucor, Lichtheimia, and Rhizomucor. Platelets' capacity to prevent Mucorales from germinating shows that these innate immune effectors are advantageous. Excessive thrombosis, on the other hand, causes thrombocytopenia, which makes surgical intervention for diagnosis and therapy unfavorable.
T helper cells (Th) are noted to play a key role in the clearance of pathogenic fungi, which is mediated by the secretion of distinct cytokines. Interferon-γ secreted by Th-1 cells is regarding protective immunity against fungi, whereas Th-2 responses elevate susceptibility to fungal invasion.,, Th-17 cells are termed for their high levels of interleukin (IL)-17 production, and they have also been linked to mucosal protection against fungus. Mucorales-specific T-cells belonging to both CD4+ and CD8+ subsets were detected during infection in a study on mucormycete-specific T-cells in patients with invasive mucormycosis. Furthermore, Mucorales-specific T-cell cytokine profiles revealed that the most prevalent cytokines were IL-4 (Th-2 cytokine), IFN-, and IL-10 (Th-1 cytokine), followed by IL-17.
Quantitative (neutropenia) or qualitative abnormalities in phagocytic cell activity allow for uncontrolled hyphal development and invasive infection. Hyperglycemia and acidosis, in particular, are known to impede phagocytic cell chemotaxis and killing activity against Mucorales through weakening oxidative and nonoxidative processes.
Lymphopenia was found to be related with disease severity and progression in COVID-19, and it is decreased significantly in severe cases,,, suggesting that lymphocyte reduction decreases immunity to mucormycosis.
| Fungal Pneumonias Can Resemble Covid-19|| |
Some fungal illnesses have symptoms that are similar to COVID-19 such as fever, cough, and shortness of breath. To identify if a person has a fungal infection or COVID-19, laboratory testing is required. COVID-19 and a fungal infection might occur in the same patient.,
Fever, cough, and shortness of breath are symptoms of other fungal infections such as Valley fever (coccidioidomycosis), histoplasmosis, and blastomycosis, which are comparable to COVID-19 and bacterial pneumonias. These fungi can only be found in dirt. People are infected by inhaling fungi that are present in the air.
If COVID-19 testing is negative, clinicians should examine fungal pneumonias as a probable cause of respiratory disease. It is worth noting that these fungi can appear at the same time as COVID-19.,
In persons with severe COVID-19, scientists are still learning about aspergillosis (fungal infections caused by the fungus Aspergillus). In the past, scientists believed that aspergillosis only affected those who had very damaged immune systems. However, aspergillosis is becoming more common in people who do not have a compromised immune system but have severe viral respiratory infections such as influenza. COVID-19-related pulmonary aspergillosis has been reported in several recent studies (corrective and preventive action).,,
Patients admitted to the hospital with COVID-19 are at risk for healthcare-associated infections,, such as candidemia or Candida-related bloodstream infections., In individuals with severe COVID-19, fungal and bacterial resistant to antimicrobial therapy have also been reported.
However, outbreaks of Candida auris have been documented in COVID-19 units of acute care hospitals since the start of the epidemic. During the COVID-19 pandemic, modifications in normal infection control methods, such as reduced availability of gloves and gowns, or reuse of these items, and modifications in cleaning and disinfection techniques, may have contributed to these outbreaks.
Among 1988 patients with COVID-19 admitted to intensive care units, 7 had fungemia (7/1988; 0.03%), among whom six had CAC. The mortality of the limited CAC cases was high and greatly exceeded that of patients with COVID-19 but without candidemia (100% (6/6) vs. 22.7% (452/1988)). Patients with fungemia were Candida albicans, Candida glabrata, and Rhodotorula mucilaginosa.
| Prevention of Fungal Infections in Patients with Covid-19|| |
Mucormycosis is difficult to prevent because it is transferred by inhaling mold spores in soil, rotting vegetables or bread, or compost piles. Mucormycosis is usually not passed from person to person, but it is found in the environment.
The possibility of aspergillosis must be considered in patients with severe COVID-19 who have abnormal respiratory function, even if they do not have apparent risk factors for aspergillosis.
In patients with severe COVID-19 fungal co-infections, early detection, and surveillance for Candida and antifungal resistance diseases (e.g., C. auris, azole-resistant Aspergillus) are critical to minimizing death from COVID-19.
| Conclusions|| |
Mucormycosis is one of serious opportunistic infections and economic cost that can associated with COVID-19 infection. Much is stay unclear about the consequences of SARS-CoV-2 virus and its correlations with other diseases.
The use of steroid drugs for treating COVID-19 may partially explain the surge in these fungal infections, along with weakened immune systems from COVID-19; corticosteroids impair migration, ingestion, and engulfment activity in human macrophages. Hyperglycemia and acidosis have been shown to inhibit phagocytic cell chemotaxis and killing activity against Mucorales by weakening both oxidative and nonoxidative mechanisms.
Mucormycosis has a high mortality rate and can be seen in other parts of the worlds is possible because Mucorales are found in environment so it may be found in any part in spite of they are not contiguous from person to another. Physicians have to prescribe the right dose of cortisone. We should ensure that people who have diabetes should keep monitoring their sugar levels. As well as, we have to wear two masks, because it can be found in air, especially places like construction sites.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ghuman H, Voelz K. Innate and adaptive immunity to mucorales. J Fungi (Basel) 2017;3:55-59.
Al-Khikani FH. Dermatophytosis a worldwide contiguous fungal infection: Growing challenge and few solutions. Biomed Biotechnol Res J 2020;4:117. [Full text]
Al-Khikani FH, Ayit AS. Major challenges in dermatophytosis treatment: Current options and future visions. Egypt J Dermatol Venerol 2021;41:1. [Full text]
Al-Khikani FH, Almosawey HA, Abdullah YJ, Al-Asadi AA, Hameed RM, Hasan NF, et al
. Potential antiviral properties of antifungal drugs. J Egypt Womens Dermatol Soc 2020;17:54. [Full text]
Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al.
Epidemiology and outcome of zygomycosis: A review of 929 reported cases. Clin Infect Dis 2005;41:634-53.
Al-Khikani FH, Ayit AS. Prospects in immunomodulatory activity of amphotericin B in viral infection: Promising developing therapeutic branch. J Curr Re Sci Med 2020;6:65.
Obayes AK. Amphotericin B from antifungal to antiviral therapy: Promising modern therapeutic branch. Res Results Pharmacol 2020;6:26.
Al-Khikani FH. Amphotericin B, the wonder of today's pharmacology science: Persisting usage for more than seven decades. Pharm Biomed Res 2020;6:77.
Al-Khikani FH. Amphotericin B as antiviral drug: Possible efficacy against COVID-19. Ann Thorac Med 2020;15:118-24. [Full text]
Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012;54 Suppl 1:S23-34.
Dhrubo J , Kushal N, Beduin M and Dhananjoy S. SAPROPHYTIC PARASITE AND MYCOSIS BY BLACK FUNGUS. ejpmr, 2021;8: 742-746.
Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: An Analysis Based on Decade Long Structural Studies of SARS Coronavirus. J Virol 2020;94:41-47.
Al-Khikani FH, Almosawey HS. Be conscious to be healthy: An initiative to prevent recurrent urinary tract infection in Iraqi women. Hamdan Med J 2020;13:89-90.
Al-Khikani FH. Challenges in fungal treatment: A serious public health problem. Indian J Med Specialities 2020;11:171.
Al-Khikani FH. COVID-19: Containment strategies and management options. J Nat Sci Med 2020;3:221.
Falah AK. Major factors associated with worldwide dermatophytosis predominance. MGM J Med Sci 2020;7:232.
Prakash H, Chakrabarti A. Global epidemiology of mucormycosis. J Fungi (Basel) 2019;5:99-105.
Scott MM, Williams KW, Rossi J, Lee CE, Elmquist JK. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J Clin Invest 2011;121:2413-21.
Spreer A, Rüchel R, Reichard U. Characterization of an extracellular subtilisin protease of Rhizopus microsporus and evidence for its expression during invasive rhinoorbital mycosis. Med Mycol 2006;44:723-31.
Walsh TJ, Gamaletsou MN. Treatment of fungal disease in the setting of neutropenia. Hematology Am Soc Hematol Educ Program 2013;2013:423-7.
Pagano L, Ricci P, Tonso A, Nosari A, Cudillo L, Montillo M, et al.
Mucormycosis in patients with haematological malignancies: A retrospective clinical study of 37 cases. GIMEMA Infection Program (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto). Br J Haematol 1997;99:331-6.
Waldorf AR, Diamond RD. Neutrophil chemotactic responses induced by fresh and swollen Rhizopus oryzae spores and Aspergillus
fumigatus conidia. Infect Immun 1985;48:458-63.
Perkhofer S, Kainzner B, Kehrel BE, Dierich MP, Nussbaumer W, Lass-Flörl C. Potential antifungal effects of human platelets against zygomycetes in vitro
. J Infect Dis 2009;200:1176-9.
Noorifard M, Sekhavati E, Jalaei Khoo H, Hazraty I, Tabrizi R. Epidemiology and clinical manifestation of fungal infection related to Mucormycosis in hematologic malignancies. J Med Life 2015;8:32-7.
Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, et al
. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through γδ T-cell IL-17 production in a murine model of sepsis. Infect Immun 2010;78:4714.
Hameed RM, Al-Ibraheemi MK, Al-Khikani FH, Hasan NF, Almosawey HA, Al-Asadi AA. The possible role of immunoglobulin A monoclonal antibodies against COVID-19 infection. Matrix Sci Med 2020;4:96. [Full text]
Falah AK, Hameed R, Almosawey H. Immunological prospects of tamoxifen as modern antiviral therapy. J Mar Med Soc 2020;22:273.
Potenza L, Vallerini D, Barozzi P, Riva G, Forghieri F, Zanetti E, et al.
Mucorales-specific T cells emerge in the course of invasive mucormycosis and may be used as a surrogate diagnostic marker in high-risk patients. Blood 2011;118:5416-9.
Chinn RY, Diamond RD. Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: Relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. Infect Immun 1982;38:1123-9.
Kadhim AS, Abdullah YJ. Serum levels of interleukin-6, ferritin, C-reactive protein, lactate dehydrogenase, D-dimer, and count of lymphocytes and neutrophils in COVID-19 patients: Its correlation to the disease severity. Biomed Biotechnol Res J 2021;5:69. [Full text]
Falah AK, Hameed R. COVID-19 treatment: Possible role of itraconazole as new therapeutic option. Int J Health Allied Sci 2020;9:101.
Al-Khikani FH. Immunomodulatory effect of amphotericin B enhances antiviral activity. Indian J Med Specialities 2020;11:111.
Hoenigl M. Invasive fungal disease complicating COVID 19: When it rains it pours. Clin Infect Dis 2020;14:106.
Al-Khikani FH. Surveillance 2019 novel coronavirus (COVID-19) spreading: Is a terrifying pandemic outbreak is soon. Biomed Biotechnol Res J 2020;4:81-2.
Al-Khikani FH. The role of blood group in COVID-19 infection: More information is needed. J Nat Sci Med 2020;3:225.
Benedict K, Kobayashi M, Garg S, Chiller T, Jackson BR. Symptoms in blastomycosis, coccidioidomycosis, and histoplasmosis versus other respiratory illnesses in commercially insured adult outpatients – United States, 2016–2017. Clin Infect Dis 2020;23:109.
Posteraro B, Torelli R, Vella A, Leone PM, De Angelis G, De Carolis E, et al. Pan echinocandin resistant Candida glabrata bloodstream infection complicating COVID 19: A fatal case report. J Fungi (Basel) 2020;6:208
Bertolini M, Mutti MF, Barletta JA, Falak A, Cuatz D, Sisto A, et al.
COVID-19 associated with AIDS-related disseminated histoplasmosis: A case report. Int J STD AIDS 2020;31:1222-4.
Al-Khikani FH. Pulmonary mycoses treated by topical amphotericin B. Biomed Biotechnol Res J 2020;4:123. [Full text]
Koehler P, Bassetti M, Chakrabarti A, Chen SC, Colombo AL, Hoenigl M, et al.
Defining and managing COVID-19-associated pulmonary aspergillosis: The 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis 2021;21:e149-62.
Marr KA, Platt A, Tornheim JA, Zhang SX, Datta K, Cardozo C, et al. Aspergillosis Complicating Severe Coronavirus Disease. Emerg Infect Dis 2021;27:290.
Benedetti MF, Alava KH, Sagardia J, Cadena RC, Laplume D, Capece P, et al.
COVID-19 associated pulmonary aspergillosis in ICU patients: Report of five cases from Argentina. Med Mycol Case Rep 2021;31:24-8.
Obayes AK, Hasan F. The forgotten role of methenamine to prevent recurrent urinary tract infection: Urgency for reuse 100 years after discovery. Pharm Biomed Res 2020;6:247-50.
Al-Khikani FH. Trends in antibiotic resistance of major uropathogens. Matrix Sci Med 2020;4:108.
Al-Khikani FH. Antimicrobial resistance profile among major bacterial pathogens in Southern Babil, Iraq. Galician Med J 2020;27:E202036.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al.
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.
Beer KD, Jackson BR, Chiller T, Verweij PE, Van de Veerdonk FL, Wauters J. Does pulmonary aspergillosis complicate coronavirus disease 2019? Crit Care Explor 2020;2:e0211.
Al-Khikani FH, Kadim BJ, Ayit AS, Abidalali MH. Evaluation cephalosporins resistance in pathogenic bacteria isolated clinically. World News of Natural Sciences. Int Sci J 2020;31:44.
Arastehfar A, Shaban T, Zarrinfar H, Roudbary M, Ghazanfari M, Hedayati MT, et al. Candidemia among Iranian Patients with Severe COVID 19 Admitted to ICUs. J Fungi (Basel) 2021;7:128.