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Surge Of Mucormycosis Among COVID-19 Recovered: Early Diagnosis And Treatment Protocols

Author: Dr. Harshbardhan Kr. Govinda

MBBS, MD, FCCM, FID, MEM, Fellowship in Critical Care, Medicine and Diabetes (Liverpool UK), Chief Medical Director, Mediser (Himalaya) Hospital, Sipara, Patna

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Severe coronavirus created a huge distress worldwide; and disease pattern of COVID range from mild to moderate life threatening pneumonia associated with severe bacterial and fungal co-infections. Co-morbidities like diabetes, pulmonary disease and immunocompromised conditions makes patients more vulnerable to grow several opportunistic co-infections. Mucormycosis is one of that opportunistic fungal infections. Mucormycosis is a life threatening invasive fungal infection caused by fungi belonging to the class mucorales. Due to excessive use of steroids in management of COVID-19, mucormycosis is rising speedily and becoming a major cause for mortality. Global prevalence impact of mucormycosis varied from 0.005 to 1.7 per million populations. India in comparison to other developed countries has nearly 80 times higher prevalence of mucormycosis (0.14 per 1000) in a recent estimate of year 2019-2020 or it can be said that the cases of mucormycosis is maximum in India. India has reported more than 8.5 thousand of mucormycosis cases till 22 May 2021. Diagnosis remains a big challenge in mucormycosis. Amphotericin B is used as the first line therapy for the treatment of mucormycosis. Posaconazole and Isavuconazole are also used in the management of mucormycosis.

Keywords: Mucormycosis, Amphotericin B, COVID-19, Posaconazole



COVID-19 pandemic is pursuing to be a major trouble worldwide. Numerous treatments have been shown to progress survival in COVID-19 [1]. The disease model of COVID-19 can range from mild to life threatening pneumonia with linked bacterial and fungal co-infections. Co-morbidities like diabetes, pulmonary disease and immunocompromised conditions makes patients more vulnerable to grow several opportunistic co-infections. Information shows that progress of severe infections such as oropharyngeal candidiasis, Pneumocystis jiroveci pneumonia, pulmonary aspergillosis, bloodstream candida infections, mucormycosis, etc. are frequent in patients with COVID-19 [2]. COVID-19 patients or critically ill patients admitted to ICU are likely to build up fungal co-infections [3]. Various infections are complicating the course of severe COVID-19, mucormycosis is one of them. It is an unusual but serious infection and a rising cause for the mortality and morbidity for the COVID-19 immunocompromised patients. Glucocorticoid therapy proved to be effective in improving the COVID patient’s survival, possibly increased the risk of mucormycosis [1, 4]. Exclusive use of steroids in managing COVID-19 can also suppress immunity and opportunistic fungal infection colonise easily.  It became crucial to alert that, COVID-19 patients can build up further fungal infections during any stage of disease, particularly severely ill patients [5]. Mucormycosis cause hasty worsening of eyes, leading to everlasting loss of vision. If patients brain is affected by mucormycosis it quickly leads to paralysis, organ failure, other complications and in the end death [6]. India is facing a high mortality rate of mucormycosis (45-90%). This may be due to the delay in diagnosis and the high cost in management of mucormycosis [7].


Mucormycosis – New Concern in COVID World

Life threatening invasive fungal infection mucormycosis is caused by fungi belonging to the class mucorales. Zygomycosis is also used as an alternating name for mucormycosis [8]. Mucormycosis is rare but serious fungal infection. Fungi of this family are present everywhere in nature and also related in decaying of fruits and vegetables. The transmission takes place all the way through inhalation, inoculation, or ingestion of spores present in environment. These fungi rise speedily and have black/brown appearance in lab and also known as ‘Black Fungus’ [9-11]. The first case of mucormycosis was published by Arnold Paltauf in 1885 and named mycosis mucorina. When the cases of mucormycosis were diagnosed and the occurrence has enlarged it showed that diabetes patients are at high incidence of mucormycosis becoming the most ordinary jeopardy globally. The prevalence of mucormycosis is mounting; precise incidence of mucormycosis is not recognized because of not many populations based studies [12]. Global prevalence impact of mucormycosis varied from 0.005 to 1.7 per million population, India in comparison to other developed countries has nearly 80 times higher prevalence of mucormycosis (0.14 per 1000) in a recent estimate of year 2019-2020 or it can be said that the cases of mucormycosis is maximum in India.  Diabetes is one of the factors related to increase the incidence of mucormycosis and it is noteworthy that India has second largest population with diabetes. Moreover, mucormycosis is also interconnected with extensive use of corticosteroids, even patients with diabetes also reported cases of mucormycosis with short use of corticosteroids [13]. Mucormycosis cases in people with COVID-19 have shown a sharp rise, India has reported more than 8.5 thousand of mucormycosis cases till 22 May 2021 [14]. Mucormycosis is caused by certain types of agents known as molds which are called as mucormycetes. The most common fungi causing mucormycosis are [9, 15]:

  • Rhizopus species
  • Syncephalastrum species
  • Mucor species
  • Cunninghamella bertholletiae
  • Lichtheimia (formerly Absidia) species
  • Rhizomucor species
  • Apophysomyces species


Based on the localization, mucormycosis can be classified into 5 types with their usual symptoms [9, 15, 16]:

  1. Symptoms of Rhino cerebral (sinus and brain) mucormycosis includes:
  • One-sided facial swelling
  • Headache
  • Nasal or sinus congestion
  • Black lesions on nasal bridge or upper inside of mouth that quickly become more severe
  • Fever
  1. Symptoms of Pulmonary (lung) mucormycosis includes:
  • Fever
  • Cough
  • Chest pain
  • Shortness of breath
  1. Symptoms of Gastrointestinal mucormycosis includes:
  • Abdominal pain
  • Nausea and vomiting
  • Gastrointestinal bleeding
  1. Cutaneous (skin) mucormycosis resembling to blisters or ulcers, and blackness at the area can also occur, other symptoms includes:
  • Pain
  • Warmth
  • Excessive redness
  • Swelling around a wound
  1. Disseminated mucormycosis may engage kidneys, brain, spleen, heart, skin, and other organs can also be affected with symptoms attributed to these organ systems


Mucormycosis among COVID Recovered Patients, Immunocompromised and Diabetic Patients

As discussed molds of mucormycosis are found in nature, but they do not cause difficulty generally. There are factors which are accountable to raise the risk of mucormycosis. Someone with immunocompromised condition are more susceptible for the life threatening infections and immunocompromised condition accounts for the major risk factor for mucormycosis. Uncontrolled diabetes, especially those with ketoacidosis and patients with cancer, receiving immunosuppressive agents are at high risk of mucormycosis [9, 16].

More often by breathing in mold spores, most people develop this infection, and also infection develops if the spores enter through cut or wound. People with recent history of hematopoietic stem cell transplantation with immunosuppressive drugs to avoid rejection during transplantation are at risk to get infection like mucormycosis. Moreover, individuals receiving immunosuppressive drugs for any other cause are also at high risk of mucormycosis.

As discussed patients with diabetes especially when not controlled can develop ketoacidosis, in which ketones are produced by the body. There is doubt on the precise reason of mucormycosis in diabetic patients but it may be more correlated with excess of iron present in tissues. Investigators consider that mold of mucormycosis nurture and multiply on availability of excess iron.

There are more conditions that increase the risk of mucormycosis like HIV/AIDS, use of contaminated medical equipment near or on open wound, excessive use of corticosteroids, strong anti-inflammatory medications, skin trauma including burns or other injury to the skin, extreme malnourishment, and unlawful drug use involving needles. Today COVID-19 is a new threat to increase the risk of mucormycosis.

Generally, these fungal infections are successfully countered by our body’s immune system, whereas use of corticosteroid for the treatment of COVID-19 suppresses the immune system, leading the patients more prone to these fungal infections. Therefore, it becomes very important to use steroids safely and to identify the symptoms of mucormycosis.

Furthermore, patients in ICU undergoing oxygen therapy, where humidifier is used are more vulnerable to fungal infection due to the exposure of moisture. Looking at all these factors, COVID-19 patients face a high risk of mucormycosis making their survival more difficult [17-18].

Altogether COVID-19 infection along with comorbid conditions, and use of immunosuppressant are escalating the risk of one of the rare but life threatening infection mucormycosis [19].



The outcomes may be improved by the early diagnosis and augments the survival. Identification of risk factors, review of clinical manifestations, early use of imaging modalities and prompt initiation of diagnostic methods based on histopathology, cultures and advanced molecular techniques are the broad categories for diagnosis [12].

  1. Clinical Diagnosis

Mucormycosis is featured by tissue necrosis consequential from angioinvasion and thrombosis, but low sensitivity and specificity in clinical approach to diagnosis is the concern. As mentioned, the most general clinical appearance of mucorales infection are rhino-cerebral, pulmonary, soft tissue, and disseminated disease; however, virtually any organ can be affected. Aspergillus, Fusarium, Pseudallescheria and Scedosporium species may also produce the resembling features. Patient showing symptoms like cranial nerve palsy, diplopia, sinus pain, proptosis, periorbital swelling, orbital apex syndrome, and ulcers of the palate should be carefully measured as ‘red flag or warning sign’. Computerized tomography (CT) scan, specify the presence of mucormycosis, as the reverse halo sign (RHS). Presence of RHS in CT scan is a powerful pointer of mucormycosis. Positron emission tomography-computed tomography (PET/CT) with [18F]-fluorodeoxyglucose (FDG) is also ­­­an imaging method which is not broadly used yet.

  1. Microscopic examination and culture

The keystones of diagnosis of mucormycosis are microscopy (histopathology and direct microscopy) and culture of various clinical specimens.

  • Histopathology: A classic analysis is based on the expression of fungal hyphae typical for mucormycetes in biopsies of affected tissues, or bronchoalveolar lavage (BAL) in patients with pulmonary mucormycosis. The presence of fungus as a pathogen in the specimen from a culture contaminant is crucial to define whether there is blood vessel invasion, but this can be differentiated by histopathology and making it a very significant diagnostic tool. Grocott methenamine-silver (GMS) and Periodic acid-Schiff (PAS) stains are the strains that can help to highlight the fungal wall as the mucorales genera make classically non-pigmented, wide, thin-walled, ribbon-like hyphae with no or few septations (pauciseptate) and right-angle branching as compared to other molds. Although PAS shows superior visualization compared to GMS.
  • Direct microscopy: Direct microscopy of KOH wet mounts can be used for fast presumptive analysis of mucormycosis, as recommended by experts of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium (ECMM/MSG ERC). The visualization of the typical fungal hyphae can be augmented by using fluorescent brighteners such as Blankophor and Calcofluor White collectively with KOH; in this case it requires a fluorescent microscope.
  • Culture: Identification to the genus and species level, and eventually antifungal susceptibility testing is possible by culture specimen. It is one of the important diagnostic tool for mucormycosis. Mucorales are thermotolerant and are able to grow rapidly at temp of 37oC.
  • Serology: Variable success has been appraised by Enzyme-linked immunosorbent assays, immunoblots, and immunodiffusion tests. Enzyme-linked immune spot (ELISpot) assay identified the mucorales specific T cells.
  • Molecular assays: Polymerase chain reaction (PCR), restriction fragment length polymorphism analyses (RFLP), DNA sequencing of defined gene regions, and melt curve analysis of PCR products are the molecular based assays used for the identification of mucorales. The internal transcribed spacer or the 18S rRNA genes are been targeted by many of the molecular assays. Right now the recommended assay as valuable add-on tools that complement conventional diagnostic procedures is molecular assays [12,20,21].



As the mortality rate of mucormycosis range from 40% to 80%, it is very important to treat mucormycosis effectively. There are multiple model approaches for the successful treatment of mucormycosis. The current treatment and management approaches are shared below (figure 1):

  1. Anti-fungal means for mucormycosis:

Only liposomal Amphotericin B (L-AmB) is recommended as the first line treatment for mucormycosis and other Amphotericin B lipid complex (ABLC) could also be used. Moreover, for neonates and pediatric patients L-AmB and ABLC were suggested as first line treatment. Recently, Isavuconazole is also studied as first line treatment and Posaconazole studied as the salvage therapy for mucormycosis.

  • L-AmB and ABLC: The European Conference on Infections in Leukemia (ECIL) in 2017 and the European Confederation of Medical Mycology (ECMM) in 2019 powerfully suggested L-AmB as the first line therapy for mucormycosis and AMB is considered as the drug of choice for the treatment of mucormycosis. The suggested dose of L-AmB and ABLC is 5mg/kg/day, the dose can range from 1mg/kg/day to 10 mg/kg/day. Doses more than 10mg/kg/day does not increase the serum level. Although dosages beyond 5 mg/kg/day have not been proved to be more successful for mucormycosis, but may be considered on an individual basis.
  • New triazoles: Ergosterol from fungal cell membrane is diminished by the triazoles. Fluconazole, Itraconazole, and Voriconazole among the antifungal have little or no activity against mucorales. Recent triazoles like Posaconazole and Isavuconazole have better in vitro activity against mucorales.  Posaconazole and Isavuconazole are recommended in mucormycosis. Posaconazole is considered as first line therapy for mucormycosis where AmB is totally contraindicated. Presently, Posaconazole (oral suspension 400 mg twice daily with meals, or 200 mg four times daily when administered without food) may be considered as salvage treatment of mucormycosis. Although Isavuconazole might be a better option, as it has a broad spectrum activity and is in its biologically active form. Isavuconazole is available in both I.V. and oral form and is administered with a loading dose of 200 mg twice daily for 2 days and 200 mg thereafter, no need for dose adjustment in kidney, liver failure or obesity is required; and has excellent oral bioavailability.
  • Combination treatment: Combination therapy is not recommended as the first lined treatment due to the lack of solid evidence of their efficacy. Some studies displayed that there are synergistic effects of AmB with Caspofungin (CAS), Posaconazole with CAS and Isavuconazole with CAS but for Azoles with Echinocandins showing lack of synergy. More trials need to be established to evaluate the toxicity, drug interaction and cost of therapy.
  1. Surgery for mucormycosis:

In mucormycosis therapy, surgical resection of necrotic tissues is considered as center of therapy. Better effect is noted in surgical debridement with combination of medical therapy. The benefits of surgery are highly recommended whenever possible.

  1. Adjunctive therapy for mucormycosis:

This therapy is used to reverse the immunosuppression which is considered as a pillar for mucormycosis therapy. Steroids therapy should be discontinued and alternate options should be considered. Researchers studied iron chelators as potential agent for reducing iron availability which eventually inhibits fungal growth. L-AmB, Micafungin, and Deferasirox are also established as an effective approach. The functionality of neutrophils is improved by hyperbaric oxygen (HBO) treatment. HBO enhances cellular immune system and tissue repair and exerts synergistic effects with anti-microbial agents. Granulocyte (macrophage) colony-stimulating factor or Interferon- has been planned as adjunct therapy. All the above points need to be established with more potential evidence data and requires more randomized studies [8,21-24].


Figure 1: Algorithm for the treatment of mucormycosis is described below in the chart.



COVID-19 remains the major trouble worldwide and linked with severe and opportunistic bacterial and fungal co-infections. Mucormycosis is one of that opportunistic co-infection. Life threatening invasive fungal infection mucormycosis is caused by fungi belonging to the class mucorales. Epidemiology and mortality of mucormycosis is increasing rapidly. Mucormycosis is rare yet a serious life threatening disease affecting patients with diabetes. Immunocompromised conditions and especially COVID-19 patients due to excessive use of steroids are at greater risk of getting mucormycosis. Diagnosis is one of the major challenge in mucormycosis. Methods like CT scan, MALDI-TOF etc. showed some noticeable results but more validation is needed. Amphotericin B is recommended as the first line therapy for treating mucormycosis. Posaconazole is also used as an essential drug for the treatment, Isavuconazole, a new azole has shown promising results in the management of mucormycosis. Overall, early diagnosis and timely management of mucormycosis is necessary to get the better outcome and these strategies can also account to reduce the high rate of mortality associated with mucormycosis.



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