10.6092/issn.2531-7342/13627
While combating the second wave of COVID-19, India has now been afflicted by another epidemic caused by mucormycosis, a life-threatening opportunistic infection. Due to their immune-suppressed status, COVID-19 patients in India are now more likely to develop mucormycosis during or after treatment. Uncontrolled diabetes, irrational use of steroids, as well as the severity of COVID-19 can all contribute to the growth of mucormycosis. Risk mitigation strategies that could be used to control the rise of mucormycosis-related COVID-19 patients should be evaluated. The purpose of this article is to explore the modifiable risk variables that are involved in the medical management of COVID-19 patients, as well as the mechanisms through which they raise the risk. This overview also includes a brief discussion of mycology and how the disease pattern varies depending on the regions of the body affected. In this article, we detailed about the early detection and treatment of mucormycosis in COVID-19 patients.
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Italian Journal of Mycology
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Mucormycosis in COVID-19: modifiable risk factors and its mitigation in India
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Ital J Mycol
Swathi Swaroopa Borra
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Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
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Webb BJ, Ferraro JP, Rea S, Kaufusi S, Goodman BE, Spalding J (2018) Epidemiology and clinical features of invasive fungal infection in a US health care network. Open Forum infectious diseases 5(8):ofy187. https://doi.org/10.1093/ofid/ofy187
Mucormycosis in COVID-19: modifiable risk factors and its mitigation in India
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                IJM - Italian Journal of Mycology
                ISSN 2531-7342 - Vol. 51 (2022): 11-22
                Journal homepage: https://italianmycology.unibo.it/

Review

     Mucormycosis in COVID-19: modifiable risk factors and its
                       mitigation in India

    Sherin Mary Shaji, Sadagoban Gopal Krishnamoorthy, Swathi Swaroopa Borra

Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty,
Nilgiris, Tamil Nadu, India

Corresponding author e-mail: swathimasthani@hotmail.com


Article info
Received 14/10/2021; accepted 7/02/2022
https://doi.org/10.6092/issn.2531-7342/13627

Abstract
While combating the second wave of COVID-19, India has now been afflicted by another epidemic caused by
mucormycosis, a life-threatening opportunistic infection. Due to their immune-suppressed status, COVID-19
patients in India are now more likely to develop mucormycosis during or after treatment. Uncontrolled diabe-
tes, irrational use of steroids, as well as the severity of COVID-19 can all contribute to the growth of mucor-
mycosis. Risk mitigation strategies that could be used to control the rise of mucormycosis-related COVID-19
patients should be evaluated. The purpose of this article is to explore the modifiable risk variables that are
involved in the medical management of COVID-19 patients, as well as the mechanisms through which they
raise the risk. This overview also includes a brief discussion of mycology and how the disease pattern varies
depending on the regions of the body affected. In this article, we detailed about the early detection and treat-
ment of mucormycosis in COVID-19 patients.

Keywords
Mucormycosis, COVID-19, Risk factors, Mycology


1. Introduction

COVID-19 is a rapidly developing healthcare hazard that began as a cluster pneumonia outbreak in
Wuhan, China. India has been among the countries severely hit by the pandemic (Hiscott et al., 2020).
During the second wave of COVID-19, the country was hit by another epidemic, mucormycosis,
widely known as “Black Fungus” which has wreaked havoc on the healthcare system, and because
of their immunosuppressed status, COVID-19 patients are more susceptible to bacterial and fungal
infections. The rise in prevalence of diabetes Mellitus (DM) in the Indian population makes these
COVID-19 patients more prone to develop mucormycosis. A meta-analysis of 600 publications from
2000 to 2017 comprising 851 cases of mucormycosis worldwide cited the following risk factors for
mucormycosis: DM (40%), trauma (33%), hematological malignancies (HemeM) (32%), diabetic
ketoacidosis (20%), neutropenia (20%), no underlying disease (18%), solid organ transplant (14%),
burns (11%), natural disasters (5%) (Jeong et al., 2019). In Asia, DM is the most common risk factors
of mucormycosis (Prakash and Chakrabarti, 2019). Surveillance of 15 tertiary hospitals in Australia
identified 74 cases of mucormycosis from 2004 to 2012; only 8 patients (10.8%) were previously
healthy (Kennedy et al., 2016).

Department of Agricultural and Food Science in partnership with the Italian Mycological Society (UMI).
The journal is hosted and maintained by ABIS-AlmaDL. © 2022 The Authors. This work is licensed under CC BY 4.0
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    Globally, India was reported with maximum number of mucormycosis cases (71%) with an
estimated prevalence of 140 cases per million population (Prakash et al., 2019). Moreover, India
has the second-large of the population aged 20–79 years with DM (John et al., 2021). In reality,
DM is the single most common risk factor for mucormycosis in India, with a report of over 50% of
cases of mucormycosis. A multicenter study on mucormycosis in India reported 57% of patients with
uncontrolled DM and 18% by diabetic ketoacidosis (Prakash et al., 2019).
    The spike in mucormycosis could be linked to poor care of pre-existing diabetes, overuse of
steroids, and prolonged Intensive Care Unit stays. Post-tuberculosis, chronic renal failure, and stay
in intensive care units are new risk factors for the disease especially in developing countries (Prakash
and Chakrabarti, 2019). This review will be helpful in giving comprehensive coverage of the risks
involved with medical treatment, as well as how to avoid them. This article focuses on the risk factors
for Mucormycosis in COVID-19 patients, particularly in India, where the frequency is relatively high
when compared to other countries. This study used published case reports and case series from India
to show risk factors for Mucormycosis in COVID-19 patients, and it also raised a question for future
research on mechanical ventilation-associated Mucormycosis in COVID-19 patients.

2. Mycology

Mucormycosis is one of the most lethal fungal diseases caused by Mucorales. The most commonly
isolated Mucorales from humans are from the genera Rhizopus, Mucor, Rhizomucor, Cunninghamella,
and Absidia (Hoffmann et al., 2013). Rhizopus is the most common causative genus among Mucorales
in human infections, with a fatality rate of 46% (Revannavar et al., 2021). Depending on the species,
the site of infection would be different. The angioinvasive features of the fungus are assumed to be
due to a link between a protein in the fungus and a protein called GRP78 on the endothelium of the
host (Ibrahim et al., 2012). The interaction is depicted in full in the Figure 1.




        Fig. 1 - Interaction between spore coat protein (COTH) and GRP78 leading to angioinvasion by fungi.




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3. Epidemiology

Looking into the general epidemiological data of mucormycosis, Webb et al. (2018) in a large network
of hospitals and clinics in the USA from 2006 to 2015, only 1.1% of 3,375 invasive fungal infections
(IFIs) were due to Mucorales and incidence was 0.3 cases/100,000 per year. The underlying cause
seems to be DM (36.1%), immunosuppressive therapy (61.1%), hematopoietic stem cell transplant
(HSCT) (11.1%), HemeM (19.4%) (Webb et al., 2018). Another study conducted by Kontoyiannis
et al. (2016), reported that there were 555 mucormycosis-related hospitalizations among 47 million
inpatients admitted (prevalence of 0.12 per 10,000 discharges) from 560 hospitals in the USA from
2005-2014. National Hospital Discharge Data Base survey of France, from 2001 to 2010 found that
1.5% of 35,876 invasive fungal infections were due to mucormycosis (Bitar et al., 2014) and the
incidence of mucormycosis in France was 0.7 per million and 1.0 per million in 2006 (Bitar et al.,
2009). A study in Spain reported 19 cases of mucormycosis were diagnosed from 2007 to 2015
(incidence 3.2 per 100,000) (Guinea et al., 2017).
   During the second wave of COVID-19 in May 2021, India accounted for nearly half of all cases
worldwide. Although mucormycosis is rare, the incidence has increased globally over the past two
decades, 13 particularly in France, Belgium, Switzerland, and India. However, India has the highest
number of mucormycosis occurrences when compared to other countries (Singh et al., 2021). The actual
incidence of mucormycosis in India is unknown due to a scarcity of population-based investigations.
The second wave of COVID-19 had a significant impact on India, with the peak number of daily
recorded cases being slightly more than 0.4 million on May 7, 2021, and has subsequently fallen.
Even though the number of newly reported cases has reduced, India still contributed to approximately
45% of the new cases detected globally and nearly 34% of the deaths globally during the third-week
of May 2021. The accurate incidence/prevalence could be more in mucormycosis, due to undiagnosed
cases, difficulty in collecting the sample from deep tissue and low sensitivity of diagnostic methods.
   The Leading International Fungal Education (LIFE) portal has assessed the burden of severe fungal
infections globally. Conferring to approximation, the annual prevalence of mucormycosis could be
around 10,000 cases globally, barring India. Subsequently, the addition of Indian data, the estimate of
mucormycosis rise to 910,000 cases globally. A computational-based approach assessed the prevalence
of mucormycosis at 140 cases per million populations in India, with the prevalence ranging between
137,807 cases to 208,177 with the mean of 171,504 (SD: 12,365.6; 95% CI: 195,777–147,688) and a
mean attributable mortality at 65,500 (38.2%) per year (Prakash et al., 2019). Because India has the
world’s second-largest diabetic population, the Indian population is more vulnerable to mucormycosis.
The number of cases of mucormycosis increased during the second wave of COVID-19, worsening
the situation in hospitals. As of 28th May 2021, the total number of mucormycosis cases reported in
India was 14,872. Gujarat leads the way with 3726 cases, followed by Maharashtra. Mucormycosis
has also been reported in the states of Rajasthan, Andhra Pradesh, Karnataka, Haryana, Madhya
Pradesh, Uttarakhand, and Delhi (Raut et al., 2021.) As announced by Mr. Harsh Vardhan, the former
Health Minister of India, there are over 40,000 cases of mucormycosis reported as of 28 June 2021
(Ministry of Health, 2021). Mucormycosis has been declared an epidemic in several Indian states and
has been classified as a notifiable disease.

4. Route of exposure

Inhalation, ingestion, and open wounds exposure of spores are the most typical methods of infection.
Inhalation spreads spores in pulmonary and rhino-orbital-cerebral mucormycosis, whereas ingestion
or wounds spreads spores in gastrointestinal and cutaneous mucormycosis. The cilia will propel the


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spores to the throat, where they will be removed by the gastrointestinal tract. Infected nasal turbinate
or alveoli develop in vulnerable patients (Ibrahim et al., 2012). The spores are distributed in the
bloodstream due to their angio-invasive properties.

5. Clinical presentation of mucormycosis in COVID-19

In susceptible individuals, the infection is characterized by ischemic necrosis of the tissue caused
by angio-invasion by the hyphae following spore inhalation. Mucormycosis is classified into several
types relying on the affected area (Table 1), such as rhino-orbital-cerebral, pulmonary, cutaneous,
gastrointestinal, renal, and diffuse mucormycosis (Nishanth et al., 2020). Clinical manifestations will
also vary depending on location (John et al. 2021).
   The most common type of mucormycosis in COVID-19 patients is rhino-orbital cerebral
mucormycosis, followed by pulmonary and gastrointestinal mucormycosis. Patients with
gastrointestinal mucormycosis have a poor prognosis when compared to the former. Patients with
pulmonary mucormycosis were more likely to develop disseminated mucormycosis (Singh et al.,
2021).

 Table 1 - Classification of mucormycosis based on location and their manifestations (John et al., 2021).
 Type of mucormycosis                   Clinical presentation
 Rhino-orbital cerebral                 Fever, ulceration or necrosis of the nose, swelling around the eyes or on the
 mucormycosis                           face is known as periorbital swelling. Vision impairment, ophthalmoplegia,
                                        sinusitis, headache
 Pulmonary mucormycosis                 Pneumonia, fever with hemoptysis
 Gastrointestinal mucormycosis          Abdominal pain, hematemesis, peritonitis
 Cutaneous mucormycosis                 Localized hardening of the tissue, single, painful, ecthyma like lesion
 Renal mucormycosis                     Flank pain, fever

6. Predisposing factors of mucormycosis in general and COVID-19

The general predisposing factors for mucormycosis is poorly controlled DM, hematological
malignancy, neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplant
recipients, immunosuppression or chemotherapy, autoimmune or rheumatic disorders, human
immunodeficiency virus infection, peritoneal dialysis, iron overload states, malnutrition, trauma,
burns, and prior receipt of “voriconazole” (Reid et al., 2020) out of which the most common
predisposing factors for the occurrence of mucormycosis is found to be Diabetes mellitus, steroid
therapy, and uncontrolled severe COVID-19.

7. The mechanism by which each risk factor can induce mucormycosis (Fig. 2)

7.1. Uncontrollable DM
It is unsurprising that India accounts for around half of all mucormycosis cases worldwide, given
that it is the country with the second-highest number of diabetes patients (Prakash et al., 2019). The
risk of acquiring hyperglycemia in people with pre-existing DM is extremely significant. This can
be explained by a problem with pancreatic islets, which can lead to insulin resistance. In the diabetic
population, natural killer cells, such as TNF, are reduced, whereas the number of pro-inflammatory
macrophages increases (Prakash et al., 2019). An increase in blood glucose levels can suppress the


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antiviral response and on the other hand increased serum iron levels in diabetic ketoacidosis create a
favorable environment for the formation of spores.

7.2. Steroid therapy-induced immunosuppression and hyperglycemia
Steroid therapy, which typically lasts 2-14 days, can cause hyperglycemia. The sequestration of
CD4+ T-lymphocytes in the reticuloendothelial system is one process by which corticosteroids cause
immunosuppression (Barshes et al., 2004). Steroids can reduce islet cell insulin synthesis while
increasing endogenous glucose production, leading to hyperglycemia. It also impairs phagocyte
function, making invasive infections more likely (Tamez-Pérez et al., 2015).

7.3. Severe COVID-19
The risk of mucormycosis increases as the severity of the ailment worsens. In this state, the IFN-γ
response is delayed, and the inflammatory response is heightened. Because of the cytokine storm, a
fertile environment for spores is created. A prolonged hospital stay is another factor that can prolong
the severity and risk of infection. In severe COVID-19, the number of lymphocytes decreases, SARS-
CoV-2 infection may affect CD4+ and CD8+ T-cells, which are involved in the pathological process
of COVID-19 infection. Mucorales-specific T-cells (CD4+ and CD8+) produce cytokines such as
interleukin (IL) 4, IL-10, L-17 and interferon-gamma (IFN-γ) that damage the fungal hyphae. As a
result, lymphopenia could increase the risk of developing mucormycosis (Revannavar et al. 2021;
Singh et al., 2021).
   The major reason that Mucorales spores appear to proliferate in people with COVID-19 seems to
be high blood sugar (new-onset hyperglycemia, diabetes steroid-induced hyperglycemia), oxygen
deprivation (hypoxia), reduced phagocytic activity owing to immunosuppression (steroid mediated,
SARS-CoV-2 mediated or background comorbidities) acidic medium (diabetic ketoacidosis [DKA]),
metabolic acidosis, increased iron levels (increased ferritins), and in combination with several other
factors such as prolonged hospitalization with or without mechanical ventilation. (Singh et al., 2021).




           Fig. 2 - Mechanism by which each risk factor increases the susceptibility to mucormycosis
           (Tamez-Pérez et al., 2015; Prakash et al., 2019; Singh et al., 2021; Revannavar et al., 2021).


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8. Diagnosis
The most crucial element in the treatment of mucormycosis is the diagnosis, because the longer it takes
to detect the disease, the higher the probability of death. Histological analysis confirms the diagnosis,
which is then verified by a culture test (Fig. 3). Based on the symptoms and indicators listed in Table
1, the presence of mucormycosis has been verified. Because the number of mucormycosis patients
is expected to increase during COVID-19, a medical team should be on hand to provide immediate
access to imaging instruments as well as histological and mycological research. Diabetic patients
with sinusitis or pneumonia-like symptoms should be evaluated immediately, and diabetic patients on
dialysis are at risk of mucormycosis and should be treated as high-risk patients. COVID-19 patients
on steroid medication should also be monitored carefully.




     Fig. 3 - Diagnostic methods used to confirm mucormycosis (Georgiadou et al., 2011).



   The following are some indications of mucormycosis that can be seen on a CT scan (Georgiadou
et al., 2011).
   • Halo sign
   • Reverse halo sign
   • Vessel occlusion in pulmonary angiography
   If orbital involvement is suspected, a Magnetic Resonance Imaging (MRI) should be performed
after a CT scan to determine the extent of the infracted area/necrotized tissue (Cornely et al., 2019).



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9. Management

By July 19th, a minimum of 11 different Indian-specific treatment guidance for COVID-19 Associated
Mucormycosis (CAM) were available (Aranjani et al., 2021). In general, most of the national
guidelines warn to optimize missing corticosteroids use and control diabetes along with immediate
and extensive radiology-guided surgical intervention as treatment choice (Aranjani et al., 2021). Most
commonly followed was 2019 global guidance on mucormycosis by the European Confederation
of Medical Mycology (ECMM) and Mycoses Study Group Education and Research Consortium
(Cornely et al., 2019) and Code Mucor was considered compendious among them, with a treatment
algorithm that suits every substage (Honavar, 2021). In general, most national guidelines warn about
controlling diabetes and optimizing corticosteroids use. Immediate and extensive radiology-guided
surgical intervention was the treatment of choice.
    The India-centric guideline by ECMM and the International Society for Human and Animal
Mycology (ISHAM) for stage 4 disease, recommends extensive debridement of external infected
tissues, including bones and repeated procedures in case of recurrence (Rudramurthy et al., 2021). All
the guideline recommends the use of systemic antifungal agents without any prophylactic therapy. The
Indian Council of Medical Research (ICMR) (ICMR, 2021) recommends administering antifungal
therapy for at least 4 to 6 weeks and liposomal amphotericin B (AmB, 5 mg kg-1 per day) with slow
infusion. Dose escalation up to 10 mg kg-1 per day is recommended if the infection spreads to the CNS
(DGHS, 2021). Azoles (Isavuconazole or posaconazole) are suggestive if AmB is contraindicated.
The Fungal Infection Study Forum and ECMM/ISHAM recommends itraconazole when AmB or the
primary azoles are unavailable (Rudramurthy et al., 2021; FISFTRUST, 2021).
    Given the risk of fatality, a clinical choice about how to proceed following the diagnosis should
be made as soon as possible. In general, mucormycosis in COVID-19 is treated with a combination
of surgical and antifungal therapies (CDC, 2022). It’s also critical to pinpoint the patient’s trigger
element and eliminate it. For best results, the debridement technique should be repeated as needed
(Skiada et al., 2018). Modifications can be made depending on the availability of the medications
listed in the Figure 4 (Cornely et al., 2019).

10. Recommendations based on ICMR guidelines

The ICMR recommendation (Tamez-Pérez et al., 2015) has been amended to lower the risk of
mucormycosis, according to the present situation.
• It’s important to keep your blood glucose levels in check
• Monitor the chances of hyperglycemia during post-COVID-19 as there is a risk for new onset of
   diabetes Mellitus and pre-existing diabetes
• Steroids should be administered cautiously with short course (5-10 days) and low doses in
   COVID-19 patients with continuous blood glucose monitoring and should be avoided at the
   occurrence of mucormycosis.
• Use humidifiers while on oxygen supplementation
• Keep an eye out for signs and symptoms of mucormycosis while in the hospital
• Rapid surgical intervention along with antifungal therapy has to be immediately administered




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     Fig. 4 - Anti-fungal therapy to be given for mucormycosis (Cornely et al., 2019).

11. Understanding the cases reported in India and other countries

Diabetes mellitus and steroid medication, as previously stated, are the most common risk factors
among the cases documented. Various published case reports (Supplementary Table 1) showed that
steroid medication can raise blood sugar levels and hence needs to be under control. The majority of
the patients were in a critical condition requiring mechanical ventilation, necessitating a prolonged
stay in the hospital.

12. Further research

More research is needed to determine whether mechanical ventilation increases the risk of
mucormycosis. The risk of lung damage after mechanical breathing has already been discussed
(Ragaller and Richter, 2010). Mechanical ventilation is considered to increase inflammatory response
and, as a result, threat to patient which is shown in Figure 5.

13. Conclusion

In light of the current situation in India, it is critical to address this life-threatening fungal infection.
Mucormycosis prevalence and mortality is very high in Indian COVID-19 patients related to non-
judicious steroid use, high incidence of diabetes mellitus, delays in seeking treatment and diagnosing
and challenges in managing advanced disease condition. It is necessary to pre-empt the risk factors of
Mucormycosis case by case to curtail the outbreaks. Although the impact of mechanical ventilation-


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     Fig. 5 - Can mechanical ventilation increase the risk of Mucormycosis in COVID-19? (KF = Kupffer Cells).



induced mucormycosis remains unproven, careful monitoring need to be done and this study also
emphasizes the need of early diagnosis of the disease for reducing mortality. Lowering the severity
of COVID-19 and reducing the length of hospital stay is utmost important to minimize the hospital-
acquired mucormycosis. Some recommendations to make during COVID-19 management include
judicious use of steroids, hyperglycemia management, and lowering the severity of COVID-19,
extensive debridement of external infected tissues and bones in severe cases, administering liposomal
amphotericin B (AmB) as first-line therapy and Azoles a second-line therapy if AmB contraindicated.

Ethical Considerations
This is a review article and the Institutional ethical committee has confirmed that no ethical approval is required.

Conflict of Interest
The authors have no relevant financial or non-financial interests to disclose.

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