1-S2.0-S1477893923000170-Main - 2024-08-07T202626.797

Travel Medicine and Infectious Disease 52 (2023) 102557
Contents lists available at ScienceDirect
Travel Medicine and Infectious Disease

journal homepage: www.elsevier.com/locate/tmaid
Surge of mucormycosis during the COVID-19 pandemic

Paulami Dam a, Marlon H. Cardoso b, c, d, Sukhendu Mandal e, Octávio L. Franco b, c,
Pınar Sağıroğlu f, Osman Ahmet Polat g, Kerem Kokoglu h, Rittick Mondal a,
Amit Kumar Mandal a, i, **, Ismail Ocsoy j, *
a
Chemical Biology Laboratory, Department of Sericulture, Raiganj University, North Dinajpur, West Bengal, 733134, India
b
S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil
c
Centro de Análises Proteômicas e Bioquímicas, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, Brazil
d
Instituto de Biociências (INBIO), Universidade Federal de Mato Grosso do Sul, Cidade Universitária, Campo Grande, Mato Grosso do Sul, Brazil
e
Laboratory of Molecular Bacteriology, Department of Microbiology, University of Calcutta, 700019, India
f
Department of Medical Microbiology, School of Medicine, Erciyes University, Kayseri, Turkey
g
Department of Ophthalmology, Erciyes University, Kayseri, Turkey
h
Department of Otolaryngology, Erciyes University School of Medicine, Kayseri, Turkey
i
Centre for Nanotechnology Science (CeNS), Raiganj University, North Dinajpur, West Bengal, 733134, India
j
Department of Analytical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, 38039, Turkey
A R T I C L E I N F O A B S T R A C T
Keywords: Patients with respiratory viral infections are more likely to develop co-infections leading to increased fatality.
Black fungus Mucormycosis is an epidemic amidst the COVID-19 pandemic that conveys a ‘double threat’ to the global health
Mucorales fraternity. Mucormycosis is caused by the Mucorales group of fungi and exhibits acute angioinvasion generally in
Mucormycosis
immunocompromised patients. The most familiar foci of infections are sinuses (39%), lungs (24%), and skin
COVID-19
DKA
tissues (19%) where the overall dissemination occurs in 23% of cases. The mortality rate in the case of
Angioinvasion disseminated mucormycosis is found to be 96%. Symptoms are mostly nonspecific and often resemble other
Liposomal amphotericin B common bacterial or fungal infections. Currently, COVID-19-associated mucormycosis (CAM) is being reported
from a number of countries such as the USA, Turkey, France, Mexico, Iran, Austria, UK, Brazil, and Italy, while
India is the hotspot for this deadly co-infection, accounting for approximately 28,252 cases up to June 8, 2021. It
strikes patients within 12–18 days after COVID-19 recovery, and nearly 80% require surgery. Nevertheless, the
mortality rate can reach 94% if the diagnosis is delayed or remains untreated. Sometimes COVID-19 is the sole
predisposing factor for CAM. Therefore, this study may provide a comprehensive resource for clinicians and
researchers dealing with fungal infections, intending to link the potential translational knowledge and pro
spective therapeutic challenges to counter this opportunistic pathogen.
1. Introduction unembellished angioinvasive fungal infection with acute incidence,

rapid progression, and high fatality [3]. Moreover, it is reported as the
During deadly pandemics or epidemics, there are occurrences of co- second most prevalent mould infection that affects immunocompro
infections, which are often understudied. Patients with respiratory viral mised patients [4]. The fungal casual agents mainly belonging to the
infections are more likely to develop one or more co-infections, leading Mucorales group are ubiquitous in nature and are generally present in
to disastrous diseases with increased morbidity and mortality [1]. Both decaying organic matter [5,6]. Currently, COVID-19 patients are pre
in the 1918 influenza outbreak and in the 2009 H1N1 influenza senting with several bacterial or fungal co-infections [7,8]. While
pandemic, history witnessed the fatalities associated with co-infections opportunistic fungal infections represent a matter of concern, mucor
[2]. The COVID-19 pandemic and mucormycosis co-infection are vivid mycosis co-infections are rare, but substantially complicate the health
examples currently faced by mankind. Mucormycosis is an status of COVID-19 patients and overall outcomes [9]. As part of the
* Corresponding author.
** Corresponding author. Chemical Biology Laboratory, Department of Sericulture, Raiganj University, North Dinajpur, West Bengal, 733134, India.
E-mail addresses: [email protected] (A.K. Mandal), [email protected] (I. Ocsoy).
https://doi.org/10.1016/j.tmaid.2023.102557
Received 20 October 2021; Received in revised form 7 November 2022; Accepted 15 February 2023
Available online 20 February 2023
1477-8939/© 2023 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
P. Dam et al. Travel Medicine and Infectious Disease 52 (2023) 102557
ECMM’s (European Confederation of Medical Mycology) ‘One World These genera exhibit significant variation in geographical regions.
One Guideline’ project, authors recruited from 33 countries (UN re Apophysomyces infection is not found in Europe or Africa, whereas the
gions) analyzed the existing studies on mucormycosis management and genus Lichtheimia is prevalent in Europe [20]. This variation in infection
presented a consensus guideline that addressed regional disparities [10]. prevalence might be due to biotic or abiotic factors like temperature,
Notably, this co-infection is now increasing worldwide, and India is the humidity or the presence of organic content associated with the optimal
worst hit. India is grappling with a sharp rise of COVID-19 cases in a growth of the causal agents in different geographical locations. In India,
more fatal second wave compared to the first one. Mucormycosis or Rhizopus sp. (79.7%) is the main cause of the disease, and Apophysomyces
‘Black Fungus’ infections are reported to co-affect COVID-19 patients, variabilis (7.9%) comes in second place [21]. Rhizopus arrhizus is the
with about 70% of the global mucormycosis cases reported in March predominant fungus of the Rhizopus genus in India, but cases of Rhizopus
2021 [2,11]. We have reviewed its causal agents, determinants, distri microsporus and Rhizopus homothallicus are reported to be increasing
butions, clinical manifestations, pathogenesis pattern, virulence factors, [22]. In this country, Lichtheimia sp. are widely found in alkaline soils
clinical case reports, diagnosis methods, and management procedures with low nitrogen content and cause 0.5%–13% of cases [22]. Other rare
along with the futuristic drugs in the pipeline. We have also predicted species that contribute to mucormycosis in India are reported to be
the possible reasons for its sudden increase in several countries, as well Rhizomucor pusillus, Mucor irregulari, Saksenaea erythrospora and Tham
as a plausible future trend of fungal co-infections during the next waves nostylum lucknowense [22].
of the COVID-19 pandemic. When Aspergillosis is compared with mucormycosis, a lot of parallels
and some significant distinctions are observed [23]. Both infections are
2. Taxonomy of mucormycosis causing fungi caused by inhaling spores followed by the formation of invasive hyphal
structures, subsequent invasion and obstruction in blood vessels in
In the preceding morphology-based classification system, fungi support of the hematogenous spread [24]. The characterization of
reproducing by ‘zygospore’ were assigned under the phylum Zygomy Mucorales is based on their rapid proliferation and formation of
cota [12], which was not validated and was discarded due to a lack of distinctive mycelia. The single-celled asexual spores/sporangiospores
molecular phylogenetic support. Consequently, its subphylum Mucor are produced endogenously within the sporangium, a large spore sac
omycotina was designated as ‘incertae sedis’, which means a taxon not that is even visible to the naked eye [14,18]. Often, merosporangia
allocated to a higher taxon [13]. Walther and co-workers, in their re (elongated with countable spores) or sporangiola (globular with
view, presented the fact that the Mucoromycotina was improperly cited countable spores) are seen in place of sporangia (globular with
under the subphylum Glomeromycota in several articles [14]. Later, in numerous spores). They are accordingly named depending on their
the phylogenetic analysis, it was revealed that zygomycetes were shape and quantity of sporangiospores inside them [14]. Unique for the
described by two new clades sharing paraphyletic connection: phylum order Mucorales is columella, which is a noticeable sterile mid-vesicle
Mucoromycota and phylum Zoopagomycota [15]. Mucoromycota was within the sporangium and becomes prominent after the liberation of
placed as a sister clade to the Ascomycota and Basidiomycota. Mucor the spores [18]. They produce pigmentless, broad (having an irregular
omycota predominantly involves three subphyla i.e., Glomeromycotina, diameter of approximately 5–20 μm), slender-walled, ribbon-shaped
Mortierellomycotina, and Mucoromycotina, where the latter one is hyphae along with a small number of occasional septae (also called
comprised of the orders Mucorales (commonly decomposers and para pauciseptate) and right-angled branches [25]. Hence, they are typically
sites of plants), Umbelopsidales (e.g., endophytes and saprobes), and characterized by these features and described as aseptate fungi. The
Endogonales (e.g., ectomycorrhizas and saprobes) [15]. Distinctively, hyphae might have different widths with pleated, ruffled or fragmented
Zoopagomycota includes the order Entomophthorales [15]. Because of forms [26]. Thick-walled globular structures may develop in the hyphal
the phylogenetic distance of Mucorales and Entomophthorales, the term tip that might convert to a spore-forming body and eventually, on
‘zygomycosis’ (infection caused by zygomycetes) was discarded in maturation, might disperse to air [26].
favour of ’mucormycosis’ (infection associated with the order Mucorales
as the causal agent) and ’entomophthoromycosis’ (infection associated 4. Determinants and distribution of mucormycosis
with the order Entomophthorales as the causal agent) [14]. In immu
nocompetent individuals from subtropical and tropical areas and espe For the onset of this fungal infection, diabetes mellitus (DM) and DM-
cially from developing countries, entomophthoromycosis results in associated ketoacidosis (DKA) (in the case of Asia), as well as haema
long-term subcutaneous and mucocutaneous infections. In contrast, tological malignancy and solid organ/bone-marrow transplantations (in
mucormycosis exhibits acute angioinvasion in people with compromised the case of Europe and USA) represent the major risk factors. Moreover,
immune systems, in the case of developing or developed countries, and history of other surgeries, trauma, neutropenia, protein-calorie malnu
accounts for high fatality rates [16,17]. trition, autoimmune disease, chronic kidney disease or renal failure, HIV
infection, deferoxamine therapy, corticosteroid therapy, etc. are also
3. Salient features of mucorales reported to be on the list of risk factors across the globe [27,28]. Along
with human health conditions, other factors like seasonal variation,
The order Mucorales includes 55 genera and 261 species, of which 38 survival from natural disasters, etc., contribute to the predisposing
species are known to cause mucormycosis infection in humans [14]. agents [29,30]. Jeong and team investigated the cases during the
Mucorales, unlike other ascomycetes fungi, require a greater level of 2000–2017 time period and reported that DM was more frequently
humidity for survival, growth, and spore germination [18]. Roden and observed in 340 patients out of 851 cases (40%) suffering from mucor
colleagues reported a variable extent of pathogenicity caused by mycosis, whereas steroid use, haematological malignancy, solid organ
different genera of Mucorales. Based on the clinical context, the major transplantation and neutropenia were seen in 33%, 32%, 14%, and 20%
genera include Rhizopus (47%), Mucor (18%), Cunninghamella (7%), of the cases respectively. Patients from African or Asian countries were
Saksenaea (5%), Absidia (5%), Apophysomyces (5%), and Rhizomucor found to be prone to DM. Among the major trauma-related cases, 33% of
(4%), as detected in the tissue samples of mucormycosis-infected pa cases were observed in case of accidents (motor vehicle-related and
tients [19]. In a recent review, it was mentioned that Rhizopus is the others) and 30% of cases were involved with health-related issues,
predominant genus, accounting for about 48% of the cases, where including gynaecological, gastrointestinal, orthopaedic and cardiovas
Rhizopus arrhizus single-handedly contributed to 33% of the cases, fol cular procedures. About 5% of the cases were documented in survivors
lowed by Mucor (14%) and Lichtheimia (13%) [20]. Infection by Cun of natural disasters (tsunami or tornado) [20]. As per the US-based study
ninghamella resulted in a considerably greater fatality (77%) than that of (1992–1993) by Rees and colleagues, 17.3 cases/million population/
the other Mucorales [19,20]. year were recorded for the infection among 2.94 million populations in
2
three cumulative countries (Alameda, San Francisco, and Contra Costa), [51–59]. The most familiar foci of infections were reported to be in the
where the predisposing factors included chronic lung disease (9.3%), sinuses (39%), lungs (24%), and skin tissues (19%) [60] where
DM (9.9%), non-haematological malignancy (14.7%) and, interestingly, dissemination occurred in 23% of these cases [30]. The mortality rate
HIV infection (47.4%) [31]. But mucormycosis cases gradually dis was found to be 96% for disseminated mucormycosis, 85% for
played a sharp increase worldwide. For instance, in Japan, cases climbed gastrointestinal-infected patients, and 76% for pulmonary infection
from 0.01% to 0.16% within twenty years (1969–1989) [32]. This up [30]. Infant skin and gut are more vulnerable in comparison with adults
ward trend of mucormycosis was also noted in European countries like [61]. DM was found to be associated with rhinocerebral mucormycosis
Belgium, Spain, France, and Switzerland. In Belgium, as per a ten-year cases, whereas haematological malignancies were linked with dissemi
(2000–2009) study report, the cases increased to 0.148 cases/10,000 nated infection. Trauma was associated with cutaneous mucormycosis,
patients from 0.019 cases/10,000 patients, with an average increase of and a history of solid organ transplantation was involved in the cases of
0.058 cases/10,000 patients [33]. Belgian patients with haematological pulmonary, gastrointestinal or disseminated mucormycosis [20]. Clin
malignancies were found to be the individuals most vulnerable to ical manifestation patterns in India are parallel with the worldwide
mucormycosis. A ten-year (1997–2006) case analysis report from France trend. Rhino-orbital-cerebral mucormycosis (with/without brain
showed that 0.7 cases/million population were documented in 1997, involvement) is the most common example in India, followed by cuta
which amounted to 1.2 cases/million population in 2006. DM and the neous and pulmonary infections [21]. (Fig. 1).
arbitrary use of antifungal drugs were thought to be the main reasons for Rhino-Orbital-Cerebral mucormycosis Rhino-orbital-cerebral
this rise in France [34]. In Spain, 1.2 cases of mucormycosis were mucormycosis is the most common type of mucormycosis. After
observed among 100,000 patients admitted before 2006, but in the inhaling the sporangiospores into nasal mucosa, the infection pro
2007–2015 period, the cases increased to 3.3 per 100,000 patients [35]. liferates from the sinuses to the brain via the orbital area [62]. General
According to the analysis, 52.6% of patients were suffering from both non-ocular signs and symptoms are fever, headaches, facial numbness
trauma or surgical wounds and haematological malignancies, and 68% and pain, often accompanied by nerve palsy, nasal discharge, nasal ul
of patients received antifungal drugs [35]. Nevertheless, in Switzerland, ceration, sinusitis, hemiplegia, eschars (black necrotic tissues), and
a sharp rise in clinical cases was documented after 2003 (6.3 cases/100, mental deterioration [27]. Initial symptoms resemble bacterial sinusitis
000 admissions/year) in comparison with the time before 2003 (0.57 [63]. The ocular symptoms are reported to be eye pain, visual changes,
cases/100,000 admissions/year) [36]. The risk factors were found to be proptosis, chemosis, ptosis, ophthalmoplegia, orbital cellulitis, and
variable, and the study revealed that several reasons might have trig periorbital discolouration along with necrosis [27]. Imaging studies
gered the invasive cases, including the use of antifungal drugs such as reveal thick mucosal lining, sinusitis with mild to severe lesions, and
caspofungin and/or voriconazole, etc., the high number of allogeneic erosion of nasal septal bones, orbital, and jawbones. However, extended
bone marrow transplants or immunosuppressive drugs [36]. However, infection exhibits soft tissue infiltration, orbital cellulitis, optic neuritis,
the mucormycosis burden in different countries such as Algeria, bone rarefaction, infarcts, intracranial abscess, and skull bone erosion.
Argentina, Australia, Belgium, Brazil, Cameroon, Canada, Chile, The infection route follows the sino-nasal or retro-orbital region,
Colombia, Czech Republic, Denmark, Dominican Republic, France, ethmoid-sphenoid sinus and/or superior orbital fissure. It reaches the
Greece, India, Ireland, Japan, Jordan, Kazakhstan, Kenya, Korea, brain by the perineural pathway or the way through the cribriform plate
Malawi, Mexico, Nigeria, Norway, Pakistan, Philippines, Portugal, [27]. The pterygopalatine fossa was found to be the reservoir of fungi
Qatar, Romania, Russia, Serbia, Spain, Thailand, Ukraine, United [62]. The mortality rate harshly increases soon after cranial invasion
Kingdom (UK), USA and Republic of Uzbekistan were thoroughly [63]. Cerebral infection can also be acquired through dissemination
reviewed by Prakash and team [27]. from a distant organ following a hematogenous path [27].
The mucormycosis burden in India was 0.14 cases per 1000 popu Pulmonary mucormycosis Pulmonary mucormycosis clinical pat
lation, with 38.2% deaths per year during the pre-COVID-19 period terns are often misinterpreted as pulmonary Aspergillosis. Patients
[37]. The usual occurrence of mucormycosis in India is estimated to be frequently have a high fever (>38 ◦ C) that does not respond to broad-
70-times higher than global data [22]. However, an individual health spectrum antibiotics. Symptoms include nonspecific cough and rarely
facility in India has recorded three successive case series of mucormy dyspnea, hemoptysis, and pleuritic chest pain. Diabetic patients are
cosis: 129 cases over the subsequent ten years (from 1990 to 1999), 178 often accompanied by endobronchial or tracheal lesions, especially in
cases in five years (from 2000 to 2004) and 75 cases in an diabetics, resulting in airway obstruction and lung collapse [30,64,65].
eighteen-month timeline (from 2006 to 2007) [38–40]. The total count Chest imaging of a patient with pulmonary mucormycosis exhibits lung
increased from an average of 25 cases/year (1990–2007) to an average infiltration and consolidation, thick wall cavity, multiple nodules,
of 89 cases/year (2013–2015) [41]. Several researchers from various pleural effusion, hilar/mediastinal lymphadenopathies, pneumothorax
regions of the nation also published numerous reports regarding this or air crescent signs [27]. The reversed halo sign is the classic feature of
infection in diverse risk categories [42–48]. However, it is clear that pulmonary mucormycosis, which is generally found to be unilateral
mucormycosis cases exhibit an increasing trend. In a recent study of 388 (usually the upper lobe is associated, followed by the lower lobe and
mucormycosis cases, the mortality rate was found to be 46.7%, which middle lobe, respectively), seldom bilateral, hilar/mediastinal [27].
was significantly associated with poorly managed DM (56.8%) and Cutaneous mucormycosis Cutaneous mucormycosis is classified
trauma (10.2%) [41]. Most cases and mortality incidents were reported into primary cutaneous mucormycosis involving the direct inoculation
in North India (82.7%), and cases of post-tubercular mucormycosis were onto the skin by the degeneration of cutaneous barrier-breach and sec
notably observed [27,41]. ondary cutaneous mucormycosis where dissemination from other
infected areas (generally rhinocerebral infection) seeds the disease.
5. Clinical manifestations Primary can be classified as (i) localized infection (limited to superficial
or deep skin tissues in 32–56% cases) and (ii) deep infection (extends to
According to the clinical spectrum or the epidemiological features of bones or muscles in 24–52% cases) [27]; whereas 16–20% of the cases
mucormycosis, the infection includes chromoblastomycosis, myce exhibit hematogenous dissemination and secondary mucormycosis [27,
tomas, sinusitis, and superficial (Tinea nigra), subcutaneous, cutaneous, 66]. Clinically, the infection is formed as dry, but rapidly growing ulcers
and systemic phaeohyphomycosis [49,50]. Based on the clinical associated with an erythematous halo. Secondary cutaneous mucormy
demonstration and foci of infection, mucormycosis is classified into five cosis often involves necrotic lesions, including erythematous edges and
main clinical patterns: (A) rhinocerebral; (B) cutaneous; (C) pulmonary; eschar as well as necrosis on orbital, nasal or palatal tissues, i.e. the
(D) gastrointestinal; (E) disseminated; and also other rare patterns, rhinocerebral route [67].
including peritonitis, endocarditis, osteomyelitis, renal infection etc. Gastrointestinal mucormycosis Gastrointestinal infections are an
3
Fig. 1. Different types of mucormycosis clinical mani

festation. Based on the clinical manifestation and foci
of infection, mucormycosis is classified into four main
clinical patterns: rhino-orbital-cerebral infection affects
the sinuses, orbital area and can be transmitted to the
brain; pulmonary mucormycosis infects the respiratory
system; gastrointestinal mucormycosis commonly at
tacks the large intestine, stomach and small intestine;
cutaneous mucormycosis is limited to superficial or
deep skin tissues, and occasionally extends to the bones
or muscles. Pathologic symptoms are manifested as the
result of infection caused by the fungi, which belong to
the order Mucorales. Tissue biopsy during laboratory
analysis enables visualization of typical Mucorales
characteristics from tissue samples collected from
infected areas of mucormycosis patients.
uncommon pattern of clinical manifestation that primarily target the same cluster, whereas Lictheimia sp. appeared in a different cluster.
large intestine (~43.2%) followed by the stomach (~33%) and small Rhizopus sp. is often isolated from patients with rhino-orbital-cerebral
intestine (~28.4%). The stomach is commonly targeted in adults, mucormycosis and forms a prominent single cluster within the phylo
whereas the intestine is considerably involved in children [68]. Symp genetic tree. Cunninghamella sp. and Rhizomucor sp. are more common in
toms are nonspecific and the diagnosis is often missed or impeded. patients with pulmonary disease. Such clustering can be observed be
Symptoms include fever, abdominal pain, gastrointestinal bleeding, tween Rhizomucor pusillus and Cunninghamella bertholletiae. Rhizomucor
bowel change, etc. [69]. It is significantly found in premature neonatal variabilis is found in a separate clade with Mucor sp. A closure look at the
cases and patients with malnutrition, reaching a mortality rate of 85% phylogenetic tree revealed three various clades: Clade 1, which consists
[68]. of cutaneous mucormycosis predominant species Apophysomyces sp.,
Disseminated mucormycosis All of the above-mentioned infections Lichtheimia sp. and Saksenaea sp.; Clade 2 includes Rhizopus sp., the most
might evolve into the disseminated type of mucormycosis, which in prominent rhino-orbital-cerebral mucormycosis causative organism;
volves two or more widely distant organ systems. These are highly rare and Clade 3 includes Mucor sp., which is present in almost all clinical
and usually occur in critically immunocompromised people or patients manifestations, even though Mucor sp. elicits the predominance of
who received deferoxamine therapy [70]. Dissemination commonly cutaneous mucormycosis. The prevalence of causative organisms for
arises from the lungs, gastrointestinal tract, trauma, or deep cutaneous pulmonary mucormycosis is found within Clade 1 only. It can be hy
lesions. However, the brain is a usual target area after angioinvasion, pothesized that the Mucorales causative organism may show any type of
and metastatic lesions are also discovered in the heart, liver, spleen, and clinical manifestations based on the predominant condition; however,
other organs [30]. the type of mucormycosis is based on the species dominance, well
Phylogenetic analysis In the present review, we provide a phylo determined from the phylogenetic tree.
genetic analysis of the causative Mucorales organism [20] based on its
ITS regions using MEGA7 [71] and the neighbor-joining method [72] on 6. Pathogens and their virulence factors
the Jukes-Cantor model [73] by applying 1000 bootstrap replications
(Fig. 2). The virulence factors associated with various types of mucormycosis
We have tried to focus the phylogenetic relationship on the varied are an interesting parameter to understand the epidemiology of the
clinical manifestation of mucormycosis. It has been noted in past studies disease, particularly when the disease has many clinical manifestations,
that several predisposing conditions are associated with various clinical and is caused by several fungal causal agents of a given Mucorales order.
manifestations [20]. The role of the causative agents in the varied Moreover, Rhizopus and Mucor species are found to be the most preva
clinical manifestations may have a specific influence on the type of lent agents for this disease. Additionally, the reported virulence genes of
mucormycosis. The phylogenetic study has been carried out upon such a Rhizopus arrhizus have been retrieved from the National Center for
backdrop to find the segregation of the different Mucorales genera that Biotechnology Information (NCBI) database (https://www.ncbi.nlm.nih
is reflected in clinical manifestations. Compared with other genera, .gov/), and each gene was subjected to protein-protein Blast analysis to
Apophysomyces sp., Lichtheimia sp. and Saksenaea sp. were more obtain its occurrence in species of other Mucorales groups. Frt1, Fet3,
commonly found in patients with cutaneous mucormycosis. In the Mpp, rfs, bycA, cotH, chi3 are the major virulence genes reported asso
phylogenetic tree, Apophysomyces sp. and Saksenaea sp. appeared in the ciated with Rhizopus arrhizus pathogenesis [74–76]. It has been found
4
Fig. 2. The Neighbor-joining tree is based on ITS

sequences of the causative agents of mucorales. The
bootstrap value is shown at the branch node from
1000 replicants. The phylogenetic tree represents
three varied clades: Clade 1 is composed of predom
inant species Apophysomyces spp., Lichtheimia spp.
and Saksenaea spp.that cause cutaneous mucormy
cosis; Clade 2 is composed of Rhizopus spp, the most
prominent causal agent for rhino-orbital-cerebral
mucormycosis; and Clade 3 includes Mucor spp,
which shows almost all clinical manifestations.
that many of these genes are distributed in species of Rhizopus, Mucor, an additional source for the development of a new type of
Lichtheimia, Apophysomyces, Phycomyces, Absidia, Parasitella, and mucormycosis.
Thamnidium, many of which are not reported as pathogenic strains.
Based on the abundance of these virulence genes among various closely 7. Pathogenesis and host defense
associated and so far identified pathogenic and non-pathogenic genera,
a significant concerns still arise, as the non-pathogenic species might The genome sequence in Rhizopus arrhizus is extremely repetitive
become pathogenic due to virulence genes. This possibility makes them compared to other fungi, with several transposable genetic elements,
Fig. 3. Molecular mechanism of mucormycosis

pathogenesis: interaction of Mucorales with host
endothelial cells and host factors impacting the im
mune response. Acidifying factors present in the
host’s blood vessels induce the release of iron from
host carrier proteins (e.g., transferrin, lactoferrin,
ferritin, among others). Consequently, the concen
tration of free irons increases in the blood serum.
Additionally, a higher concentration of glucose, free
iron and ketone bodies, including β-hydroxybutyrate
(BHB) (as found in DKA patients), increases GRP78
expression in the host endothelium. Fungal CotH in
teracts with GRP78 and promotes angioinvasion.
Fungal ferric iron reductase and siderophores help to
absorb the maximum iron available and facilitate
fungal growth and proliferation in Mucorales. Higher
concentrations of glucose, free iron, and BHB also act
as the positive regulators of fungal growth. Moreover,
ketone bodies and free iron present in the serum
inhibit the host immune response cascades. In
contrast, sodium bicarbonate (NaHCO3) can reverse
this phenomenon.
5
accounting for nearly 20% of the genome [77]. An ancestral time-dependent manner [94]. Platelets secrete pro-inflammatory and
whole-genome duplication, along with the recent gene duplication anti-inflammatory cytokines and chemokines, leading to the activation
events, have provided shreds of evidence in support of the amplification of monocytes and dendritic cells. However, natural killer (NK) cells also
of several gene families related to energy production, cell growth, signal produce chemokines and cytokines [85]. NK cells exhibit cytotoxic ef
transduction, as well as fungal virulence proteins (e.g., aspartic protease, fects against Rhizopus arrhizus hyphae and damage the structure when
etc.) leading to substrate-degradation and angioinvasion in the host assisted by perforin and other antifungal factors [95].
[77]. Mucormycosis has been characterized by extensive angioinvasion
(Fig. 3) with limited inflammatory response, which leads to thrombosis 8. Mucormycosis: amidst COVID-19 period
in the blood vessels and necrosis of neighbouring tissues [78]. Tissue
necrosis inhibits the accumulation of the immune cells into the foci of The actual prevalence of mucormycosis is hard to determine, due to
infection and promotes angioinvasion that, subsequently, may lead the the lack of a population-based investigation. Kanwar and colleagues
pathogens to spread to several target organs. Hence, pathogen interac hypothesized that the actual number of COVID-19-associated mucor
tion with the endothelium of blood vessels is thought to be the crucial mycosis (CAM) cases is likely to be much higher than those reported due
stage in its pathogenesis. Rhizopus, dead or alive, damages the endo to challenges faced during diagnosis or detection, aided by emerging
thelial cells, followed by adhesion and phagocytosis [79]. case reports [96]. During the COVID-19 period, many studies were re
Researchers have recognized glucose-regulated protein 78 (GRP78) ported globally on CAM complicating COVID-19 or vice-versa. The cases
as a unique receptor present in the host endothelium that selectively have been documented in the USA, Turkey, France, Mexico, Iran,
interacts with Rhizopus [80]. Moreover, higher glucose and iron con Austria, UK, Brazil, and Italy, etc. Still, the number of cases reported was
centrations, usually found in DKA patients (Fig. 3), were reported to far less than in India, which emerged as a global hotspot of CAM
increase GRP78 expression and facilitate angioinvasion in a infection (Table 1).
receptor-dependent mode [80]. These findings shed light on the reason Mucormycosis, colloquially called the deadly ‘black fungus’ in India,
that DKA patients have been vulnerable to mucormycosis. Another has been increasing dramatically throughout the past months since the
fungal ligand, CotH (spore coat protein homologs), was found in ‘second wave’ of the pandemic hit India. As per the central government’s
Mucorales (Fig. 3). Therefore, CotH-GRP78 interaction was considered recommendation, states declared it as a ‘Notifiable Epidemic’ under the
to be the key strategy in specific host-pathogen interaction during Epidemic Diseases Act, 1897, and urged people to follow ICMR, India,
mucormycosis pathogenesis [81,82]. In order to install an infection, for the screening, diagnosis, and management [97]. Moreover, every
fungal spores have to penetrate and evade the host immune system for case has been documented by the Department of Health, Govt. of India
further spore germination and hyphal growth. The study confirms that and Integrated Disease Surveillance Project (IDSP) surveillance system
the immunocompetent hosts do not necessarily develop mucormycosis [97]. The national capital of India, Delhi, issued ‘The Delhi Epidemic
[83]. As sporangiospores are readily aerosolized and released into the Diseases (Mucormycosis) Regulations, 2021’ to combat the fungal
atmosphere, the respiratory tract is the most common entry point for the infection immediately after declaring it an epidemic [98]. India had
pathogen [84]. An immunocompetent host exhibits several defence accounted for more than 28,252 cases up to June 8, 2021, and Maha
strategies against fungal invasion, including innate immunity, me rashtra (6339), and Gujarat (5486) reported approximately half of the
chanical barriers of skin/mucosa, and nutritional immunity (i.e., gen cases [99]. Black fungus infection is striking patients within 12–18 days
eration of the iron-poor environment), etc. [85]. For successful after COVID-19 recovery, and nearly 80% require surgery. Nevertheless,
pathogenesis, metal nutrients (e.g., iron) are required to be absorbed by the mortality rate can reach 94% if the diagnosis is delayed or untreated
the microbes for their growth. In turn, the host organism regulates the [100].
concentration of available metals to defend itself from microbial in From September 2020 to December 2020, Patel and colleagues su
vaders [86]. The strategy of narrowing iron availability by binding it to pervised a multicenter epidemiological investigation across India to
the sequestering proteins like transferrin, lactoferrin, and ferritin pre assess the consequence of CAM cases and found a prevalence of 65.2%, i.
sent in the host, is considered the universal host defence mechanism e. 187 of 287 mucormycosis patients were affected by COVID-19.
against fungal invasion [87,88]. During lower iron availability, fungi Interestingly, it was a 2.1-fold hike in mucormycosis cases if compared
produce high-affinity ferric iron reductase and synthesize iron-chelators to the mucormycosis cases of September 2019–December 2019 [101].
or ’siderophores’ to absorb the maximum iron available [87] (Fig. 3). Not only DM but also COVID-19 was the sole predisposing factor in
Rhizopus secretes rhizoferrin, a polycarboxylate-type siderophore [89]. 32.6% of CAM patients, but COVID-19-related hypoxia and erroneous
Notably, DKA patients are reported to have high levels of free iron in use of steroidal drugs were also found to be associated with CAM inci
serum, which aids the growth of Rhizopus arrhizus at a range of acidic pH dence [101]. In this particular timeline, the mortality rate was 45.7%,
(7.3–6.88) [88]. with no distinction between CAM and non-CAM cases [101]. Report 1 of
Mononuclear and polymorphonuclear phagocytic cells are respon the COSMIC study (January 1, 2020–May 26, 2021) conducted by Sen
sible for host defence and pathogen killing by oxidative and non- and team, which involved rhino-orbital-cerebral mucormycosis and
oxidative mechanisms [83,90,91]. Macrophages phagocytose the managed by Indian ophthalmologists, was recently published. It showed
invaded spores. Spores that escape from the macrophage defence and that Gujarat (22%) and Maharashtra (21%) are the worst hit states
germinate into newly synthesized hyphae stimulate chemotaxis of [102]. The patients’ mean age was found to be 51.9 years with male
neutrophils, which phagocyte these fungal pathogens [85,92]. Neutro dominance (71%) and oxygen support (57%), steroid use (87%), as well
phils produce reactive oxygen species (ROS), cationic peptides, perforin, as DM (78%) reported as the predisposing factors [102].
and other enzymes for pathogen degradation. These cells also express Rhino-orbital-cerebral mucormycosis tended to begin between the 10th
pro-inflammatory cytokines, including TNF-α, IL-1, INF-γ, etc. that to 15th days after COVID-19 detection. Herein, 56% developed the
induce other inflammatory cells to trigger the host’s immune response disease during COVID-19 and 44% exhibited delayed onset. Overall
[85]. In addition, Rhizopus hyphae activate TLRs (toll-like receptors) mortality was found to be 14% after the final follow-up [102].
present on the phagocytes (e.g., polymorphonuclear neutrophils) and
bind to PAMPs (pathogen-associated molecular patterns) of the path 9. Prevalence of CAM: statistical perspective from clinical case
ogen surface. TLRs, along with the other receptors, perform a critical reports
role in fungal recognition and activate the signalling cascade in host
cells [84,93]. Platelets with their granule-dependent mechanism adhere The odds ratio was performed to determine the association between
to fungal hyphae and conidia [94]. They facilitate hyphal damage by the outcome status (died or discharged) of patients affected by mucor
inhibiting hyphal elongation and conidia germination in a mycosis and different prognostic factors of those patients. Data from
6
P. Dam et al.
Table 1
Worldwide clinical case reports on COVID-19 associated mucormycosis (CAM).
Origin No. Age, Sex Comorbidity/Past Symptoms COVID-19 Treatment received for Mucormycosis Mucormycosis Clinical presentations Fungi Antifungal Surgery Outcome References
of medical history associated with Confirmed/ COVID-19 Confirmed/ type isolated treatment
cases COVID-19 Suspected And Suspected
Active/
Recovered
USA 2 36/M Type-II DM, DKA – Confirmed Remdesivir Confirmed Rhino-cerebral Proptosis, periorbital – Amphotericin No Died [164]
edema and B,
conjunctival isovuconazole,
chemosis, optic disc micafungin
pallor, retinal
whitening
48/M Type-II DM, DKA – Confirmed Remdesivir, Confirmed Rhino-cerebral Right eye proptosis, Rhizopus sp. Amphotericin No Ongoing
convalescent plasma right upper eyelid B,
and intravenous eschar, and isovuconazole
dexamethasone conjunctival chemosis
USA 1 60/M Type-I DM, asthma, Dyspnea, Confirmed/ Remdesivir, Confirmed Rhino-Orbital Proptosis, Rhizopus sp. Amphotericin Yes Died [165]
hypertension, hypoxia, ARDS Active Dexamethasone, opacification of B, Caspofungin,
hyperlipidemia Convalescent plasma sinuses, erythema and Posaconazole
edema of the eyelids,
conjunctival
chemosis.
USA 1 41/M Type-I DM Loss of taste, Confirmed/ Steroids and Confirmed Rhino-cerebral Deep radiating pain in – IV abelcet Yes Discharged [166]
cough Active hydroxychloroquine, nose, black eschar in
palate, necrotic
mucosa in nasal
sinuses, intracranial
7
abscess, sinus
thrombophlebitis,
vein thrombosis,
extensive granulation
in sinus.
USA 1 79/M DM, hypertension Fever, rigor, dry Confirmed/ Ceftriaxone, Suspected Pulmonary Extensive bilateral Rhizopus Amphotericin B Yes Discharged [53]
cough, severe Active Azithromycin, pneumonia and new arrhizus, to a long-
shortness of development of Aspergillus term acute
breath, Remdesivir, bilateral upper lobe fumigatus care facility
tachycardia Dexamethasone cavitations
USA 1 68/M Type-II DM, Nonproductive Confirmed/ Remdesivir, Confirmed Cutaneous Purplish skin Rhizopus Amphotericin Yes Died [113]
hypertension, cough, non- Active Hydroxychloroquine, discoloration, microsporus B, Posaconazole

chronic kidney bloody diarrhea, Methylprednisolone infection burrowing
disease, obstructive fever, respiratory Convalescent plasma towards omentum,
sleep apnea, symptoms extending deep in the
orthotopic heart right chest cavity,
transplantation musculature and
sternal wound.
USA 1 56/M End-stage renal Fatigue, Confirmed/ Methylprednisone, Confirmed Pulmonary Dense consolidation Rhizopus Amphotericin Yes Died [96]
disease on shortness of Discharged and tocilizumab, in right lower lobe azygosporus B,
hemodialysis breath, readmitted after convalescent plasma with lung necrosis, posaconazole,
hemoptysis 5 days necrotic tissue and isavuconazole
purulent exudate in
lungs
USA 1 33/F Hypertension, Vomiting, cough, Confirmed/ Remdesivir, Confirmed Rhino-orbital- Acutely altered – Amphotericin B No Died [125]
asthma, untreated shortness of Active Convalescent plasma cerebral mental status, left eye
breath, mild ptosis, proptosis,
(continued on next page)
P. Dam et al.
Table 1 (continued )
Active/
Recovered
diabetic tachycardia, fixed dilated pupil,

ketoacidosis hypertension, complete
and tachypnea ophthalmoplegia,
secretions in palate,
cerebral edema
USA 1 49/M Insignificant Fever, cough, Confirmed/ Ceftriaxone, Confirmed Pulmonary Tension Rhizopus sp. Amphotericin Yes Died [138]
shortness of Active Azithromycin, pneumothorax with B.
breath, Remdesivir, bronchopleural
pneumonia Dexamethasone, fistula, necrotic
Convalescent plasma, pleural empyema
Tocilizumab
Turkey 11 61-88/M: DM, hypertension, ARDS Confirmed/ Dexamethasone Confirmed Rhino-orbital Eye proptosis, Mucor sp. Amphotericin Yes Discharged: [167]
9, F: 2 hyperthyroidism, Active ophthalmoplegia, B, Voriconazole 4 Died: 7
COPD, coronary orbital pain,
artery disease, conjunctival
renal failure, hyperemia/chemosis,
myelodysplastic ptosis, fixed and
syndrome, dilated pupil,
endophthalmitis,
vision loss
Turkey 1 56/F DM Hypoxia, Confirmed/ Broad-spectrum Confirmed Rhino-cerebral Proptosis in the right Mucor sp. Amphotericin B Yes Died [168]
hyperglycemia, Recovered antibiotics, eye, restricted eye
8
electrolyte corticosteroids movements, edema

imbalance and (methylprednisolone) and color change in
metabolic the nasal area
acidosis
France 1 55/M Follicular Fever Confirmed/ Systemic steroids Confirmed Pulmonary – Rhizopus Amphotericin B No Died [169]
lymphoma Active microsporus,
Aspergillus
fumigatus
Mexico 1 24/F DM, DKA, obesity Hypoxia, Confirmed/ – Confirmed Rhino-cerebral Left facial pain, lid - Amphotericin B No Died [170]
Respiratory Active swelling, edema &
failure proptosis, maxillary
hypoesthesia,

hyperemic
conjunctiva, swelling
and proptosis of
sinuses
Iran 2 40/F None Respiratory Confirmed/ Remdesivir, Confirmed Rhino-orbito Bilateral visual loss, – Amphotericin B Yes Died [171]
symptoms Active levofloxacin, cerebral periorbital pain,
dexamethasone complete
blepharoptosis,
ophthalmoplegia,
mild proptosis,
opacifications of
sinuses and spaces,
necrotic tissues in
sinuses
54/M Type-II DM – Confirmed/ Remdesivir, Confirmed Rhino-orbital Orbital pain, – Amphotericin Yes Discharged
Active levofloxacin, periorbital swelling, B; Posaconazole
dexamethasone vision loss,
P. Dam et al.
Active/
Recovered
blepharoptosis,
proptosis, chemosis,
unilateral
opacifications,
blackish necrotic
tissues
Iran 1 61/F – – Confirmed/ Remdesivir, interferon- Confirmed Rhino-orbital Hemifacial numbness, – Systemic Yes Outcome not [108]
Recovered and alpha, and systemic decreased visual antifungal mentioned
readmitted after corticosteroid. acuity, chemosis, drugs
1 week black eschar on the
skin, proptosis, frozen
eye, complete loss of
vision, fixed
mydriasis, complete
opacification of sinus,
mucosal necrosis
Iran 1 50/F Type-II DM, Dry cough, Confirmed/ Remdesivir, Confirmed Rhinosinusitis Facial swelling, facial Rhizopus Amphotericin B Yes Discharged [172]
hypertension, shortness of Recovered and Dexamethasone numbness, periorbital oryzae after 28 days
gastric bypass breath, myalgia, readmitted after edema, erythema,
surgery fatigue 5 days necrotic eschars on
the palate and nasal
turbinates
9
Austria 1 53/M Myelodysplastic Fever, ARDS Confirmed/ Tocilizumab, Confirmed Pulmonary – Rhizopus Not No Died [173]
syndrome, Active Prednisolone during microsporus administered
depression. postmortem
UK 1 22/M Necrotic N.A. Confirmed/ N.A. Confirmed Disseminated Florid fibrinous Mucorales Not NA Died [174]
hemorrhagic Active during pericarditis administered
pancreatitis postmortem containing fungal
hyphae, thrombotic
endocarditis
Brasil 1 86/M N.A. Acute diarrhea, Confirmed/ Ceftriaxone, Confirmed Gastrointestinal Two giant gastric – Not No Died [105]
cough, dyspnea, Active azithromycin, ulcers with dirty administered
and fever oseltamivir, debris and a deep
hydrocortisone hemorrhagic base

Italy 1 66/M Respiratory Arterial Confirmed/ Hydroxychloroquine, Confirmed Pulmonary Buried cavitary Rhizopus sp Amphotericin No Died [109]
symptoms hypertension, Active lopinavir-ritonavir, lesions in the lingula B,
urinary tract piperacillin- of the left lung upper isavuconazole
infection tazobactam, lobe, rupture of the
levofloxacin cavities previously
observed in the
pleural space and
bilateral pleural
effusion
India 1 Middle- Newly detected DM Fever Confirmed/ – Confirmed Rhino-orbito- Left eye ptosis, facial Rhizopus sp. Amphotericin B Yes Discharged. [175]
aged/F Active cerebral pain,
ophthalmoplegia,
vision acuity loss,
orbital apex
syndrome,
opacification of
sinuses, polypoidal
P. Dam et al.
Active/
Recovered
mass into sinuses with

pus, acute infarct
India 1 32/F DM None Confirmed – Confirmed Rhino-orbital/ Left eye complete – Amphotericin B Yes Discharged [176]
during Paranasal ptosis and left facial due to
hospitalization/ pain, nasal pus, financial
Active opacification of constraints.
sinuses, subperiosteal
abscess, optic neuritis
India 23; Age range DM: 21, – Confirmed: 23/ Systemic Confirmed: 23 Paranasal: 23, – – Amphotericin B Yes Ongoing [177]
M: not Hypertension: 14, Recovered and corticosteroids Intraorbital: 10,
15, mentioned Renal failure: 1 readmitted: 19 Intracranial: 2
F: 8 & Active: 4
India 6 46.2–73.9/ Type-II DM: 6 – Confirmed:6/ Prednisolone, Confirmed: 5, Rhino-orbito- Periocular swelling, – Amphotericin Yes Not known [178]
M:6, F:0 Recovered and dexamethasone, suspected: 1 cerebral: 5, drooping of eyelids, B, posaconazole
readmitted: 5 & methylprednisolone Rhino-orbital: 1 limitation of ocular
Active: 1 (except one case) movements, and
painful loss of vision.
India 1 55/M DM, hypertension, Fever, dry cough, Confirmed/ Dexamethasone, Confirmed Pulmonary Pleural cavity, pleural Rhizopus Amphotericin B Yes Discharged [9]
ischemic breathlessness Active remdesivir effusion microsporus (scheduled)
cardiomyopathy,
end-stage renal
disease
10
India 1 50/M – – Confirmed/ – Confirmed Rhino-orbito- Sinus thrombosis, Rhizopus sp. Amphotericin B No Died [179]
Recovered cerebral conjunctival
congestion, chemosis,
corneal edema,
sinusitis,
panophthalmitis,
proptosis
India 1 38/M Insignificant High grade fever, Confirmed/ Remdesivir, Confirmed Sino-orbital/ Eye swelling and Rhizopus Amphotericin B Yes Discharged [180]
body ache, Active methylprednisolone, Rhino-orbital pain, malaise, oryzae
cough, shortness dexamethasone proptosis, chemosis,
of breath periorbital cellulitis,
partial

ophthalmoplegia,
polypoidal mucosal
thickening in sinuses
India 10 37-78/ DM, hypertension, – Confirmed/ Steroids: 6, Confirmed Rhino-orbito- Facial pain, nasal - Amphotericin B Yes Died: 4 [181]
M:9, F:1 chronic kidney Active Tocilizumab: 1, cerebral block, mucosal Discharged:
disease. remdesivir: 6 thickening of sinuses, 5 Lost
bony erosion, follow-up: 1
India 25 30-74/ DM, Hypertension, – Confirmed: 11/ – Confirmed Rhino-orbito- Unilateral facial - Amphotericin B Yes Died: 2, [182]
M:22, F:3 Leukemia Active cerebral: 6, swelling, retro-orbital Discharged
Rhino-orbital: pain, ptosis, headache or lost to
19 follow up: 23
India 17 39-73/ DM – Confirmed/ Steroids: 16 Confirmed Maxillofacial Facial swelling, - Amphotericin B Yes Died: 6, [183]
M:15 F:2 Active or and rhino- headache, orbital Discharged:
recovered and cerebro-orbital cellulitis, proptosis, 11
readmitted loss of vision,
sinusitis, maxillary
necrosis, edema,
various countries and India, reported by several authors as mentioned in

References
Table 1, were selected to carry out statistical analyses. Here, the
outcome status of the patients is considered as the response variable and
[184]
[185]
the other variables, i.e., age (in years), gender (male or female), co
morbidity factors (diabetes, renal related disease, hypertension, etc.),
discharged:
location of the mucormycosis (rhino-orbital-cerebral, pulmonary, etc.),
Outcome
Died:4,
antifungal treatment by amphotericin B (yes or no), and surgery (yes or
Died
no) are considered as prognostic factors. The odds ratio (OR) and cor
6 responding 95% confidence interval (CI) are carried out for India and
the rest of the world to highlight the significance of the outcome status
Surgery
over the several above-mentioned prognostic factors. This study

Sinusitis, pansinusitis, Rhizopus sp., Amphotericin B Yes
No
revealed that OR of <1 indicates that the presence of prognostic factors

Amphotericin B
is less harmful in relation to expected death for the patients. The reverse
Vancomycin,
Antifungal
result of OR, i.e., OR of >1, specifies the presence of prognostic factors

treatment
that are more harmful to the patients, in relation to an expected fatal

outcome. From the data set, we found that patients from different age
groups are affected by mucormycosis worldwide, including in India.
Mucor sp.
Considering the world data (except India), we found that a 22-year-old

isolated
Clinical presentations Fungi
young male patient was affected by and died from mucormycosis, and an
88-year-old man also died from mucormycosis. These data exemplify
–
right orbital cellulitis,
how a wide range of age groups are affected by this disease with a mean
conjunctival edema,
soft tissue necrosis,
proptosis, sinusitis,
apex or extraconal
exposure keratitis.
(standard deviation; SD) age of 53.39 (SD = 17.25) years. Similar

Eyelid edema,
findings are also observed for India, where the minimum age of the
involvement,
involvement
intracranial
affected patient was a 23-year-old male, and the maximum was a 78-
year-old male. The summary of the patient’s age data is observed with
a mean age of 52.65 (SD = 13.18) years. In both the cases, the mean age
of the patients was found near to 50 years old, which is also reported by
Treatment received for Mucormycosis Mucormycosis
Rhino-Orbital
Sen and colleagues (2021). For the sake of statistical analysis of OR, we
separated the age of the patients into two non-overlapping age groups:
Orbital
(i) patients having an age less than or equal to 50 years old; (ii) and
type
patients who are more than 50 years old. For the global data, the OR of
the patients > 50 years old compared to ≤ 50 years old is 1.5 (95% CI:
Confirmed: 6,
suspected: 4
Confirmed/
Confirmed
0.2184–10.3039), which indicates that patients aged > 50 years have

Suspected
1.5 times high mortality chance than those ≤ 50 years old. However, the
reverse trend has been noted for the Indian context, where the OR of the
patients ≤ 50 years old compared to those > 50 years old is 2.333 (95%
sitagliptin/metformin
methylprednisolone,
CI: 0.6172–8.8206). The result indicates that Indian patients aged ≤ 50

Dexamethasone,
years old had a more than twofold higher mortality rate than patients
dexamethasone,
Meropenem,
>50 years old. Gender-wise infection occurring by the disease has also
tocilizumab,
oseltamivir,
remdesivir
COVID-19
been reported in India and the remaining world. Globally, it has been
found that among all mucormycosis-affected patients, almost 75% were
male (74.19%), and the remaining 25.81% were females infected by
mucormycosis, whereas in India, more than 80% male (80.41%) and
Suspected And
Confirmed/
Confirmed/
19.59% of females were diagnosed with mucormycosis. In the context of

Confirmed
Recovered
COVID-19
death by mucormycosis within the gender classification, it has been

Active/
Active
found that male patients have a 1.8-fold higher mortality rate than fe
males in India (OR: 1.8056; 95% CI: 0.3020–10.7960). However, based
associated with
on world data, females were found to present 1.5-fold higher mortality

Breathlessness,
generalized
rate than males (OR: 1.5; 95% CI:0.2184–10.3039).

tachypnea,
Symptoms
COVID-19
pyrexia,
Amphotericin B drug has been widely used as an antifungal treat

malaise
ment for mucormycosis in India and worldwide. It has been observed

–
that 100% of patients in India had been treated with Amphotericin B,

Comorbidity/Past
while more than 90% of patients (92.86%) were treated with Ampho
medical history
tericin B in other countries. It has been found that almost 99% of cases in
DM, Diabetes
ketoacedosis
India and 71% of mucormycosis cases in the world (except India) were
reported with Rhino-orbital-cerebral location. DM among mucormycosis
DM
patients was also diagnosed with a maximum number of occurrences.

Approximately 95% of patients in India were diagnosed as having DM
No. Age, Sex
M:8, F:2
and 75% of patients in the remaining countries were detected as having

27-67/
60/M
DM with one of the comorbidity factors. A similar finding was also re
ported in a study by Sen and colleagues (2021), in which DM was re

cases
ported with a maximum number of cases in India associated with

10
of
mucormycosis. The most important analytical finding was observed for

the patients who have undergone surgery to recover from mucormy
Origin
India
India
cosis. The OR of the patients who have undergone surgery compared to

those without surgery was found to be 0.0406 (0.0021–0.8038) for India
11
and 0.1123 (0.0054–2.3314) for all the other countries. In other words, cell-mediated immune response and affecting both CD4 + and CD8+ T
it was found that patients who were not given surgery had almost 25- cells [105]. The most severe COVID-19 cases exhibit a significant drop in
times higher mortality chances compared to those who underwent sur the absolute lymphocyte number (lymphopenia), especially T cells.
gery in India, and more than 9-times mortality rate worldwide. This Mucorales-specific T cells secrete various cytokines and directly damage
analysis reveals that surgery within the stipulated time saved more lives. the fungal hyphae. Reduction of T lymphocytes in the case of COVID-19
may be linked with the poorest disease outcome and high risk of
10. Probable Reasons Behind Covid-19 Associated opportunistic fungal infections [109]. Disruption of iron homeostasis is a
Mucormycosis classic factor for COVID-19 [110]. SARS-CoV-2 interacts with haemo
globin via ACE2 and CD147 receptors and a cascade of events occurs
COVID-19 and mucormycosis exhibit shared risk factors and high along with the viral endocytosis. This results in haemoglobin malfunc
mortality rates. Zhou and colleagues (2020) reported that 50% of tion, hemolysis, and release of heme [110]. Another reason might lie in
COVID-19 patients died due to underlying secondary bacterial co- the SARS-CoV-2 spike glycoprotein, which mimics ‘hepcidin’, the key
infections [103]. In this regard, fungal co-infections are an add-on to regulator of iron metabolism in host cells [110]. Thus, a severe
COVID-19 fatalities [104]. We anticipate the following reasons for the COVID-19 case leads to the presentation of hyperferritinemia [111]. As a
surge in mucormycosis cases during COVID-19. People with risk factors clinical marker of the inflammatory response, Ferritin stimulates
are predisposed to the infection. However, presenting COVID-19 alone SARS-CoV-2 pathogenesis [112]. Ferritin binds and stores iron in the
and without traditional risk factors of mucormycosis is sufficient to build cell. Nevertheless, a high ferritin level leads to the accumulation of more
a predisposing environment, as seen in the case of reports [105]. Pa intracellular iron, which results in tissue injury by ROS [111]. In addi
tients infected by SARS-CoV-2 are supported with mechanical ventila tion, macrophage activation and the cytokine storm (e.g., elevated IL-6)
tion and acquire the risk of ventilator-associated infection or nosocomial trigger hepcidin upregulation, ferritin production and lower iron export,
infections due to prolonged hospital stays. Patients acquire the infection thus causing cellular iron overload [110,111]. The consequent tissue
from electrocardiogram (ECG) leads, contaminated intramuscular in injury results in the export of free iron into the blood circulation and
jections, adhesive tapes, or hospital environment airways [40]. Re stimulates Mucorales fungal pathophysiology. COVID-19 is linked to
searchers anticipated that people with poorly controlled DM were at widespread lung parenchymal illness, including diffuse alveolar dam
higher risk of reinfection with COVID-19, which is attributable to an age, hyaline membrane development, interstitial lymphocyte infiltra
impaired adaptive immune response [106,107]. In addition, freshly tion, and the production of vascular microthrombi. These lung
harboured glucocorticoid-induced diabetes during COVID-19 manage abnormalities can take weeks to heal, providing an appropriate envi
ment adds fuel to the flames [108]. Patel and researchers already proved ronment for fungal growth [113]. COVID-associated pulmonary endo
that 78.7% of CAM patients were provided with steroids during thelialitis (ROS-mediated and ferritin-free iron-catalyzed) in blood
COVID-19 management [101]. Steroid-induced immunosuppression vessels exposes the body to fungal adhesion and invasion [110]. The
and immune deregulation (during or just after COVID-19 recovery) SARS-CoV-2 spike glycoprotein induces endoplasmic reticulum stress
predispose patients to opportunistic fungal infection, i.e. mucormycosis, and further increases GRP78 expression [114], almost five times more
leading to their readmission into hospitals [108]. COVID-19 victims than normal [111]. Endothelialitis, as a single stress factor, also upre
produce significantly high levels of inflammatory cytokines (cytokine gulates GRP78 expression. Interestingly, SARS-CoV-2 uses the same
storm), including IL-2R, IL-6, IL-10, TNF-α etc., resulting in impaired GRP78 receptor for internalizing into host cells [114]. Thus, it clears the
Fig. 4. Probable reasons for the mucormycosis surge

as a COVID-19 co-infection in India. In both diabetic
and non-diabetic COVID-19 patients, corticosteroidal
drugs reduce immunity, cause immune deregulation
and raise blood sugar levels. The new onset of steroid-
induced diabetes and immune suppression may act as
the predisposing factor for mucormycosis. With
COVID-19, disease progression demands more oxygen
cylinders and intubation in patients and prolonged
hospital stay, increasing the risk of nosocomial fungal
infections. Due to the massive second wave outbreak
of SARS-CoV-2 in India, the health infrastructure
collapsed, and in turn, unhygienic and contaminated
instruments were used to attend the hospitalized
cases.The abrupt use of nutraceuticals might have
caused iron overload, i.e., a conventional risk factor
for mucormycosis and/or zinc overload, contributing
to the suitable settings for fungal growth. Moreover,
the over-use of antimicrobial medications results in
the eradication of symbiotic bacteria from the host
body. It is hypothesized that such factors and the
SARS-CoV-2 variants (that have caused disease
severity) may have triggered the increased case
numbers of co-infections, i.e., mucormycosis in cur
rent circumstances.
12
way for Mucorales Pathogenesis and virulence. Moreover, acidosis and detection of mucormycosis where the ‘red flag or warning signs’ should
hyperglycemic stress conditions induce endothelial GRP78 and fungal be of primary concern [124]. For instance, diplopia, proptosis, cranial
CotH, building the perfect storm for mucormycosis [111]. nerve palsy, sinus soreness, periorbital puffiness, palatine ulcer, or
During the first wave of the COVID-19 pandemic, India did not orbital apex syndrome indicate rhino-orbital-cerebral mucormycosis
witness any significant rise in fungal infection cases. During the second [124]. Angioinvasion and vascular thrombosis result in tissue necrosis,
wave, India’s SARS-CoV-2 infections broke pandemic records, with over which is frequently a late indication of mucormycosis [125].
300,000 positive test results daily for a week. On April 26, 2021, India Medical imaging Computerized tomography (CT) scan, Magnetic
had the world’s largest daily tally of new COVID-19 infections resonance imaging (MRI) and/or endoscopy can further be used to
(360,960), raising the country’s total number to 16 million cases, next determine the degree of infection [108]. In the case of patients with
only to the United States of America (USA) and more than 200,000 suspected pulmonary mucormycosis, CT is advised to detect the reversed
deaths [115]. India has the second largest diabetes population (65.1 halo sign (a region of the lungs with ground-glass opacity along with the
million) globally, with 70% of uncontrolled diabetes causes [37], which ring of consolidations) which is a classic hallmark for pulmonary
is adeptly predisposing the Indian community to an upsurge in mucor mucormycosis. In addition, CT pulmonary angiograms look for vessel
mycosis. Furthermore, it is well known that reinfections can occur [116, occlusions in the lungs [10,126]. If rhino-orbital-cerebral mucormycosis
117] and, therefore, recovered patients from the first wave of infection is suspected, cranial CT or MRI is advised. In case of its invasion into the
were infected once again during the second wave, even when these in eyes or the brain, MRI with high sensitivity is recommended instead of
dividuals were in the ‘long-COVID’ period [118]. Reinfections, being CT. If mucormycosis is confirmed, regular body imaging involving the
higher during the second wave [115], make the patients vulnerable to brain, thorax or abdomen should be done to determine the degree of the
co-infections. After recovery, most people drop their guards (e.g., infection or dissemination [10]. PET/CT (positron emission tomogra
masks), and fungal pathogens may take advantage when entering phy/computerized tomography) using [18F]-fluorodeoxyglucose (FDG)
through the nasal path and invade the body with lower immunity. can also be employed in the near future for greater sensitivity [127].
Moreover, the UK variant (B.1.1.7) and Indian variant (B.1.617) of Histopathology and Culture techniques Mucormycosis is gener
SARS-CoV-2 were predominant during this second wave of the ally suspected on the basis of direct microscopic analysis of the samples.
pandemic, and they exhibited an advantage over the pre-existing strains For better visualization of the hyphae with more optical brightness, the
[115] and might have caused greater disease severity. Eventually, blankophor and calcofluor white (fluorescent brighteners) are used
co-infections increase with disease severity. Tropical and subtropical along with potassium hydroxide (KOH) [128]. The infection is
humid climates, as well as high ambient temperatures in most regions of confirmed after visualizing typical hyphal characteristics using hema
India, create an ideal setting for the growth of these fungi and may toxylin and eosin stain, periodic acid Schiff stain and/or Grocott-Go
contribute to the infection burden [37]. In this context, CAM has been mori’s methenamine silver stain [25,26,129]. Due to tissue processing,
rising while the healthcare settings in India are facing challenges due to pseudo-septae can be formed or a 45◦ angle of branching can be
the breakdown of infrastructure, lack of sufficient medication and sur deformed. Hence, the wide and asymmetrical ribbon-shaped hyphal
gical equipment and the low number of healthcare professionals structure is a more consistent feature for microscopic analysis [10]. In
compared to admitted patients. Mucormycosis might have been caused acute lesions, hemorrhagic infarcts, coagulative necrosis, angioinvasion,
by the use of contaminated medical equipment [29] (Fig. 4). The second neutrophil infiltration (in non-neutropenic patients), and perineural
wave of COVID-19 in India was associated with a drastic drop of oxygen invasion (PNI) are the distinctive characteristics; while, in chronic le
saturation in patients, thus resulting in the crisis of oxygen cylinders sions, the pyogranulomatous inflammation (PI), and often hyphae
[119]. The use of industrial/non-medical grade oxygen with contami enclosed by the Splendore-Hoeppli phenomenon are observed [10].
nated water to treat the maximum number of patients might be a pre However, lesions are nonspecific. Diagnosis based on histological
disposing factor for mucormycosis, as it is not efficiently purified like characteristics is difficult and often misidentified as Aspergillosis [10].
medical oxygen [120]. The demand for immunity-boosting supplements Therefore, to overcome such bottlenecks, immunohistochemistry tech
increased during the pandemic [121]. Iron overload (a traditional risk niques can be used along with monoclonal antibodies (mAbs). These
factor for mucormycosis) and zinc overload might be contributing to the mAbs act against specific Mucorales and permit the differentiation be
appropriate environment for fungi growth. Zinc deficiency has long tween mucormycosis and aspergillosis [126,130]. For the preliminary
been known to hamper fungal proliferation by inducing stress [122]. identification of fungi up to the genus and species level (and antifungal
The arbitrary use of nutraceuticals and medicines represents the major susceptibility testing), the solid media culture is useful, followed by
concern for mucormycosis co-infection in the Indian scenario. Symbiotic macroscopic and microscopic identification [10,128].
microbiota protects the body from pathogen invasion and proliferation Molecular methods The confirmed genus and species level identi
[123]. Over-usage of various antibiotics in patients during the treatment fication demands sensitive molecular methods. Molecular analysis is
of COVID-19 is attributable to the elimination of symbiotic microbial robustly supported and favoured over histomorphology. For instance,
populations and predisposition to co-infections (Fig. 4). internal transcribed spacer (ITS) sequencing is encouraged over Matrix-
assisted laser desorption ionization-time of flight (MALDI-TOF) because
11. Mucormycosis diagnosis of its limitations [10,131]. Varied types of modern, specific and sensitive
tools such as nested PCR, RFLP coupled nested PCR, qPCR,
Co-infections are challenging to diagnose. The patient might have PCR/high-resolution melting analysis (HRMA), and PCR combined with
harboured the organism before the viral infection. It could also be electrospray ionization mass spectrometry (PCR/ESI-MS), etc. can be
associated with a pre-existing infection or might have been acquired as a used for rapid detection of the pathogen. The prime target of these tools
nosocomial infection [2]. Detection or diagnosis technologies to identify is 18S rDNA, 28S rDNA, the cytochrome b (cyt b) gene, the mitochon
a wide variety of possible infections and antibiotic resistance are drial gene rnl, CotH gene, and ITS region for R. arrhizus, Mucor sp.,
preferred. Nevertheless, early diagnosis of any co-infection is mandatory R. microsporus [10,126,132,133].
to restrict harmful consequences [2]. Physicians should check the Serology Various techniques, including ELISA, immunoblots, β-D-
medical history i.e., risk factors and symptoms, before further pro glucan test, and immunodiffusion tests are usually used to detect
ceeding with imaging, laboratory diagnosis and other available tech mucormycosis infection [134]. Mucorales-specific T-cells can be detec
niques. If a mucormycosis infection is suspected, tissue biopsy involving ted by the enzyme-linked immunospot (ELISpot) assay [135]. During
microscopic examination or fungal culture analysis and other known sandwich ELISA, a monoclonal antibody named 2DA6 appears to be
methods should be opted for after collecting tissue samples from infec extremely reactive with cell wall fucomannan of the Mucor sp [136].
ted areas or body fluid. Algorithms have been recommended for prompt Nevertheless, a lateral flow immunoassay detecting fucomannan is more
13
convenient than ELISA and may potentially be used in point-of-care tests tests could allow large-scale screening and thus enable earlier treatment
[136]. of mucormycosis patients before it develops into its severe forms.
Metabolomics-Breath Test This approach can be used to detect the
volatile organic compounds in the expired breath of mucormycosis pa 12. Mucormycosis management
tients. Koshy and colleagues performed a breath volatile metabolite
profile of invasive mucormycosis-causing fungus (R. arrhizus var. dele Angioinvasive hyphae are expected to induce necrosis and throm
mar, Rhizopus arrhizus var. arrhizus, R. microsporus) by using GC–MS and bosis. Complex pathogenesis makes it hard for antifungal medicines to
concluded that there is a distinct breath profile for the three causative penetrate. Thus, vigorous surgical debridement is mandatory as a part of
fungal agents; they suggested this as a non-invasive diagnostic method treatment [138]. Risk stratification based on disease severity, rapid and
for invasive mucormycosis [137]. Such real-time, metabolomics-breath early detection, reversal of primary predisposing factors (if applicable),
Fig. 5. Diagnostic and therapeutic pathway for invasive mucormycosis infection. Computerized Tomography scan (CT scan), Magnetic Resonance Imaging (MRI),
Positron Emission Tomography/Computed Tomography scan (PET/CT scan), Hematoxylin and Eosin stain (H&E stain), Grocott Methenamine-Silver and Periodic
Acid-Schiff stain (GMS & PAS stain), Internal Transcribed Spacers (ITS), Matrix-Assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF-
MS), Polymerase Chain Reaction (PCR), PCR-High Resolution Melting Analysis (PCR-HRMA), PCR-Electrospray Ionization/Mass Spectroscopy (PCR-ESI/MS),
Enzyme-Linked Immunosorbent Assay (ELISA), Enzyme-Linked Immunospot assay (ELISpot assay), Lateral Flow Immunoassay (LFI assay), and Gas Chromatography-
Mass Spectrometry (GC-MS).
14
surgical debridement of damaged tissue, effective antifungal medication 13. Futuristic drugs in the pipeline
(monotherapy or combination therapy), reversal of immunosuppression
(e.g., cessation of chemotherapy or enhancing neutrophils) and possible Mucorales infection, exhibiting a high level of antifungal resistance
control of predisposing comorbidities are the fundamental strategies to most antifungal drugs found in the market, demands novel thera
(Fig. 5) for the management of mucormycosis [17,139]. According to peutic agents for competent treatment. As monotherapy displays sub
the universal instruction of EMCC, the first-line antifungal regimen in optimal efficacy, combination therapy might be a potential approach in
cludes high-dose liposomal amphotericin B (5 mg-10 mg kg− 1 per day). the near future [152]. A clinical trial (Phase II) is ongoing to evaluate the
In contrast, moderate-strength posaconazole and isavuconazole are efficacy of combined therapy for pulmonary mucormycosis involving
strongly recommended as a treatment [10]. Posaconazole amphotericin B deoxycholate inhalation with intravenous (IV) ampho
delayed-release tablets or infusions, if available, are preferred over tericin B, compared to only IV amphotericin B [153]. Another study on
posaconazole oral suspensions. Most azoles are fungistatic drugs that act the evaluation of Isavuconazonium Sulfate for the management of
in the metabolic pathways to inhibit fungal growth [140,141]. Due to invasive mucormycosis in neonates is under Phase II clinical trial [154].
the high toxicity, amphotericin B deoxycholate is not advised (although Various drugs are under in vivo experiments in model organisms
it may be the only alternative in resource-constrained situations) [10]. (Fig. 6). Fosmanogepix (APX001) via manogepix targets Gwt1 protein,
Amphotericin B lipid complex improves the safety profiles of patients which interferes with the glycosylphosphatidylinositol (GPI)
[142]. In a study on rhino-orbital-cerebral mucormycosis patients, post-translational modification pathway and inhibits inositol acylation
whoever received the treatment of amphotericin B-lipid formulation on the fungal cell surface, along with GPI-anchored proteins needed for
along with caspofungin combination therapy exhibited better thera fungal growth and virulence. In murine models, fosmanogepix was
peutic success and longevity than people treated with amphotericin B found to be effective when treating pulmonary mucormycosis caused by
lipid complex alone [143]. Nevertheless, polyenes (e.g., amphotericin B)
and echinocandins (e.g., caspofungin) show synergistic effects, as echi
nocandins destroy some glucan on the fungal cell wall, which unmasks
immune epitopes and accelerates phagocytosis by the host defence cells
[139]. Early-stage diagnosis of mucormycosis and the treatment by
using antifungal drugs such as amphotericin B increases the rate of
survival by 40%–80% [144].
The cornerstone of mucormycosis management is the surgical exci
sion of necrotic tissues. The surgical intervention combined with proper
systemic antifungal drugs has been proven to considerably enhance
survival in pulmonary mucormycosis compared to antifungal treatment
alone [139]. Researchers revealed that surgical treatment was successful
in 22 individuals with rhino-orbital-cerebral mucormycosis and local
control enhanced the survival rate [145]. Therefore, adjunctive therapy
to reverse the risk factors is essential. It is known that relapsed or re
fractory malignancy and chronic neutropenia are the primary agents for
mucormycosis-associated mortality [146]. For example, adjunctive
therapy to reverse neutropenia in haematological patients by hemato
poietic growth factors or by white blood cell (WBC) transfusions should
be encouraged. Immunosuppressed patients (as seen in autoimmune
disease) should switch to alternative non-steroidal therapy to restore
their immunity. Rigorous control of hyperglycemia of diabetic/DKA
patients should be monitored. In this regard, reversing acidemia with
sodium bicarbonate can partly limit the ability of Rhizopus arrhizus to
infiltrate the vascular endothelium and restore host iron chelation along
with neutrophil functioning [147]. Thus, iron chelators are potential
options for adjunctive therapy. Hyperbaric oxygen is another option that
improves neutrophil efficiency, reverses acidosis, and inhibits fungal
proliferation [148]. Based on limited in vitro evidence,
immune-augmentation approaches such as administering granulocytes
(e.g., macrophages), colony-stimulating factors or interferon have been
advocated as treatment options [149,150]. In a study by Grimaldi and
colleagues, an immunodeficient trauma patient with chronic mucor
mycosis was effectively treated with a combination of interferon-gamma
and a monoclonal antibody named nivolumab [151]. Therapy and Fig. 6. Mechanism of action of futuristic drugs/agents for mucormycosis
management of mucormycosis do not involve any limited time duration. treatment [1]. Fosmanogepix (APX001) targets GWT1 protein, which modu
Decisions are taken on an individual level. As per the principle, the lates glycosyl phosphatidylinositol (GPI) post-translational modification
antifungal medications for mucormycosis are continued until all clinical pathway and inhibits inositol acylation in the fungal cell membrane [2]. bycA
manifestations are resolved; laboratory tests, as well as imaging signs mRNA is the negative regulator for hyphal growth that, in turn, is inhibited by
and symptoms, are resolved using serial analysis, and continue until the calcineurin. Thus, calcineurin is the positive regulator for hyphal growth and
immunosuppression has been reversed [10,139]. Finding a new drug the introduction of virulent traits [3]. Calcineurin inhibitors block calcineurin
and appear likely to be a potential futuristic drug for mucormycosis infection.
design and target is of the utmost importance for efficient treatment. In
Additionally, ergosterol is the primary factor acting to induce the expression of
this context, multicenter studies and meta-analytic research should be
virulent fungal traits [4]. Statins inhibit HMG-CoA reductase acting in the
involved in developing more novel strategies. mevalonate pathway, as well as ergosterol synthesis [5]. VT-1161 inhibits
fungal CYP51 and blocks ergosterol synthesis [6] Anti-CotH antibody targets
CotH proteins which are widely present in the Mucorales surface and prevents
invasion augmenting opsonophagocytosis.
15
Rhizopus arrhizus [155]. Calcineurins can suppress bycA mRNA expres References
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Travel Medicine and Infectious Disease 52 (2023) 102557

Contents lists available at ScienceDirect

Travel Medicine and Infectious Disease

Surge of mucormycosis during the COVID-19 pandemic

1. Introduction unembellished angioinvasive fungal infection with acute incidence,

Fig. 1. Different types of mucormycosis clinical mani­

Fig. 2. The Neighbor-joining tree is based on ITS

Fig. 3. Molecular mechanism of mucormycosis

Travel Medicine and Infectious Disease 52 (2023) 102557

diabetic tachycardia, fixed dilated pupil,

electrolyte corticosteroids movements, edema

Travel Medicine and Infectious Disease 52 (2023) 102557

Travel Medicine and Infectious Disease 52 (2023) 102557

mass into sinuses with

Travel Medicine and Infectious Disease 52 (2023) 102557

various countries and India, reported by several authors as mentioned in

over the several above-mentioned prognostic factors. This study

revealed that OR of <1 indicates that the presence of prognostic factors

result of OR, i.e., OR of >1, specifies the presence of prognostic factors

that are more harmful to the patients, in relation to an expected fatal

Considering the world data (except India), we found that a 22-year-old

right orbital cellulitis,

(standard deviation; SD) age of 53.39 (SD = 17.25) years. Similar

0.2184–10.3039), which indicates that patients aged > 50 years have

CI: 0.6172–8.8206). The result indicates that Indian patients aged ≤ 50

19.59% of females were diagnosed with mucormycosis. In the context of

death by mucormycosis within the gender classification, it has been

on world data, females were found to present 1.5-fold higher mortality

rate than males (OR: 1.5; 95% CI:0.2184–10.3039).

Amphotericin B drug has been widely used as an antifungal treat­

ment for mucormycosis in India and worldwide. It has been observed

that 100% of patients in India had been treated with Amphotericin B,

patients was also diagnosed with a maximum number of occurrences.

and 75% of patients in the remaining countries were detected as having

ported in a study by Sen and colleagues (2021), in which DM was re­

ported with a maximum number of cases in India associated with

mucormycosis. The most important analytical finding was observed for

cosis. The OR of the patients who have undergone surgery compared to

Fig. 4. Probable reasons for the mucormycosis surge

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Fig. 1. Different types of mucormycosis clinical mani

Amphotericin B drug has been widely used as an antifungal treat

ported in a study by Sen and colleagues (2021), in which DM was re