Folia Microbiologica (2022) 67:363–387

https://doi.org/10.1007/s12223-021-00934-5

REVIEW

Mucormycosis: risk factors, diagnosis, treatments, and challenges

during COVID‑19 pandemic
Ayushi Sharma1 · Anjana Goel1

Received: 20 June 2021 / Accepted: 15 November 2021 / Published online: 26 February 2022
© Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i. 2022

Abstract
Mucormycosis is a deadly opportunistic disease caused by a group of fungus named mucormycetes. Fungal spores are
normally present in the environment and the immune system of the body prevents them from causing disease in a healthy
immunocompetent individual. But when the defense mechanism of the body is compromised such as in the patients of dia-
betes mellites, neustropenia, organ transplantation recipients, and other immune-compromised states, these fungal spores
invade our defense mechanism easily causing a severe systemic infection with approximately 45–80% of case fatality. In the
present scenario, during the COVID-19 pandemic, patients are on immunosuppressive drugs, glucocorticoids, thus are at
high risk of mucormycosis. Patients with diabetes mellitus are further getting a high chance of infection. Usually, the spores
gain entry through our respiratory tract affecting the lungs and paranasal sinuses. Besides, they can also enter through dam-
age into the skin or through the gastrointestinal route. This review article presents the current statistics, the causes of this
infection in the human body, and its diagnosis with available recent therapies through recent databases collected from several
clinics and agencies. The diagnosis and identification of the infection were made possible through various latest medical
techniques such as computed tomography scans, direct microscopic observations, MALDI-TOF mass spectrometry, serol-
ogy, molecular assay, and histopathology. Mucormycosis is so uncommon, no randomized controlled treatment studies have
been conducted. The newer triazoles, posaconazole (POSA) and isavuconazole (ISAV) (the active component of the prodrug
isavuconazonium sulfate) may be beneficial in patients who are refractory to or intolerant of Liposomal Amphotericin B.
but due to lack of early diagnosis and aggressive surgical debridement or excision, the mortality rate remains high. In the
course of COVID-19 treatments, there must be more vigilance and alertness are required from clinicians to evaluate these
invasive fungal infections.

Abbreviations CKD Chronic kidney disease

DM Diabetes mellitus RHS Reverse halo symbol
PMN Polymorphonuclear phagocytes PET Positron emission tomography
COVID-19 Coronavirus disease 2019 CT Computed tomography
IFI Invasive fungal infections FDG Fluorodeoxyglucose
VORI Voriconazole CAPA Pulmonary aspergillosis
HSCT Hematopoietic stem cell transplant MALDI-TOF Matrix-assisted laser desorption/ionization
POSA Posaconazole time-of-flight
SOTR Solid organ transplant recipients MIC Minimum inhibitory concentration
HemeM Hematological malignancies ELISpot Enzyme-linked immune spot
ICU Intensive care units PCR Polymerase chain reaction
COPD Chronic obstructive pulmonary disease RFLP Restriction fragment length
polymorphisms
* Anjana Goel DNA Deoxyribonucleic acid
anjanagoel2000@gmail.com; anjana.goel@gla.ac.in 18S rRNA 18S ribosomal RNA
Ayushi Sharma ROCM Rhino-orbital-cerebral mucormycosis
ayushi.sharmabsc15@gmail.com SSTI Soft tissue infection and skin
ECMM European Confederation of Medical
1
Department of Biotechnology, Institute of Applied Sciences Mycology
& Humanities, GLA University, 281 406, Mathura, UP, India

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PTM Posttraumatic mucormycosis susceptibility which are killed by human phagocytes, that can
RCT​ Randomized controlled trials elaborate their virulency factor (Chamilos et al. 2008). In the
FDA Food Development Authority pathogenesis of mucormycosis, iron metabolism is crucial
ECIL European Conference on Leukemia (Petrikkos and Tsioutis 2018). It was clinically observed that
Infections patients with iron overload are more prone to the mucormyco-
sis (Ribes et al. 2000). On the other hand, deferoxamine stim-
ulates in vitro fungal development by acting as a Mucorales
Introduction siderophore (Boelaert et al. 1993). Furthermore, improved
serum iron supply in people with acidosis, which is partly
Mucormycosis is a fungal infection generally caused by attributable to transferrin's decreased affinity for free iron
the filamentous molds, and it belongs to the mucorals and at pH below 7.4, may increase mucormycosis susceptibility
entomophthorales order (Chakrabarti et al. 2006). Mucorales (Artis et al. 1983). Mucormycosis has a penchant to attack
can be found in a variety of habitats including dirt, rotting blood vessels, causing thrombosis and tissue necrosis as a
plant matter, bread, and dust (Lazar et al. 2014). Mucorales result (Danion et al. 2015). Angioinvasion may be aided by
infections can be contracted by inhalation of spores, absorp- the endothelial cell association with fungal spores (Spellberg
tion of infected meals, or inoculation of damaged surfaces or et al. 2005a, b). Interaction with endothelial cell receptors in
injuries (Lelievre et al. 2014). Mucormycosis is most common the host can also facilitate endothelial cell damage and fun-
in highly immunocompromised hosts in developing countries gal dissemination. There are some excellent discussions of
(Nasa et al. 2017; Wang et al. 2018). In developed economies, pathogenesis that can be found elsewhere (Skiada et al. 2018).
mucormycosis is commonly seen in patients with a bad progno- Besides this, COVID-19 has already claimed the lives of
sis regulated diabetes mellitus (DM). Furthermore, people suf- over a million people around the world. Supportive care is crit-
fered from trauma are also prone to mucormycosis (Petrikkos ical in the management of COVID-19 in the absence of a via-
et al. 2012a, b). Mucormycosis has a strong proclivity for ble vaccination or antiviral medication. Only glucocorticoids
invading blood vessels, causing necrosis, thrombosis, and and remdesivir are often effective in COVID-19. Glucocorti-
tissue infarction (Moreira et al. 2016a, b). Some belonging coids are affordable and widely available, and they have been
genera of Mucorales are Rhizopus, Lichtheimia (formerly found to lower mortality in COVID-19 hypoxemic individuals
Absidia), Mucor, Cunninghamella, Rhizomucor, Apophysomy- (Sterne et al. 2020). In contrast, glucocorticoids can raise the
ces spp., and Saksenaea (Petrikkos et al. 2012a, b; Riley et al. risk of subsequent infections. Furthermore, the virus’s immu-
2016). However, Cunninghamella, Rhizomucor, and Sakse- nological dysregulation, as well as the use of immunomodula-
naea are predicted to show similar classes of the genera (Jeong tory medicines like tocilizumab, may enhance the likelihood of
et al. 2019). Although, some species display significant varia- infection in COVID-19 patients (Kumar et al. 2021).
tion due to their origin and geographical features. For instance,
Apophysomyces reside in a subtropical and tropical environ-
ment (Corzo-León et al. 2018), where it can cause principle Epidemiology and incidence
cutaneous contamination (Bonifaz et al. 2014), widespread soft
tissue necrosis necrotizing fasciitis (Rodríguez et al. 2018). Mucormycosis becomes more popular in the last two dec-
Absorption or inhalation of sporangiospores or inoculation ades around the world, especially in Belgium, France,
of conidia by puncture trauma or wounds are the initial steps India, and Switzerland (Ambrosioni et al. 2010; Lelievre
in the pathogenesis of mucormycosis (Lelievre et al. 2014; et al. 2014; Saegeman et al. 2010). Mucormycosis is seen
Petrikkos et al. 2012a, b). Mucormycosis nosocomial out- in immune compromised patients in the community (Jeong
breaks have been attributed to surgical instruments, infected et al. 2019). From 2001 to 2010, the National Hospital Dis-
bandages, and breathing systems, but they are exceedingly charge database in France reported 35,876 invasive fungal
rare (Gamarra et al. 2018). Polymorphonuclear phagocytes infections (IFIs), with mucormycosis accounting for 1.5%
(PMNs) and mononuclear destroy hyphae and fungal spores in of IFIs (Bitar et al. 2014). Mucormycosis incidence rose
healthy young people using oxidative killing mechanisms and from 0.7 per million in 1997 to 1 per million in 2006 in
nonoxidative killing mechanisms (Kontoyiannis and Lewis France while nineteen cases of mucormycosis were diag-
2006). Deficiencies in phagocytic behavior encourage the nosed in a single-center sample in Spain during 2007 to
organism’s survival or development (e.g., defects in phago- 2015 (incidence 3.2 per 100,000) compared to 1.2 cases
cyte function or neutropenia). Acidosis and hyperglycemia, per 100,000 from 1988 to 2006 (Guinea et al. 2017). Simi-
in particular, hinder phagocytic killing and chemotaxis. The larly, three cases were also treated in a tertiary hospital in
enzyme ketone reductase is also generated by Rhizopus, which Switzerland, Geneva, between 1989 and 2003, compared to
allows it to expand in acidic and glucose-rich conditions like 16 cases between 2003 and 2008 (Ambrosioni et al. 2010).
ketoacidosis (Ibrahim et al. 2012). Mucorales have a natural The increment in treatment were the consequences of rise

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in immunocompromised victims as well as the use of caspo- Table 1  Different forms of clinical observations and their possible
fungin and voriconazole (VORI) (Ambrosioni et al. 2010). symptoms (Petrikkos and Drogari-Apiranthitou 2011)
The appearance of mucormycosis rose from 1.7/1000 in Medical structures Indicators and clinical epitome
2001 to 6.2/1000 in 2004, according to a prospective moni-
Pulmonary •Dyspnea
toring survey of 25 transplant institutes in the United States,
•Chest pain
although the events of other opportunistic molds remained •Hemoptysis
steady (Park et al. 2011). In comparison, IFIs were found Rhinocerebral, rhino-orbito- •Headache
in 121 of 3228 (3.7%) hematopoietic stem cell transplant cerebral •Facial pain
(HSCT) beneficiaries in an inspection of 11 Italian trans- •loss of vision
•Lethargy
plant centers (Pagano et al. 2007). The diagnostics feasibil-
•Brownish
ity, use of prophylactic azoles, immunocompromised victims •Black eschar on palate
(particularly organ transplant recipients) leads to the sig- •Blood-stained nasal discharge
nificant rise in cases of mucormycosis (Lamoth et al. 2017; •Chemosis
•Ophthalmoplegia
Saegeman et al. 2010). Specially, patient with prophylactic
•Ptosis
POSA53 has been seen to be more prone to mucormycosis. •Periorbital cellulitis
In a retrospective study conducted at Duke University •Dysfunction of cranial nerves
during 2009–2013, 24 episodes of IFIs were discovered in Proptosis
patients with HemeM or solid organ transplant recipients Gastrointestinal •Non specific
oDiarrhea
(SOTRs) receiving POSA (n 148) or VORI prophylaxis (n 14
oAbdominal pain
16) (Lamoth et al. 2017). The most common breakthrough oMelena
IFI was mucormycosis, which accounted for 9 of the 24 oHematemesis
(37.5%) episodes (Lamoth et al. 2017). Despite the above- •Depend on site involved
mentioned patterns, mucormycosis remains uncommon. Cutaneous •Resemble ecthyma gangrenosum
•Painful lesions
Between 2006 and 2015, a study of the Intermountain
•Necrotizing fasciitis
Health sector, a vast US chain of hospitals and clinics, •Cotton-like growth
found 3374 IFIs in 3154 topics (Webb et al. 2018). Muco- Focal •Mediastinitis
rales are found in 1.1% of IFIs (0.3 cases a 100,000 per •Endocarditis
year on average). On the other hand, HemeM (19.4%), DM •Osteomyelitis
•Peritonitis
(36.1%), immunosuppressive therapy, and HSCT (11.1%)
•Otitis external
were among the underlying diseases (61.1%) (Webb et al. •Pyelonephritis
2018). From January 2005 to June 2014, a survey of more •Corneal infection
than 560 hospitals in the United States (US) serving 104 Disseminated •Stroke
million patients found 555 mucormycosis-related hospitali- •Pneumonia
•Subarachnoid hemorrhage
zations among more than 47 million inpatient experiences
•Cellulitis
(prevalence of 0.12 per 10,000 discharges) (Kontoyiannis •Brain abscess
et al. 2016). Table 1 •Gangrene
From 2003 to 2010, the nationwide inpatient sample in
the US found 5346 reports of mucormycosis amongst more
than 319 million hospitalizations (incidences of less than 10-year study from Southern India (Tamilnadu) showed
0.01% of all hospitalizations in the US) (Zilberberg et al. an annual incidence of 18. over 4 cases per year dur-
2014). Six percent of mucormycosis patients have no known ing 2005–2015 (Manesh et al. 2019). Another study from
risk factors. From 2004 to 2012, 74 cases of mucormyco- Tamilnadu reported 9.5 cases per year during 2015–2019. A
sis were discovered in 15 tertiary hospitals across Australia multi-center study across India reported 465 cases from 12
(Kennedy et al. 2016). Eight patients (10.8%) had previ- centers 21 months; the study reported an annual incidence
ously been stable, in which trauma is a factor in seven of of 22 cases per year and an average of 38.8 cases for each
this immune-competent patients (Kennedy et al. 2016). participating center (A. Patel et al. 2020). Though invasive
Mucormycosis affects only a small percentage of infants aspergillosis is given importance among invasive mold
(Elgarten et al. 2018). In just 24 h, two international reg- infections in intensive care units (ICUs), a multi-center study
istries were established. Between 2005 and 2014, two for- in Indian ICUs reported mucormycosis in a considerable
eign registrations in up to twenty-four countries reported (14%) number of patients (Chakrabarti et al. 2019). Sindhu
only 63 cases in children (aged 19 years) (Pana et al. 2016). et al. reported mucormycosis at 12% in ICU patients at a
In conclusion, mucormycosis is still uncommon, but cer- single center from North India. Without population-based
tain factors (discussed later) significantly raise the risk. A estimates, it is difficult to determine the exact incidence and

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prevalence of mucormycosis in the Indian population. The one case. Three (37.5%) of the participants had no typical
computational-model-based method estimated a prevalence risk indicators for mucormycosis (Hanley et al. 2020a, b; Do
of 14 cases per 100,000 individuals in India (Koffi et al. Monte et al. 2020; Pasero et al. 2020a, b). In seven cases,
2021). The cumulative burden ranged between 137,807 and COVID-19 caused acute respiratory distress syndrome. In
208,177 cases, with a mean of 171,504 (SD: 12,365.6; 95% five of the cases, the serum creatinine level was elevated,
CI: 195,777–147,688) and mean attributable mortality at while in the other three, the details were unavailable. Two
65,500 (38.2%) deaths per year (Koffi et al. 2021; Prakash of the participants had symptoms that suggested mucormy-
and Chakrabarti 2019). The data indicates that the estimated cosis (rhino-orbital mucormycosis), while the rest acquired
prevalence of mucormycosis in India is nearly 70 times mucormycosis after receiving COVID-19 medication (typi-
higher than the global data, which were estimated to be at cally between 10 and 14 days in the hospital) (Mekonnen
0.02 to 9.5 cases (with a median of 0.2 cases) per 100,000 et al. 2021a, b; Werthman-Ehrenreich 2021a, b). In two of
persons (Prakash and Chakrabarti 2019). the individuals, the diagnosis was made after death (Hanley
Three and two instances were reported from the US and et al. 2020a, b; Do Monte et al. 2020). Mucormycosis was
India, respectively, out of the eight cases documented so far seen in the rhino-orbitocerebral (n = 3), pulmonary (n = 3),
(including the index case). Brazil, Italy, and the UK each stomach (n = 1), and disseminated (n = 1) areas. Except for
reported one instance (Hanley et al. 2020a, b; Do Monte the index case, everyone died. Fifteen hospitalized patients
et al. 2020; Pasero et al. 2020a, b). The median (range) age with COVID-19 infection acquired bloodstream candida
was 57.5 (22–86), and seven of the participants were men. infections in one cluster from New Delhi, India. Ten of them
Diabetes mellitus (n = 4.50%) was the most common pre- had a Candida Auris infection, and six of them died (60%)
disposing factor, as diabetes was previously undetected in (Chowdhary et al. 2020a, b). Invasive fungal infections were

Fig. 1  Risk factors for mucormycosis

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Folia Microbiologica (2022) 67:363–387 367

found in 26.7% of 135 individuals with COVID-19 infection, and 2017, which included 851 cases of mucormycosis from
mainly candida. Patients with invasive fungal illnesses had a around the country: natural disasters (11%), burns (11%),
greater mortality rate, which could be lowered greatly with SOTR (14%), no underlying condition (18%), neutropenia
the right treatment. (20%), diabetic ketoacidosis (20%), HemeM (32%), trauma
An increased incidence of the invasive fungal disease has (33%), and DM (40%) (Jeong et al. 2019). Figure 1
been linked to corticosteroid medication and a history of In Asia, the most common risk factor for mucormyco-
chronic lung disease (White et al. 2020). Similarly, significant sis is diabetes mellitus (DM), while in North America and
incidences have been reported in Pakistan (23/147, 15.6%) and Europe, HemeM and organ transplants are far more popular
Italy (30/108, 27.7%), with the authors claiming that the devel- (Jeong et al. 2019). While COVID-19-associated pulmonary
opment of invasive fungal infections modifies the disease’s aspergillosis (CAPA) has got a lot of attention (Arastehfar
natural history (Arastehfar et al. 2020; Nasir et al. 2020). et al. 2020; Koehler et al. 2021). The presence of risk fac-
tors, consistent radiography, and evidence of Aspergillus in
tissue culture or microscopy are all used to diagnose CAPA
Risk factors for mucormycosis (Koehler et al. 2021). Invasive mold infections have similar
risk factors, clinical symptoms, and radiological findings.
The progression of mucormycosis has been linked to a As a result, CAM diagnosis is considerably more difficult.
number of factors, including the following: poorly regulated Mucormycosis may be underdiagnosed due to a lack of clini-
DM1, HemeM with neutropenia, HSCT48, SOTRs, immu- cal suspicion and difficulty isolating the pathogenic fungi.
nosuppression or chemotherapy, rheumatic or autoimmune Furthermore, biomarkers for invasive aspergillosis, such
disorders, human immunodeficiency virus infection, peri- as beta-d-glucan and galactomannan are not accessible for
toneal dialysis, iron overload states, malnutrition, trauma, mucormycosis.
burns, and prior receipt of VORI (Dimaka et al. 2014; To our knowledge, this is the first instance of suspected
Husain et al. 2017; Kennedy et al. 2016; Kontoyiannis pulmonary mucormycosis arising following COVID-19
et al. 2005; Lanternier et al. 2012a, b; Moreira et al. 2016a, treatment that has been effectively handled. Severity has
b; Pana et al. 2016). Mucormycosis appears to protect been linked to diabetes mellitus (Apicella et al. 2020). Fur-
immunocompetent people (Radner et al. 1995), although thermore, diabetes patients who are inadequately controlled
infections have been identified after soft tissue damage, or may develop overt or covert renal impairment. Multiple risk
local cutaneous including rhino-orbital, cutaneous, and dis- factors or concomitant conditions, combined with increased
seminated infections (Blauwkamp et al. 2019; Tribble et al. immunosuppression caused by glucocorticoids, raise the net
2018). The following risk factors were established in a latest state of immune suppression in severe COVID-19 patients,
meta-statistics of 600 publications published between 2000 predisposing them to invasive mold infections. Table 2

Table 2  Risk factors associated with patients in Indian geographical regions

Factors Manesh et al. 2019 (Manesh Prakash et al. 2019 (Prakash Patel et al. 2020 (A. K. Priya et al. 2020
et al. 2019) et al. 2019) Patel et al. 2020) (Priya et al. 2020)

Duration (year) 10 3 2 4
Origin/location in India South India North and South India West India (Gujrat) South India
Case rises 184 388 27 38
Neutropenia - 18 - -
Chronic alcoholism - 28 - -
Pulmonary disease - 21 2 -
Skin brach 20 31 6 8
Hematological and solid organ 14 23 1 2
malignancy
HSCT 4 1 - -
DM 120 172 15 29
CKD 1 27 1 2
HIV - 3 - -
Steroid therapy - 30 6 -

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Poorly controlled diabetes mellitus (3.7%) HSCT patients investigated by 11 Italian transplant
centers, but only one case of mucormycosis was diagnosed
Mucormycosis is a well-known impediment of largely (Pagano et al. 2007).
unregulated DM (Jeong et al. 2019; A. Patel et al. 2020),
and it is linked to innate immunity defects like phagocy-
tosis, chemotaxis, and killing by PMNs, as well as mac- Organ transplant recipients
rophages/monocytes (Geerlings and Hoepelman 1999).
DM is the proximate cause of mucormycosis in 27–52% Mucormycosis is a relatively uncommon impediment in
cases (Kennedy et al. 2016; Kontoyiannis et al. 2016; Webb SOTRs (Husain et al. 2017). Based on statistics from 23
et al. 2018). The rhinocerebral type of mucormycosis is US centers that make up the Transplant-Associated Infec-
more common in diabetics with ketoacidosis (Roden et al. tion Surveillance Network, the average annual incidence
2005). The sinuses are the most prominent initial source of of mucormycosis among SOTRs was 0.07% from 2001 to
involvement, and they may even extend to the orbit, brain, 2006 (Park et al. 2011). University of Pittsburgh’s researcher
and bone. In diabetes-associated pulmonary, mucormycosis, identified ten cases of mucormycosis among SOTRs and
or disseminated infections are rare, (Rapidis 2009) unlike in analyzed 106 cases previously published between 1970
transplant patients or recipients with HemeM (Kontoyiannis and 2002 (Almyroudis et al. 2006). Just 22 IMIs (6.9%)
et al. 2016; Webb et al. 2018). were mucormycosis, according to the Prospective Antifun-
gal Therapy Alliance list, which tracked 333 IMIs among
SOTRs transplanted at 25 centers between 2004 and 2008
(Husain et al. 2017). From 1995 to 2012, only one case of
Hematological malignancies mucormycosis (Lichtheimia) was found among 362 heart
with neutropenia transplant patients in only one center (Rabin et al. 2015).
Song and colleagues looked at 174 cases of mucormycosis
Chemotherapy-induced innate host defense neutropenia, in renal transplant patients from 123 papers written between
deficiencies, mucociliary dysfunction, and phagocytic 1970 and 2015 (Song et al. 2017). As a whole, 42.5% of peo-
dysfunction all raise the chances of contamination (Park ple died (Song et al. 2017). Between 1998 and 2009, Brazil-
et al. 2011). In victims with neutropenia and HemeM, ian researchers found only one case of mucormycosis among
mucormycosis is a severe but life-threatening complica- 908 renal transplant recipients who were monitored until
tion (Kontoyiannis et al. 2005; Lanternier et al. 2012a, b; July 2015 (Guimarães et al. 2016). Numerous case reports
Pana et al. 2016). Mucormycosis is a fungal infection that and limited sequence of mucormycosis in SOTRs have been
can affect HSCT recipients, especially those who have graft reported, including liver, kidney (Clark et al. 2018), heart,
versus host complication (Kontoyiennis et al. 2010; Marr and lung recipients (Bhaskaran et al. 2013).
et al. 2002).
Between 1985 and 1999, 27 (0.6%) of 5589 patients who
received HSCT at the Fred Hutchinson Cancer Research Immunocompetent host
Center in Seattle experienced confirmed or suspected mucor-
mycosis. Seven hundred sixty-five cases of mucormycosis In India, 3–26% of mucormycosis cases have been recorded
were included in a later sample of 1248 allogeneic HSCT from the immunocompetent host, compared to 18–19% glob-
recipients transplanted between 1998 and 2002 at that hos- ally (Jeong et al. 2019; Roden et al. 2005). Cutaneous or
pital (incidence 0.4%) (Garcia-Vidal et al. 2008). The mean isolated renal mucormycosis were common in the Indian
prevalence of mucormycosis was 0.48% in a report of 16,200 patients. However, trauma is a risk factor in 7.5–22% of
HSCT recipients from 23 transplant centers in the US from mucormycosis cases in India. The majority of the patients
March 2001 to September 2015 (Kontoyiennis et al. 2010). present with cutaneous mucormycosis after trauma, burns,
However, a systematic study of HSCT and SOTRs at Johns and nosocomial infections at the surgery or injection site
Hopkins Hospital (Baltimore, MD) found that mucormy- (Manesh et al. 2019). Another study from North India
cosis was responsible for 8.5% of invasive mold infections reported that 9% of the mucormycosis cases are nosocomial
between 2000 and 2009 (Kontoyiennis et al. 2010). in origin (A. Chakrabarti et al. 2009).
The Centre for International Blood and Marrow Trans- Contaminated intramuscular injections and surgery, adhe-
plant Research gathered registry data from almost sixty- sive tapes, and endobronchial tubes were sources of infec-
six transplant centers around the world and found up to 72 tion in nosocomial mucormycosis (C. Kumar et al. 2017).
cases of mucormycosis during the first year of postlogeneic Isolated renal mucormycosis in an immunocompetent host is
HSCT (incidence 6.0/1000), which was close to previous an emerging entity in India. The pathogenesis of the disease
years (Riches et al. 2016). IFIs were found in 121 of 3228 is still not known (Devana et al. 2019). Other predisposing

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Table 3  Antifungal drugs used to treat mucormycosis: a summary of recommendations

Antifungal agent Dose Duration Source

Posaconazole • Posaconazole IV/tablet: 1 × 300 mg from day 6 months (Greenberg et al. 2006; Graves et al. 2016; A.
2, 2 × 300 mg day 1 Skiada et al. 2011)
• Oral suspension: 2 × 400 mg/day or
4 × 200 mg/day
Amphotericin B CNS participation: 1 mg/100 g per day LAMB Usually 6–12 weeks (Shoham et al. 2010; Walsh et al. 2012)
(ABCL, AMB, No CNS participation: 0.5 mg/100 g per day
LAMB) LAMB
Combination • Isavuconazole or posaconazole and LAMB (Kyvernitakis et al. 2016; Rodriguez et al. 2018;
• LAMB + echinocandin Vujanovic et al. 2017)
Isavuconazole IV or PO: 3 × 200 mg day 1, 1 × 200 mg/day 3 months (oral/iv/both) (DiPippo et al. 2019; Maertens et al. 2016;
from day 3 Mellinghoff et al. 2018)

factors associated with mucormycosis in India are chronic coexist, as in the case of a diabetic patient (Aggarwal et al.
kidney disease (CKD), steroid therapy, pulmonary tubercu- 2015). Nonetheless, certain characteristics should boost the
losis, and chronic obstructive pulmonary disease (COPD) fear of intrusive pulmonary mucormycosis. Table 3
(Patel et al. 2020; Prakash et al. 2019). A history of previous voriconazole prophylaxis or the
CKD is a new risk factor for mucormycosis in India occurrence of breakthrough fungal infection in an immuno-
(Prakash and Chakrabarti 2021). Studies reported that mucor- compromised patient receiving antifungal agents functional
mycosis patients had CKD in 9–32% of cases (Chakrabarti against Aspergillus (Chamilos et al. 2005). Corzo-Leon and
et al. 2019; A. Patel et al. 2020). Similarly, a study from colleagues suggested an algorithm for detecting rhinocer-
Turkey reported that 18% of the patients with mucormycosis ebral mucormycosis in diabetic patients. A cranial nerve
had chronic renal insufficiency (Kursun et al. 2015). Pulmo- palsy, sinus pain, diplopia, periorbital swelling, proptosis,
nary tuberculosis and COPD were seen in 7–46% of patients and palate ulcers orbital apex syndrome are among the signs
with mucormycosis (Jeong et al. 2019; Patel et al. 2020). A and symptoms that can be called “red flags” (Corzo-León
few cases of breakthrough mucormycosis after voriconazole et al. 2018).
treatment were reported in India (Sharma et al. 2017). Other Mucormycosis is said to be associated with numerous
risk factors reported in India included intravenous drug use, nodules and pleural effusion on radiography (Chamilos et al.
autoimmune disease, HIV infection, immunosuppressant 2005). The reverse halo symbol (RHS) is another CT scan
drugs, malnutrition, and ICU stay. finding that seems to suggest the existence of mucormycosis.
The RHS was seen in 15/16 patients (94%) within a week
of the disease in a new review of consecutive thoracic CT
Diagnosis scans of leukemic patients with neutropenia. Other radio-
logic observations, like numerous nodules, appeared later.
Clinical diagnosis The investigators suggested that the appearance of the RHS
on CT was a good indication of pulmonary mucormycosis
A high index of suspicion, identification of host conditions, in neutropenic leukemic patients with pulmonary infection.
and rapid evaluation of clinical symptoms are all needed The CT scans of 24 patients with lung mucormycosis were
for the diagnosis of mucormycosis. Diplopia in a diabetic similar to the CT scans of 96 patients with suspected lung
patient or pleuritic pain in a neutropenic patient may be aspergillosis in another report. The RHS was more preva-
signs of infection, prompting the use of imaging techniques lent in mucormycosis patients (54%) than in aspergillosis
and the eventual collection of specimens for histology, patients (6%, P.001), while certain airway-invasive char-
microbiology, and advanced molecular research. As stated acteristics, such as clusters of centrilobular nodules, bron-
earlier, rhinocerebral, pulmonary, soft tissue, and dissemi- chial wall thickening, and peribronchial consolidations were
nated infection are the most frequent clinical manifestations more frequent in aspergillosis patients (Jung et al. 2015).
of Mucorales infectious disease (Petrikkos et al. 2012a, b). Although these results aren't definitive, they can be seen as
Mucormycosis is characterized by tissue necrosis, however, an initial point for more intensive medical laboratory stud-
the appearance and syndrome-based methods of diagnosis ies. The positron emission tomography-computed tomog-
lack sensitivity and accuracy. Other fungi, such Aspergillus raphy (PET/CT) with [18F]-fluorodeoxyglucose (FDG) is
or Fusarium, may cause similar complications. Furthermore, yet another emerging imaging strategy that may ultimately
in tuberculosis-endemic countries, the two infections can help in the management and diagnosis of mucormycosis (Liu

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370 Folia Microbiologica (2022) 67:363–387

et al. 2013). Endobronchial ultrasound-guided fine-needle culture. When assessed by individuals with expertise in
aspiration is indeed a helpful screening technique (Haas fungal detection, Alvarez et al. (2009) found that morpho-
et al. 2017). logical characteristics alone could provide high accuracy.
However, morphological specimen classification is chal-
Culture and microscopic examination lenging and may be due to speciation failures (Frater et al.
2001).
Direct and histopathology microscopy and different clini- ID32C kit (bio Merieux, Marcy lÉtoile, France) and API
cal culture specimens are diagnosing mucormycosis’s cor- 50CH (bioMerieux) (Ramani et al. 1998) have been success-
nerstones. Mediclinic samples are examined under direct fully used for the recognition of R. pusillus, and Lichtheimi-
microscopy, specifically using optical brighteners such as acorymbifera as well as Mucor species. Both tests failed
Calcofluor and Blankophor (Frater et al. 2001; Lass-Flörl to differentiate M. circinelloides and M. rouxii. L. ramosa
2009). Clinical samples that are white allow for a quick pre- is detected using ID32C and positive melezitose assimila-
liminary analysis of mucormycosis (Lass-Flörl et al. 2007). tion (Schwarz et al. 2007). MALDI-TOF mass spectrometry
Mucorales hyphae have a variable diameter (6–25 m), are (matrix-assisted laser desorption/ionization time-of-flight)
nonseptate or pauci-septate (Monheit et al. 1984), and have is a promising instrument, but it has not yet been validated
an irregular, ribbon-like shape. for all Mucorales (Schrödl et al. 2012). M. circinelloides has
The branching angle varies, with wide-angle (90°) bifur- high MICs for posaconazole, as well as Cunninghamella
cations being common. On hematoxylin and eosin parts, and Rhizopus for amphotericin B. (Vitale et al. 2012) The
fungal elements are easily visible. Gomori’s silver staining MIC against amphotericin B has also increased in certain
is often used to illuminate fungal hyphae, allowing for a apophysomyces isolates (Alvarez et al. 2009; Bonifaz et al.
more detailed analysis of anatomy (Lass-Flörl 2009). Inflam- 2014). The role of such data in patient care is uncertain,
mation, whether neutrophilic or granulomatous, dominates requiring further investigations.
tissue histopathologic results in a few cases. Inflammation
appears to be absent especially in immunocompromised
patients (Spellberg et al. 2005a, b). The presence of promi-
nent infarcts and angioinvasion characterizes the invasive Serology
disease. A perineural invasion can be present when the nerve
structures are involved. As compared to nonneutropenic A reasonable test such as enzyme-linked immunosorbent
patients, neutropenic patients have a more severe angioin- assays (Sandven and Eduard 1992), immunoblots (Wysong
vasion (Frater et al. 2001). and Waldorf 1987), and immunodiffusion were evaluated
Histopathological examination of tissue samples is not based on the degree of their effectiveness. In three hema-
always capable of distinguishing Mucorales hyphae with tological patients who developed invasive mucormycosis,
Aspergillus or morphological characteristics related to fungi. an enzyme-linked immunospot (ELISpot) assay has been
Tissue identification, on the other hand, is an important diag- used to identify Mucorales-specific T cells. Additionally,
nostic tool because it distinguishes between the existence of Mucorales-specific T cells were used in the infected patients
fungi as a pathogen in a tissue and the presence of a culture to recover over the disease (Potenza et al. 2011). Although,
contaminant. Mucorales grow quickly on most fungal cul- there will be further studies towards the use of these special
ture media, like Potato dextrose and sabouraud agar incu- T cells as surrogate diagnostic markers.
bated at 25–30 °C (3 to 7 days) (Chakrabarti et al. 2006;
Ribes et al. 2000). A microaerophilic condition increases
culture yield for certain varieties (Lass-Flörl and Mayr
2009). Surprisingly, even though fungal hyphae are visible Molecular assays
in the histopathologic examination, only 50% of fungal cul-
tures are positive. Since hyphae are brittle, they could be Conventional PCR, RFLP, and DNA sequencing of identi-
harmed as a result of tissue manipulation. fied gene regions (Machouart et al. 2006; Nagao et al. 2005;
Shirley and Scott 2016) and melt curve analysis of PCR
Antifungal susceptibility testing and species products are all examples of molecular-based assays (Kasai
identification et al. 2008). Many of the essays mentioned above can be
used to detect or identify Mucorales. The internal tran-
Characterization of organisms is critical for having a scribed spacer or the 18S rRNA genes are the focus of the
deeper epidemiological knowledge of mucormycosis and majority of molecular assays (Lass-Flörl and Mayr 2009).
could aid epidemic investigations. Mucorales fungi are eas- Several studies have been conducted using paraffin-embed-
ily distinguishable from Aspergillus fungi when grown in ded or fresh tissue samples, formalin-fixed, with varying

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Folia Microbiologica (2022) 67:363–387 371

Table 4  Forms of S. no Infection site Percentage of cases Source

mucormycosis
1 Disseminated 15–23% (Riley et al. 2016)
2 Rhino-orbital-cerebral 25–39% (Dimaka et al. 2014)
mucormycosis (ROCM)
3 Gastrointestinal 2–11% (Bernardo et al. 2016)
4 Cutaneous/soft tissue 19–26% (Li et al. 2013)
5 Pulmonary 24–30% (Lamoth et al. 2017)
6 Other sites (joints/bone, Rare (Moreira et al. 2016a, b)
peritoneum, heart)

results. The studies performed for sensitivity (70–100%) and 2016). Matrix-assisted laser desorption/ionization-time of
specificity (not measured to 100%) shows varied results, but flight tends to be another tool with high precision for sepa-
a lower number of patients examined being a critical short- rating mould from cultures (Cao et al. 2018; Gholinejad-
coming. Since the efficacy of these in-house assays has not Ghadi et al. 2018). Next-generation sequencing can detect
been extensively tested and clinically evaluated, they cannot IMIs in blood samples which could lead to earlier detection
be put forward as a single, stand-alone in clinical routine of these infections (Blauwkamp et al. 2019).
diagnostics, this approach is used. Molecular diagnosis from
blood and serum has yielded positive clinical results in 39% Clinical features of mucormycosis
of cases (Guinea et al. 2017; Ino et al. 2017; Millon et al.
2016). When opposed to culture, early diagnosis and overall Mucormycosis is divided into six types based on anatomic
confirmed culture-proven cases were achieved using molec- localization (see Table 4). Roden et al. (2005) investigated
ular-based diagnosis from serum. At this time, molecular- the common sites of the infection in the 929 cases of the
based diagnostic assays may put forth as useful supplements mucormycosis. The investigated locations were lungs (24%);
to traditional diagnostic procedures (Yang et al. 2016). sinuses (39%); soft tissue infection and skin (SSTI) (19%)
and disseminated (23%). In the study, it was observed that
Advancement in the diagnosis 15 patients having cancer were chosen from a group of 154
patients in which 6 patients have rhino-orbital-cerebral
Histopathology and culture are used to diagnose mucormy- mucormycosis (ROCM), while 92 have pulmonary disease.
cosis (Hamilos et al. 2011). Mucorales are prone to vascular In contrary, 222 patients out of 337 with DM were found to
invasion and tissue damage in the organs they infect (Ribes be affected by sinus disease while 145 having ROCM. In
et al. 2000). Tissue infarction occurs when blood vessels a study conducted by European Confederation of Medical
become thrombosed. Consequently, a black eschar may Mycology (ECMM) registered 230 cases of mucormycosis
form. Gram stain is ineffective on Mucorales. Mucorales between 2005 and 2007 in European countries. The pro-
have long (10–20 µm in diameter) nonseptate ribbon-like found cases were of ROCM (27%), lungs (30%), dissemi-
hyphae with branches at right angles in tissue specimens nation (15%), and SSTI (26%) (Skiada et al. 2011). Dur-
(Frater et al. 2001). ing 2005–2007, France was also reports the mucormycosis
Mucormycotic infections may cause neutrophilic, granu- cases of ROCM (25%), lungs (28%), dissemination (18%),
lomatous, or nonspecific inflammatory changes, as well as and SSTI (20%) (Lanternier et al. 2012a, b). Between 2004
angioinvasion or infarcts in some cases (Frater et al. 2001). and 2012, underlying diseases in an Australian cohort of
Fine needle aspiration biopsy may be used to confirm the 74 patients with mucormycosis included HemeM (49%),
diagnosis when focal pulmonary nodules or masses are pre- corticosteroids (53%), DM (29%), chemotherapy (43%),
sent (Haas et al. 2017; Sharma et al. 2017). Even if histopa- autoimmune disease/rheumatological (12%), and no implicit
thology reveals the characteristic organism, cultures can be disease (11%) (Kennedy et al. 2016). Trauma was the cause
negative. Grinding tissue specimens for culture also results of seven of the eight patients that had no previous underly-
in hyphae damage due to the scarcity of septations which ing illness.
prevents growth in culture. In mucormycosis, serological
tests for D-glucan and Aspergillus galactomannan are nega- ROCM
tive (Pyrgos et al. 2008). For certain organisms (e.g., Rhizo-
pus, Mucor, Rhizomucor, Lichtheimia), quantitative PCR Mucormycosis is a fungal infection that can spread from
in serum or tissue is available and may be superior to cul- the sinuses to the oral mucosa, palate, brain and bone, orbit
ture (Hata et al. 2008; Rickerts et al. 2006; Shigemura et al. (Li et al. 2013). ROCM is the name given to this clinical

13
372 Folia Microbiologica (2022) 67:363–387

condition. Patients with poorly treated diabetes mellitus are of consolidation is referred to as the RHS (Stanzani et al.
more likely to develop ROCM. But it may also happen in 2012). Patients with suspected or confirmed fungal pneu-
SOTRs and other immunocompromised hosts (Lanternier monia, including PulM (n ¼ 37), IPA (n ¼ 132), and fusa-
et al. 2012a, b). In patients with poorly regulated diabetes, riosis (n ¼ 20), were analyzed by researchers from the MD
dental procedures can be a risk factor for ROCM (Prabhu Anderson Cancer Center in Houston, TX. RHS was found
et al. 2018). Dental infections can lead to destructive infec- in 7/37 (19%) of PulM patients and 1/132 (0.8%) of IPA
tions of the mandible or maxilla (Aras et al. 2012; Prabhu patients. A retroactive review from 2003 to 2012 at a single
et al. 2018). Headache, fever, nasal inflammation, facial cancer center found 16 cases of PulM in 752 subsequent
pain, palatine mucosa eschar, or dark nasal and periorbital cases of acute myeloblastic or lymphoblastic leukemia. RHS
swelling are some of the signs and symptoms of the problem with a capacity of 94% (15 of 16) was seen in 186 CT scans
(Augustine et al. 2017). taken during the first week of disease. Other CT observa-
Cellulitis, chemosis, proptosis, and blurred vision are tions such as pleural and nodules effusion were uncommon
all signs of orbital invasion (Mattingly and Ramakrishnan during the first week (12 and 6%, respectively), but occurred
2016). Intracranial progression through direct extension or in 55 and 64%, respectively, after the first week. The CT
angioinvasion can happen quickly (within days). A high characteristics of 24 patients with PulM (proven or probable)
mortality rate is linked to brain involvement (Vogt et al. and 96 patients with IPA were matched by South Korean
2017). Rhizopus oryzae was found to be responsible for researchers (proven or probable) (Jung et al. 2015). RHS
85% of ROCM in a French analysis, compared to just 17% was included in 54% of PulM subjects but just 6% of IPA
of non-rhinocerebral mucormycosis (p < 0.001) (Lanternier subjects (p < 0.001). On the other hand, airway signals were
et al. 2012a, b). For a good outcome from ROCM, aggres- much more frequent in IPA than in PulM (i.e., clusters of
sive and rapid care is needed, including resection/surgical centrilobular nodules) (Jung et al. 2015).
debridement as well as medical therapy (Guinea et al. 2017). The development or reversal of lung lesions can be
LFAB at a high dose should be given at the same time. ISAV tracked using serial chest CT scans (Choo et al. 2014; Nam
(Ananda-Rajah and Kontoyiannis 2015) and amphotericin et al. 2015; Wahba et al. 2008). From 1997 to 2016, con-
B (Greenberg et al. 2006) are FDA-approved mucormycosis solidation of GGOs, nodules/mass lesions, or a halo was the
treatments, while POSA has been used off-label as a step- most frequent initial lesions on CT in a cohort of 20 immu-
down therapy or salvage (Manesh et al. 2016). nocompromised patients with PulM at a single center (90%)
(Nam et al. 2015). RHS, air crescents, and central necrosis
were often seen on follow-up CT scans in 15 patients, and
Pulmonary involvement these morphological characteristics were associated with
histological observations of pulmonary hemorrhage, arterial
Involvement of the lungs (Nam et al. 2015), perilesional thromboses, and lung tissue infarction. Invasive tracheobron-
ground-glass opacities (GGOs) (Hammer et al. 2018), cen- chitis caused by Mucorales or other molds has been reported
trilobular nodules, “reverse halo sign” (RHS), air-crescent in manually ventilated patients in ICUs, with a 93.5% overall
sign (Dykhuizen et al. 1994) obar consolidation or peribron- mortality rate (Lin et al. 2017). DM in 58% and chronic lung
chial (Jung et al. 2015), upper lobe predominance (Jamadar disease in 39% were found in cohort. Between 2000 and
et al. 1995), pleural effusions (Dykhuizen et al. 1994), and 2012, MD Anderson researchers observed 75 subsequent
bronchopleural fistula (Hammer et al. 2018) are the affected patients with PulM and hematological diseases (Lewis et al.
locations through invasion of active environment. Necrotiz- 2014). Within 4 weeks, 28 people (37.3%) died. Acute Phys-
ing pneumonia may occur when pulmonary vessels are iology and Chronic Health Evaluation (APACHE II) rank-
invaded (Lee et al. 2016). Aspergillus spp. causes offensive ing, extreme lymphopenia, and high serum lactate dehydro-
ulcerative tracheobronchitis at the lung transplant anasto- genase level were all independent risk factors for accelerated
motic site recipients, but Rhizopus tracheobronchitis has development and death (Lewis et al. 2014). In 36 patients
also been reported (Grossi et al. 2000). All but one patient with presumed IFIs and HemeM, pulmonary CT angiogra-
in each group had HemeM. By concomitant sinusitis, logisti- phy was performed. The findings were associated with arte-
cal regression analysis and VORI prophylaxis were impor- rial artery interruption and were found in 5/5 proven cases
tantly associated with PulM. Further, pleural effusions and and 5/7 possible IFIs (Stanzani et al. 2012). However, the
CT findings of 10 nodules were importantly connected with test’s usefulness is still debatable. Overall mortality rates for
PulMs (Dykhuizen et al. 1994). PulM vary from 50 to 70%, but rates for extrathoracic dis-
Many researchers noticed that RHS is much more semination reach 90% (Lee et al. 2016). Surgical resection
widespread in PulM than IPA (Jung et al. 2015). Central (along with medical therapy) can be lifesaving in the case
GGO emphasis surrounded by a crescent or stable ring of localized PulM (Mills et al. 2018).

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Folia Microbiologica (2022) 67:363–387 373

Cutaneous involvement due to the rarity of mucormycosis. However, LFAB can be

employed as first-line treatment to cure the mucormycosis
Involvement of the cutaneous mucormycosis can manifest as disease (Rüping et al. 2009; Anna Skiada et al. 2013). Tria-
a localized or disseminated disease in immunocompromised zole with Mucorales activity was approved by the FDA to
individuals. Traumatic injury (Jeong et al. 2019), surgery treat adult mucormycosis while, POSA, having Mucorales
(Tilak et al. 2009), fires (Ledgard et al. 2008), natural haz- activity, was used as salvage and induction therapy (Jenks
ards (Austin et al. 2014), war (Tribble et al. 2018), insect or et al. 2018; Schwarz et al. 2019). Subsequently, surgical
animal bites (Lechevalier et al. 2008), and also the inocula- debridement serves an essential supporting role, especially
tion of infected soil, trees, grasses, thorns, or water (Lewis when there is the participation of the soft tissue or rhino
et al. 2014) cause cutaneous mucormycosis in immunocom- cerebral (Arendrup et al. 2014; Anna Skiada et al. 2013).
petent hosts (Losee et al. 2002). Mucormycosis is a fungal The importance of reversing underlying risk factors such
infection that spreads quickly across the subcutaneous tis- as glucocortico steroid discontinuation/taper, neutropenia
sues, skin, bone, and fascia. A total of 16 cases of posttrau- resolution, deferoxamine discontinuation, diabetes regula-
matic mucormycosis (PTM) and 85 cases of nontraumatic tion, and immunosuppressant reduction cannot be overstated
mucormycosis were identified by French researchers. PTM (Arendrup et al. 2014; Tissot et al. 2017).
patients ranged from nontraumatic mucormycosis patients in Many antifungals are immune to Mucorales. The most
many ways, such as cutaneous localization, rarity of underly- active agents include LFAB (Arendrup et al. 2014; Schwarz
ing disease, short time before diagnosis, better 90-day sur- et al. 2019) and the newer triazoles, POSA and ISAV (Marty
vival rate, and the species involved. et al. 2016; Schwarz et al. 2019). On the other hand, the
In tropical and subtropical regions, apophysomyces and echinocandins and VORI had deficient activity against Muc-
saksenaea have become the most common species caus- orales (Schwarz et al. 2019).
ing localized cutaneous mucormycosis (Page et al. 2008). Mucormycosis has been treated with LFAB for a long
Many of the isolates were apophysomyces trapezi form in time (Arendrup et al. 2014; Anna Skiada et al. 2013). ISA
a cluster of 13 cases of PTM in Joplin after a tornado. In and POSA have primarily been used as salvage therapy in
a survey of 230 cases of mucormycosis conducted by the patients who have developed resistance to or intolerance to
ECMM registry, 39 patients had PTM and 35 (85%) were LFAB (Schwarz et al. 2019). Mucorales resistance study
immunocompetent, with surgical or other trauma serving as in vitro may aid in treatment selection, but the clinical util-
the predisposing factor (Skiada et al. 2011). The need for ity of such testing is unknown due to a lack of evidence
aggressive and immediate surgical debridement, as well as linking susceptibility testing to results. Since mucormycosis
medical treatment, is critical (Lelievre et al. 2014; Losee can spread quickly, LFAB should be started as soon as the
et al. 2002). disease is suspected (Arendrup et al. 2014). A 6-day delay
in AmB-based therapy was linked to a twofold increased
Gastrointestinal tract involvement risk of death at 12 weeks after diagnosis between 1989 and
2006. 70 patients with HemeM and mucormycosis took part
The introduction of gastrointestinal tract by 2–11% in patient in a single-center study. Although no RCTs have been con-
with mucormycosis develop gastrointestinal (GI) involve- ducted. Many studies indicate that LFAB outperforms AmB
ment which is fatal (Antony et al. 2015; Nandwani et al. deoxycholate in terms of efficacy and protection. For mucor-
2015). In a study of 31 cases of gastrointestinal mucormyco- mycosis, high-dose LFAB (5–10 mg/kg/day) for a minimum
sis, 13 (42%) the stomach and 16 (52%) of the cases included of 6–8 weeks is assumed as first-line therapy. In one study of
the intestine. Hepatic presence is quite uncommon in the SOTRs, patients treated with LFAB had a mortality rate of
present scenario (Bernardo et al. 2016; Tuysuz et al. 2014). 15.4% (4/26) compared to 59.6% (28/47) for patients treated
However, as per the suggestions, hospital therapy and sur- with AmB deoxycholate (Sun et al. 2010). The use of LFAB
gical resection combined with aggressive surgery can be (rather than AmB deoxycholate) was related to decreased
curative in this case (Tuysuz et al. 2014). mortality, in multivariate analysis (Sun et al. 2010). Sho-
ham et al. confirmed 28 cases of mucormycosis treated with
Therapy LFAB from five medical centers in the US (Shoham et al.
2010). Immunosuppressive or HemeM treatment was found
Mucormycosis is an uncommon phenomenon causing in 54% of the cases. The most common sites of involvement
a deadliest opportunity in the affected patients. Several were the lungs (50%), sinuses (29%), and skin (14%) (18%).
research groups from the global organization are working on In 32% of cases, full remissions (CRs) or partial remissions
this problem. Many suggestions and therapy treatments are (PRs) were obtained. The overall survival rate was 39%. In
provided by the researchers. Several researchers’ advice that another study, concurrent surgery was done in 46% of the
randomized controlled trials (RCTs) have not been possible cases with a 31% survival rate. Mucormycosis was found

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374 Folia Microbiologica (2022) 67:363–387

to be the cause of death in 15 patients (36.6% mortality). breakthrough fungemia infection (BFI), which resulted in
Even though several therapies were used, although, the use prolonged neutropenia and leukemia relapse. Therapeutic
of LFAB was connected to survival and a better response medication surveillance of triazoles like VORI and POSA
(Rüping et al. 2009). The ideal period of therapy has yet was being proposed to control therapy for IMIs (Patterson
to be established, but recommendations supported by the et al. 2016), but considering ISAV’s excellent bioavailability.
ESCMID and ECMM suggest continuing antifungal care It is uncertain whether regular monitoring of ISAV levels is
till the disease has now been fully resolved by clinical and required (Natesan and Chandrasekar 2016). In a small sam-
imaging evaluation as the risk has been permanently cor- ple, after 14 days of treatment, the values were 2.86 mg/L
rected (Arendrup et al. 2014). and 4.4 mg/L, respectively. In a small sample, seven cancer
In vitro, both ISAV and POSA (Bagshaw et al. 2018) patients had levels of 2.86 mg/L after 14 days of therapy and
have an action against several molds and fungi, including 4.4 mg/L after 42 days of therapy. The patients were diag-
Mucorales (Jenks et al. 2018; Perfect et al. 2018) although nosed from existing mucormycosis. Moreover, high dose of
this amount of activity for both agents varies depending on the medicine was associated with negative impact (Furfaro
the organisms and Mucorales genus (Denis et al. 2018). In et al. 2019).
refractory cases of mucormycosis, both POSA and ISAV Despite this, no conclusive correlation between ISAV
have shown to be useful as adjunctive therapy or salvage threshold levels and effectiveness or toxicity has been estab-
(Graves et al. 2016; Natesan and Chandrasekar 2016). lished yet. In India, current guidelines indicate 0.5–1 mg/kg/
According to van Burik et al., 91 patients with mucormy- day intravenous methylprednisolone for 3 days in moderate
cosis were treated with POSA as salvage therapy, with 60% instances and 1–2 mg/kg/day in severe instances are very
achieving PR or CR after 12 weeks and 21% remaining helpful (Mahajan et al. 2020). Dexamethasone (6 mg per day
stable. PR and CR rates of 75 and 65%, respectively, were for a maximum of 10 days) is recommended by the National
found in a study of 96 reported case reports of POSA care for Institute of Health in patients who are ventilated or require
mucormycosis (Vehreschild et al. 2013). Full responses were supplementary oxygen, but not in milder instances (Beigel
achieved with POSA in 8/12 (67%) of patients in a small et al. 2020). COVID-19 has pathophysiologic characteris-
study (Manesh et al. 2016). Following initial treatment with tics that may allow secondary fungal infections, such as a
LFAB, sequential therapy with POSA to complete therapy proclivity for causing extensive lung illness and subsequent
was effective (Epstein et al. 2016; Tobón et al. 2016). For alveolo-interstitial pathology, which may increase the like-
patients with mucormycosis who have failed LFAB172 or lihood of invasive fungal infections. Second, COVID-19’s
POSA, ISAV has shown to be a successful recovery therapy immunological dysregulation, which includes lower num-
(Denis et al. 2018; Natesan and Chandrasekar 2016). In the bers of T lymphocytes, CD4 + T cells, and CD8 + T cells,
VITAL study, patients with disseminated mucormycosis may disrupt the immune system. Therefore, remediation of
were given ISAV. which was an open-label, nonrandomized such phenomenon is still challenging to prevent the occur-
study (Marty et al. 2016). First-line therapy (n ¼ 21), anti- rence of disease. Figure 2
fungal agent(s) (n ¼ 5), refractory disorder (n ¼ 11), and
intolerance to previous is among the indications for using
ISAV. progression (5%), PR (14%), CR (5%), and stable Combination antifungal therapy
(30%) were the most common responses (51%). In the Fungi
Scope Registry, these 37 mucormycosis patients were paired The mucormycosis therapy was provided in patients in con-
with 33 LFAB-treated controls. junction with several antifungal agents for diagnosing the
At care day 84, both arms had similar all-cause mortality intractable cases (Tacke et al. 2014); however, RCTs are
(43% with ISAV; 50% with AmB). The FDA has approved inadequate (Candoni et al. 2015).
ISAV for the treatment of invasive aspergillosis and invasive Pagano et al. in their study found 32 patients with evi-
mucormycosis in adults in the United States (Perfect et al. dence-based mucormycosis treated with such a variation
2018). The European Medicines Agency has approved ISAV of LFAB and POSA from two main European registries
for the treatment of mucormycosis when AmB is ineffec- between 2007 and 2012. During a 3-month observation, 11
tive. ISAV is given as a loading dose (372 mg isavuconazo- (34%) of patients had CRs, 5 (16%) 9 (28.1%) died of pro-
nium sulfate [equivalent to 200 mg ISAV] every 8 h for six gressive mucormycosis, while the rest were healthy. Combi-
doses) and a maintenance dose (372 mg isavuconazonium nation therapy was not shown to be superior to monotherapy
sulfate [equivalent to 200 mg ISAV] every 8 h for six doses). in a retrospective review of patients with mucormycosis
Table 5 complicating HemeM. The effectiveness of combined anti-
In a retroactive survey of 100 leukemia patients who fungal therapy for mucormycosis is unknown due to lack of
received ISAV as a single individual for prophylaxis, 13 evidence. Hence, there is a need of experimental setup for
patients (including four cases of mucormycosis) experienced observing the alterations in the given therapy.

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Folia Microbiologica (2022) 67:363–387 375

Table 5  Conditional behavior of mucormycosis under different pathogenic treatments and their forms (Petrikkos and Drogari 2011)
Mucormycosis activators Treatment Symptoms (in the
form of frequency)

Uncontrolled diabetes mellitus Fe usage by zygomycetes for growth/ Impairment of •Rhinocerebral

Diabetic ketoacidosis neutrophil activation (functional neutropenia) •Pulmonary
•Sino-orbital
•Cutaneous
Hematological malignancies Hematopoietic stem cell Prolonged neutropenia •Pulmonary
transplantation (HSCT) •Cutaneous Sinus
•Sino-orbital
Prolonged treatment with corticosteroids autoimmune Defects in neutrophils and macrophages, •Renal
disease hypocomplementemia, cortico- steroid induced diabetes •Cutaneous
•Gastrointestinal
•Disseminated
•Rhino-cerebral
Intravenous illicit drug use/HIV infection Injection of spores contained in drugs •Cerebral
•Cutaneous
•Heart
•Disseminated
•Renal
•Rhinocerebral
Solid organ transplantation (SOT)/graft versus host disease Cellular immune suppression, corticosteroid-induced •Sinus
(GVHD) diabetes •Pulmonary
•Rhinocerebral
•Cutaneous
disseminated
Iron/aluminum chelation therapy with deferoxamine (DFO), Fe usage by Zygomycetes for growth Fe-DFO action as •Disseminated
iron overload siderophore •Pulmonary
•Cerebral
•Gastrointestinal
•Rhinocerebral
•Cutaneous
Prolonged use of broad-spectrum antifungal agents •Sever infection •Sino-pulmonary
(itraconazole, voriconazole and caspofungin)
Soft tissue or Skin breakdown trauma/burn/insect bite/surgical Direct cutaneous inoculation with high number of spores •Cutaneous
wound •Pulmonary
•Rhinocerebral
•Gastrointestinal
•Sino-orbital
Miscellaneous Neonatal prematurity Malnourishment •Replacement of normal bacterial biota •Pulmonary
Prolonged use of broad-spectrum antimicrobial agents •Ingestion of spores •Sino-orbital
•Rhinocerebral
•Gastrointestinal
•Cutaneous

Surgical therapy (51.7% survival, p < 0.005). Several researchers have worked
on the treatment of mucormycosis. In a study, 230 cases
Resection or surgical debridement plays a vital role as an of mucormycosis were observed from the European coun-
adjunctive treatment in mucormycosis patients (Riley et al. tries to identify the factors responsible for better survival
2016). An extensive study was carried out to check the sur- rate during 2005 to 20,017. The adjunct factors were LFAB
vival rate over the 929 victims of mucormycosis. The study treatment (p ¼ 0.006), surgery (p < 0.001), and trauma (p ¼
reported that survival rates were 57% for surgery, 61% for 0.02) (A. Skiada et al. 2011). However, the overall survival
AmB, and 70% for AmB plus surgery (Roden et al. 2005). was higher (70.2%) with surgical debridement plus POSA
In another study, 178 cases of mucormycosis from an Indian and AmB in a cohort of 174 renal transplant recipients with
tertiary care center; 74% of patients had ailing regulated dia- mucormycosis than with antifungal therapy (32.4%), no
betes were recorded (Chakrabarti et al. 2006). Although, the therapy (0%) or surgery alone (36.4%) (Song et al. 2017).
combination of AmB and surgical debridement resulted in a Overall mortality was 52% in 90 cases of SOTRs among
substantially higher survival rate (79.6%) than AmB alone ROCM (Sun et al. 2010). Surgery and LFAB were both

13
376 Folia Microbiologica (2022) 67:363–387

Fig. 2  Different treatments of mucormycosis

linked to improved survival rate (Song et al. 2017). Conse- successful in one patient with ROCM (Reed et al. 2006). Six
quently, SSTI, rhinocerebral mucormycosis, and the cases patients with invasive mucormycosis were diagnosed using
of pulmonary disease were seen to be effectively diagnosed deferiprone (an iron chelator) after receiving initial care with
by surgical therapy (Chretien et al. 2016; Anna Skiada et al. surgery, echinocandins, step-down therapy with POSA, and
2013; Sun et al. 2010). In addition to it, surgical resection combination therapy with polyenes, in a retrospective study
combined with medical therapy can be curative when PulM in Thailand (Chitasombat and Niparuck 2018). Three of
is localized (Coffey et al. 1992). the six patients died after 180 days. Twenty patients with
confirmed or suspected mucormycosis were randomized
to receive either LFAB plus placebo or LFAB plus defera-
Iron chelators sirox (Spellberg et al. 2012). At 90 days, the deferasirox
party had a slightly higher mortality rate (82 vs. 22%, p ¼
Deferasirox is a kind of iron-chelating agent that increases 0.01). Although guidelines from the 6th European Confer-
longevity in mice with diabetic ketoacidosis (Ibrahim et al. ence on Leukemia Infections (ECIL-6) suggests the avoid-
2007). Deferasirox was seen to be very effective in patients ance of deferasirox for the remediation of the mucormycosis
against the LFAB treatment. Furthermore, Deferasirox was (Schwarz et al. 2019; Tissot et al. 2017).

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Folia Microbiologica (2022) 67:363–387 377

Table 6  Patient groups, intervention and their salvage treatment during mucormycosis (Vujanovic et al. 2017)
Treatment Patient group Intervention

Fever driven or • unresponsive to antibiotics, Febrile neutropenia, imaging–reverse halo, Liposomal amphotericin B
Empirical galactomannan negative; other atypical presentation or multiple nodules
Prophylaxis • graft versus host disease or Prolonged neutropenia Posaconazole DR intravenous or tablet
• SOT adult, Prolonged neutropenia, heart, and lung 2 × 300 mg day 1, 1 × 300 mg from day 2
• Immunocompromised due to a previous mucormycosis diagnosis Isavuconazole intravenous or per oral
3 × 200 mg days 1–2, 1 × 200 mg/day from day
3, or 1 × 200 mg/day from day 1
In the same patient, surgical resection and
the last medicine effective as a secondary
prophylactic, switch from amphotericin B to
posaconazole after 3–6 weeks if practicable
Salvage • Refractory disease Isavuconazole intravenous or per oral
• Toxicity to primary therapy 3 × 200 mg days 1–2, 1 × 200 mg from day 3
Posaconazole DR tablet or intravenous
2 × 300 mg day 1, 1 × 300 mg from day 2
Amphotericin B, lipid formulations, 5–10 mg/
kg (lower dose in patients with renal toxicity)

Salvage therapy offers the low cost comparatively with other alternatives
(Davari et al. 2003). Despite of the available solutions, the
Salvage therapy is provided when patient does not respond raise in breakthrough IFIs (bIFI) in patients using vucona-
to the normal first-line treatment with amphotericin B. The zole prophylaxis is also raise the concern. Although, the
assessment of antifungal medication failure, necessitates cau- choice of antifungal for secondary prophylaxis is a typical
tion (Dimaka et al. 2014). Patients with mucormycosis fre- clinical question. Moreover, secondary prophylaxis reacts
quently have co-existing fungal and bacterial infections, as with immunocompetent patient to control the infectious dis-
well as non-infectious diseases such as leukemic infiltration, ease. The treatment satisfactorily controls the rate of mucor-
medication toxicity, or organ failure, which can make measur- mycosis through the antifungal medication. (Almyroudis
ing therapy response difficult. Furthermore, an initial paradox- et al. 2006). Table 3 shows the list of prophylactic, empiric,
ical deterioration, reported in cancer patients with pulmonary and therapeutic interventions.
mycoses (including mucormycosis) in the context of neutro-
phil recovery, could be misinterpreted as a treatment failure
(Prakash et al. 2019). Switching to a different class of anti- Clinician observations and medical advices
fungal agents is the general principle of salvage therapy. How- for mucormycosis and COVID‑19 disease
ever, Mucorales is only susceptible to two types of antifungal
drugs. In this case, the options are to increase the LAMB dose COVID-19 infection has a peculiar threat from mild to fatal
or switch to posaconazole or isavuconazole. Table 6 pneumonia and associated secondary bacterial or fungal
infections. Due to comorbidity and an immunocompromised
Role of antifungal prophylaxis state, the death rate is high which allowing mucormycosis
to thrive (Salehi et al. 2020). A cluster of reports on rhino-
It is still under investigation that whether anti-Mucorales orbital mucormycosis post-COVID-19 disease is available
antifungals should be used for primary or secondary proph- among a number of other opportunistic infections, includ-
ylaxis in high-risk individuals. Presently, posaconazole is ing oropharyngeal candidiasis, pulmonary aspergillosis, and
strongly suggested as a main prophylactic to prevent IFI jiroveci pneumonia (Chowdhary et al. 2020a, b). Accord-
(particularly mucormycosis) in the patients suffering from ing to a recent article, India accounts for 71% of all CAM
severe neutropenia (Lee et al. 2016). Monitoring serum cases, with an accurate number of 140 instances per mil-
posaconazole levels during prophylaxis is also displayed lion (John et al. 2019, Prakash and Chakrabarti 2019). This
to document appropriate antifungal absorption and therapy is attributable to a number of factors, including the largest
compliance, as undetectable serum levels increase the risk population of the country and second-highest population of
of breakthrough infections; however, isavuconazole could be persons aged 20 to 79 with diabetes mellitus (IDF 2019). It
another option based on the results of a recent clinical trial was found that 50% of the CAM patients were diabetic, 18%
(NCT03019939) (Chitasombat and Kontoyiannis 2016). The had diabetic ketoacidosis, and 57% had diabetes mellitus
adoption of posaconazole and isavuconazole prophylaxis that was uncontrolled. As per the reports from the clinical

13
 Table 7  Case reports on medical history of COVID 19 and associated mucormycosis disease
378

Case no Male/female Phase of Medical history Therapy implemented Predisposing aspect Histological Symptom Clinical manifestation Alive/dead Reference
COVID-19 for mucormycosis examination duration

13
(days)

1 Male/60 Severe Diabetes High-dose steroid for Hyperglycemic Non-septate hyphae 12 •Oedema Dead Mehta and
COVID 19. steroid for •Periorbital facial pain Pandey 2020
Methylprednisolone COVID-19 •Acute vision loss
2 Male/22 Severe Pancreatitis High-dose steroid for Steroid for COVID Non-septate hyphae 27 •Diagnosed as Rhino- Dead Hanley et al. 2020a, b
COVID Linezolid 19-treatment orbito-cerebral
Meropenem mucormycosis
•Disseminated to
oLymph nodes
oHeart
oBrain
oKidney
3 Female/33 Severe Diabetes Asthma No steroids Remdesivir DKA Diabetic Non-septate hyphae 2 •Diagnosed as Dead Werthman-
hypertension Vancomycin ketoacidosis Rhihino-orbital Ehrenreich 2021a, b
mucormycosis
•Necrosis in
oNasal
oPalate
oLeft eye ptosis
oConfused mental
status
oOphthalmoplegia
proptosis
4 Male/66 Severe Hypertension Hydroxychloroquine Lymphopenia Non-septate hyphae 21 •Diagnosed as Dead Pasero et al. 2020a, b
Lopinavir–ritonavir Pulmonary
mucormycosis in
lungs
•Necrotic empyema
•Spontaneous
pneumothorax
5 Male/49 Severe Normal Dexamethasone Steroid for COVID- Non-septate hyphae 21 •Diagnosed as Dead Placik et al. 2020
Tocilizumab 19 treatment Pulmonary
Remdesivir mucormycosis in
Ceftriaxone lungs
•Necrotic empyema
•Spontaneous
pneumothorax
Folia Microbiologica (2022) 67:363–387
 Table 7  (continued)
Case no Male/female Phase of Medical history Therapy implemented Predisposing aspect Histological Symptom Clinical manifestation Alive/dead Reference
COVID-19 for mucormycosis examination duration
(days)

6 Male/60 Severe Diabetes, asthma, Dexamethasone Hyperglycemia, Non-septate hyphae 5 •Diagnosed as Dead Mekonnen et al. 2021a,
hypertension, Remdesivir steroid for Pulmonary b
hyperlipidemia Convalescent plasma COVID-19 mucormycosis
therapy (single dose) •Gastric ulcers
•Acute diarrhea
•Melena
•Severe anemia
•Fever
Folia Microbiologica (2022) 67:363–387

7 Male/86 Severe Hypertension Hydrocortisone for Steroid for COVID- Non-septate hyphae 21 •Diagnosed as Dead Do Monte et al. 2020
COVID-19 19 treatment Pulmonary
Ceftriaxone mucormycosis with
Azithromycin Bronchopulmonary
Oseltamivir fistula
•Pulmonary infiltrates
•Parenchymal
thickening of the
whole left lung
•Cavitary lesions
•Pleural effusion
•Opacity of the left
maxillary sinus
8 Female/ 40 Mild None Remdesivir Short-term Non-septate hyphae 8 •Diagnosed as Dead Veisi et al. 2021
Levofloxacin corticosteroid Rhinoorbital
Dexamethasone therapy mucormycosis
•Opacifications of
paranasal sinuses
9 Male/38 Mild Remdesivir Short-term Confirmed with CT 18 •Diagnosed as rhino- Alive Maini et al. 2021
Dexamethasone corticosteroid scan orbital mucormycosis
therapy
10 Male/54 Severe Non-insulin- Remdesivir Short-term Non-septate hyphae 12 •Diagnosed as Alive Veisi et al. 2021
dependent Levofloxacin corticosteroid rhino-orbitocerebral
diabetes mellitus Dexamethasone therapy mucormycosis
(DM) •Unilateral
opacifications of the
left orbit
•Paranasal sinuses

13
379
 Table 7  (continued)
380

Case no Male/female Phase of Medical history Therapy implemented Predisposing aspect Histological Symptom Clinical manifestation Alive/dead Reference
COVID-19 for mucormycosis examination duration

13
(days)

11 Male/41 Mild Diabetes mellitus Steroids and Developed diabetic Confirmed with CT 16 •Tissue necrosis Alive Alekseyev et al. 2021
hydroxychloroquine ketoacidosis scan from angioinvasion
(DKA) and subsequent
thrombosis
•Diagnosed as
rhinocerebral
mucormycosis
12 Male/72 Severe Steroidinduced Ramdevpir Methyl Impaired immune Non-septate hyphae 9 •Diagnosed as sino- Alive Chennamchetty
diabetic, prednisolone functioning orbital mucormycosis et al. 2021
hypothyroid convalescent plasma (2 •Pneumothorax
doses) Diagnosed as
pulmonary
mucormycosis
13 Male/68 Severe Heart transplant Remdesivir Previously under Non-septate hyphae 13 •Purplish skin Dead Khatri et al. 2021
recipient Hydroxychloroquine immunosuppressive discoloration with
Diabetes Convalescent plasma medication for fluctuant swelling
mellitus infusion (single dose) transplantation was noted in the right
Methylprednisolone axilla
Prednisone taper •Diagnosed as
cutaneous
mucormycosis
14 Female/32 Mild Uncontrolled Not mentioned Immunosuppression Confirmed with CT 18 •Opacification of the Alive Saldanha et al. 2021
diabetes Left eye due to COVID 19 scan left ethmoid
complete ptosis •Maxillary
and left facial •Frontal sinus
pain
Folia Microbiologica (2022) 67:363–387
Folia Microbiologica (2022) 67:363–387 381

observations, mucormycosis can show in six different clini- management alternatives. The advancement in the clinical
cal presentations based on the location of fungal prolif- trials advice to use the surgical procedures for the treatment
eration and dissemination. The pulmonary, rhinocerebral, of mucormycosis. This study provides the most recent con-
gastrointestinal, cutaneous, and disseminated systems are sensus recommendations for the management of mucormy-
among them (Spellberg et al. 2005a, b). The rhino cerebral cosis in different clinical scenarios. The current scenario of
form is the most prevalent, followed by the pulmonary and COVID-19 pandemics and the rapid rise in the incidence
cutaneous types (Petrikkos et al. 2012a, b). of mucormycosis paves the way to a better understanding
Sarkar et al. recently reported the occurrence of orbital and the possibilities of the invention of newer management
mucormycosis in 10 patients with concurrent COVID-19 techniques and treatment protocols to reduce the percentage
diseases. All of them had diabetes, with four of them hav- morbidity and mortality associated with such disease.
ing been diagnosed with DKA and the other five developing
DKA while on COVID-19 corticosteroid medication. For Acknowledgements The authors are deeply thankful to Kamal
Kishore, Assistant Professor, Department of Civil Engineering, GLA
mucormycosis, intravenous dexamethasone and liposomal University for their exceptional support to complete this review article.
amphotericin B were used. Ventilator and remdesivir were His enthusiasm, knowledge and exacting attention to detail have been
the useful practice to combat the situation in the patients. an inspiration during drafting this review article.
In a report, four patients–but lost their vision permanently,
and just one patient recovered with good ocular and systemic Declarations
outcomes (Sarkar et al., 2021). It means that the complete
dependencies over the remedials were also not efficient Conflict of interest The authors declare no competing interests.
to cater the wide cases of mucormycosis and COVID-19.
The situation was differed case by case. Although, the
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