mucormycosis in india: unique features

Supplement article

Mucormycosis in India: unique features

Arunaloke Chakrabarti and Rachna Singh*

Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Summary Mucormycosis remains a devastating invasive fungal infection, with high mortality

rates even after active management. The disease is being reported at an alarming

frequency over the past decades from India. Indian mucormycosis has certain unique

features. Rhino-orbito-cerebral presentation associated with uncontrolled diabetes is

the predominant characteristic. Isolated renal mucormycosis has emerged as a new

clinical entity. Apophysomyces elegans and Rhizopus homothallicus are emerging species

in this region and uncommon agents such as Mucor irregularis and Thamnostylum

lucknowense are also being reported. This review focuses on these distinct features of

mucormycosis observed in India.

Key words: Mucormycosis, epidemiology, diabetes, Rhizopus oryzae, Apophysomyces elegans, renal infection.

Introduction

Fungi belonging to the class Zygomycetes and order

Mucorales often cause devastating angioinvasive fungal

infections, primarily in patients with underlying risk

factors.1 These moulds gain entry into the human

body via respiratory tract or skin, and less commonly

through the gastrointestinal tract, eliciting an acute

inflammatory response.2 Under favourable conditions

such as those in immunocompromised hosts, they

invade the blood vessels, causing extensive vessel

thrombosis and ischaemic tissue necrosis.2,3 Most of

these infections are rapidly progressive and exhibit

high mortality (~50%) even after active management;

the mortality rates approach nearly 100% among

patients with disseminated disease.3–6 The principal

risk factors implicated in mucormycosis include

uncontrolled diabetes and diabetic ketoacidosis,

prolonged steroid therapy, persistent neutropaenia,

desferoxamine therapy, haematological malignancies,

illicit use of intravenous drugs, autoimmune disorders,

prophylaxis with voriconazole or echinocandins, and

the breach of cutaneous or mucous membrane barrier

due to trauma, burns and surgical wounds.1,2 How-

ever, it has also been described in patients with no

underlying disease.1,2

The emergence of mucormycosis is being reported

globally, with an alarming rise in the number of cases

from developing countries including India.1,2,4,7–9 The

precise epidemiology of this disease in developing

world is not well known due to limited data as a result

of sub-optimal awareness, inadequate reporting and

diagnostic facilities at many of the healthcare centers.1

However, the available literature suggests a consider-

able variation between the developing and developed

nations, with differences in the prevalence, risk factors

and causative agents involved.1,4–7 Certain peculiari-

ties have been observed in cases of mucormycosis in

India compared with the western world, including a

high incidence of this disease; uncontrolled diabetes

and diabetic ketoacidosis as the principal risk factor;

rhino-orbito-cerebral (ROC) form as the most common

clinical presentation; isolated renal mucormycosis as a

new entity; and a wide and varied spectrum of patho-

gens involved in such infections.1 Seasonal variations

in incidence of mucormycosis with respect to tempera-

ture, rainfall and humidity have also been noted.10 In

Correspondence: Dr Arunaloke Chakrabarti, Professor and Head, Depart-

ment of Medical Microbiology, Postgraduate Institute of Medical Educa-

tion and Research (PGIMER), Chandigarh 160012, India.

Tel.: +91-172-2755173/2755155/2747990. Fax: +91-172-2744401.

E-mail: [email protected]

*Present address: Centre for Microbial Biotechnology Panjab University

Chandigarh India

Submitted for publication 28 December 2013

Revised 21 April 2014

Accepted for publication 22 April 2014

© 2014 Blackwell Verlag GmbH

Mycoses, 2014, 57 (Suppl. 3), 1–6 doi:10.1111/myc.12243

mycosesDiagnosis,Therapy and Prophylaxis of Fungal Diseases

this review, we highlight these distinct features of

mucormycosis with reference to India.

High incidence

An upsurge of mucormycosis is being reported

throughout the world over the past two decades,

however, the rise in developing countries including

India has been phenomenal.1,2,4,7–9 Three consecu-

tive case series on mucormycosis have been reported

from a single tertiary-care centre in India: 129 cases

over 10 years (1990–1999), 178 cases during the

subsequent 5 years (2000–2004) and then 75 cases

in an 18 month period during 2006–2007.4–6 Many

other Indian centres have also subsequently pub-

lished multiple series of this disease in different risk

groups.10–13 This increasingly high incidence of

mucormycosis in India has been attributed primarily

to a continued increase in the patient population

with uncontrolled diabetes, which is a one of the

major risk factors for this disease in developing coun-

tries.1 In fact, India has the second largest diabetic

population globally (65.1 million),14 with nearly

70% of these cases being those of uncontrolled diabe-

tes.15 Environmental factors, such as tropical and

sub-tropical humid climate and high environmental

temperature in most parts of India, further provide

an optimum set-up for survival of these fungi, and

perhaps contribute to the disease prevalence.1 Better

awareness, expertise and diagnostic facilities in many

of the healthcare centres have also significantly con-

tributed to an increased recognition of this disease

over the past years.3

Majority of the reported cases from India have been

those of proven mucormycosis, diagnosed based on

culture and histopathology.3 Very few authors have

included probable mucormycosis in their series. It

should be noted, however, that proven cases would

be smaller in number compared with the actual

magnitude of mucormycosis, owing to the often non-

specific clinical signs and symptoms associated with

this disease and low sensitivity of the presently avail-

able diagnostic modalities.3 In the absence of a

population-based study, the exact prevalence of mu-

cormycosis in India remains difficult to elucidate.3

However, on the basis of data available from certain

groups of patients, the disease prevalence appears to

be nearly 0.16% amongst diabetics and 1.2%

amongst renal transplant recipients, with most of

these cases manifesting as the ROC form.16,17 Also,

gastrointestinal mucormycosis reportedly occurs in

nearly 20% of all operated cases of neonatal

enterocolitis in one center.18 In fact, the frequency of

gastrointestinal mucormycosis was found to be so

high in that centre that clinicians suspect the dis-

ease in any neonate having intestinal perforation. We

recently reviewed Indian literature for the past five

decades (1960–2012), and developed a computational

model to determine the burden of mucormycosis.

The results reveal an overall mucormycosis preva-

lence of 0.14 cases per 1000 population in India,

with the prevalence range between 208 177 and

137 807 cases (Mean: 171 504; SD: 12 365.6; 95%

CI: 195 777–147 688) and a mean of 65 500

(38.2%) attributable deaths per year.19

Based on the clinical presentations, ROC is the

most common form of mucormycosis in India, possi-

bly due to its association with uncontrolled diabetes

and diabetic ketoacidosis.1,3,20 According to the mul-

tiple case series reported from our tertiary care centre

in North India, the prevalence of different clinical

types amongst mucormycosis cases is: ROC (48–55%), cutaneous (13–15%), pulmonary (7–17%), dis-

seminated (5–12%), gastrointestinal (5–13%) and iso-

lated renal (5–14%).4–6 Likewise, in a meta-analysis

of all the zygomycosis cases reported from India, Di-

wakar et al. describe an overall prevalence of ROC

(58%), cutaneous (14%), pulmonary (6%), dissemi-

nated (7%), gastrointestinal (7%) and isolated renal

(7%).21 This is consistent with the global trend,

wherein pulmonary and sinus infections (with/with-

out central nervous system involvement), followed by

cutaneous type have been found to be the most

prevalent.22–25 Cases of necrotising fasciitis due to

zygomycetes, occurring via contaminated intramuscu-

lar injections, are also a common finding.7,26 This

happens due to compromise in healthcare practices

and the use of contaminated needles. In addition,

majority of the patients (60%) with cutaneous infec-

tions due to Apophysomyces elegans are from

India.1,7,27 The patients are usually immunocompe-

tent individuals, who acquire the infection following

penetrating trauma or burns.1,7,27 However, no corre-

lation between the environmental prevalence of this

fungus and clinical cases has been described yet.1

Furthermore, nosocomial mucormycosis is also being

reported from this country, though traditionally the

disease was considered to be community acquired.1

In a study from our centre, 9% of all mucormycosis

cases were found to be nosocomial in origin. These

patients acquired infection either at the site of the

ECG leads or the adhesive tapes, or from contami-

nated intramuscular injections, or from air in the

hospital environment.4


Mycoses, 2014, 57 (Suppl. 3), 1–62

A. Chakrabarti and R. Singh

Diabetes as a risk factor

The risk factors for mucormycosis differ significantly

amongst the developed and developing world.1,7 While

haematological malignancies and transplants are des-

ignated as the key risk factors for mucormycosis in

developed nations, the disease is majorly associated

with uncontrolled diabetes with or without ketoacido-

sis in developing countries including India.1,7 Nearly

24–64% of the mucormycosis cases reported from

India are in patients with uncontrolled diabetes, with

or without ketoacidosis.4–6,21 Although other risk fac-

tors have also been implicated, the overwhelming

number of mucormycosis cases with uncontrolled dia-

betes overshadows their role.1,7 This is possibly linked

to a large diabetic population in such countries, as dis-

cussed previously.1 Unless complication develops, these

patients avoid seeking medical attention.3 In India, a

considerable number (16–23%) of diabetics remain

undiagnosed of their underlying disease before presen-

tation of mucormycosis; mucormycosis, in fact, acted

as diabetes-defining illness in those cases.4,5 The mean

informed duration of diabetes was found to be

6.7 � 4.6 years before acquiring mucormycosis.16

Amongst the diabetic patients, poorly controlled

type II diabetes is the most common risk factor for

mucormycosis, being involved in nearly 44–88% of

the cases mainly from north to south India, with

nearly half of them exhibiting ketoacidosis.4–6,10,21

Type I diabetes (10–15%) and secondary diabetes have

also been detected in some patients.5,28,29 In contrast,

diabetes was the risk factor in only 36% of the global

series of 929 cases,24 17% of the Trans-European

series,25 16% of France series,30 6% of Belgium ser-

ies31 and 18% of Italy series.23 It should be noted,

however, that as confounding factors, renal failure

and alcoholism related chronic liver disease have also

been detected in patients along with diabetes in

India.4

Several factors relate the unique predisposition of

diabetic patients to mucormycosis. Firstly, diabetes and

ketoacidosis render the phagocytic cells dysfunctional.

Both neutrophils and macrophages exhibit an

impaired chemotaxis and defective killing by both oxi-

dative and non-oxidative pathways under such condi-

tions, although the precise mechanisms mediating

these remain to be elucidated.32–34 Secondly, patients

with diabetic ketoacidosis have an acidic serum pH

with elevated levels of free iron, which is a major

nutrient element governing susceptibility to Muco-

rales.32,35,36 Thirdly, elevated levels of glucose and

iron, similar to those observed during diabetic

ketoacidosis, increase the expression of GRP-78. GRP-

78 is a glucose-regulated protein belonging to the

HSP-70 family, which is mainly present in the endo-

plasmic reticulum where it mediates several cellular

processes as a chaperon, including protein folding,

degradation of misfolded proteins, regulation of

calcium homeostatis and sensing the endoplasmic

reticulum stress.32,37–41 Recent studies indicate that a

fraction of GRP-78 is also translocated to the cell sur-

face in many cell types,41 wherein it acts as the recep-

tor mediating penetration and damage of endothelial

cells by Mucorales, leading to the observed angioinva-

sion.32 Mice with diabetic ketoacidosis have an

increased expression of GRP-78 in sinus, lungs and

brain, and anti-GRP-78 serum can protect such mice

from mucormycosis, indicating a plausible role of

GRP-78 overexpression in susceptibility of diabetics to

this disease.32,39

It is generally believed that distinct clinical presenta-

tions of mucormycosis are associated with specific

underlying risk factors, with ROC, pulmonary, gastro-

intestinal and cutaneous types occur in patients with

diabetes, haematological malignancies or neutropae-

nia, severe malnutrition, and trauma or burns respec-

tively.1,4–7 However, uncontrolled diabetes has been

found as the major factor in all types of mucormycosis

in India except the isolated renal form, although

ROC manifestation remains the most common clinical

type and is significantly associated with uncontrolled

diabetes.1,4–7,20,21

As the majority of Indian patients have diabetes and

metabolic acidosis as the major risk factors, the princi-

pal management modalities in such cases include a

control of hyperglycaemia and prompt reversal of

ketoacidosis, along with surgical debridement and

amphotericin B therapy.3 It is hypothesised that a

decrease in diabetes-associated mucormycosis in USA

in recent years may be attributed to an increased use

of statins in diabetic patients and the inhibitory action

of statins against mucoralean agents.42 Although sta-

tins are regularly prescribed in Indian patients with

diabetes, no fall in the number of diabetes-associated

mucormycosis cases has been reported from this coun-

try.3 Therefore, a detailed study is required for assess-

ing the role of statins against mucormycosis. Among

the different clinical types of mucormycosis, cutaneous

and rhino-cerebral types have a better survival rate

due to possibility of an early diagnosis. Though major-

ity of the Indian patients have rhino-cerebral presenta-

tion, the mortality rate of mucormycosis remains high

(nearly 50%) in India.4 This is largely due to a delay in

seeking medical attention, diagnosis and therapy.3


Mycoses, 2014, 57 (Suppl. 3), 1–6 3

Mucormycosis in India

Isolated renal mucormycosis

Apart from the common clinical types, isolated renal

mucormycosis in apparently healthy hosts is being

reported as a new clinical entity in India.4–6,43

Although the kidney is involved in nearly 22% cases

of disseminated mucormycosis,44 isolated renal muco-

rmycosis is described rarely in literature. Other than

India, case series of isolated renal mucormycosis has

also been reported from China.45–47 However, majority

of the patients (75%) suffering from isolated renal mu-

cormycosis in India are apparently healthy individu-

als;4–6 in contrast, in China, majority of the reported

cases possess risk factors for developing mucormycosis,

except the paediatric population.45–47

These patients with isolated renal mucormycosis had

acute presentations. They developed fever, flank pain,

haematuria or anuria.4 Although renal tuberculosis,

rapidly progressive glomerulonephritis and acute pyelo-

nephritis may present similarly, enlarged unilateral or

bilateral infarcted non-functioning kidneys (no contrast

excretion) with low attenuation areas on imaging

strongly suggest renal mucormycosis.48 With increased

awareness and the combination of clinical and radiolog-

ical findings at our tertiary-care centre in North India,

majority of these cases were diagnosed antemortem, as

in 32 (76.2%) of 42 patients in a meta-analysis.4–6 In

spite of antemortem diagnosis, mortality remained high

(~50%) due to difficulty in managing such patients.4–6

It is still not clear how the fungus enters the kidney,

without developing lesion in other organs in majority

of patients. Lungs may be the portal of entry, as an

additional focus in lungs has been observed in a few

patients on autopsy.49 Ascending route may also be

the portal of entry, as additional lesion in the urinary

bladder has been noted in a recent report.50 Once

fungi gain entry into the main vessels of kidney, they

can cause cortical and medullary infarction leading

to renal failure.51 A detailed investigation of such

patients is required to clarify the unexplained patho-

genesis of this mucormycosis.

Spectrum of Mucorales fungi

There is a wide spectrum of mucoralean fungi causing

human infections. Globally, Rhizopus, Mucor and Licht-

heimia (formerly Absidia or Myocladus) spp. represent

the most frequent causative agents of this disease,

accounting for 70–80% of all cases (Fig. 1).1,4,7,52

Apophysomyces, Saksenaea, Rhizomucor, Cunninghamella,

Cokeromyces, Actinomucor and Syncephalastrum spp.

have also been reported rarely.1,4,7,52 In India, Apo-

physomyces elegans is the second most common causa-

tive agent, after Rhizopus oryzae (Fig. 1).4,5

Although Mucorales are considered opportunistic

pathogens, Apophysomyces elegans and Saksenaea vasifor-

mis can initiate disease in apparently normal hosts, fol-

lowing penetrating trauma during accidents in tropical

and sub-tropical areas.1,7,27,52 Majority of these patients

present with cutaneous mucormycosis only and do not

have any underlying disease; only a few patients mani-

fest rhino-cerebral and pulmonary infections, and have

risk factors for developing mucormycosis.1,7,52 Intrigu-

ingly, Apophysomyces elegans does not produce spores in

the environment easily; its sporulation is induced in the

laboratory with care.53 It is therefore unclear as to how

the patients with pulmonary, renal or disseminated mu-

cormycosis acquire this agent from environment.3

Rarely, Cunninghamella bertholletiae, Rhizomucor pusillus

and Rhizopus microsporus can also initiate infections in

immunocompetent individuals.52,54,55

Many uncommon species have also been implicated

in infections in India. Rhizopus homothallicus has been

reported for the first time from patients with cavitary

pulmonary mucormycosis.56 Mucor irregularis, that

was initially considered to be involved in an emerging

endemic cutaneous mucormycosis limited to China,

has been reported from a case of rhino-facial

Figure 1 Aetiological agents of zygomy-

cosis. The data shown are from studies

by Chakrabarti et al. [4–6] (India), Moha-

patra et al. [59] (India), Skiada et al. [25]

(Europe), Lanternier et al. [22] (France)

and Pagano et al. [23] (Italy).


Mycoses, 2014, 57 (Suppl. 3), 1–64


mucormycosis in India.57 Recently, a new mucoralean

fungus, Thamnostylum lucknowense has been isolated

from a patient with rhino-orbital mucormycosis.58

Conclusions

The epidemiology of mucormycosis in India is intrigu-

ing, and varies significantly from the developed

nations. The estimated number of cases in India seems

to be alarmingly high, with uncontrolled diabetes

being the most important risk factor. Certain con-

founding factors like renal failure and hepatic diseases

have also been detected along with diabetes in muco-

rmycosis patients; a detailed multicentric study is

therefore warranted to precisely determine the associa-

tion of diabetes with this invasive mycosis in India.

ROC form remains the most common clinical presenta-

tion, albeit due to its association with diabetes. Iso-

lated renal mucormycosis amongst immunocompetent,

young individuals is an emerging entity in India.

Although isolated renal infections have been reported

from China as well, but the majority of patients in

China have pre-disposing risk factors for developing

mucormycosis, except the paediatric population. The

disease is highly aggressive but the mode of acquisi-

tion and spread of the fungus through the body are

not yet known, and demand urgent investigation.

Cutaneous infections in apparently healthy individuals

due to traumatic implantation of Apophysomyces ele-

gans are also a common finding in India, although

uncommon in other countries. The precise ecology,

epidemiology and taxonomy of this fungus are not

well understood, and further studies on these aspects

would provide valuable insights into the presence of

mucoralean agents in environment, the susceptible

hosts and the mode of fungal acquisition and spread.

Acknowledgment

The position of RS is supported by funding from Coun-

cil of Scientific and Industrial Research (CSIR), Govt.

of India in the form of Senior Research Associateship

(Scientists’ pool scheme).

Conflict of interest

None.

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