mucormycosis in india: unique features
TRANSCRIPT
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
© 2014 Blackwell Verlag GmbH
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
© 2014 Blackwell Verlag GmbH
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).
© 2014 Blackwell Verlag GmbH
Mycoses, 2014, 57 (Suppl. 3), 1–64
A. Chakrabarti and R. Singh
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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Mycoses, 2014, 57 (Suppl. 3), 1–66
A. Chakrabarti and R. Singh