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A multicenter observational study on the epidemiology, risk factors, management and outcomes of mucormycosis in India

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Objectives: To describe the epidemiology, management, and outcome of subjects with mucormycosis; and, to evaluate the risk factors associated with mortality. Methods: We conducted a prospective observational study involving consecutive subjects with proven mucormycosis across 12 centers from India. The demographic profile, microbiology, predisposing factors, management, and 90-day mortality were recorded; risk factors for mortality were analyzed. Results: We included 465 subjects. Rhino-orbital mucormycosis was the most common (315/465, 67.7%) presentation followed by pulmonary (62/465, 13.3%), cutaneous (49/465, 10.5%), and others. The predisposing factors included diabetes mellitus (342/465, 73.5%), malignancy (42/465, 9.0%), transplant (36/465, 7.7%), and others. Rhizopus species (231/290, 79.7%) were the most common followed by Apophysomyces variabilis (23/290, 7.9%), and several rare Mucorales. Surgical treatment was performed in 62.2% (289/465) of the subjects. Amphotericin B was the primary therapy in 81.9% (381/465), while posaconazole was used as combination therapy in 53 (11.4%) subjects. Antifungal therapy was inappropriate in 7.6% (30/394) of the subjects. The 90-day mortality rate was 52% (242/465). On multivariate analysis, disseminated and rhino-orbital (with cerebral extension) mucormycosis, shorter duration of symptoms, shorter duration of antifungal therapy, and treatment with amphotericin B deoxycholate (vs. liposomal) were independent risk factors of mortality. A combined medical and surgical management was associated with a better survival. Conclusions: Diabetes mellitus was the dominant predisposing factor in all forms of mucormycosis. Combined surgical and medical management was associated with better outcomes. Several gaps surfaced in the management of mucormycosis. The rarer Mucorales identified in the study warrant further evaluation.
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Original article
A multicentre observational study on the epidemiology, risk factors,
management and outcomes of mucormycosis in India
A. Patel
1
,
2
, H. Kaur
3
, I. Xess
4
, J.S. Michael
5
, J. Savio
6
, S. Rudramurthy
3
, R. Singh
7
,
P. Shastri
8
, P. Umabala
9
, R. Sardana
10
, A. Kindo
11
, M.R. Capoor
12
, S. Mohan
13
,
V. Muthu
14
, R. Agarwal
14
, A. Chakrabarti
3
,
*
1)
Department of Infectious Diseases, Sterling Hospital, Ahmedabad, India
2)
Department of Internal Medicine, University of South Florida, Tampa, FL, USA
3)
Department of Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4)
Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
5)
Department of Clinical Microbiology, Christian Medical College, Vellore, India
6)
St John's Medical College Hospital, Bangalore, India
7)
Department of Microbiology, JIPMER, Pondicherry, India
8)
Intensive Care Medicine, Sir Ganga Ram Hospital, New Delhi, India
9)
Department of Microbiology, Nizam's Institute of Medical Sciences, Hyderabad, India
10)
Department of Microbiology, Indraprastha Apollo Hospital, New Delhi, India
11)
Department of Microbiology, Sri Ramachandra Medical College, Chennai, India
12)
Vardhman Mahaveer Medical College and Safdarjang Hospital, New Delhi, India
13)
Department of Microbiology, Christian Medical College, Ludhiana, India
14)
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
article info
Article history:
Received 27 August 2019
Received in revised form
12 November 2019
Accepted 17 November 2019
Available online xxx
Editor: M. Paul
Keywords:
Diabetes
Invasive fungal infection
Mould
Mucormycosis
Rhizopus
Zygomycosis
abstract
Objectives: To describe the epidemiology, management and outcome of individuals with mucormycosis;
and to evaluate the risk factors associated with mortality.
Methods: We conducted a prospective observational study involving consecutive individuals with
proven mucormycosis across 12 centres from India. The demographic prole, microbiology, predisposing
factors, management and 90-day mortality were recorded; risk factors for mortality were analysed.
Results: We included 465 patients. Rhino-orbital mucormycosis was the most common (315/465, 67.7%)
presentation followed by pulmonary (62/465, 13.3%), cutaneous (49/465, 10.5%), and others. The pre-
disposing factors included diabetes mellitus (342/465, 73.5%), malignancy (42/465, 9.0%), transplant (36/
465, 7.7%), and others. Rhizopus species (231/290, 79.7%) were the most common followed by Apophy-
somyces variabilis (23/290, 7.9%), and several rare Mucorales. Surgical treatment was performed in 62.2%
(289/465) of the participants. Amphotericin B was the primary therapy in 81.9% (381/465), and pos-
aconazole was used as combination therapy in 53 (11.4%) individuals. Antifungal therapy was inappro-
priate in 7.6% (30/394) of the individuals. The 90-day mortality rate was 52% (242/465). On multivariate
analysis, disseminated and rhino-orbital (with cerebral extension) mucormycosis, shorter duration of
symptoms, shorter duration of antifungal therapy, and treatment with amphotericin B deoxycholate
(versus liposomal) were independent risk factors of mortality. A combined medical and surgical man-
agement was associated with a better survival.
Conclusions: Diabetes mellitus was the dominant predisposing factor in all forms of mucormycosis.
Combined surgical and medical management was associated with better outcomes. Several gaps surfaced
in the management of mucormycosis. The rarer Mucorales identied in the study warrant further eval-
uation. A. Patel, Clin Microbiol Infect 2019;:1
©2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
*Corresponding author. A. Chakrabarti, Department of Medical Microbiology, Postgraduate Institute of Medical Education &Research, Chandigarh 160012, India.
E-mail address: arunaloke@hotmail.com (A. Chakrabarti).
Contents lists available at ScienceDirect
Clinical Microbiology and Infection
journal homepage: www.clinicalmicrobiologyandinfection.com
https://doi.org/10.1016/j.cmi.2019.11.021
1198-743X/©2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Clinical Microbiology and Infection xxx (xxxx) xxx
Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
Introduction
Mucormycosis is being increasingly diagnosed worldwide,
particularly in India [1]. The rising trend is due to the increased
awareness, advances in diagnostic techniques, and the increase in
the prevalence of predisposing factors [2,3]. Mucormycosis mainly
occurs in immunosuppressed hosts, including those with haema-
tological malignancies, transplant recipients and in people with
uncontrolled diabetes mellitus [4,5]. The Mucorales have a unique
capability of angio-invasion causing vasculitis and thrombosis of
vessels, resulting in large areas of infarction and necrosis [4,6,7].
Poor drug penetration in devitalized tissue mandates the need for
surgical debridement.
In low- and middle-income countries including India, mucor-
mycosis is associated with high mortality (45%e90%) [8e12]. The
probable reasons include a delay in diagnosis and the high cost of
managing mucormycosis. Many single-centre studies suggest that
the epidemiology of mucormycosis is different in India compared
with the developed world [3,8,12,13]. However, the existing data
are from small studies, and there is a lack of a prospective, multi-
centre data on mucormycosis from developing countries. Herein,
we describe the epidemiology, predisposing factors, microbiology,
management and outcome of patients with mucormycosis in India.
We also evaluate whether combined surgical and medical treat-
ment is associated with better outcomes in patients with
mucormycosis.
Methods
We conducted a prospective observational study from 1 January
2016 to 30 September 2017 at 12 tertiary-care centres across India
(see Supplementary material, Table S1). The study protocol was
approved by the Institute Ethics Committee of all the individual
participating centres, and a written informed consent was obtained
from all the study subjects. The study is registered at the clinical
trial registry of India (ctri.nic.in; CTRI/2016/02/006644).
Study objectives
The study objectives were to describe the epidemiology, risk
factors, treatment practices and 90-day mortality of individuals
with mucormycosis. This was an exploratory study in which we also
evaluated the risk factors for mortality.
Study participants
All consecutive individuals with proven mucormycosis were
enrolled in this study. We dened proven mucormycosis as those
individuals with clinically compatible disease and the demonstra-
tion of fungi in the tissue (or body uids) either by direct micro-
scopy (broad ribbon like aseptate hyphae), culture or molecular
methods. All participants received treatment at the discretion of
the treating physician.
Study procedure
We collected the following information on a standardized case
report form (see Supplementary material, Appendix S1): (a) de-
mographic details; (b) clinical features; (c) predisposing factors
(diabetes mellitus, glucocorticoid therapy, transplant, malignancy,
immunosuppression, and others) (participants with multiple risk
factors were graded in a hierarchical manner, for example, if the
patient had undergone stem cell transplantation and also devel-
oped prednisolone-induced diabetes, then stem cell transplant was
considered the primary risk factor, and not diabetes); (d) co-morbid
illnesses (ischaemic heart disease, chronic kidney disease, chronic
liver disease, chronic respiratory illnesses, and others); (e) site of
disease (pulmonary, rhino-orbital with or without cranial exten-
sion, cutaneous, renal, gastrointestinal and disseminated); (f) his-
topathological and microbiological ndings; (g) details of
treatment given (antifungal agent, dose and duration of antifungal
agent, nature of surgical treatment); and (h) mortality at 90 days.
The exposure variable was chosen to be combined surgical and
medical management with all other variables assumed as potential
confounders. Participants who left the hospital against medical
advice were assumed to be dead for the purpose of mortality
analysis (worst-case scenario analysis). We also performed a
sensitivity analysis by excluding these individuals.
Processing of sample
Tissue samples, such as nasal/sinus tissue biopsies and biopsies
from ulcers, were subjected to conventional microscopy, culture,
histopathological examination or molecular diagnostic techniques,
as appropriate. Microscopy was performed using the KOH-
calcouor mount method. The patient samples were also inocu-
lated onto two sets of Sabouraud dextrose agar and one tube of
braineheart infusion agar. The positive cultures were identied by
their macroscopic and microscopic characteristics, and through
sequencing of the internal transcribed spacer (ITS) region of rDNA.
The tissue samples submitted for histopathological examination
were examined using haematoxylin &eosin, periodic acid Schiff or
Gomori's methenamine silver stain.
The genomic DNA extraction was attempted from deparafnized
blocks [14], using phenol-chloroform-isoamyl extraction after tis-
sue digestion with proteinase K and lysis buffer (100 m
M
TriseHCl
(pH 8.5), 0.5
M
EDTA, 10% SDS and 5
M
NaCl) [15]. The 18S region of
rDNA was amplied using semi-nested PCR with the Mucorales-
specic primers ZM1 (5
0
-ATTACCATGAGCAAATCAGA-3
0
), ZM2 (5
0
-
TCCGTCAATTCCTTTAAGTTTC-3
0
) and ZM3 (5
0
-CAATCCAAGAATT
TCACCTCTAG-3
0
), as described by Bialek et al.[14], while the ITS2
was amplied using the panfungal primers ITS3 and ITS4 [16].
Amplication of the human GAPDH gene (forward primer: 5
0
-
GGATTTGGTCGTATTGGG-3
0
; reverse primer: 5
0
-GGAAGATGGTG
ATGGGATT-3
0
) and TriseEDTA (TE) buffer without template DNA
acted as positive and negative controls, respectively. The amplicons
were subjected to gel electrophoresis. The bands were excised and
puried using a gel extraction kit (Qiagen, Hilden, Germany). The
amplicons were sequenced using the BigDye terminator cycle
sequencing ready reaction kit (version 3.1; Applied Biosystems,
Foster City, CA, USA). The reaction products were analysed on an
ABI Prism 3100 automated DNA analyser. Consensus sequences
were obtained using
BIONUMERICS
software (version 7.5; Applied-
Maths, Ghent, Belgium). The sequences were compared with the
GenBank/International Society for Human and Animal Mycology
(ISHAM) Barcode and Centraalbureau voor Schimmelcultures (CBS)
databases to identify the agents.
Statistical methods
The data were analysed using the commercial statistical package
SPSS 21.0 for MS-Windows (IBM Inc., Chicago, IL). The descriptive
statistics are presented as frequencies, mean with standard devia-
tion (SD), or median and interquartile range (IQR), as appropriate.
The categorical variables were compared using chi-square test (or
Fischer's exact test) while the differences between continuous data
were analysed using ManneWhitney test or KruskaleWallis test, as
appropriate. We also performed competing risk analysis to correct
for the various variables that could be inuenced by the time bias,
namely mortality. A multivariate Cox regression analysis was
A. Patel et al. / Clinical Microbiology and Infection xxx (xxxx) xxx2
Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
performed for identifying factors predicting mortality, by including
variables that were signicant (p <0.05) on univariate analysis.
Survival curves were constructed to study the effect of combined
(surgical and medical) versus medical management on the time to
mortality using Cox proportional hazard analysis. A p-value <0.05
was considered as signicant.
Results
A total of 485 individuals were diagnosed with mucormycosis
during the study period, of whom 20 were excluded (incomplete
case record forms). Among the 465 individuals enrolled, 438
(96.5%) were adults. The median (IQR) age of the study population
(323/465, 69.5% men) was 48 (35e58.5) years (Table 1). Medical co-
morbid illnesses including chronic kidney disease (93/465, 20.0%)
and cardiovascular diseases (67/465, 14.4%) were noted in 37.6%
(175/465) of the participants (Table 1). The median (IQR) duration
of symptoms before admission was 12 (7e30) days. Rhino-orbital
mucormycosis (315/465, 67.7%) was the most common form fol-
lowed by pulmonary (62/465, 13.3%), and cutaneous (49/465, 10.5%)
mucormycosis (Table 1).
Predisposing factors
Most (410/465, 88.2%) of the participants had underlying risk
factors (Table 2). Uncontrolled diabetes mellitus was the most
common risk factor for all forms of mucormycosis, except cuta-
neous and renal (Table 2). Interestingly, in 44 (12.9%) of the 342
individuals with diabetes, their diabetes was diagnosed during the
evaluation of mucormycosis. The median (IQR) duration of diabetes
was 48 (3e120) months, and 81.6% had uncontrolled disease (me-
dian (IQR) HbA1c, 10.2 (8e12)); 14.6% (50/342) presented with
diabetic ketoacidosis. Fifty per cent (7/14) of the participants with
isolated renal mucormycosis did not have an identiable risk factor,
whereas trauma (26/49, 53.1%) was the most common predisposing
factor in cutaneous mucormycosis (Table 2).
Diagnosis
The diagnosis of mucormycosis was made by direct microscopy
in 406/465 (87.3%) participants. Histopathology demonstrated
aseptate hyphae in 340/465 (73.1%) participants. Culture identied
the aetiological agent in 290/465 (62.4%) cases (Table 2). Among the
culture-positive (n¼290) participants, Rhizopus spp. were the most
common (231; 79.7%). Of the Rhizopus spp., Rhizopus arrhizus was
isolated from 174/231 (75.3%) participants followed by Rhizopus
microsporus and Rhizopus homothallicus (Table 2). The other
Mucorales isolated include Apophysomyces variabilis (23/290; 7.9%),
Mucor spp. (16/290; 5.5%), Lichtheimia corymbifera (10/290; 3.4%),
and others (Table 2).
Molecular detection was attempted in 68 histopathology blocks
where the culture was negative. Mucorales were identied in 21
cases (Rhizopus spp. (n¼12), Mucor spp. (n¼5), Lichtheimia spp.
(n¼3), Apophysomyces variabilis (n¼1)); nucleic acid could not be
extracted in 47 cases. Non-mucorales species were identied in one
of the histopathology blocks (Aspergillus spp.).
Treatment
Combined medical and surgical management was performed in
62.2% (289/465) of the participants. The surgical management rates
ranged from 21% (13/62) for pulmonary mucormycosis to 79.6%
(39/49) for cutaneous disease (Table 2). Radical surgery was feasible
only in 107/289 (37%) participants, while the remainder underwent
debulking. Ten (46/465) per cent of the participants left the hospital
against medical advice before initiation of therapy, due to nancial
constraints. Amphotericin B was used in 381 (81.9%) of the 465
participants (liposomal: 62.4% (238/381); deoxycholate: 37.6%
(143/381)). Amphotericin B was changed from liposomal to deox-
ycholate preparation in 4.2% of these individuals because of the
high cost of therapy. A combination of antifungal agents was used
in 22.1% (87/394) of the participants. The most common combi-
nation used was posaconazole (53/87, 60.9%) along with ampho-
tericin B. Other agents combined with amphotericin B included
caspofungin (n¼3), isavuconazole (n¼1), itraconazole (n¼8),
voriconazole (n¼17), deferasirox (n¼6) and uconazole (n¼5).
The median (IQR) duration of the antifungal treatment was 15
(range 1e381) days.
Outcome
The 90-day mortality rate was 52.0% (242/465 participants). The
duration of symptoms before hospitalization was signicantly less
in non-survivors (median, 10 versus 15 days). The presence of co-
morbid medical illnesses was associated with a signicantly
reduced survival (Table 3). A higher survival was observed in par-
ticipants who received combined medical and surgical treatment (p
0.001), and patients receiving the liposomal compared with the
deoxycholate preparation of amphotericin B (p 0.03). As the dura-
tion of antifungal therapy, duration of hospital stay and surgical
treatment are affected by the immortal time bias, we performed
competing risk analyses (competing risk: death; time factor: hos-
pital stay). The subhazards ratio (SHR) for these factors (days of
antifungal therapy: SHR 1.004, 95% CI 1.002e1.006, p 0.0001;
combined surgical and medical management: SHR 2.2151, 95% CI
1.625e3.018., p 0.0001) remained statistically signicant even after
adjusting for the competing risk (mortality). On excluding the
participants who left the hospital against medical advice (n¼112),
the results were similar except that solid organ malignancy,
immunosuppressant therapy was more frequent and the time to
diagnosis was signicantly longer in deceased subjects (see
Supplementary material, Table S2).
Table 1
Baseline characteristics of patients with mucormycosis
Total (n¼465)
Age*, in years 48 (35e58.5)
Male sex 323 (69.5)
Comorbid illnesses
Any
a
175 (37.6)
Chronic kidney disease 93 (20)
Cardiovascular 67 (14.4)
Pulmonary 30 (6.5)
Liver disease 24 (5.2)
Neurological 18 (3.9)
Others 1 (0.2)
Duration of symptoms*, days 12 (7e30)
Time to diagnosis*, days 1 (1 4)
Clinical presentation
Rhino-orbital 315 (67.7)
with brain involvement 103
without brain involvement 212
Pulmonary 62 (13.3)
Cutaneous 49 (10.5)
Renal 14 (3.0)
Gastrointestinal 12 (2.6)
Disseminated 13 (2.8)
All values are represented as number (%) or as median (interquartile range)
(indicated by *) unless otherwise stated. All the percentages are provided for
the total number of participants in the study (n¼465).
a
A given participant may have had one or more co-morbid illnesses.
A. Patel et al. / Clinical Microbiology and Infection xxx (xxxx) xxx 3
Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
On a multivariate analysis, the duration of symptoms before
hospitalization, the site of involvement (rhino-orbital mucor-
mycosis with cranial extension and disseminated disease), and
treatment with deoxycholate amphotericin B preparation were
associated with increased mortality. On the other hand, com-
bined surgical and medical management and the duration of
antifungal therapy were independently associated with better
survival (Table 4). The median duration of hospital stay was 16
(6e32)days.Themedian(IQR)timetodeathwas32(23e41)
days; this was signicantly longer (median 58 days versus
12 days) in those with combined medical and surgical man-
agement (Fig. 1).
Table 2
Risk factors, microbiology, diagnosis and treatment characteristics of patients with mucormycosis according to the site of involvement. ROM, rhino-orbital mucormycosis;
ROCM, rhino-orbital mucormycosis with cerebral extension
Skin
(n¼49)
ROM
(n¼212)
Kidney
(n¼14)
Gastrointestinal
(n¼12)
Lung
(n¼62)
ROCM
(n¼103)
Disseminated
(n¼13)
Total (n¼465) p value
Risk factors
No risk factor 3 (6.1) 22 (10.4) 7 (50%) 3 (25) 5 (8.1) 11 (10.7) 4 (30.8) 55 (11.8) 0.0001
One risk factor 32 (65.3) 148 (69.8) 3 (21.4) 7 (58.3) 39 (62.9) 82 (79.6) 5 (39.5) 316 (68)
Two risk factors 10 (20.4) 31 (14.6) 2 (14.3) 2 (16.7) 10 (16.1) 6 (5.8) 3 (23.1) 64 (13.8)
Three or more risk factors 4 (8.2) 11 (5.1) 2 (14.3) 0 8 (12.9) 4 (3.9) 1 (7.7) 30 (6.4)
Individual risk factors
Diabetes mellitus 19 (38.8) 175 (82.5) 5 (35.7) 3 (25) 44 (71) 88 (85.4) 8 (61.5) 342 (73.5) 0.0001
Diabetes control 0.49
Uncontrolled 14 140 5 3 35 76 6 279
Controlled 4 33 0 0 7 9 2 55
Not known 1 2 0 0 2 3 0 8
Diabetic ketoacidosis
a
2 (10.5) 23 (13.1) 0 1 (33.3) 7 (15.9) 16 (18.2) 1 (12.5) 50 (14.6) 0.64
Transplant
Solid organ 2 (4.1) 11 (5.2) 4 (28.6) 0 11 (17.7) 1 (1.0) 1 (7.7) 30 (6.5) 0.0001
Haematopoietic 1 (2) 4 (1.9) 0 0 1 (1.6) 0 0 6 (1.3) 0.84
Malignancy
Haematological 2 (4.1) 18 (8.5) 1 (7.1) 1 (8.3) 9 (14.5) 3 (2.9) 1 (7.7) 35 (7.5) 0.20
Solid organ 1 (2) 2 (0.9) 0 1 (8.3) 1 (1.6) 1 (1.0) 1 (7.7) 7 (1.5) 0.23
Steroids 2 (4.1) 5 (2.4) 0 2 (16.7) 4 (6.5) 3 (2.9) 1 (7.7) 17 (3.7) 0.15
Immunosuppressants 3 (6.1) 12 (5.7) 4 (28.6) 0 11 (17.7) 3 (2.9) 1 (7.7) 34 (7.3) 0.0001
Trauma 26 (53.1) 2 (0.9) 0 1 (8.3) 0 3 (2.9) 0 32 (6.9) 0.0001
Burns 2 (4.1) 0 0 0 0 0 1 (7.7) 3 (0.6) 0.001
Presence of co-morbid illnesses 9 (18.4) 81 (38.2) 3 (21.4) 5 (41.7) 30 (48.4) 41 (39.8) 6 (46.2) 175 (37.6) 0.04
Aseptate hyphae on smear 39 (79.6) 198 (93.4) 5 (35.7) 3 (25) 54 (87.1) 97 (94.2) 10 (76.9) 406 (87.3) 0.0001
Culture positivity 30 (61.2) 132 (62.3) 2 (14.3) 5 (41.7) 40 (64.5) 69 (67.0) 8 (61.5) 290 (62.4) 0.001
Histopathological diagnosis 33 (67.3) 165 (77.8) 13 (92.9) 9 (75.0) 34 (54.8) 73 (70.9) 13 (100) 340 (73.1) 0.001
Organism identied
b
0.16
Rhizopus
c
11 114 0 2 32 65 7 231 (80.8) 0.28
Rhizopus arrhizus 8 880 2 20544 176
Rhizopus homothallicus 0110 0 641 22
Rhizopus microporus 3150 0 662 32
Rhizopus asexualis 000 0 010 1
Rhizomucor spp. 1 2 0 0 1 0 0 4 (1.4)
Apophysomyces variabilis 15 2 2 2 0 1 1 23 (7.9)
Lichtheimia corymbifera 1 4 0 0 4 1 0 10 (3.5)
Saksenaea vasiformis 1 1 0 0 0 0 0 2 (0.7)
Mucor spp. 1 9 0 1 3 2 0 16 (5.5)
Cunninghamella bertholletiae 1 1 0 0 1 0 0 3 (1.0)
Syncephalastrum racemosum 0 1 0 0 0 0 0 1 (0.4)
Treatment
Surgery 39 (79.6) 152 (71.7) 9 (64.3) 8 (66.7) 13 (21.0) 60 (58.3) 8 (61.5) 289 (62.2) 0.0001
Any antifungal 38 (77.6) 183 (86.3) 12 (85.7) 9 (75.0) 54 (87.1) 87 (84.5) 11 (84.6) 394 (84.7) 0.74
Amphotericin B 35 (71.4) 177 (83.5) 12 (85.7) 8 (66.7) 51 (82.3) 87 (84.5) 11 (84.6) 381 (81.9) 0.37
Liposomal 15 114 10 4 32 55 8 238 0.04
Deoxycholate 20 63 2 4 19 32 3 143 0.30
Posaconazole 5 (10.2) 29 (13.7) 3 (21.4) 2 (16.7) 8 (12.9) 6 (5.8) 0 53 (11.4) 0.37
Voriconazole 2 (4.1) 9 (4.2) 0 0 6 (9.7) 0 0 17 (3.7) 0.06
Isavuconazole 0 0 0 0 0 0 1 (7.7) 1 (0.2) 0.0001
Itraconazole 0 6 (2.8) 0 0 0 2 (1.9) 0 8 (1.7) 0.65
Fluconazole 2 (4.1) 0 0 0 1 (1.6) 2 (1.9) 0 5 (1.1) 0.25
Caspofungin 0 2 (0.9) 0 0 1 (1.6) 0 0 3 (0.6) 0.88
Amphotericin and posaconazole
combination
5 (10.2) 29 (13.7) 3 (21.4) 2 (16.7) 8 (12.9) 6 (5.8) 0 53 (11.4) 0.25
Duration of symptoms, days 14 (7e25) 12.5 (7e30) 15 (10e20) 14 (6.3e37.5) 15 (7e30) 10 (7e20) 15 (6.5e52.5) 12 (7e30) 0.74
Time to diagnosis, days 3 (1e6.5) 1 (1e3) 6.5 (2.8e16.5) 7 (3e13) 3 (1e9.3) 1 (1e1) 1 (1e1) 1 (1e1) 0.001
Duration of hospital stay, days 15 (6e23.5) 17 (5.3e31) 24 (7.5e46) 24 (9.8e33.5) 16 (8e35.5) 11 (3e30) 26 (11.5e51) 16 (6e32) 0.99
90-day mortality 28 (57.1) 82 (38.7) 7 (50) 8 (66.7) 38 (61.3) 71 (68.9) 8 (61.5) 242 (52) 0.98
All values are represented as number (%) or median (interquartile range) unless otherwise stated.
a
Percentages are those among diabetic participants.
b
Percentages are those among culture-positive cases. The remaining percentages are for the total number of participants having a particular site of involvement, mentioned
in the rst row of the table.
c
Total species identied: 218; 13 species not identied for logistical reasons.
A. Patel et al. / Clinical Microbiology and Infection xxx (xxxx) xxx4
Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
Discussion
We report the largest prospective multicentre study describing
the epidemiology, predisposing factors, diagnosis, management
practices and outcome of mucormycosis in India. Diabetes mellitus
(73.5%) was the predominant risk factor. We observed a high
mortality rate and identied several risk factors associated with
mortality, including disseminated or rhino-orbital mucormycosis
with cranial extension, shorter duration of symptoms, shorter
duration of antifungal therapy, and the use of amphotericin B
deoxycholate. A combined surgical and medical management was
associated with better survival.
The prevalence of mucormycosis has been variably reported
from different centres [1], partly because of the divergent risk
factors prevalent in different settings [3,8,17,18]. Data from a global
fungal infection registry reports haematological malignancy (63%)
to be the most important underlying condition for mucormycosis
[10]. In contrast, uncontrolled diabetes was the main predisposing
factor in the current study. The situation might also be similar in
other low- and middle-income countries, where diabetes is prev-
alent [19]. Interestingly, 11.8% of the cases of mucormycosis had no
apparent risk factors, especially in those with isolated renal
mucormycosis. The most common pathogen in our study was
R. arrhizus (similar to other studies) [20e22]. Apophysomyces
Table 3
Characteristics of survivors and non-survivors with mucormycosis
Survivors (n¼223) Non-survivors
(n¼242)
p value
Age, in years 45 (34e58) 48.5 (36e60) 0.20
Male sex 161 (72.2) 162 (66.9) 0.22
Adult patients 210 (94.2) 228 (94.2) 0.98
Duration of symptoms
a
, days 15 (7e30) 10 (7e20) 0.0001
Predisposing factors
None 31 (13.9) 24 (9.9) 0.21
One 151 (67.8) 165 (68.2)
Two 32 (14.3) 32 (13.2)
Three or more 9 (4.0) 21 (8.7)
Individual predisposing factors
Diabetes mellitus 162 (72.6) 180 (74.4) 0.67
Uncontrolled diabetes 131/162 (80.9) 148/180 (82.2) 0.66
Diabetic ketoacidosis 20/162 (12.3) 30/180 (16.7) 0.26
Transplant
Solid organ 12 (5.4) 18 (7.4) 0.37
Haematopoietic 3 (1.3) 3 (1.2) 1.00
Malignancy
Haematological malignancy 15 (6.7) 20 (8.3) 0.53
Solid organ malignancy 0 7 (2.9) 0.02
Steroids 11 (4.9) 6 (2.5) 0.16
Immunosuppressants 12 (5.4) 22 (9.1) 0.13
Trauma 14 (6.3) 18 (7.4) 0.62
Burns 1 (0.4) 2 (0.8) 1.00
Co-morbid illnesses
b
63 (28.3) 112 (46.3) 0.0001
Chronic kidney disease 31 (13.9) 62 (25.6)
Cardiovascular 25 (11.2) 42 (17.4)
Pulmonary 10 (4.5) 20 (8.3)
Liver disease 5 (2.2) 19 (7.9)
Neurological 5 (2.2) 13 (5.4)
Others 0 1 (0.4)
Site of mucormycosis 0.0001
Rhino-orbital
with brain involvement 32 (14.3) 71 (29.3)
without brain involvement 130 (58.3) 82 (33.9)
Pulmonary 24 (10.8) 38 (15.7)
Cutaneous 21 (9.4) 28 (11.6)
Renal 7 (3.1) 7 (2.9)
Gastrointestinal 4 (1.8) 8 (3.3)
Disseminated 5 (2.2) 8 (3.3)
Microbiology
Rhizopus spp. 96 (43.0) 135 (55.8) 0.16
Other species 25 (11.2) 30 (12.4)
c
Time to diagnosis, days 1 (1-4) 1 (1-4.3) 0.61
Treatment
Amphotericin B 0.0001
Deoxycholate 57 (25.6) 70 (28.9)
Liposomal 135 (60.5) 103 (42.6)
Amphotericin and posaconazole combination 32 (14.3) 21 (8.7) 0.89
Duration of antifungal therapy, days 21 (13e41) 6 (2e16) 0.0001
Combined surgical and medical management 171 (76.7) 73 (30.2) 0.0001
Hospital stay, days 24 (15e42) 8 (3e20.3) 0.0001
All values are represented as number (%) or median (interquartile range) unless otherwise stated. The percentages are for the survivors (n¼223) or non-survivors (n¼242), as
applicable unless otherwise stated.
a
Duration of symptoms represent the time between onset of symptom to admission.
b
Many patients had more than one co-morbid illness.
c
The time to diagnosis indicates the time since admission till achieving the diagnosis of mucormycosis.
A. Patel et al. / Clinical Microbiology and Infection xxx (xxxx) xxx 5
Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
variabilis was the most common agent responsible for cutaneous
mucormycosis, consistent with previous knowledge [23]. We also
isolated a larger proportion of R. microsporus,A. variabilis and
R. homothallicus, which are abundantly present in soil samples from
India [24] and are emerging pathogens in this country [24e26].
We identied several challenges in managing mucormycosis in
our study including a delay in seeking health care, the lack of
knowledge among physicians, and nancial constraints. In fact,
cutaneous mucormycosis was diagnosed after considerable delay,
despite being easily amenable to diagnostic sampling, and possibly
explains the high (57.1%) mortality observed. A combination of
antifungal agents was prescribed in 22.1% of patients, despite the
lack of any recommendation for this practice [27]. Further, the use
of improper antifungals (voriconazole, itraconazole, uconazole)
for management seen in a sizeable proportion of our participants,
highlights the lacunae in knowledge among physicians. A signi-
cant proportion of our participants were unable to afford treatment
or had to be switched from liposomal amphotericin to the deoxy-
cholate preparation because of nancial constraints.
Participants who underwent combined medical and surgical
management had a signicantly better outcome, similar to previous
experience [28]. Surgical debridement of the necrosed tissue
probably enables better penetration of antifungal agents, thereby
improving outcomes. The surgical rate was highest in those with
rhino-orbital mucormycosis. Unfortunately, even in rhino-orbital
disease, radical surgery was not feasible in all individuals. Mortal-
ity was signicantly high in patients with intracranial extension,
where most were inoperable. Despite appropriate antifungal ther-
apy, mortality was high among participants who were inoperable,
suggesting a need for early diagnosis and better therapeutic
strategies.
Finally, our study is not without limitations. Although an
epidemiological study, we were unable to assess the exact inci-
dence or prevalence of mucormycosis in different risk groups.
Although we have described the predisposing factors, we were not
able to assess the strength of association of these risk factors,
because of the absence of a control group. However, the study
provides a rough estimate of proven mucormycosis cases (about 40
cases on average over a 21-month period from each of the
participating centres) in India, which is much higher compared
with world literature [10,21]. We have reported the treatment
outcome of mucormycosis from a heterogeneous population
(various risk factors and different sites of involvement), so drawing
conclusions for individual clinical presentations is difcult. Simi-
larly, the study results may not be generalizable to centres where
haematological malignancy and transplantation are the dominant
risk factors. Though the nancial toxicity seems apparent, we
have not performed a formal health economic analysis. The pro-
spective study design, the detailed description of the microbiology
and management practices, and challenges faced in a low- and
Table 4
Cox regression analysis of factors predicting mortality in patients with mucormycosis
Adjusted HR (95% CI) p value
Duration of symptoms, days 0.99 (0.98e0.99) 0.009
Malignancy
None
a
-
Solid 3.01 (0.65e13.98) 0.16
Haematological 1.33 (0.74e2.39) 0.34
Presence of co-morbid illnesses 1.52 (1.15e2.02) 0.06
Number of risk factors
None
a
-
One 1.67 (0.93e2.99) 0.08
Two 0.67 (0.31e1.45) 0.31
Three or more 0.87 (0.38e1.98) 0.75
Site of involvement
Rhino-orbital without cranial involvement
a
-
Cutaneous 1.38 (0.79e2.42) 0.25
Solid organ (lung, kidney, gastrointestinal) 1.12 (0.73e1.71) 0.60
Rhino-orbital with cranial involvement 1.91 (1.30e2.79) 0.001
Disseminated 2.81 (1.23e6.41) 0.014
Duration of antifungal therapy, days 0.96 (0.95e0.97) 0.0001
Amphotericin B therapy
None
a
-
Deoxycholate preparation 2.21 (1.12e4.38) 0.023
Liposomal 1.25 (0.65e2.42) 0.51
Management
Medical management alone
a
-
Combined surgical and medical management 0.52 (0.38e0.73) 0.0001
Abbreviation: HR, hazard ratio.
Statistically signicant values are highlighted in bold type.
a
Reference category.
Fig. 1. Mortality (90-day) in participants with mucormycosis who underwent com-
bined medical and surgical management (solid line) versus those managed medically
(dotted line). The time to death was signicantly less in those managed only medically.
A. Patel et al. / Clinical Microbiology and Infection xxx (xxxx) xxx6
Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
middle-income country setting are the major strengths of the
current study. Further, being a multicentre study from different
regions of India, the results may be widely applicable.
In conclusion, mucormycosis is a serious problem in India with a
high mortality. Uncontrolled diabetes mellitus was the major pre-
disposing factor. A combined surgical and medical management was
associated with better outcomes. The rarer Mucorales identied in
our study warrant further evaluation. The gaps in knowledge iden-
tied in the study need to be addressed urgently and effectively.
Transparency declaration
The authors have submitted completed ICMJE forms to the
corresponding author. On behalf of all authors, the corresponding
author declares that they received funds from the Fungal Infection
Study Forum to conduct the study. There were no other conicts of
interest. Mylan Pharmaceuticals provided an educational grant to
the Fungal Infection Study Forum (a non-prot educational trust
dedicated to the study of fungal infection in India). The Fungal
Infection Study Forum supported the study from the same fund.
Acknowledgements
We thank Dr (Prof.) Gul Motwani, ENT Department, Vardhman
Mahaveer Medical College and Safdarjang Hospital, New Delhi; Dr
Rupa Vendantam, Professor of Otorhinolaryngology, Head of
Department of ENT III at Christian Medical College, Vellore; Dr Hena
Butta, Indraprastha Apollo Hospitals, New Delhi; Dr Sandhya Sun-
daram, Professor and Head, Department of Pathology, Sri Ram-
achandra Medical College and Research Institute, Chennai; and Prof.
Aroma Oberoi and Dr Eshani Dewan, Department of Microbiology,
Christian Medical College, Ludhiana. We wish to acknowledge
Mylan Pharmaceuticals who supported the study through an
educational grant given to Fungal Infection Study Forum.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.cmi.2019.11.021.
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Please cite this article as: Patel A et al., A multicentre observational study on the epidemiology, risk factors, management and outcomes of
mucormycosis in India, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2019.11.021
... Hailing from the order Mucorales, Rhizopus is the most common species in the world. Apart from that, Mucor and Lichtheimia are the predominant causative agents in Europe, whereas Apophysomyces is the Asian, primarily Indian, counterpart [6,9]. The clinical spectrum includes five forms, primarily rhinocerebral, pulmonary, cutaneous, gastrointestinal, and disseminated disease [9]. ...
... Apart from that, Mucor and Lichtheimia are the predominant causative agents in Europe, whereas Apophysomyces is the Asian, primarily Indian, counterpart [6,9]. The clinical spectrum includes five forms, primarily rhinocerebral, pulmonary, cutaneous, gastrointestinal, and disseminated disease [9]. Uncontrolled hyperglycaemia, steroid and immunomodulatory therapy, haematological malignancy (HMs) and haematopoietic stem cell transplantation (HSCT), solid organ malignancy (SOM) and transplant (SOT), persistent neutropenia, and iron overload are among the most notorious risk factors of IM [7,9]. ...
... The clinical spectrum includes five forms, primarily rhinocerebral, pulmonary, cutaneous, gastrointestinal, and disseminated disease [9]. Uncontrolled hyperglycaemia, steroid and immunomodulatory therapy, haematological malignancy (HMs) and haematopoietic stem cell transplantation (HSCT), solid organ malignancy (SOM) and transplant (SOT), persistent neutropenia, and iron overload are among the most notorious risk factors of IM [7,9]. ...
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COVID-19 has been responsible for widespread morbidity and mortality worldwide. Invasive mucormycosis has death rates scaling 80%. India, one of the countries hit worst by the pandemic, is also a hotbed with the highest death rates for mucormycosis. Cancer, a ubiquitously present menace, also contributes to higher case fatality rates. All three entities studied here are individual, massive healthcare threats. The danger of one disease predisposing to the other, the poor performance status of patients with all three diseases, the impact of therapeutics for one disease on the pathology and therapy of the others all warrant physicians having a better understanding of the interplay. This is imperative so as to effectively establish control over the individual patient and population health. It is important to understand the interactions to effectively manage all three entities together to reduce overall morbidity. In this review article, we search for an inter-relationship between the COVID-19 pandemic, emerging mucormycosis, and the global giant, cancer.
... Of the more than 20 species of mucoralean fungi known to cause infections in humans [1], Rhizopus arrhizus (synonym, Rhizopus oryzae) is responsible for the majority of life-threatening infections worldwide in both paediatric and adult populations [2][3][4][5][6][7][8][9][10][11]. It accounts for~90% of cases of rhino-orbital-cerebral mucormycosis (ROCM), especially in those with poorly controlled diabetes mellitus and ketoacidosis [5,9,10,[12][13][14][15][16][17][18][19][20][21][22][23], but also in ostensibly immunocompetent individuals [24][25][26]. In addition, it is the leading cause (~70% of all cases) of pulmonary, gastrointestinal, cutaneous, and sub-cutaneous disseminated mucormycosis in immunocompromised individuals with haematological malignancies, solid organ and stem cell transplant recipients, and those receiving high-dose intravenous corticosteroids [7,9,. ...
... A disadvantage of the LFD is its inability to detect Mucorales other than R. arrhizus, such as Lichtheimia species, which are the second most important cause of mucormycosis in Europe after R. arrhizus [11,106,107] or Apophysomyces species and Rhizopus microsporus, which, alongside R. arrhizus, are important causes of COVID-19-associated mucormycosis [8,9,21,65,108,109]. To negate this, we have developed an Apophysomyces-specific mAb (JD4) and a pan-Mucorales-specific mAb (TG11) for incorporation into a multiplex LFD alongside KC9. ...
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... India contributes to the highest number of mucormycosis cases across the world due to its climatic conditions and the presence of large number patients with uncontrolled diabetes mellitus, the major predisposing factor for mucormycosis [7]. India has been hard-hit by the COVID-19 pandemic and thus was expected to have a large number of CAM cases. ...
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... Several other studies conducted during the pandemic and even before the pandemic supported the findings for the same. [2,[21][22][23][24][25][26][27] In addition, the literature cites that the mucormycosis cases were higher among the COVID-positive with a history of hospitalization. [11,22,26] In contrast, our study observed mucormycosis in COVID-positive with a history of home isolation and hospitalization and also among COVID-negative patients. ...
... [11,14,15,20,21] Most of the CAM patients did not have any illness at the time of CAM (n = 38), and very few of them were hypertensive [ Table 2]. This finding in our study is in contrast to the observations made by Patel A et al., [19,22] wherein they reported that 58.6% of patients had more than one comorbidity. ...
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... The management of mucormycosis essentially involves control of hyperglycemia or any other risk factor, optimal surgical debridement, and medical management with antifungal agents. Previous published literature showed that that survival was 70% when treated with both amphotericin and surgical debridement, 61% with amphotericin deoxycholate, 57% with surgery alone and only 3% in patients who underwent no treatment [18]. Amphotericin B is the antifungal drug of choice for mucormycosis. ...
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Background: With the ongoing serious COVID-19 pandemic in India, mucormycosis, colloquially called as black fungus, has emerged as a serious fungal infection in patients who were earlier infected with COVID 19 virus. The prevalence of mucormycosis in India is approximately 140 per million population which is roughly 80 times more than that in the developed countries.The aim of our study was to analyse the clinicopathological profile of COVID19 positive patients presenting with mucormycosis to the Department of Pathology, Government Medical College, Jammu. Methods: We, here present 60 COVID positive patients, who had later on presented clinically as mucormycosis, along with radiological evidence of the same which was then confirmed on histopathology. Results: Mucormycosis was more common in male patients with male: female ratio of 4:1. All the 60 cases presented as rhino-orbital-cerebral mucormycosis as their clinical presentation. Among various predisposing factors, diabetes mellitus came out to be the most common contributing factor. Conclusion: COVID 19 has set a fertile ground for development of life threatening infection like mucormycosis because of the various predisposing factors involved. Keeping in mind the fatality of this infection the diagnostic study for this opportunistic pathogen should not be ignored in case the patient is COVID-19 positive and immunosuppressed
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Purpose: Amidst the ongoing coronavirus disease 2019 (COVID-19) pandemic, India experienced an epidemic of COVID-19-associated rhino-orbito-cerebral mucormycosis (ROCM). This study aimed to describe the epidemiology and elucidate the risk factors for developing COVID-19-associated ROCM, comparing the risk factors among COVID-19 patients with and without ROCM. Methods: This case-control study included all COVID-19-associated ROCM patients treated at our hospital from May 1 to July 30, 2021. Controls included age- and sex-matched COVID-19 patients without ROCM, who were treated during the same time (exact matching, in 1:2 ratio). Matched pair analysis using conditional logistic regression was performed to examine the association of various risk factors with the development of ROCM in COVID-19 patients. Results: The study included 69 patients with COVID-19-associated ROCM and 138 age- and gender-matched controls. Epidemiologically, COVID-19-associated ROCM predominantly affected males (59/69, 85%), in their early 50s (mean 52 years), with 48% (33/69) of patients being from medical resource-constrained settings. On multivariate conditional logistic regression, elevated serum glycated hemoglobin (HbA1c) (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.78), blood glucose (OR = 1.008, 95% CI: 1.003-1.013), and C-reactive protein (CRP) (OR = 1.07, 95% CI: 1.02-1.17) were associated with increased odds of developing COVID-19-associated ROCM. Patients with undetected diabetes mellitus with increasing HbA1c (OR = 3.42, 95% CI: 1.30-9.02) and blood glucose (OR = 1.02, 95% CI: 1.005-1.03) (P = 0.02) had a higher probability of developing COVID-19-associated ROCM than patients with established DM. Conclusion: Uncontrolled DM evidenced by elevated HbA1c and blood glucose levels, exacerbated by COVID-19-induced proinflammatory state indicated by elevated CRP, is the principal independent risk factor for COVID-19-associated ROCM. Middle-aged males with undetected DM, from a resource-constraint setting, are particularly at risk.
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Mucormycosis is an angio-invasive fungal infection, associated with high morbidity and mortality. A change in the epidemiology of mucormycosis has been observed in recent years with the rise in incidence, new causative agents and susceptible population. The rise has been perceived globally, but it is very high in the Asian continent. Though diabetes mellitus overshadow all other risk factors in Asia, post-tuberculosis and chronic renal failure have emerged as new risk groups. The rhino-cerebral form of mucormycosis is most commonly seen in patients with diabetes mellitus, whereas, pulmonary mucormycosis in patients with haematological malignancy and transplant recipients. In immunocompetent hosts, cutaneous mucormycosis is commonly seen following trauma. The intriguing clinical entity, isolated renal mucormycosis in immunocompetent patients is only reported from China and India. A new clinical entity, indolent mucormycosis in nasal sinuses, is recently recognized. The causative agents of mucormycosis vary across different geographic locations. Though Rhizopus arrhizus is the most common agent isolated worldwide, Apophysomyces variabilis is predominant in Asia and Lichtheimia species in Europe. The new causative agents, Rhizopus homothallicus, Mucor irregularis, and Thamnostylum lucknowense are reported from Asia. In conclusion, with the change in epidemiology of mucormycosis country-wise studies are warranted to estimate disease burden in different risk groups, analyse the clinical disease pattern and identify the new etiological agents.
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Mucormycosis due to Mucorales is reported at large numbers in uncontrolled diabetics across India, but systematic multicenter epidemiological study has not been published yet. The present prospective study was conducted at four major tertiary care centers of India (two in north and two in south India) during 2013-2015 to compare the epidemiology, treatment strategies and outcome of mucormycosis between the two regions. Molecular techniques were employed to confirm the identity of the isolates or to identify the agent in biopsy samples. A total of 388 proven/probable mucormycosis cases were reported during the study period with overall mortality at 46.7%. Uncontrolled diabetes (n = 172, 56.8%) and trauma (n = 31, 10.2%) were the common risk factors. Overall, Rhizopus arrhizus (n = 124, 51.9%) was the predominant agent identified, followed by Rhizopus microsporus (n = 30, 12.6%), Apophysomyces variabilis (n = 22, 9.2%) and Rhizopus homothallicus (n = 6, 2.5%). On multivariate analysis, the mortality was significantly associated with gastrointestinal (OR: 18.70, P = .005) and pulmonary infections (OR: 3.03, P = .015). While comparing the two regions, majority (82.7%) cases were recorded from north India; uncontrolled diabetes (n = 157, P = .0001) and post-tubercular mucormycosis (n = 21, P = .006) were significantly associated with north Indian cases. No significant difference was noted among the species of Mucorales identified and treatment strategies between the two regions. The mortality rate was significantly higher in north Indian patients (50.5%) compared to 32.1% in south India (P = .016). The study highlights higher number of mucormycosis cases in uncontrolled diabetics of north India and emergence of R. microsporus and R. homothallicus across India causing the disease.
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The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign. Microscopy (direct and on histopathology) and culture are the cornerstones of diagnosis. Molecular assays can be used either for detection or identification of mucormycetes, and they can be recommended as valuable add-on tools that complement conventional diagnostic procedures. Successful management of mucormycosis is based on a multimodal approach, including reversal or discontinuation of underlying predisposing factors, early administration of active antifungal agents at optimal doses, complete removal of all infected tissues, and use of various adjunctive therapies. Our armamentarium of antifungals is slightly enriched by the addition of two newer azoles (posaconazole and isavuconazole) to liposomal amphotericin B, which remains the drug of choice for the initial antifungal treatment, according to the recently published guidelines by ECIL-6, as well as those published by ECMM/ESCMID. Despite the efforts for better understanding of the pathogenesis, early diagnosis and aggressive treatment of mucormycosis, the mortality rate of the disease remains high.
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Mucormycosis is being increasingly reported from all over the world.…
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Purpose: We aimed to evaluate a PCR-based technique for the diagnosis of mucormycosis and the identification of fungi from fresh tissue specimens in patients with rhino-orbito-cerebral-mucormycosis (ROCM). Methodology: Fifty cases of ROCM were included in the study. Conventional identification was performed using microscopy and culture. Molecular diagnosis was performed by amplifying the ribosomal DNA using pan-fungal ITS primers and semi-nested Mucorales-specific primers of the 18S region. The amplified products were sequenced to identify the agents. The utility of PCR-RFLP of the 18S region of rDNA was evaluated to identify the Mucorales. Results: The ROCM cases were diagnosed by the demonstration of aseptate ribbon-like hyphae in biopsy specimens collected from the patients. Isolation was possible in 24 (48 %) samples. The ITS2 PCR confirmed mucormycosis in 27 cases (54 %; CI 59.4-68.2). By comparison, Mucorales-specific PCR was able to amplify DNA and the sequence enabled the identification of Mucorales speciesin all the patients. PCR-RFLP of the 18S region of rDNA could only identify the agent to genus level. Conclusion: The molecular technique was able to identify Mucorales species in 26 (42 %) cases that were negative by culture. Mucorales-specific semi-nested PCR targeting the 18S region is a better technique than ITS2 PCR for diagnosis. PCR-RFLP of the 18S region helps in identification to genus level.
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Mucormycosis is an emerging infectious disease with high rates of associated mortality and morbidity. Little is known about the characteristics of mucormycosis or entomophthoromycosis occurring in Mexico. A search strategy was performed of literature published in journals found in available databases and theses published online at Universidad Nacional Autónoma de México (UNAM) library website reporting clinical cases or clinical case series of mucormycosis and entomophthoromycosis occurring in Mexico between 1982 and 2016. Among the 418 cases identified, 72% were diabetic patients, and sinusitis accounted for 75% of the reported cases. Diabetes mellitus was not a risk factor for entomophthoromycosis. Mortality rate was 51% (125/244). Rhizopus species were the most frequent isolates (59%, 148/250). Amphotericin B deoxycholate was used in 89% of cases (204/227), while surgery and antifungal management as combined treatment was used in 90% (172/191). In diabetic individuals, this combined treatment approach was associated with a higher probability of survival (95% vs 66%, OR = 0.1, 95% CI, 0.02-0.43' P = .002). The most common complications were associated with nephrotoxicity and prolonged hospitalization due to IV antifungal therapy. An algorithm is proposed to establish an early diagnosis of rhino-orbital cerebral (ROC) mucormycosis based on standardized identification of warning signs and symptoms and performing an early direct microbiological exam and histopathological identification through a multidisciplinary medical and surgical team. In summary, diabetes mellitus was the most common risk factor for mucormycosis in Mexico; combined antifungal therapy and surgery in ROC mucormycosis significantly improved survival.
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Background Limited data exists for epidemiology and outcomes of various agents causing mucormycosis in various clinical settings from developing countries like India. Objectives To study the epidemiology and outcomes of various agents causing mucormycosis in different clinical settings in a tertiary care hospital from South India. Patients and methods We reviewed details of 184 consecutive patients with culture proven mucormycosis with consistent clinical syndrome and supporting features from September 2005 to September 2015. Results The mean age of patients was 50.42 years; 70.97% were male. Unlike developed countries, R. microsporus (29/184; 15.7%) and Apophysomyces elegans (20/184; 10.8%) also evolved as important pathogens in addition to R. arrhizus in our setting. Paranasal sinuses (136/184; 73.9%) followed by musculoskeletal system (28/184;15.2%) were the common areas of involvement. Apophysomyces elegans typically produced skin and musculoskeletal disease in immune‐competent individuals with trauma (12/20; 60%) and caused significantly lower mortality (p‐0.03). R. microsporus was more common in patients with hematological conditions (25% vs 15.7%) and was less frequently a cause for sinusitis than R. arrhizus (27.58% vs 10.9%). The overall mortality was 30.97%. Combination therapy with surgery and antifungals offered the best chance for cure. Conclusions Agents causing mucormycosis may have unique clinical and epidemiological characteristics. This article is protected by copyright. All rights reserved.
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Objectives: To examine the contemporary epidemiology, clinical manifestations, diagnosis and causative pathogens of mucormycosis. The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored. Data sources: Ovid MEDLINE and Ovid EMBASE from January 2000 to January 2017. Study eligibility criteria: Published case reports/series of proven/probable mucormycosis. Participants: Patients ≥18 years old METHODS: Patient characteristics, disease manifestations and causative pathogens were summarised descriptively. Categorical variables were assessed by Chi-square test or Fischer's exact test, and continuous variables by the Wilcoxon Mann-Whitney or Kruskal Wallis test. Risk factors for the different clinical manifestations of mucormycosis were identified using multivariate logistic regression. Results: Initial database searches identified 3619 articles of which 600 (851 individual patient cases) were included in the final analysis. Diabetes mellitus was the commonest underlying condition (340/851, 40%) and was an independent risk for rhino-orbital-cerebral mucormycosis (ROCM) (OR 2.49; 95%CI 1.77-3.54; P<0.001). Underlying haematological malignancy was associated with disseminated infection (OR 3.86; 95%CI 1.78-8.37; P=0.001), whilst prior solid organ transplantation was associated with pulmonary (OR 3.19; 95%CI 1.50-6.82; P=0.003), gastrointestinal (OR 4.47; 95%CI 1.69-11.80; P=0.003), or disseminated mucormycosis (OR 4.20; 95%CI 1.68-10.46; P=0.002). Eight genera (24 species) of Mucorales organisms were identified in 447/851 (53%) cases, whereby Rhizopus spp. (213/447, 48%) was the most common. Compared to other genera, Rhizopus spp. was predominantly observed in patients with ROCM (75/213, 35% versus 34/234, 15%; P<0.001). Death was reported in 389/851 (46%) patients. Mortality associated with Cunninghamella infections was significantly higher than those caused by other Mucorales (23/30, 71% versus 185/417, 44%; P<0.001). However, Cunninghamella spp. was isolated primarily in patients with pulmonary (17/30, 57%) or disseminated disease (10/30, 33%). Conclusions: Findings from the current review have helped ascertain the association between various manifestations of mucormycosis, their respective predisposing factors and causative organisms.
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Mucormycosis is a devastating infection caused by Mucoralean fungi (Mucormycotina, Mucorales). Data concerning the global epidemiology of mucormycosis are scarce and little is known about the characteristics of mucormycosis in Iran. In this study, we aimed to understand the distribution of this infection in Iran retrospectively and to ascertain whether the patterns of infection are associated with specific host factors or not. A total of 208 cases were included in this study occurring during 2008-2014 and were validated according to (EORTC/MSG) criteria. A rising trend as significant increase from 9.7% in 2008 to 23.7% in 2014 was observed. The majority of patients were female (51.4%) with median age of 50 and the infections were seen mostly in autumn season (39.4%). Diabetes mellitus (75.4%) was the most common underlying condition and sinus involvement (86%) was the mostly affected site of infection. Amphotericin B (AmB) was the drug of choice for the majority of cases. Sixty four isolates did not show any growth in the lab and only 21 cases were evaluated by ITS sequencing, among them; Rhizopus arrhizus var. arrhizus was the dominant species. Considering the high mortality rate of mucormycosis, early and accurate diagnosis, with the aid of molecular methods may provide accurate treatments and improve the survival rate. Therefore, increased monitoring and awareness of this life-threatening disease is critical.
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The prevalence of mucormycosis is reportedly high in India, although the studies are mainly from north and south India only. We analysed the mucormycosis cases at tertiary care centres of West India. We retrieved the clinical details of all the patients with probable and proven mucormycosis diagnosed at Sterling Hospital and ID clinic at Ahmedabad, Gujarat over the period from 1 January 2013 through 30 April 2015. The data were analysed to determine demography, risk factors, underlying diseases, site of infection and outcome of these patients. A total of 27 patients with the median age of 50 (16-65) years were diagnosed with mucormycosis during the period. Rhino-orbital-cerebral mucormycosis was the most common (51.9%) presentation. Majority (55.6%) of the patients had uncontrolled diabetes with or without ketoacidosis; 25.9% patients had no underlying disease and most of them (85.7%) had cutaneous mucormycosis. In this group, the mortality was 25.9% and an equal percentage of patients were lost to follow up; 14 (51.9%) patients could complete 6 weeks of amphotericin B therapy. All patients who completed antifungal therapy survived except one. Like other parts of India, uncontrolled diabetes was the predominant risk factor for mucormycosis in our group. Patients completing 6 weeks of amphotericin B treatment were likely to survive.