Advances in Infectious Diseases, 2013, 3, 263-268
Published Online December 2013 (http://www.scirp.org/journal/aid)
http://dx.doi.org/10.4236/aid.2013.34040
Open Access AID
263
Invasive Fungal Sinusitis in Immunocompromised
Patients: A Multicenter, University Hospital
Experience in Shiraz
Mohsen Moghadami1, Hossein Ruzbahani2, Parisa Badiee3*, Abolhassan Faramarzi4,
Payam Peymani1, Kamran Bagheri Lankarani1
1Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Internal Medicine, Shiraz Uni-
versity of Medical Sciences, Shiraz, Iran; 3Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran; 4Department of Otolaryngology, Shiraz University of Medical Sciences, Shiraz, Iran.
Email: peymani.payam@gmail.com
Received September 28th, 2013; revised October 28th, 2013; accepted November 6th, 2013
Copyright © 2013 Mohsen Moghadami et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Objective: It is to determine the causes of invasive fungal sinusitis in p atients of Shiraz University hospitals, Iran. Me-
thods: This cross-sectional study was conducted during 18 months (from 21 March 2009 till 22 September 2010) in
three Shiraz University Hospitals. Thirty-six patients with sings of invasive fungal sinusitis were enrolled, and tissue
samples were investigated for histop athology, culture and antifungal suscep tibility test. The laboratory results with host
factor and sinus computed tomography scan were evaluated for classification of patients as proven, probable and possi-
ble invasive fungal sinusitis. Results: Thirty-five patients have involved with at least one risk factor (immune compro-
mised disease, diabetes mellitus, or use of immune suppressed drugs). Radiological findings of parasinus invasion or
necrosis were present in 20 patients. By histopathology, 21 patients were considered as proven, from these, 17 samples
had positive growth. The culture aetiology agents were 4 Candida, 8 Aspergillus, and 5 Mucor. All positive culture
samples were matched with histopathology findings. Significant associations were considered for radiologic finding and
histopathology and culture (p < 0.05). From 8 patients with mucormycosis histopathology, 6 suffered from diabetes
mellitus. None of the antifungal agents were effective on these three types of infections. Conclusion: DM is the most
common predisposing factor for IFS followed by ALL and AML. The most common aetiology of IFS was found to be
Aspergillus fumigant followed by Mucormycosis and Candida. None of antifungal agents could successfully cover all
the species.
Keywords: Fungal Sinusitis; Mucor Mycosis; Aspergillus; Invasive Fungal
1. Introduction
Opportunistic fungal infections are usually results of im-
munosuppression and immunodeficiency. Currently sev-
eral etiologies of immunosuppression lead to increase
prevalence of invasive fungal infection (IFI) including
leukemia, diabetes mellitus (DM), AIDS, solid organ
transplantation, bone marrow transplan tation and chemo-
therapy [1]. All these conditions result in neutropenia
which should be treated with wide-spectrum antibiotics.
IFI is considered as an important complication of neutro-
penia which is suspected with persistent fever for 72 - 96
hours after treatment with broad-spectrum antibacterial
antibiotic [1-3]. However, since the culture methods are
insensitive and radiologic findings are nonspecific, the
diagnosis of invasive fungal infection remains a chal-
lenge [4]. An intern ational consensus on th e diagnosis of
opportunistic invasive fungal infections in immunocom-
promised patients with cancer and hematopoietic stem
cell transplants was established by the Invasive Fungal
Infections Cooperativ e Group of the Europ ean Organiza-
tion for Research and Treatment of Cancer (EORTC) and
the Mycoses Study Group of the National Institu te of Al-
lergy and Infectious Diseases (MSG-NIAID) [5,6]. Delay
in the treatment of invasive fungal infection during neu-
tropenia causes high mortality in p a tients with transplants
and hematological malig nancy [4,5,7 ]. The unc ertainty in
*Corresponding a uthor.
Invasive Fungal Sinusitis in Immunocompromised Patients:
A Multicenter, University Hospital Experience in Shiraz
264
disease diagnosis results in under- or overtreatment of in-
vasive fungal infection. Despite the availability of seve-
ral new antifungal agents, in cluding triazoles and echino-
candins, the effectiveness of antifungal therapy remains
uncertain and the effectiveness of neutrophil recovery
may not be sufficient if the recovering neutrophils are
dysfunctional [8].
Invasive fungal sinusitis (IFS) is a rare disease largely
attributable to Aspergillus and Mucor in patients with stem
cell transplants and hematological disease [9]. Though the
mortality of IFS in immunocompromised patients ranges
from 50% to 80% [7,9,10], early physical findings are non-
specific and ambiguous (i.e., nasal obstruction, purulent dis-
charge, and epistaxis). Water’s view plain radiogr aphs do
not distinguish invasive fungal sinusitis from chronic al-
lergic sinusitis. Bony erosion and tissue destruction are
often found only in the advanced stage by computed to-
mography [11,12]. Recent introduction of serial Asper gil-
lus galactomannan antigen test may provide early evi-
dence of IF S. As data regard ing this issue are scarce in ou r
region of southern Iran, we performed this study to deter-
mine the epidemiology of IFS and the drug sensitivities
of the etiological factors in Shiraz, southern Iran.
2. Materials and Methods
2.1. Study Population
This was a cross-sectional study being performed in Iran
during a 1.5-year period from 21 March 2009 till 22 Sep-
tember 2010 including 36 immunosuppressed patients
who were further diagnosed to have IFS. Patients with
solid organ transplant, hematopoietic stem cell trans-
plants, hematological disease (including severe aplastic
anemia, pure red cell aplasia, and hematological malig-
nancy), AIDS and sinusitis diagnosed during their ho spi-
tal stay were enrolled in this study. Demographic features,
history of bone marrow transplant, history of neutropenia
(ANC < 500/mL), hematological disease status, underly-
ing medical diseases, prolonged corticosteroid therapy
(>3 weeks), receiving nucleoside analogue and T-cell sup-
pressor during the previous 3 months and congenital im-
munodeficiencies were recorded in a questionnaire. The
study protocol was approved by the institutional review
board of Shiraz University of Medical Sciences and all re-
quired patients provided their informed written consents.
2.2. Sinusitis Diagnosis
During the study period, those immunosuppressed pa-
tients who developed sinusitis were routinely underwent
sinus X-ray evaluation and afterwards, otolaryngologist
was consulted for focal evaluation and tissue culture. CT
and MRI sinus study, surgical biopsy and debridement
were performed according to clinicians’ decision.
IFS was diagnosed according to EORTC/MSG-NIAID
consensus criteria in 2008 [5,6]. The host factors in-
cluded prolonged neutropenia (<500 neutrophils/mm3 for
>10 days) temporally related to the onset of fungal dis-
ease, receipt of an allogeneic stem cell transplant, pro-
longed use of corticosteroids, immunosuppressive agents,
or nucleoside analogues during the past 90 days. The cli-
nical criteria included imaging showing sinusitis plus at
least one of the following three signs: acute localized
pain, nasal ulcer with black eschar, extension from the
paranasal sinus across the bony barrier. The microbiolo-
gical criteria included culture or isolation of fungus from
surgical material or sinus aspirate samples, and detection
of Aspergillus galactomannan antigens in serum. All the
samples were cultured in Sabouraud Dextrose Agar me-
dia and sensitivity to amphotericin B 1, capsofungin ace-
tate, voriconazole, itracon azole, ketokonazo l were further
examined.
2.3. Proven, Probable, and Possible Invasive
Fungal Sinusitis
Proven, probable, and possible IFS were defined mainly
according to the EORTC/MSG-NIAID criteria [5,6]. Pro-
ven IFS was defined by the presence of fungi associated
tissue damage on histopathologic examination of a bio-
psy specimen; or positive culture result, consistent with
infection, from a sample obtained aseptically from a cli-
nically or radiologically abnormal site. Probable IFS was
defined by the presence of at least one host factor crite-
rion, one microbiological criterion, and one clinical crite-
rion. Possible IFS was defined by the presence of at least
one host factor criterion and one clinical criterion.
2.4. Statistical Analysis
Statistical analyses were performed using the SPSS soft-
ware, version 16.0 (SPSS Inc., Chicago, Ill., USA). The
chi-square test was used to compare the proportions be-
tween groups. The results are expressed as mean ± SD
and proportions as appropriated. A two-tailed p-value
less than 0.05 was considered statistically significant.
3. Results
Overall we included 36 patients among whom there were
15 (41.6%) man and 21 (58.4%) women. The mean age
of the patients was 40 years with maximum age of 70
years. Sixteen (44%) of the patients were diagnosed to
have DM. Thirty patients had at least one co-morbidities
or sinus destruction. The most common predisposing
condition was ALL in 5 and AML in 5 follow ed by sinus
surgery in 3, CML in 3, CLL in 1, major β-thalassemia in
2, aplastic anemia in 1, Hodgkin's lymphoma in 1, non-
Hodgkin’s lymphoma in 2 and other diseases (congenital
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Invasive Fungal Sinusitis in Immunocompromised Patients:
A Multicenter, University Hospital Experience in Shiraz
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265
immmunodeficiencies, polycythemia vera) in 7. Bone
marrow transplantation was performed in 19.4% of pa-
tients. Overall, 47.2% received immunosuppressant and
41.7% received cytotoxic agents. Twenty-three patients
were on anti-fungal treatment at time of inclusion in the
study. Regarding clinical signs, 31 (86.1%) had nasal
congestion while 30 (83.3%) had facial pain and 18 (50%)
had epistaxis. Ocular involvement was reported in 9 pa-
tients and 11 patients had neurological involvement. Uni-
lateral involvement of VII nerve and bilateral involve-
ment of III were the most common neurological compli-
cations. Radiological signs of sinus invasion were report-
ed in 20 (55.6%) patients out of which 18 (50%) h ad cli-
nical signs of nasal, orbital or palate involvement. Severe
neutropenia was reported in 11 (30.6%) of patients (Ta-
ble 1).
Overall 21 samples tested positive for KOH including
1 Yeast and Boding Yeast, 3 Pseudo Hyphae, 9 Septated
Hyphae and 8 Non sep tated Hyph ae. Howe ver 16 samples
had positive cultures including 4 Candida (2 Candida al-
bicans, 1 Candida glabrata and 1 Candida krusei), 6 As-
pergillus flavus, 1 Aspergillus fumigates and 5 Mucor-
mycosis. The culture results had 100% concordance with
KOH results (Table 2). Posaconazole and Fluconazole
were found to have intermediate sensitivity (SDD). This
means that the resistance can be overcome by increase in
dose. Mucormycosis infection was significantly associ-
ated with DM (p < 0.05). Fifteen out of 18 patients with
signs of local invasion were further found to be proven
infection (p < 0.05). The most common aetiology of IFS
was found to be Aspergillus fumigates followed by Mu-
cormycosis and Candida. None of antifungal could suc-
cessfully cover all the species. Voriconazole was found
to be appropriate for treatment of Aspergillus and Can-
dida while Amphotericin B was found to be appropriate
for treatment of Mucormycosis. Posaconazole was found
to be effective on both Aspergillus and Mucormycosis.
4. Discussion
In most developing countries, increased prevalence of
resistant fungal infections and lack of appropriate diag-
nostic facilities is an important health issue. In addition,
the number of patients suffering from immunodeficien-
cies is increasing dramatically in these countries. In this
study we found that DM is the most common predispos-
ing factor for IFS followed by A LL and AML. The most
common aetiology of IFS was found to be Aspergillus
fumigates followed by Mucormycosis and Candida. Chen
and colleagues [13] demonstrated that IFS occurred in
1.77% of hospitalized patients with hematological disor-
ders. IFS caused significantly higher mortality in AML
patients with prolonged neutropenia (>10 days). IFS de-
veloped more frequently in patients with AML, myelo-
dysplastic syndrome, and aplastic anemia, but not at all
in patients with lymphoma/myeloma. In the literature re-
view, most patients with lymphoma who developed IFS
are recipients of myeloablative allogeneic stem cell trans-
plants [14-18]. Compared with other subtypes of hema-
tological malignancy, patients with AML have signifi-
cantly higher risk of IFS. The risk of developing IFS in
AML relates to neutropenia and less to the intensity of
chemotherapy regi mens.
Prolonged neutropenia in patients with myeloid ma-
lignancies may contribute to underlying disease, intensity
and dosage of chemotherapy, colony-stimulating factor,
and concurrent medication. Invasive mold infection often
occurs when a large burden of spores from an environ-
mental source is deposited on mucosal membranes lack-
ing an effective phagocytic host defense [19]. Using cy-
tokine growth factors to decrease the period of chemo-
therapy-associated neutropenia and using laminar air
flow rooms for protection against IFS [20] may reduce
the risk of IFS after allogeneic stem cell transplantation
[21].
The clinical mycological spectrum of IFS is limited in
patients with stem cell transplants and hematological dis-
ease [14-18]. Aspergillus and Mucor are the main mold
found in biopsy, however, the prevalence is highly vari-
able in different geographic regions [14-18,22,23]. Chen
and colleagues [13 ] founded that Aspergillus flavus (44%)
was the most common isolate which is in concordance
with our study. Aspergillus flavus, with its uniqu e ability
to survive at higher temperatures, is the predominant pa-
thogen in countries, including most of the Middle East,
Table 1. Clinical and host factors of local invasion in 36 patients suffering from invasive fungal sinusitis (IFS).
Number Admission in pr evious 3 months DM Radiological signs of local invasion Tissue necrosis signs
Proven 21 12 12 18 15
Probable 4 1 2 1 2
Possible 7 2 1 0 0
No IFS 4 2 1 1 1
ALL 36 17 16 20 18
Invasive Fungal Sinusitis in Immunocompromised Patients:
A Multicenter, University Hospital Experience in Shiraz
266
Table 2. Culture and antibiogram results of 36 patients suffering from invasive fungal sinusitis (IFS).
Organism Antifungal Resistant Sensitive Range MIC 50% MIC 90%
Amphotericin B 5 3 0.5 - 16 0.75 16
Ketoconazole 0 8 0.5 - 3 1 3
Itraconazole 2 6 0.047 - 32 0.125 32
Posaconazole 0 8 0.047 - 0.19 0.19 0.19
Caspofungin 0 8 0.32 - 0.5 0.094 0.75
Aspergillus
(n = 7)
Voriconazole 0 8 0.94 - 0. 5 0.19 0.5
Amphotericin B 0 5 0.063 - 0.75 0.125 0.75
Ketoconazole 1 4 0.25 - 4 0.25 4
Itraconazole 4 1 0.29 - 6 4 0.29 64
Posaconazole 0 5 0.75 - 2 0.75 2
Caspofungin 4 1 0.14 - 32 4 32
Mucormycosis
(n = 5)
Voriconazole 3 2 1.15 - 16 1.25 16
Amphotericin B 0 4 0.5 - 1 0.75 1
Ketoconazole 1 3 0.125 - 32 1 32
Itraconazole 3 1 0.032 - 32 2.5 32
Posaconazole 2 2 0.094 - 32 0.25 32
Caspofungin 0 4 0.125 - 0.29 0.125 0.29
Voriconazole 0 4 0.032 - 0.75 0.25 0.75
Nystatin 0 4 4.6 - 9.25 4.6 9.25
Candida
(n = 4)
Fluconagole 1 3 0.25 - 64 24 64
Amphotericin B 5 12 0.063 - 61 0.5 4
Ketoconazole 2 15 0.125 - 32 1 2
Itraconazole 9 8 0.032 - 64 0.29 32
Posaconazole 2 15 0.047 - 32 0.19 2
Caspofungin 4 13 0.125 - 32 0.125 4
Total
(n = 16)
Voriconazole 3 14 0.032 - 16 0.25 2
Africa, and Southeast Asia [24,25]. Rare IFS in Asia and
Africa were reported, the clinical response varies differ-
ently with fungal sub types, and fu rther epidemio logy stu -
dy should be investigated. Mucormycosis is an emerging
cause of IFS with a rapid fatal course in patients with he-
matological disorders [26,27]. Effective treatment for
Mucormycosis should be investigated.
The symptoms and signs of paranasal sinusitis (such as
nasal discharge, stuffiness, epistaxis, periorbital swelling,
and maxillary tenderness) are nonspecific for IFS [28].
Symptoms and signs such as nose ulceration, eschar of
the nasal mucosa, black necrotic lesions, and perforation
of the hard palate are more specific, but these findings
are present only at an advanced stage [29]. The use of CT
and MRI in the diagnos is of invasive fungal sinusitis has
been reported [12]. Diagnostic radiological evidence of
invasive fungal sinusitis includes erosion of sinus walls,
extension of infection to neighboring structures, and ex-
tensive skull base destruction. However, most patients do
not have classic findings in the early phase of invasive
fungal sinusitis. Earlier diagnosis by using serial Asper-
gillus galactomannan antigen test in the modern medical
era to detect IFS, may lead to early introduce anti-fungal
agent and surgical debridement, and potentially decreas-
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Invasive Fungal Sinusitis in Immunocompromised Patients:
A Multicenter, University Hospital Experience in Shiraz 267
ed morbidity and mortality in high risk patients.
5. Conclusion
In conclusion, DM is the most common predisposing fac-
tor for IFS followed by ALL and AML. The most com-
mon aetiology of IFS was found to be Aspergillus fumi-
gant followed by M ucorm y c osi s and Candida. None of an-
tifungal agents could successfully cover all the species.
6. Acknowledgments
This research project was financially supported by Health
Policy Research Center affiliated with Shiraz University
of Medical Sciences. Also, there is no conflict of interest
to be declared regarding this manuscript.
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