Invasive Fungal Sinusitis in Immunocompromised Patients: A Multicenter, University Hospital Experience in Shiraz

doi:10.4236/aid.2013.34040

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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: [email protected]

Received September 28th, 2013; revised October 28th, 2013; accepted November 6th, 2013

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:

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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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