Mycopathologia DOI 10.1007/s11046-015-9881-6
Alternaria-Associated Fungus Ball of Orbit Nose and Paranasal Sinuses: Case Report of a Rare Clinical Entity Zoran Pesic • Suzana Otasevic • Dragan Mihailovic Sladjana Petrovic • Valentina Arsic-Arsenijevic • Dragan Stojanov • Milica Petrovic
•
Received: 17 March 2014 / Accepted: 25 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Alternaria-associated fungus ball of maxillar, ethmoidal paranasal sinuses, nasal cavity and orbit with bone erosion is extremely rare. Till recently, only two cases of this infection in immune competitive patients have been reported. We are herein describing the case of immune-competent woman who suffered of nasal congestion for 10 years. Patient was treated for tumor-like lesion in right maxillar sinus, where propagation in right nose cavity, right ethmoidal cells and right orbita was present. The organism that was seen in surgical removal of fungal debris by histological study, in using mycological testing, was proven as Alternaria alternata. Combination of surgical intervention and treatment with itraconazole eradicated fungal infection, and the disease was not relapsed in follow-up period of 2 years.
Keywords Fungal ball Paranasal sinuses Alternaria alternata Diagnosis Treatment
Z. Pesic (&) Department of Maxillofacial Surgery, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia e-mail: [email protected]
S. Petrovic D. Stojanov Department of Radiology, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia
S. Otasevic Department of Microbiology and Immunology, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia D. Mihailovic Department of Pathology, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia
Introduction For a long time, fungal sinusitis was considered as rare disorder, but it is now being reported with increasing frequency throughout the world [1]. The most common type of noninvasive form is allergic fungal sinusitis (AFS). A fungus ball, noninvasive form also, that has replaced the erstwhile misnomer ‘mycetoma’ [2, 3], is an overgrowth of fungal elements, which can fills one or more paranasal sinuses. It is not rare that patients with fungus ball may have a history of recurrent and allergic sinus infections [4]. In both
V. Arsic-Arsenijevic Department of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia M. Petrovic Department of Prosthodontics, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia
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Mycopathologia
mention entities, the symptoms can be similar to bacterial sinusitis, which may lead to maltreatment of patients if microbiological analysis is not carried. Aspergillus spp. and the Dematiaceous family, that is including Bipolaris spp., Curvularia spp., Alternaria spp. and rare Mucor spp., can provoke hypersensitivity and may play a role in chronic allergic sinusitis [5, 6]. Alternaria spp. have generally been considered as nonpathogenic or contaminants in routine laboratory mycological analyses. Hypersensitivity to Alternaria spores antigens, however, has long been recognized as a cause of allergic rhinosinusitis and pulmonary disease [7]. Alternaria fungal sinusitis cannot be seen frequently in the literature, especially in immune-competent patients [8]. We will herein report one case of noninvasive Alternaria alternata sinusitis involving maxillar and ethmoidal paranasal sinuses as well as nasal walls of affected side with bone erosion and destruction of medial and inferior orbital walls, the form that is described by some authors as a ‘destructive noninvasive’ fungal sinusitis [5].
Case Report A 63-year-old woman, a physiotherapist in the hydrospa center, was admitted to the local Department of Maxillofacial Surgery because of 10-year history of nasal congestion present on right side of the nose and occasional headaches sensitive to analgetic therapy. The patient denied other medical problems including diabetes, immunodeficiency and asthma. Diagnostics procedure included computed tomography (CT) of cranium and viscerocranium, which proved tumorous mass in the right maxillar sinus and destruction of lateral nasal wall right ethmoidal cells (Fig. 1). Inferior and medial orbital walls were destroyed, and tumorous mass was present in orbit. Based on CT results, primary diagnosis was tumor of paranasal sinuses and nuclear magnetic resonance (NMR) (Fig. 2) and angiography was performed with preoperative diagnostic procedures. There were no pathological changes on other paranasal cavities. A complete blood count, basic blood chemistries and liver panel were within normal limits. There was no increase in blood eosinophils. Tumorous formation was extirpated, and samples were sent for histopathological and microbiological examination.
123
Fig. 1 CT of patient with fungal balls, destruction of lateral nasal wall and thickening of maxillary bone
Numerous septated, branching hyphal forms were found in biopsies sample by using the Alcian bluePeriodic acid Schiff (AB PAS, pH 2.5) and Jones’ methenamine silver stained methods in histological analyses (Fig. 3). This examination did not ascertain presence of neoplastic formation cells, which could be reason for bone destruction. Bacterial and mycological analyses were carried out by using standard protocols. Colonies that were fast grown on Sabouraud dextrose agar (without gentamycin and cycloheximide, incubated at 26 °C) have a suede like with dark gray pigment. Septated hyphae, which are light to dark brown with goldenbrown macroconidia and had three transverse and one longitudinal septa (5–6 9 22–23 lm), were microscopically morphological characteristics of isolated fungi (Fig. 4). Morphometric characteristics were obtained by applying of laboratory universal computer images analyses (LUCIA, CzeckRepubl). Based on the morphological and morphometric characteristics, the isolated fungal culture was identified as Alternaria spp. [9]. Isolated species was sent to CBS Fungal Biodiversity Centre of Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands, where it was identified as A. alternata (100 % ITS identity—identification
Mycopathologia
Fig. 4 Macroconidiae of Alternaria alternata (9400)
Fig. 2 NMR of patient with tumoroid formation in maxillary sinus and right nasal cavity
Fig. 3 Wide hyphal forms in extirpated material stained by Alcian blue-Periodic acid Schiff (9400)
number dH23847)). Neither other fungal species, nor pathogenic or opportunistic bacteria, were isolated from the material. Broth dilution method was used for in vitro antifungal susceptibility testing, with the goal to determine minimum inhibitory concentration (MIC) of amphotericin B, itraconazole and voriconazole against clinical isolates of conidia forming molds
EUCAST E.DEF 9.1 [10]. In addition, disk diffusion method was performed for amphotericin B, nystatin, itraconazole, miconazole, ketoconazole, fluconazole and voriconazole (Abtek Biological Ltd, England). Testing in vitro showed satisfactory efficiency of amphotericin B, nystatin, itraconazole and miconazole and low susceptibility of Alternaria alternata to ketoconazole, and resistances to fluconazole and voriconazole. Immediately, after obtaining positive results of histological and mycological analyses, an empiric therapy of itraconazole was prescribed, which was continued after the results of in vitro antifungal susceptibility testing (5 days—2 9 200 mg/day following with three cycles of 2 9 100 mg/day for 15 days). Besides standard microbiological analyses and antifungal susceptibility examination, the patient was evaluated for biomarkers of invasive mycoses and aero-allergies. Serological testing was negative for Candida mannan and Aspergillus galactomannan antigen (Bio-Rad, France). Low positivity obtained for anti-Candida IgM antibodies (109 U/ml), anti-Candida IgG (290 U/ml) and anti-Aspergillus IgM (220 U/ml) (Virion-Serion, Germany) [10]. The level of total IgE was low (4, 9 IU/mL). Specific IgE was present in diagnostic nonspecific level for several common pollens including tea tree, feathers and for antigens of fungi Aspergillus fumigatus, Alternari atenius, Candida albicans, Cladosporium herbarum or Penicillium notatum. All allergen-specific IgE levels were lower than 0, 7 kIU/mL as determined by the PolycheckR method, (Biocheck GmbH, Germany).
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Mycopathologia
In postoperative period in next 3 months, during six control examination, it was observed relatively fast epithelization of defect’s walls (approximately 20 days). Clinical signs of infection were absent; however, in successive six mycological examinations of swabs taken from surface formed by removing fungal ball, growth of Alternaria species was proved. Three and half months from interventions and already started treatment, we reached satisfactory antifungal and symptomatic effect. This observation repeated in the same form in the following 4 months, and we did not prove any fungal colonization or infection of nasal mucosa. Over the next 2 years, the patient has not showed any symptoms, nor had any mycological positive findings or relapsed disease.
Discussion The classification of fungal sinusitis involves five subtypes: (1) acute and chronic invasive fungal sinusitis, and chronic granulomatous invasive fungal sinusitis (fungal mycetoma); (2) whereas noninvasive fungal sinusitis is composed of AFS and fungus ball [1]. Noninvasive form of this fungal infection can be observed in patients with competent immunity. Some authors classified bone erosion without the tissue invasion as ‘destructive noninvasive’ form [5]. However, bone erosion never caused any progression, invasion or relapse [5]. This is one case of A. alternata-associated fungus ball known as ‘destructive noninvasive’ fungal sinusitis in patients with long-time history (based on anamnesis data) of allergic rhinosinusitis. Unlike AFS, this form of Alternaria sinusitis is very rare. The fungi genus Alternaria is saprophytic and ubiquitous and is air- and soilborne molds. In humans, it is described as an important cause of allergic, fungal sinusitis, eosinophilic pneumonia and has been reported to be a major allergen associated with the development of asthma in children [4]. Considering the fact that patients with fungus ball are not necessarily allergic, it is not surprising that our patient with A. alternata-associated fungus ball did not show any allergic response to antigens of Alternaria tenuis, nor to other fungi antigens. It is possible that immune tolerance to fungal antigens is responsible for fast growth of molds and formation of fungus ball. A recent study which researched the effect of A. fumigatus and A. alternata on ciliary epithelium
123
in vitro, found a statistically significant inhibition of ciliary beat frequency after exposure to the solutions of these fungi. Conclusion of this survey is that these fungi effect might present a virulence factor involved in the development of fungal sinusitis [8, 11]. In addition, lymphocyte transformation testing conducted in vitro indicates that a specific immune tolerance to Alternaria organisms was found in one patient having maxillary sinus infection and osteomyelitis caused by this mold [8]. So far, destructive, noninvasive sinusitis caused by Alternaria spp. was published and described in only two cases [6, 12] where such infection was called osteomyelitis due to the presence of bone destruction. In both described cases, patients were immunocompetitive, having the immune forces on normal level, like the patient we observed. The lack of data in referent literature points out the need for publishing the experiences related to diagnosis and treatment, especially having in mind that incidence of this mycosis is permanently increasing. The successful management and treatment of fungal sinusitis, especially their different subtypes, requires a multidisciplinary observation, since the treatment strategies and prognosis are not uniform [8]. Conventional mycology, antifungal susceptibility testing and histological methods can be very useful in case patient is positive, and can show surgical intervention and use of proper antimycotic is essential that for positive outcome [5]. In postoperative longtime period, frequent control checkups of the observed patient proved that combination of surgical and effective antifungal drug therapy is efficient in the rehabilitation of the disease. Our opinion is that just one of the therapeutical options by itself cannot be sufficient in this form of fungal infection. Acknowledgments This work was financially supported partly by Serbian Ministry of Education and Science Grant No. III 41018 and Grant No. III 175034. Conflict of interest The authors declare that they have no conflict of interest.
References 1. Aribandi M, McCoy VA, Bazan C III. Imaging features of invasive and noninvasive fungal sinusitis: a review. Radiographics. 2007;27:1283–96.
Mycopathologia 2. Hathiram BT, Khattar VS. Fungus balls of the paranasal sinuses. Otorhinolar Clin. 2009;1:33–5. 3. Adhikari L, Dey S, Pal R. Mycetoma due to Nocardia farcinica. J Glob Infect Dis. 2010;2:194–5. 4. Pastor JF, Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical features. Clin Microbiol Infect. 2008;14:734–46. 5. Pagella F, Matti E, De Bernardi F, et al. Paranasal sinus fungus ball: diagnosis and management. Mycoses. 2007;50:451–6. 6. Shugar MA, Montgomery WW, Hyslop NE Jr. Alternaria sinusitis. Ann Otol Rhinol Laryngol. 1981;90(3 Pt 1):251–4. 7. Hamilos DL. Allergic fungal rhinitis and rhinosinusitis. Proc Am Thorac Soc. 2010;7:245–52. 8. Goodpasture HC, Carlson T, Ellis B, Randall G. Alternaria osteomyelitis. Evidence of specific immunologic tolerance. Arch Pathol Lab Med. 1983;107:528–30.
9. Davise HL. Medically important fungi-a guide to identification. 3rd ed. Washington: ASM Press; 1995. 10. Subcommittee on Antifungal Susceptibility Testing. (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). EUCAST technical note on the method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia–forming moulds. Clin Microbiol Infect. 2008;14:982–4. 11. Tan BK, Schleimer RP, Kern RC. Perspectives on the etiology of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2010;18:21–6. 12. Garau J, Diamond RD, Lagrotteria LB, Kabins SA. Alternaria osteomyelitis. Ann Intern Med. 1977;86:747–8.
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Alternaria-Associated Fungus Ball of Orbit Nose and Paranasal Sinuses: Case Report of a Rare Clinical Entity Zoran Pesic • Suzana Otasevic • Dragan Mihailovic Sladjana Petrovic • Valentina Arsic-Arsenijevic • Dragan Stojanov • Milica Petrovic
•
Received: 17 March 2014 / Accepted: 25 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Alternaria-associated fungus ball of maxillar, ethmoidal paranasal sinuses, nasal cavity and orbit with bone erosion is extremely rare. Till recently, only two cases of this infection in immune competitive patients have been reported. We are herein describing the case of immune-competent woman who suffered of nasal congestion for 10 years. Patient was treated for tumor-like lesion in right maxillar sinus, where propagation in right nose cavity, right ethmoidal cells and right orbita was present. The organism that was seen in surgical removal of fungal debris by histological study, in using mycological testing, was proven as Alternaria alternata. Combination of surgical intervention and treatment with itraconazole eradicated fungal infection, and the disease was not relapsed in follow-up period of 2 years.
Keywords Fungal ball Paranasal sinuses Alternaria alternata Diagnosis Treatment
Z. Pesic (&) Department of Maxillofacial Surgery, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia e-mail: [email protected]
S. Petrovic D. Stojanov Department of Radiology, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia
S. Otasevic Department of Microbiology and Immunology, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia D. Mihailovic Department of Pathology, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia
Introduction For a long time, fungal sinusitis was considered as rare disorder, but it is now being reported with increasing frequency throughout the world [1]. The most common type of noninvasive form is allergic fungal sinusitis (AFS). A fungus ball, noninvasive form also, that has replaced the erstwhile misnomer ‘mycetoma’ [2, 3], is an overgrowth of fungal elements, which can fills one or more paranasal sinuses. It is not rare that patients with fungus ball may have a history of recurrent and allergic sinus infections [4]. In both
V. Arsic-Arsenijevic Department of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia M. Petrovic Department of Prosthodontics, Faculty of Medicine, University of Nis, Blvd Zorana Djindjica 81, 18000 Nis, Serbia
123
Mycopathologia
mention entities, the symptoms can be similar to bacterial sinusitis, which may lead to maltreatment of patients if microbiological analysis is not carried. Aspergillus spp. and the Dematiaceous family, that is including Bipolaris spp., Curvularia spp., Alternaria spp. and rare Mucor spp., can provoke hypersensitivity and may play a role in chronic allergic sinusitis [5, 6]. Alternaria spp. have generally been considered as nonpathogenic or contaminants in routine laboratory mycological analyses. Hypersensitivity to Alternaria spores antigens, however, has long been recognized as a cause of allergic rhinosinusitis and pulmonary disease [7]. Alternaria fungal sinusitis cannot be seen frequently in the literature, especially in immune-competent patients [8]. We will herein report one case of noninvasive Alternaria alternata sinusitis involving maxillar and ethmoidal paranasal sinuses as well as nasal walls of affected side with bone erosion and destruction of medial and inferior orbital walls, the form that is described by some authors as a ‘destructive noninvasive’ fungal sinusitis [5].
Case Report A 63-year-old woman, a physiotherapist in the hydrospa center, was admitted to the local Department of Maxillofacial Surgery because of 10-year history of nasal congestion present on right side of the nose and occasional headaches sensitive to analgetic therapy. The patient denied other medical problems including diabetes, immunodeficiency and asthma. Diagnostics procedure included computed tomography (CT) of cranium and viscerocranium, which proved tumorous mass in the right maxillar sinus and destruction of lateral nasal wall right ethmoidal cells (Fig. 1). Inferior and medial orbital walls were destroyed, and tumorous mass was present in orbit. Based on CT results, primary diagnosis was tumor of paranasal sinuses and nuclear magnetic resonance (NMR) (Fig. 2) and angiography was performed with preoperative diagnostic procedures. There were no pathological changes on other paranasal cavities. A complete blood count, basic blood chemistries and liver panel were within normal limits. There was no increase in blood eosinophils. Tumorous formation was extirpated, and samples were sent for histopathological and microbiological examination.
123
Fig. 1 CT of patient with fungal balls, destruction of lateral nasal wall and thickening of maxillary bone
Numerous septated, branching hyphal forms were found in biopsies sample by using the Alcian bluePeriodic acid Schiff (AB PAS, pH 2.5) and Jones’ methenamine silver stained methods in histological analyses (Fig. 3). This examination did not ascertain presence of neoplastic formation cells, which could be reason for bone destruction. Bacterial and mycological analyses were carried out by using standard protocols. Colonies that were fast grown on Sabouraud dextrose agar (without gentamycin and cycloheximide, incubated at 26 °C) have a suede like with dark gray pigment. Septated hyphae, which are light to dark brown with goldenbrown macroconidia and had three transverse and one longitudinal septa (5–6 9 22–23 lm), were microscopically morphological characteristics of isolated fungi (Fig. 4). Morphometric characteristics were obtained by applying of laboratory universal computer images analyses (LUCIA, CzeckRepubl). Based on the morphological and morphometric characteristics, the isolated fungal culture was identified as Alternaria spp. [9]. Isolated species was sent to CBS Fungal Biodiversity Centre of Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands, where it was identified as A. alternata (100 % ITS identity—identification
Mycopathologia
Fig. 4 Macroconidiae of Alternaria alternata (9400)
Fig. 2 NMR of patient with tumoroid formation in maxillary sinus and right nasal cavity
Fig. 3 Wide hyphal forms in extirpated material stained by Alcian blue-Periodic acid Schiff (9400)
number dH23847)). Neither other fungal species, nor pathogenic or opportunistic bacteria, were isolated from the material. Broth dilution method was used for in vitro antifungal susceptibility testing, with the goal to determine minimum inhibitory concentration (MIC) of amphotericin B, itraconazole and voriconazole against clinical isolates of conidia forming molds
EUCAST E.DEF 9.1 [10]. In addition, disk diffusion method was performed for amphotericin B, nystatin, itraconazole, miconazole, ketoconazole, fluconazole and voriconazole (Abtek Biological Ltd, England). Testing in vitro showed satisfactory efficiency of amphotericin B, nystatin, itraconazole and miconazole and low susceptibility of Alternaria alternata to ketoconazole, and resistances to fluconazole and voriconazole. Immediately, after obtaining positive results of histological and mycological analyses, an empiric therapy of itraconazole was prescribed, which was continued after the results of in vitro antifungal susceptibility testing (5 days—2 9 200 mg/day following with three cycles of 2 9 100 mg/day for 15 days). Besides standard microbiological analyses and antifungal susceptibility examination, the patient was evaluated for biomarkers of invasive mycoses and aero-allergies. Serological testing was negative for Candida mannan and Aspergillus galactomannan antigen (Bio-Rad, France). Low positivity obtained for anti-Candida IgM antibodies (109 U/ml), anti-Candida IgG (290 U/ml) and anti-Aspergillus IgM (220 U/ml) (Virion-Serion, Germany) [10]. The level of total IgE was low (4, 9 IU/mL). Specific IgE was present in diagnostic nonspecific level for several common pollens including tea tree, feathers and for antigens of fungi Aspergillus fumigatus, Alternari atenius, Candida albicans, Cladosporium herbarum or Penicillium notatum. All allergen-specific IgE levels were lower than 0, 7 kIU/mL as determined by the PolycheckR method, (Biocheck GmbH, Germany).
123
Mycopathologia
In postoperative period in next 3 months, during six control examination, it was observed relatively fast epithelization of defect’s walls (approximately 20 days). Clinical signs of infection were absent; however, in successive six mycological examinations of swabs taken from surface formed by removing fungal ball, growth of Alternaria species was proved. Three and half months from interventions and already started treatment, we reached satisfactory antifungal and symptomatic effect. This observation repeated in the same form in the following 4 months, and we did not prove any fungal colonization or infection of nasal mucosa. Over the next 2 years, the patient has not showed any symptoms, nor had any mycological positive findings or relapsed disease.
Discussion The classification of fungal sinusitis involves five subtypes: (1) acute and chronic invasive fungal sinusitis, and chronic granulomatous invasive fungal sinusitis (fungal mycetoma); (2) whereas noninvasive fungal sinusitis is composed of AFS and fungus ball [1]. Noninvasive form of this fungal infection can be observed in patients with competent immunity. Some authors classified bone erosion without the tissue invasion as ‘destructive noninvasive’ form [5]. However, bone erosion never caused any progression, invasion or relapse [5]. This is one case of A. alternata-associated fungus ball known as ‘destructive noninvasive’ fungal sinusitis in patients with long-time history (based on anamnesis data) of allergic rhinosinusitis. Unlike AFS, this form of Alternaria sinusitis is very rare. The fungi genus Alternaria is saprophytic and ubiquitous and is air- and soilborne molds. In humans, it is described as an important cause of allergic, fungal sinusitis, eosinophilic pneumonia and has been reported to be a major allergen associated with the development of asthma in children [4]. Considering the fact that patients with fungus ball are not necessarily allergic, it is not surprising that our patient with A. alternata-associated fungus ball did not show any allergic response to antigens of Alternaria tenuis, nor to other fungi antigens. It is possible that immune tolerance to fungal antigens is responsible for fast growth of molds and formation of fungus ball. A recent study which researched the effect of A. fumigatus and A. alternata on ciliary epithelium
123
in vitro, found a statistically significant inhibition of ciliary beat frequency after exposure to the solutions of these fungi. Conclusion of this survey is that these fungi effect might present a virulence factor involved in the development of fungal sinusitis [8, 11]. In addition, lymphocyte transformation testing conducted in vitro indicates that a specific immune tolerance to Alternaria organisms was found in one patient having maxillary sinus infection and osteomyelitis caused by this mold [8]. So far, destructive, noninvasive sinusitis caused by Alternaria spp. was published and described in only two cases [6, 12] where such infection was called osteomyelitis due to the presence of bone destruction. In both described cases, patients were immunocompetitive, having the immune forces on normal level, like the patient we observed. The lack of data in referent literature points out the need for publishing the experiences related to diagnosis and treatment, especially having in mind that incidence of this mycosis is permanently increasing. The successful management and treatment of fungal sinusitis, especially their different subtypes, requires a multidisciplinary observation, since the treatment strategies and prognosis are not uniform [8]. Conventional mycology, antifungal susceptibility testing and histological methods can be very useful in case patient is positive, and can show surgical intervention and use of proper antimycotic is essential that for positive outcome [5]. In postoperative longtime period, frequent control checkups of the observed patient proved that combination of surgical and effective antifungal drug therapy is efficient in the rehabilitation of the disease. Our opinion is that just one of the therapeutical options by itself cannot be sufficient in this form of fungal infection. Acknowledgments This work was financially supported partly by Serbian Ministry of Education and Science Grant No. III 41018 and Grant No. III 175034. Conflict of interest The authors declare that they have no conflict of interest.
References 1. Aribandi M, McCoy VA, Bazan C III. Imaging features of invasive and noninvasive fungal sinusitis: a review. Radiographics. 2007;27:1283–96.
Mycopathologia 2. Hathiram BT, Khattar VS. Fungus balls of the paranasal sinuses. Otorhinolar Clin. 2009;1:33–5. 3. Adhikari L, Dey S, Pal R. Mycetoma due to Nocardia farcinica. J Glob Infect Dis. 2010;2:194–5. 4. Pastor JF, Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical features. Clin Microbiol Infect. 2008;14:734–46. 5. Pagella F, Matti E, De Bernardi F, et al. Paranasal sinus fungus ball: diagnosis and management. Mycoses. 2007;50:451–6. 6. Shugar MA, Montgomery WW, Hyslop NE Jr. Alternaria sinusitis. Ann Otol Rhinol Laryngol. 1981;90(3 Pt 1):251–4. 7. Hamilos DL. Allergic fungal rhinitis and rhinosinusitis. Proc Am Thorac Soc. 2010;7:245–52. 8. Goodpasture HC, Carlson T, Ellis B, Randall G. Alternaria osteomyelitis. Evidence of specific immunologic tolerance. Arch Pathol Lab Med. 1983;107:528–30.
9. Davise HL. Medically important fungi-a guide to identification. 3rd ed. Washington: ASM Press; 1995. 10. Subcommittee on Antifungal Susceptibility Testing. (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). EUCAST technical note on the method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia–forming moulds. Clin Microbiol Infect. 2008;14:982–4. 11. Tan BK, Schleimer RP, Kern RC. Perspectives on the etiology of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2010;18:21–6. 12. Garau J, Diamond RD, Lagrotteria LB, Kabins SA. Alternaria osteomyelitis. Ann Intern Med. 1977;86:747–8.
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