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Original article

Aspergillus species in patients with chronic rhinosinusitis Aspergillus-Arten bei Patienten mit chronischer Rhinosinusitis Virginia Cameli-Rojas,1 Sofı´a Mata-Essayag,2 Claudia Hartung de Capriles,2 Sylvia Magaldi,2 Elizabeth Garrido de Pe´rez,1 Liselotte Garrido3 and David Balderrama-Caballero4 1 Servicio de Otorrinolaringologı´a, Hospital Universitario Caracas, Universidad Central de Venezuela, Caracas, 2Servicio de Micologı´a Me´dica, Instituto de Medicina Tropical, Universidad Central de Venezuela, Caracas, 3Instituto de Anatomı´a Patolo´gica, Universidad Central de Venezuela, Caracas, Venezuela and 4Servicio de Otorrinolaringologı´a y Cirugı´a de Cabeza y Cuello, Hospital de Llerena, Badajoz, Spain

Summary

The aim of this study was to determine the frequency of Aspergillus spp. in the paranasal cavities of 40 patients with suspicion of chronic rhinosinusitis, by standard mycological as well as serological examinations. We found Aspergillus in nine of 37 patients.

Zusammenfassung

Ziel der Studie war, bei 40 Patienten mit Verdacht auf chronische Rhinosinusitis mit mykologischen und serologischen Methoden Aspergillus und seine Ha¨ufigkeit in den paranasalen Nebenho¨hlen festzustellen. Bei 9 von 37 Patienten konnte Aspergillus nachgewiesen werden.

Key words: Aspergillus, aspergillosis, chronic infection, rhinosinusitis, Venezuela. Schlu¨sselwo¨rter: Aspergillus, Aspergillose, chronische Infektion, Rhinosinusitis, Venezuela.

Introduction Mycotic chronic rhinosinusitis is a clinical entity produced by several kinds of fungi.1 The most frequent etiological agents implicated are Aspergillus spp. and dematiaceous fungi.2,3 Aspergillus spp. growing commonly in soil, in decaying vegetation and organic debris are ubiquitous on our planet. About 18 groups and 600 species of the genus Aspergillus are known but only eight species are pathogenic for man.4 In paranasal sinus the most common species that produce this illness are Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. The pathology caused by Aspergillus spp. will depend on the inmunologic state of the patients. Mycotic chronic rhinosinusitis can be classified an invasive and non-invasive disease. The invasive type can be divided in two forms: (a) depending of the illness progress: acute and chronic, and (b) depending on histological features: granulomatous and non-granulo-

Correspondence: Dr Sofı´a Mata-Essayag, Apartado Postal 47423, Caracas 1041, Venezuela. Fax: 58-212-662 10 82. E-mail: [email protected] Accepted for publication 14 June 2002

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matous. The non-invasive type is divided into: mycetoma form (fungus ball), saprophytic colonization and allergic fungal rhinosinusitis.5 There are characteristic criteria to determine the presence of mycotic chronic rhinosinusitis, such as clinical manifestations, the radiological and inmunologic patterns, and specific mycological exam for the fungus.2,5–9 However, the performance of an adequate mycological exam is the most important to diagnose this entity. As far as we know, in Venezuela few cases of rhinosinusitis by Aspergillus had been documented. The aim of this study was to determine the frequency of Aspergillus spp. in the paranasal cavities in patients with a suspicion of chronic rhinosinusitis by standard mycological examinations as the direct microscopical exam and culture of the sample, as well as by demonstration of specific precipitating antibodies to Aspergillus.

Patients and methods Selection of patients

In a 2-year period 40 adults were enrolled in this study, 20 males and 17 females whose ages ranged from 14 to 68 years. Three of these patients were excluded,

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because the samples were improperly manipulated. All patients had a diagnosis of chronic rhinosinusitis by clinical manifestations and computed tomography scans. Inclusion criteria covered preoperative clinical manifestations, family history, allergies, associated medical problems, and laboratory tests. They were hospitalized in the Otolaryngology Service at the Hospital Universitario Caracas, Venezuela. Procedures for clinical samples

All patients were subject to surgical intervention. Samples from the paranasal sinus were taken by surgical procedures under general anesthesia. The surgeries were maxilla antrostomy and/or endoscopies ethmoidectomy. Histopathological studies were performed with hematoxilin and eosin (HE). Part of the fluids and fresh tissue material was ground up in 10% KOH and Parker ink (blue–black) and then observed under a light microscope. Samples were cultured on Sabouraud glucose agar and incubated at 23–28 C. The presence of specific IgM to Aspergillus spp.10 in blood sera was determined by the double immunodiffusion technique of Ouchterlony (IDD).11 The statistic analysis was made by the Fisher test or the McNemar test.

Results Nine (24%) of 37 patients showed the presence of narrow septate hyphae with acute angle branching and/or conidiophores, vesicles and conidia of Aspergillus spp. by direct microscopic examination. In four of these nine patients, a mass Ôfungus ballÕ was found, filling the maxillary antrum as a compact network of hyphae producing the clinical manifestations. In two of these, A. niger could be isolated. One of the samples showed calcified structures compatible with Aspergillus, but the agent could not be isolated, as well as from the fourth sample. The other four (11%) of these nine patients showed a thickened mucosa, and histopathological study revealed allergic, mucines as well as Charcot–Leyden crystals, confirming the diagnosis of allergic fungal rhinosinusitis. In two of these four, A. fumigatus could be isolated. In the other two samples no fungus could be cultivated. The remaining female diabetic patient (3%) had invasive granulomatous aspergillosis extending into the frontal and parietal cerebral lobules (Fig. 1). Fungal elements were visualized for compatibility with Aspergillus, but could not be isolated. This patient died despite of treatment with amphotericin B.

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Figure 1 Tomographic computerized scan of paranasal sinus showing opacity of ethmoido-sphenoidal cavity in patient 9.

Table 1 Number of patients with diagnosis of chronic rhinosinusitis, positive to Aspergillus spp. by direct microscopic examination, culture, and precipitating antibodies.

Patient

Direct microscopic exam

Culture of the samples

Serum IgM against Aspergillus sp.

1 2 3 4 5 6 7 8 9

Positive Positive Positive Positive Positive Positive Positive Positive Positive

Aspergillus Aspergillus Aspergillus Aspergillus Negative Negative Negative Negative Negative

Positive Negative Positive Positive Positive Negative Negative Negative Negative

Total

9

4

niger niger fumigatus fumigatus

4

All the patients had chronic, non-specific inflammation characterized by a polymorphonuclear and mononuclear leukocytic infiltrate in the lamina propria of the mucosa. Only four (11%) of 37 patients showed to have precipitating anti-Aspergillus antibodies. Direct microscopic examinations of all four patients were positive and from three the fungus could be isolated (Table 1). We neither found any statistical significance between the clinical entity and sex, age, geographical precedence, nor evolution of the disease.

Discussion Mycotic chronic rhinosinusitis has been described 200 years ago. However, this entity was not analyzed mycologically until the decade of 1970. Aspergillus is the

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Aspergillus in chronic rhinosinusitis

most frequent etiological fungal agent producing rhinosinusitis, and the most important in frequency is A. fumigatus.12–14 In Venezuela, just a few publications on bronchopulmonary aspergillosis and mycotic rhinosinusitis had been published.15,16 In this study fungal etiology of chronic rhinosinusitis was confirmed, in only nine (24%) of 37 patients by microscopic examination and/or isolation of the fungus. These findings differ from those published in 1999 by Ponikau et al.,17 who reported that 82 (81%) of 101 patients with chronic rhinosinusitis had fungal elements in histopathological findings and 93% of the patients studied had allergic fungal rhinosinusitis. The aforementioned study is controversial, because the diagnostic techniques employed were extremely sensitive. Moreover, they are in disagreement with studies carried out in 1992 by Chakrabarti et al.,18 who found that 42% of the patients with clinical diagnosis of mycotic rhinosinusitis had evidence of Aspergillus by mycological studies. Our results are just slightly lower, probably because we did not select exclusively patients with suspicion of mycotic rhinosinusitis, but only chronic rhinosinusitis. Allergic fungal rhinosinusitis is a syndrome based on a host allergic response to the presence of Aspergillus antigens.19 We demonstrated precipitating anti-Aspergillus antibodies (IgM), as test systems for IgG or IgE antibodies were not available. In our study, four of nine patients had fungal rhinosinusitis, and histopathological studies showed thickened mucosa and allergic mucines with Charcot– Leyden crystals and eosinophils, and in two of them A. fumigatus could be isolated. Aspergillus species may infect cavities as paranasal sinuses with formation of mass of hyphae. As in our cases, patients with this pathology are often asymptomatic, but with time and growing of the fungus ball most develop clinical manifestations.20 The remaining patient had an invasive granulomatous sinusitis due to Aspergillus sp., extending into the endocraneal mass. This invasive entity is an acute condition, and occurs in immunocompromised patients, like in this 54-year-old diabetic female; unfortunately the fungus was not isolated. This invasive granulomatous rhinosinusitis had features similar to those of zygomycosis. Therefore, a definitive diagnosis for mycotic rhinosinusitis may only be given by exploring the clinical manifestations of this entity and evidence of the fungus by direct microscopic examination of samples, by culture or by histopathological studies of the paranasal cavities.

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