Oropharyngeal histoplasmosis : report of eleven cases and review of the literature

1. Department of Infectious Diseases, Hospital Nossa Senhora da Conceição, Porto Alegre, RS, Brazil. 2. Department of Internal Medicine, Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, RS, Brazil. 3. Faculty of Medicine, University of Passo Fundo, Passo Fundo, RS, Brazil. 4. Department of Mycology, Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, RS, Brazil. 5. Department of Internal Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. Address to: Dr. Vicente Sperb Antonello. Depto. SCIH/HF. Rua Mostardeiro 17, Bairro Independência, 91430-001 Porto Alegre, RS. Tel: 55 51 3314-5239 e-mail: vicente_antonello@hotmail.com Received in 29/04/2010 Accepted in 26/10/2010 ABSTRACT Introduction: Histoplasmosis is a systemic mycosis endemic in Brazil, especially in the State of Rio Grande do Sul, where Histoplasma capsulatum was isolated from the soil. H. capsulatum may compromise unusual areas, including the oropharynx, particularly in patients presenting disseminated histoplasmosis; which is associated with a state of immunosuppression, such as AIDS. Methods: During database analysis of a total of 265 cases of histoplasmosis, the medical records of 11 patients with histological or microbiological diagnoses of oral histoplasmosis (OH) between 1987 and 2008 were retrospectively reviewed. Results: This work reports 11 cases of OH, the majority presenting histopathological or microbiological evidence of disseminated histoplasmosis (DH). In the patients with DH, OH was the first manifestation of histoplasmosis. Five of the 11 patients discussed were HIV-seropositive with clinical and laboratory findings of AIDS. Four patients presented active pulmonary tuberculosis concomitant with histoplasmosis. Treatment was based on the use of itraconazole and amphotericin B deoxycholate. Eight patients responded successfully to therapy after one year, two did not come back for reevaluation and one died despite adequate therapy. Conclusions: Oral histoplasmosis is closely associated with immunosuppression status, especially in patients presenting AIDS; moreover, in many cases, OH is the first sign of disseminated histoplasmosis.

Histoplasmosis is a worldwide systemic mycosis caused by Histoplasma capsulatum, a dimorphic fungus that has been isolated from soil contaminated with bird or bat droppings in endemic areas, as reported in Brazil and central United States [1][2][3][4] .Infection occurs almost exclusively by inhalation of airborne conidia or mycelial fragments [1][2][3][4] .
The course of histoplasmosis can be influenced by the immune status of the host and by the quantity of infective propagules the host is exposed to 1,5,6 .Disease manifestations range from asymptomatic infection in the normal host with low-inoculum exposure, to rapidly fatal, disseminated infection in the severely immunocompromised host, emphasizing the importance of cellular immunity in defense against H. capsulatum 1 .
Disseminated histoplasmosis (DH) refers to the relentless growth of the fungus in multiple organ systems.It can develop by re-exposure to a large inoculum of the fungus or by reactivation of dormant endogenous foci 1,6 .The most important risk factors are immunosuppression, including transplantation, chronic renal disease, prolonged use of corticosteroids, acquired immune deficiency syndrome (AIDS) and age over 54 years-old 1,7 .In the last few years, AIDS has contributed to the increased incidence of DH, described in some series as up to 25% 1,6,8 .
Occasionally, as a consequence of DH, though less prevalent as a unique manifestation, H. capsulatum may involve unusual areas, such as the oropharynx.The most common sites of oral cavity affected are the tongue, palate and buccal mucosa 8 .The clinical significance of oropharyngeal lesions is primarily diagnostic.Goodwin et al showed that up to two-thirds of chronic patients with DH presented oropharyngeal involvement, which was almost invariably part of the clinical status leading to a diagnosis 6 .Oropharyngeal involvement is more frequently observed in immunocompromised patients, who often develop DH 1,5 .
This report is based on a series of 11 cases of oropharyngeal histoplasmosis (OH) observed During database analysis of a total of 265 cases of histoplasmosis, the medical records of 11 patients with histological or microbiological diagnoses of OH between 1987 and 2008 were retrospectively reviewed.The patients were referred from five public hospitals in Porto Alegre, Brazil, for definitive diagnosis.Diagnoses were determined in all cases by a combination of the following criteria: direct visualization of oropharyngeal lesion; biopsy of the lesion; and presence of characteristic yeast structures of H. capsulatum.Serology for H. capsulatum was performed on almost all patients.Patients with DH were defined as those with evidence of any other focus of infection other than the oropharynx, as analyzed by clinical examination, laboratory results and radiological data present in their records.

Baseline characteristics
Between March 1987 and October 2008, 11 patients (seven men and four women; age range, 24-66 years-old; mean 42 years-old) with H. capsulatum oral lesions positive by histological or microbiological methods, were identified in the files of the laboratory of mycology of our institution.The baseline characteristics of these patients are shown in Table 1.Five (45.5%) patients had clinical and laboratory diagnosis of AIDS before confirmation of DH and none of them were taking highly active antiretroviral therapy (HAART) regularly.CD4 counts were not available in all patients presenting with AIDS.In three cases, patients presented CD4 < 100/μL.Of the 11 patients, only two presented no evidence other than histoplasmosis in the oropharynx.In seven cases, clinical or microbiological pulmonary involvement was observed concomitant with oral histoplasmosis.Regarding patients with AIDS, four of the five described presented microbiological or histopathological evidence of DH, proving the strong association between DH and immunocompromised patients, as reported in literature 1,3,7 .Four (36.4%) patients had a history of active pulmonary tuberculosis when the diagnosis of DH was made.

Microscopy, culture, histopathology and immunodiffusion for Histoplasma capsulatum
Regarding microbiology and pathology, the organisms were morphologically consistent with the diagnosis of H. capsulatum in the biopsies performed from all cases reported, as shown in Table 2.

Treatment
Patients were treated with amphotericin B deoxycholate, itraconazole or ketoconazole.All patients were administered therapy for at least 6 months despite different treatment, except for two cases, treated exclusively with amphotericin B deoxycholate for 3 weeks.Four patients used amphotericin B deoxycholate for induction, with duration ranging from 2 to 4 weeks.Of these patients, one received ketoconazole for a further 6 months, one continued with amphotericin B deoxycholate twice weekly for a further 6 months and one patient stopped therapy after 3 weeks of initial induction.These three cases responded well to treatment.One patient, presenting with AIDS, died from systemic sepsis during therapy, despite initial induction with amphotericin B deoxycholate for 3 weeks.Seven patients received itraconazole during treatment.Duration ranged from 6 to 12 months.Five of them responded to therapy.Two patients did not return for reevaluation.In only one case, initial induction was performed with ketoconazole for two weeks, with posterior introduction of itraconazole.

Outcome
Two (18.1%) of the 11 cases never returned for reevaluation following the initial treatment.One (9.1%) patient responded initially to amphotericin, but developed sepsis and died despite treatment.The remaining cases (8 patients, 72.7%) responded well to therapy, as shown in Table 1.Patients who improved after therapy were followed for at least one year, with no sign of relapse.Three patients from the group that showed clinical improvement with therapy were HIV-seropositive.Histoplasmosis is a systemic mycosis endemic in Brazil, particularly in the State of Rio Grande do Sul, where H. capsulatum was isolated from the soil 8,9 .While most infections are asymptomatic or self-limiting, some individuals develop acute pulmonary infections or severe and progressive disseminated infection.Although hematogenous dissemination probably occurs in most patients during acute infection, progressive illness is unusual, except in immunocompromised hosts and those at the extremes of age 1 .
The clinical manifestations of DH and the timing of presentation differ based on host immunodeficiency and degree of exposure to the fungus 5 .Thus, diagnosis is made based on a combination of clinical findings, serology, light microscopy and microbiological culture of the organism 10 .
Up to 12% of DH involves the gastrointestinal tract.Lesions more often involve the colon and ileum, though can occur from the anus to the mouth 7 .Oral compromise is fairly unusual, with most of cases presented in patients with DH, as a consequence of the spread of respiratory mycosis acquired through aspiration of airborne spores found in the excreta of birds [10][11] .
Clinical presentation in the oropharyngeal area includes ulceration, nodular-ulcerative lesions, granulomas, verrucous and plaque-like lesions.Even following the outbreak of AIDS, reports of oral involvement by histoplasmosis have been rare in America and Europe 2,[10][11][12] .
This study reports 11 cases of oropharyngeal histoplasmosis, mostly with histopathological or microbiological evidence of DH.In nine cases, oral histoplasmosis was the first manifestation of DH.Five of the 11 patients presented were HIV-seropositive with clinical and laboratory findings of AIDS.Oral lesions of histoplasmosis were also the first manifestations of DH in four of the five cases presenting AIDS.
Six patients of a total of 11 were HIV-seronegative.Four patients presented active pulmonary tuberculosis concomitant with histoplasmosis (two were HIV-seropositive), one presented with lung cancer, one with Hodgkin lymphoma and one patient with chronic obstructive pulmonary disease.Only one patient had no history of concomitant illness at the time of diagnosis of histoplasmosis.
Diagnosis of histoplasmosis was achieved in all cases by fungal identification from the oral lesion.In seven cases, cultures were performed, with positive results in three cases.Immunodiffusion for Histoplasma capsulatum was performed in 10 cases, four of which were positive.
The most common symptoms presented in the cases were weight loss, asthenia, dysphagia, chronic cough and fever.The sites involved in order of frequency of oral histoplasmosis were buccal mucosa, tongue and palate.
Treatment was based on the use of itraconazole (seven patients) and amphotericin B deoxycholate (four patients).Eight patients responded well to therapy after one year, two did not return for reevaluation and one died despite adequate therapy.
In conclusion, oral histoplasmosis is closely associated with immunosuppression status, especially in patients presenting AIDS 1,2,6,[10][11][12][13] .In some cases, it is the initial indication of AIDS, as reported in literature 11,12 .Moreover, in the majority of cases, oral histoplasmosis is the first sign of DH, as observed in nine of the 11 cases presented in this article.
Awareness of the different manifestations of histoplasmosis may enable earlier diagnosis and the administration of correct therapy when a new unexplained lesion is present, especially in immunocompromised patients, leading to a clearer understanding of histoplasmosis, including the disseminated form, and improved evaluation of the disease.

TABLE 1 -Clinical features of 11 patients with oropharyngeal histoplasmosis.
from 1987 to 2008 selected from the medical records of the Laboratory of Mycology, Santa Casa Hospital Complex (Complexo Hospitalar Santa Casa), Porto Alegre, Brazil.