Histoplasmosis: presentaciones clínicas y pruebas de laboratorio en un centro brasileño

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Histoplasmosis: presentaciones clínicas y pruebas de laboratorio en un centro brasileño

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  Dirección para correspondencia: Dra. BCQ LeimannServiço de MicologiaDepartamento de Micro-Imuno-ParasitologiaInstituto de Pesquisa Clínica Evandro ChagasFundação Oswaldo Cruz Av. Brasil, 4365CEP 21045-900, Rio de Janeiro, BrazilTel.:+ 55 (21) 3865 9557Fax:+ 55 (21) 2950 9988 E-mail: leimann@centroin.com.br  Aceptado para publicación el 5 de septiembre de 2005 ©2005 Revista Iberoamericana de MicologíaApdo. 699, E-48080 Bilbao (Spain)1130-1406/01/10.00  141 Rev Iberoam Micol 2005; 22: 141-146 Histoplasmosis in a Brazilian center:clinical forms and laboratory tests Beatriz Consuelo Quinet Leimann, Cláudia Vera Pizzini, Mauro Medeiros Muniz, Priscila Carvalho Albuquerque, Paulo CezarFialho Monteiro, Rosani Santos Reis, Rodrigo Almeida-Paes,Márcia Santos Lazéra, Bodo Wanke, Maurício Andrade Pérez & Rosely Maria Zancopé-Oliveira Serviço de Micologia do Departamento de Micro-Imuno-Parasitologia do Instituto de Pesquisa Clínica EvandroChagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil Histoplasmosis, caused by the dimorphic fungus Histoplasma capsulatum , isendemic in many regions of the Americas, Asia and Africa. It has a widespectrum of clinical manifestations, from asymptomatic infection to severedisseminated disease. A retrospective study was carried out to describe theclinical forms and assess the clinical significance of the laboratory diagnostictests of patients with histoplasmosis during the period of July 1987 toDecember 2003 at Instituto de Pesquisa Clínica Evandro Chagas/ FIOCRUZ, RJ,Brazil. Seventy-four patients were included. Forty-nine percent of the cases(n=36) occurred in HIV positive patients who presented with disseminateddisease. The remaining 38 cases were classified in different clinical forms. Histoplasma capsulatum was isolated from 69.5% of the clinical specimens sentto culture. Immunodiffusion and immunoblot were positive in 72.6 % and 100%of the performed tests, respectively. Histopathologic findings suggestive of H.capsulatum were found in 63.2% of the performed exams. Serology had alower proportion of positivity amongst AIDS patients, when compared with HIVnegative patients (   X  2 = 6.65; p< 0.008). Statistical differences between AIDS andnon-AIDS patients were not observed with culture and histopathology. Thespecific role of each test varies according to the clinical form. Physicians needto know the value and limitations of the available diagnostic tests, but beforethat, they have to think about histoplasmosis and consider this clinical entity intheir differential diagnosis.Histoplasmosis, Histoplasma capsulatum , Diagnosis, AIDS Summary Key words Original  Histoplasmosis: presentaciones clínicas y pruebas delaboratorio en un centro brasileño La histoplasmosis, causada por el hongo dimórfico Histoplasma capsulatum , esendémica en muchas regiones de las Americas, Asia y Africa. Presenta unamplio espectro de manifestaciones clínicas, desde infección asintomáticahasta enfermedad diseminada severa. En el presente trabajo, se realizó unestudio retrospectivo para describir las formas clínicas y evaluar el significadode los exámenes diagnósticos de pacientes con histoplasmosis acompañadosdurante el periodo de julio de 1987 hasta diciembre de 2003 en el Instituto dePesquisa Clínica Evandro Chagas / FIOCRUZ, RJ, Brasil. Setenta y cuatropacientes fueron incluidos, cuarenta y nueve por ciento de los cuales (n=36)eran pacientes VIH positivo que presentaron enfermedad diseminada. Los otros38 casos fueron clasificados de acuerdo a diferentes formas clínicas. Histoplasma capsulatum fue aislado en el 69,5% de los especimenes clínicosenviados para cultivo. La inmunodifusión y el inmunoblot fueron positivos en el72,6% y 100% de los exámenes realizados, respectivamente. Hallazgoshistopatológicos sugestivos de H. capsulatum fueron observados en el 63,2%de los exámenes realizados. Las pruebas serológicas presentaron menorpositividad en los pacientes con sida, cuando se compararon con los pacientes VIH negativo (   X  2 = 6,65; p< 0,008). No se observó diferencia estadística entre lospacientes con y sin sida en relación al cultivo y a la histopatología. El papelefectivo de cada examen varía de acuerdo con la forma clínica. Es necesarioque los médicos conozcan el valor y las limitaciones de los exámenesdisponibles pero, antes que eso, deben pensar en la histoplasmosis e incluirlaen el diagnóstico diferencial de sus pacientes.Histoplasmosis, Histoplasma capsulatum, Diagnóstico, Sida 142 Rev Iberoam Micol 2005; 22: 141-146  Resumen Palabras clave Histoplasmosis, caused by the dimorphic fungus  Histoplasma capsulatum , is endemic in many regions of the Americas, Asia, and Africa. Its prevalence has beenestimated by histoplasmin skin test. The largest concentra-tion of positive skin reactors is found in the central area of the United States [3]. In Brazil, the positive skin reactorsprevalence ranges from 2.6 to 93.2% [19,8] depending onthe geographic region. In Rio de Janeiro, located in thesouthern region, there are areas considered to be endemicor even hyper-endemic [25,29]. Histoplasmosis has a wide spectrum of clinicalmanifestations, ranging from asymptomatic infection tosevere disseminated disease, depending on the inoculumsize, the immune status of the host and the virulence of thefungal strain. It was first reported in patients with acquiredimmune deficiency syndrome in 1982 [21] and, since1987, extrapulmonary histoplasmosis in an individual witha positive serologic test for human immunodeficiencyvirus is a case definition of AIDS according to the Centersfor Disease Control (CDC) [4]. The severe immune defectin AIDS predisposes to extrapulmonary dissemination.CD4 + Tcells appear to play the most important role in thedevelopment of cellular mediated immunity to  H. capsula-tum . Reactivation of quiescent infection occurs duringimmunosuppression [14,27].Clinical diagnosis of histoplasmosis is based uponclinical, radiological and epidemiological aspects. Labo-ratory tests for the diagnosis of histoplasmosis includeculture, fungal detection in stained smears or tissue sec-tions, antibody detection and antigen detection. The speci-fic role of each test varies according to the clinical form,since variations in sensitivity have been associated to different clinical presentations [27]. The gold standardmethod for diagnosis of histoplasmosis is the isolation of   H. capsulatum in culture with the observation of the suggestive conidial forms (macro and microconidia) aswell as its conversion of mold to yeast phase at 37°C.  H. capsulatum requires up to four weeks to grow in vitro. Fungal staining of tissue sections or body fluid smearsshow the suggestive yeast forms within macrophages and,occasionally, extracellularly. Special fungus stains such asGomori’s methinamine silver (GMS) and periodic acid-Schiff (PAS) are the ones most commonly used in histolo-gical study of mycotic diseases [5,12]. GMS is consideredthe best technique because “it provides better contrast andoften stains fungal cells that are refractory to PAS proce-dures” [5]. To avoid the limitation posed by the fact thatspecial stains do not allow adequate study of the tissueresponse to fungal invasion, haematoxylin and eosin(H&E) is recommended as the counter-stain for the GMSprocedure [5]. However, experience is required to avoidmissing small number of organisms in patients with lowfungal burden or misidentification of artifacts or other organisms, such as  Leishmania donovani and  Toxoplasmagondii in H&E stained slides or small forms of Crypto-coccus neoformans, Blastomyces dermatitidis ,  Paracocci-dioides brasiliensis ,  Candida glabrata and  Pneumocystiscarinii , as  H. capsulatum [12]. Both culture and fungalstaining are time-consuming and lacking in sensitivity [2].Serological testing is central to the diagnosis of some acute, recent, or chronic infectious diseases. Someti-mes serologic testing must be relied upon the only diag-nostic test that is practical, because the suspect etiologicagent is impossible, difficult, or dangerous to grow in cul-tures in a routine diagnostic laboratory [6]. In histoplas-mosis, the detection of patients’antibody responses offersa more rapid alternative to microbiological means of diag-nosis, and the detection of host anti-  H. capsulatum antibo-dies by immunodiffusion (ID) and complement fixation(CF) tests is often used [2]. Both the yeast and mycelialphases of the fungus produce a number of exoantigens in culture, the most important and characteristic are the H and M antigens. These two antigens are the primaryimmunoreactive constituents of histoplasmin (HMIN), the  standard diagnostic reagent used in ID and CF for manyyears [23]. ID tests identify H and M precipitins bands. Mprecipitins can be detected in patients who were exposedto  H. capsulatum or who had performed histoplasmin skintest. H precipitins are detected during active infection [12].Fewer than 20% of patients with proven histoplasmosisshow H bands [27]. An alternative approach to immunodiagnosis is the detection of anti-  H. capsulatum antibody in serum by enzyme immunoassays or Western blot assay (WB)[1,11,13,15,16,24,30,31]. Data from previous immunoas-say studies, which incorporated deglycosylated antigensfor antibody detection, has confirmed that the use of suchantigens improves test specificity.It has been demonstra-ted that WB analysis using NaIO 4 -treated H and M anti-gens is a highly sensitive method for detecting antibodiesin serum from persons with early acute pulmonary histo-plasmosis [15]. The advantages of the WB test are identi-fication of some cases of earlyinfection, before serocon-version can be detected by CF and ID, a high degree of disease specificity, and applicability to serum specimenswith anti-complementary activity. More recently, a highlysensitive and specific ELISAusing the same deglycosyla-ted antigens has been reported [10].During active infection, antigens are released intothe tissues and enter body fluids adjacent to the sites of infection, providing a basis for diagnosis by antigen detection [26]. Antigen detection is most useful in patientswith disseminated infection and also in the early phase of acute histoplasmosis. The sensitivity of antigen detectionis greater in urine than serum [26]. Molecular methods are being evaluated, but have yet to be compared with culture [26]. The polymerase chain reaction assay might bea powerful and rapid diagnostic tool for the diagnosis of histoplasmosis [18].Aretrospective study to describe the clinical formsand assess the clinical significance of the laboratory diag-nostic tests of patients with histoplasmosis at Instituto dePesquisa Clínica Evandro Chagas/FIOCRUZ, RJ, Brazilwas carried out. Materials and methods  Patients. Areview of the clinical registration formsfrom the Instituto de Pesquisa Clínica Evandro Chagas(IPEC) was performed to identify patients with the diagnosis of histoplasmosis during the period of July 1987to December 2003. The diagnosis was based on one of the followingcriteria: (1) isolation of  H. capsulatum frombiological material; (2) seropositivity for anti-  H. capsula-tum antibodies (ID or WB tests) associated with clinicaland/or radiological findings suggestive of histoplasmosiswith or without a positive epidemiological history; or (3)histopathologic findings revealing organisms consistentwith  H. capsulatum associated with clinical and radiologi-cal findings suggestive of histoplasmosis with or without apositive epidemiological history.The cases were clinically classified into nine forms[7,9,12,20]: (1) acute pulmonary – abrupt onset, fever,headache, non-productive cough, aching or constrictingsubesternal discomfort, pleuritic pain; scattered patchypneumonic infiltrates and hilar adenopathy on chest radio-graph; and a positive epidemiological history of recentexposure; (2) chronic pulmonary – malaise, fatigue, lowgrade fever, mucoid sputum, chest pain, weight loss; reti-culonodular and fibrotic lesions associated with cavitationon chest radiograph; and the presence of chronic obstruc-tive pulmonary lung disease (not obligatory); (3) acute disseminated – preceded by the pulmonary acute form inhalf of the cases; fever; hepatosplenomegaly; anemia, leukopenia, thrombocytopenia; (4) subacute disseminated – mild fever, weight loss, malaise; hepatosplenomegaly,focal lesions in various organs, most often gastrointestinaltract, adrenal gland, central nervous system, mucousmem-brane, skin; intersticial pneumonia (1/3 of cases); (5) chronic disseminated – protracted course; intermittentsymptoms; low grade fever, fatigue, weight loss; one or more lesions presenting as oropharyngeal, gastrointestinal,adrenal gland and CNS (meningitis) involvement; lungsare seldom involved; (6) disseminated in AIDS patients – fever, cough; anemia, leukopenia, thrombocytopenia;hepatosplenomegaly; pulmonary involvement with diffuseinterstitial infiltrate on chest radiograph; latter, multipleorgans involvement; (7) granulomatous mediastinitis – large caseous lymph nodes in the mediastinum; (8) cuta-neous – localized cutaneous infection with no obvious evi-dence of disseminated disease. Cutaneous lesions are either, primary from direct inoculation or secondary fromhematogenous dissemination; (9) non-defined – clinicaland serological suspected cases who could not be classi-fied in none of the preceding forms.Data were analyzed in SPSS 11.0. Proportions weretested with  2 test and differences were considered signifi-cant at 0.05 level.  Laboratory methods. Clinical specimens – sputum,bronchoalveolar lavage, bone marrow aspiration, biopsies,cerebrospinal fluid – were submitted for direct examina-tion with KOH 10% and culture on Sabouraud agar and/or staining with H&E and GMS techniques. Blood sampleswere cultured on brain heart infusion agar (BHI). Cultureswere incubated for 4 to 6 weeks at room temperature to assure isolation of fungi. The observation of white to brownish filamentous colonies on the slants, and mi-croscopic examination of slide cultures revealing septatehyaline hyphae, with globose macroconidia, and micro-conidia presuntively identify the isolates as  H. capsulatum .Conversion to oval yeast cells with single budding con-firmed the identity of the strain as  H. capsulatum .Fungalstained slides exhibiting intracellular ovoid yeasts, measu-ring 3 to 5 mm in diameter with narrow-based buddingwere consideredcompatible with  H. capsulatum .Standard diagnostic reagent used in ID was his-toplasmin, whose primary constituents are the H and Mantigens, exoantigens produced in culture by  H. capsula-tum . Seropositivity was determined by the presence of precipitins against M and/or H antigens. Western blot testwas performed with NaIO 4 -treated H and M antigens. Results Seventy-four patients were included. Age rangedfrom 15 to 74 years, with a median of 36 years. Male sex(82.4%) and white race (63.5%) predominated. Clinical forms. Forty-nine percent of the cases(n=36) occurred in HIVpositive patients who presentedwith disseminated disease. In almost one third of thesepatients (n=11) histoplasmosis was considered an AIDSdefining infection. The remaining 38 cases were classifiedin the following clinical forms: acute pulmonary: 10; chro-nic pulmonary: 9; acute disseminated: 1; subacute disse-minated: 4; chronic disseminated: 5; mediastinitis: 5; cuta-neous: 2; non-defined: 2. In HIVnegative patients,pulmonary forms, acute (n=10) and chronic (n=9), repre-sented half of the cases (Table 1).  Laboratory tests. Table 1 correlates culture, sero-logy and histopathology results to the clinical forms.  H. capsulatum was isolated from 69.5% of the clinical 143 Histoplasmosis in BrazilQuinet Leimann BC, et al.  specimens sent to culture. ID and WB were positive in72.6 % and 100% of the performed tests, respectively. His-topathologic findings suggestive of  H. capsulatum werefound in 63.2% of the performed exams. Serology had alower proportion of positivity amongst AIDS patients,when compared with histoplasmosis HIVnegative patients(  X  2 = 6.65; p< 0.008). Statistical differences between AIDSand non-AIDS patients were not observed with culture andhistopathology. Theagreementanddisagreementbetweentheresultsobtainedfromcultureandfromimmunodifusiontests(ID)ondifferentclinicalformsareshownonTable2.Resultsagreedin52.2%ofthecasesinnon-AIDSpatients.In the remaining, onlyID was positive in 39.1% and onlyculture in 8.7%. In AIDS patients culture and ID were bothpositive in 38.2% of the cases, only the ID was positive in23.5% of the patients and only the culture in 35.3%. The same analysis was performed between resultsfrom culture and histopathology. Both tests were perfor-med in eight non-HIVinfected patients: in five (62.5%)both culture and histopathology were positive. In twopatients only histopathology showed yeast-like forms suggestive of  H. capsulatum, and in one of them both testswere negative. Among the 23 AIDS patients in whom bothtests were performed, in 13 (56.5%) both were positive; inthree (13%) both were negative; in four (17.5%) just theculture was positive and in three (13%) only the histopa-thology was suggestive of  H. capsulatum . Observations on clinical forms . All cases of acutepulmonary form had a compatible epidemiological historyand clinical findings suggestive of histoplasmosis. All butone of them had positive ID titers. The one with negativeID had a positive WB. One patient with sub-acute disseminated form wasa 20-year old non-smoking young man. He had a one-year history of low fever, cough and scarce pulmonary infiltra-tes on chest x-ray. He had two episodes of hemoptysis.Several acid-fast stains and culture of sputum were repea-tedly negative and tuberculin skin test was negative. His-toplasmosis was diagnosed based on clinical findings that also included weight loss and splenomegaly, and anID seropositivity of 1:32, with H and M precipitins bands.ID for  Paracoccidioides brasiliensis and  Aspergillus spwere negative.  H. capsulatum was not isolated from spu-tum nor observed on direct microscopy of stained clinicalspecimens. Itraconazole was started and symptoms rapidlysubsided. Seven months later he presented daily low-gradefever and cavitation in the apical segment of the upper right lobe on chest x-ray. Adiagnosis of tuberculosis wasmade based on acid-fast bacilli on smear of sputum andculture positive for  Mycobacterium tuberculosis. Itracona-zole was stopped and he received rifampim, isoniazid and 144 Rev Iberoam Micol 2005; 22: 141-146 Table 1 . Positive results of the diagnostic tests in the different clinical forms of histoplasmosis.CultureIDImmunoblotHistopathologyClinical form (n)+/n(%)+/n(%)+/n(%)+/n(%)Non-AIDS Acute pulmonary (10)0/2(0)9/10(90%)1/1*(100%)Chronic pulmonary (9)7/9(77.8%)9/9(100%)2/2(100%) Acute disseminated (1)1/1(100%)1/1(100%)1/1(100%)Subacute disseminated (4)1/4(25%)4/4(100%)0/1(0)Chronic disseminated (5) 3/5(60%)5/5(100%)4/4(100%)Mediastinitis (5)3/5(60%)2/2*(100%)0/5(0)Cutaneous (2)2/2(100%)0/2(0)1/1(100%)Non defined (2)0/1(0)2/2(100%)0/1(0)Total non-AIDS (38) 14/24(58.3%)33/38(86,8%)4/4(100%)7/14(50%) AIDS (36)Disseminated (36)27/35(77%)20/35(57%)17/24(71%)Total (74)41/59(69.5%)53/73(72.6%)4/4(100%)24/38(63.2%) ID = immunodiffusion; n = sample number tested; + = positive; * = negative ID Table 2.  Agreement among the “gold standard” culture methodology and immunodiffusion test.Clinical form (n)ID + / Culture +ID + / Culture -ID - / Culture +ID - / Culture -Non-AIDS Acute pulmonary (2)2Chronic pulmonary (9)72 Acute disseminated (1)1Subacute disseminated (3)12Chronic disseminated (5)32Mediastinitis (0)Cutaneous (2)2Non defined (1)1Total non-AIDS (23)12 (52.2%)9 (39.1%)2 (8.7%) AIDSDisseminated (34)13 (38.2%)8 (23.5%)12 (35.3%)1 (3%) n = number of cases submitted to both exams; + positive result; - negative result  pyrazinamide for six months. Two months afterwards,fever returned accompanied by hemoptysis, ID test for   Aspergillus fumigatus became positive and a pulmonaryfungus ball (aspergilloma) was diagnosed on chest x-ray.Itraconazole was re-started. Asurgical resection was per-formed and  Aspergillus fumigatus was isolated from theresected fungus ball. Six months after the surgery ID for   Aspergillus became negative. ID for  H. capsulatum remai-ned positive with low titers.One case of chronic pulmonary histoplasmosis wasa 20-year old non-smoking young woman. She had a his-tory of chest pain and a chest radiograph revealing a cavi-tation at the superior segment of the right lower lobe.Acid-fast stains of sputum were negative and tuberculinskin test was negative. She was started on empirical anti-tuberculous therapy. Six months later, pulmonary imageworsened. At that time, the diagnosis of histoplasmosiswas made by the isolation of  H. capsulatum from bron-choalveolar lavage (BAL). ID titer was1:32, with M pre-cipitin band.Two patients with chronic pulmonary histoplasmo-sis had  Aspergillus sp observed on wet smear and isolatedfrom BALculture besides  H. capsulatum . One was  A. fla-vus and the other one  A. fumigatus . They both hadpositiveID for  H. capsulatum and  Aspergillus sp.The two patients with the cutaneous form werenonimmunocompromised adult men without any other manifestation of active disseminated disease. One presen-ted a verrucous lesion at the right elbow without a historyof a local injury. The other one, an army officer, presentedwith a papulonecrotic lesion on the back of his right handwith a history of crawling through a small bat inhabitedtunnel three months earlier. Except for the AIDS patients, in whom it was diffi-cult to analyze a negative serologic result, in all the other clinical forms antibody levels remained low or fluctuatebetween negative and low levels , after therapy. Two pa-tients who have had the pulmonary acute form manifestedID titers of 1:1 six years after the acute episode; a thirdone had titer of 1:2 two years after the acute episode. Onepatient with the subacute disseminated form, a 30-year oldnon-smoking man without any epidemiological history,still had a titer of 1:32 one and a half year after the diag-nosis, whilereceiving itraconazole and free of any symp-tom. Six months later, that is two years after diagnosis, thetiter was 1:4. In patients with the chronic pulmonary form,ID titers fluctuate between negative and low levels. In thethree cases of mediastinitis with seropositivity by ID, anti-body levels were low at diagnosis (1:1; 1:2) and remainedlow at two, three and five years after diagnosis, in eachone of the cases, respectively. Discussion Each one of the approaches to the diagnosis of histoplasmosis such as culture, histopathology, measure-ment of antibody titers or detection of antigens, has limi-tations. So the best approach to the diagnosis is an appro-priate combination of these methodologies. Culture andhistopathology have an important role in disseminated histoplasmosis in immunossupressed patients and in thecutaneous form. Serologic tests are useful for pulmonaryforms (acute and chronic), mediastinitis and disseminatedforms in immunocompetent patients but have limitationsin immunosupressed patients with disseminated infection.Those observations are in accordance with the pathogene-sis of  H. capsulatum and the immunology of host defenseagainst the fungus [14,27,28]. According to the literature [17,26,27], in acute pul-monary histoplasmosis, culture and histopathology have alow positivity; serology has a positivity of 80-95% andantigen detection is positive in 75-80% of the patients. Thesensitivity of antigen detection is lower in serum than inurine; also, levels of antigen in the bronchoalveolar lavagefluid can be much higher than in serum and urine. In chronic pulmonary histoplasmosis, culture is positive in50-85% of the cases, histopathology has a positivity of 40%, serology has a high positivity of 85-100% and testsfor antigen are negative. In mediastinitis, serologic testsfor antibodies are positive (~70%) and antigen tests arenegative; the histopathology of biopsies performed toexclude malignancy is positive in less than 25% of thecases. In disseminated histoplasmosis in non-immunosu-pressed patients, culture is positive in 80-90% of the cases,histopathology in 40-60%, serology in 80-100% and anti-gen detection in 80%. In disseminated histoplasmosis inAIDS patients, culture has a positivity of 90%, histopatho-logy of 40-90%, serology of 50-70% and antigen detectionof 85-95%. Severo et al. [22], from the state of Rio Grande doSul, Brazil, reported a 21-year period casuistic of 137cases. The diagnosis was mostly based on culture and histopathology. Serology wasn’t regularly performed.Acute and chronic pulmonary forms were mainly diag-nosed by histologic examination of biopsied lung tissue. Inthe disseminated forms (one acute; 91 chronic: 65 HIVpositive, nine immunosupressed, 17 with no associatedcondition) the diagnosis was based on histopathology (75 of 81 patients) or culture (42 of 56 patients). The IDperformed in 53 patients was positive in 62% of them.We have classified and grouped the patients accord-ing to the observed clinical manifestations. Although our casuistic was small in the different clinical forms, theresults of the laboratory diagnostic tests observed in our study are in accordance with the literature. Exception wasobserved for histopathologic exams in which our resultspresented a higher percentage of positivism, approachingthat observed by Severo et al. [22]. This fact could bebecause the exams were carried out on national referencecenters for systemic mycoses and histopathology of infec-tious diseases, where fungal stains are always employedand the pathologists are prepared to recognize fungalinfections.We have decided to describe a few clinical cases toillustrate clinical and laboratory aspects in the course of histoplasmosis and to point out that many times histoplas-mosis is not considered at the initial differential diagnosesand months elapse until the correct diagnosis is made. All in all, the role of each methodology used in thediagnosis of histoplasmosis varies according to the clinicalform and physicians need to know the value and limita-tions of the available diagnostic tests. But, before that, cli-nicians have to think about histoplasmosis and consider this clinical entity in their differential diagnosis; manytimes the diagnosis is missed or delayed simply becausehistoplasmosis was not considered. This is particularly truein developing countries, like Brazil, where tuberculosis, ahighly prevalent infection, is always the first, the secondand even the third thought. We thank Dr. George S. Deepe for reviewing themanuscript. The study was partially supported by a FAPERJ E-26/170.308/2002 grant. 145 Histoplasmosis in BrazilQuinet Leimann BC, et al.
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