Case Report

Paracoccidioidomycosis and Tuberculosis in AIDS Patients: Report of ‘IXvo Cases in Brazil Susie A. Nogueira, MD;* M. Julieta Caiuby, MD;* Vkia Vasconcelos, MD;* Mgrcia Halpern, MD;* Carla Gouveia, MD;* Beatriz Thorpe, MD;* Cristiani Ramparini, MD;* Juan M. Pifiero Macieira, MD;? and John S. Lambert, MD*

The acquired immunodeficiency syndrome (AIDS) epi- demic in Brazil is growing rapidly, and although most reported cases are still located in urban areas of the south- east region of the country, the disease is now beginning to spread to rural areas as well.’ In contrast to the high incidence and severity of endemic fungal disease (e.g., histoplasmosis, blastomycosis, and coccidioidomycosis) that has been associated with human immunodeficiency virus (HIV) infection in the United States,2 the association between paracoccidioidomycosis (PBM) (formerly known as South American blastomycosis) and AIDS in Latin America has not been as common as expected3z4 even though PBM is one of the systemic mycoses most fre- quently diagnosed among immunocompetent individu- als in this region. 5,6 Caused by the dimorphic fungus Paracoccidioides brasiliensis, PBM is not uniformly dis- tributed in endemic countries and is most commonly diagnosed in agricultural workers from rural areas who live in the humid tropical and subtropical regions.5,7

According to Marques et al the estimated incidence of PBM in Brazilian AIDS patients in 1992 was 0.09%.* Among the 26 reported cases, there was a 29.4% mor- tality rate. With the current increase in heterosexual trans- mission of HIV and the simultaneous spread of HIV infection to more rural areas in Latin America, it appears likely that we will see an increase in the number of indi- viduals infected concurrently with HIV and I? brasiliensis, who present with PBM as the first manifestation of AIDS1

*Infectious Disease Service and ‘Pathology Department, Hospital Uni- versitdrio Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil; and *University of Maryland Institute of Human Virology, and Johns Hopkins Fogarty International Training Pro- gram, Baltimore, Maryland.

Funded by the Johns Hopkins Fogarty International Training Program, Grant #5D43’IWOOOlO-08.

Address correspondence to Dr. John S. Lambert, The Institute of Human Virology, University of Maryland Medical Center, 725 West Lombard Street, Baltimore, MD 21201.

In a recent review Goldani and Sugar summarized the 27 cases of concurrent infection with HIV and E! brasiliensis that have been reported in the medical lit- erature.3 They stressed that PBM occurs in patients who have advanced AIDS and are not receiving prophylaxis for Pneumocystis carinii with trimethoprim-sulfamethoxa- zole (TMP/SMZ), which is also effective against I? brasiliensis. Because the clinical presentation in infec- tions with P brasiliensis is very similar to that of other opportunistic infections, such as tuberculosis (TB) and Mycobacterium-avium-complex (MAC), as well as that of lymphoma, PBM should be suspected in every AIDS patient from endemic areas.3,11,8-10

The authors describe two cases in which paracoc- cidioidomycosis was found in association with tubercu- losis as the first manifestation of AIDS. Both patients were living in urban areas of Brazil at the time of diagnosis.

CASE REPORTS

Case 1

A 48-year-old male painter, born in Minas Gerais state (in southeastern Brazil), was admitted to the Infectious Dis- ease Service of the University Hospital-Hospital Uni- versit&io Clementino Fraga Filho (HU-CFF)-Universidade Federal do Rio de Janeiro-on 9/23/91 for investigation of a cervical mass. He complained of persistent fever (39°C) without chills for a month and a rapidly growing cervical mass. One week before admission, he noted pain in this area and reported that the mass had developed a fistula and had drained spontaneously. He had no other manifestations except a weight loss of 7 kg in 45 days. On physical examination, he presented with an exten- sive mass in the left cervical and supraclavicular region, axillary and inguinal lymphadenopathy, and hepato- splenomegaly. An infiltrative lesion was also seen in his palate. There were no respiratory, nervous, or cardiovas- cular abnormalities.

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Paracoccidioidomycosis and Tuberculosis in AIDS Patients / Nogueira et al 169

The patient was born in rural Brazil and lived there until the age of 18, when he moved to Rio de Janeiro. He reported that 8 years previously he had had an accident when he received a penetrating wound in the abdomen that had needed surgical treatment; he did not know whether he had received any blood transfusions. He denied homosexual or bisexual activity and the use of intravenous drugs.

His blood profile showed 4700 leukocytes with 2% eosinophils, 15% bands, 57% neutrophils, and 14% lym- phocytes. The Westergren sedimentation rate was 130 mm/h, the hematocrit 29.8%, and the hemoglobin 9.9 g/dL. He was positive for anti-HIV antibody by enzyme- linked immunosorbent assay (ELISA) and immunofluo- rescence. Lung roentgenograms showed a nodular infiltrate in the superior aspect of the right lobe. Abdom- inal ultrasonography revealed hepatosplenomegaly and lymphadenopathy. Computerized abdominal tomography showed hepatosplenomegaly and extensive retroperi- toneal lymphadenopathy.

The patient’s stool examination revealed Strongy- Zoides stev-coralis larvae, and direct microscopy >with KOH of the mucosal lesion and pus obtained from surgical drainage of the cervical mass showed the presence of E! brasiliensis. A blood culture was negative for l? brasilien- sis. Acid-fast bacilli were also seen in the cervical lymph node, and culture of this node grew Mycobacterium tuberculosis.

The patient was treated with thiabendazole, rifampin, isoniazid, and pyrazinamide (RIP) and with amphotericin B (total dose: 1740 mg), and was subsequently given TMP/SMZ with significant clinical improvement. On 3/16/93 he was readmitted with oral candidiasis and hemiparesis resulting from a cerebral vascular accident (diagnosed by cranial computerized tomography). One month later, without evidence of active paracoccid- ioidomycosis or tuberculosis, he was transferred to a com- munity hospital.

Case 2

A 28-year-old male, born in Rio de Janeiro, was admitted to HU-CFF on 4/16/94 to evaluate and treat a draining cervical lymph node and skin lesions. He related that his disease had began 5 months earlier, presenting with fever and cervical lymphadenopathy. At presentation, his HIV- test was positive by ELISA; he had been treated empiri- cally for tuberculosis with RIP in another hospital and had improved clinically with this therapy He had also received TMP/SMZ and zidovudine. Three months later he had recurrence of fever, accompanied by arthralgias and myalgias, and he had noted that the cervical mass was inflamed and had increased in size, and that multiple skin lesions were present. The cervical lymph nodes drained spontaneously 2 months later, at which time he was

Figure 1. Case 2: Cervical lymph node coalescence, local inflam- matory reaction, and fistula formation in left anterior cervical chain.

admitted with lymph node coalescence, an intense local- ized inflammatory reaction, and a ftstula in the anterior cervical region (Figure 1). On the face and arms he also had multiple ulcerated, nonpruritic, infiltrative skin lesions with a central crust. Oral candidiasis was also present. The respiratory tract and cardiovascular system were

Figure 2. Case 2: Chest roentgenograph demonstrates discrete bilat- eral perihilar infiltrates.

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Figure 3. Case 2: Hyperplastic epidermis, granulomatous reaction in the dermis, fungal elements, and multinucleated giant cells in a skin biopsy specimen. (Hematoxylin eosin stain: original magnification X 100).

within normal limits, and no hepatosplenomegaly was present. He denied any use of injection drugs or blood transfusions but reported homosexual behavior. He also reported a herpes zoster infection a year before his admis- sion to HU-CFF Hospital.

The patient’s blood profne showed 3700 leukocytes, with 4% bands, 58% neutrophils, and 30% lymphocytes, a Westergren sedimentation rate of 120 mm/h, hematocrit of 28.3%, and hemoglobin level of 9.2 g/dL. He was pos- itive for anti-HIV antibody by ELISA and immunofluores- cence. Lung roentgenograms showed a discrete bilateral perihilar infiltrate (Figure 2); abdominal ultrasonography showed no abnormalities. The VDRL test was nonreactive; stool samples contained no parasites, and a PPD test was also nonreactive. A needle aspirate of the cervical mass showed l? brasiliensis on direct microscopy with KOH and in culture. Skin biopsy and sputum also were posi- tive for P brasiliensis. Mycobacterium tuberculosis was cultured from the lymph node secretions and from the sputum, Histopathologic examination of the skin biopsy

specimen revealed the presence of fungal elements (Fig- ure 3) a hyperplastic epidermis, a granulomatous reaction in the dermis, and multinucleated giant cells. He was treated with RIP for 9 months and with amphotericin B (accumulated dose: 2275 mg); later he was treated with itraconazole, 100 mg per day for 1 year. He improved and is now receiving prophylactic TMP/SMZ with no signs of active tuberculosis or paracoccidioidomycosis at 1 year of follow-up.

DISCUSSION

These two Brazilian patients showed the concomitant presence of two prevalent granulomatous diseases in asso- ciation with HIV infection. In both cases the first mani- festation of AIDS was the clinical presentation of the subacute form (juvenile type) of paracoccidioidomyco- sis. This systemic mycosis has been classified on the basis of its epidemiologic, immunopathologic, and clinical aspects into two polar forms: the juvenile type or sub- acute form, with lymphatic/hematogenous dissemination and characteristic involvement of the phagocytic macro- phage system, mainly in patients under 30 years of age (the anergic or negative pole); and the adult type or chronic form, in which illness usually appears directly from a primary focus or from a quiescent focus after a period of latency.8 This chronic form is slowly progres- sive, with frequent pulmonary lesions (> 90%) and usu- ally affects patients over 30 years of age, with a past history of living and working in a rural area (the hyper- ergic or positive po1e).8,11

The first patient, a 48-year-old man, probably acquired P brasiliensis while he lived in the countryside, working on the land. As a result of HIV-related immunosuppres- sion, he presented with an endogenous reactivation of the mycosis, but the clinical features of this systemic mycosis were more characteristic of the subacute than the chronic form, with high fever, rapid progression, hepatosplenomegaly, and severe weight loss, which is not commonly seen in the chronic form. However, these signs could have been attributed to the associated dissemi- nated tuberculosis that was also present, because both diseases may have similar clinical presentations. Two characteristic signs of the chronic form that was found in this patient were oral mucosal lesions and cervical lymph node enlargement with flstula formation. The radio- logic picture also was more suggestive of tuberculosis than of paracoccidiomycosis, because the lesions in the lungs in this disease are generally reticulonodular infil- trates, asymmetric, and located in the lower lobes; thus, the location of lesions in the right upper lobe in this patient was more suggestive of tuberculosis.

The second patient had a presentation typical of the juvenile (subacute form) type of paracoccidioidomyco- sis, with involvement of the reticuloendothelial system

Paracoccidioidomycosis and Tuberculosis in AIDS Patients / Nogueira et al 171

and the skin; however, the evolution of this disease was somewhat delayed and less severe, probably because of the TMP/SMX prophylaxis for PCP3 Similar results have been noted in other AIDS patients4

Both patients had fistulae and drainage from the cer- vical lymph nodes, findings that are characteristic of both tuberculosis and paracoccidioidomycosis. Although there were no complaints related to the respiratory tract, and few roentgenographic abnormalities were found1 on chest films (see Figure 2) both the fungus and mycobacteria were detected in the sputum of the second patient. As with tuberculosis, there is evidence that PBM is also acquired through respiratory tract exposure.12a13 The habi- tat of P brasiliensis is exogenous and its etiologic microniche remains unknown. The disease is not spread by direct person-to-person contact, and the infection pre- sumably results from inhalation of infective conidia that reach the distal portion of the lungs, where they trans- form into yeast cells. 5,12 Although the disease is not com- mon in the metropolitan area of the city of Rio de Janeiro, we have seen other patients with PBM from this area. In a survey performed by Wanke in Rio de Janeiro in 1976,‘* 15% of the sampled population was reactive to the para- coccidioidina intradermal skin test as compared to 60.6% found in a similar survey in a rural area of the same state.15

The diagnosis of PBM is easily made if the clinician looks by direct microscopy for fungus in the sputum, in the pus from affected lymph nodes, and in specimens from skin or mucosal lesions. Such materials usually show many yeast forms of P brasiliensis. Therefore, diagnosis is not a problem, even in the absence of sophisticated laboratory resources. l1

Paracoccidioidomycosis is commonly associated with strongyloidiasis. A previous study among 144 cases of paracoccidioidomycosis noted a prevalence of 32.4% for this helminthic disease.16 The association of PBM with tuberculosis is also not uncommon in Brazil. The fre- quency of tuberculosis was 8.9% in 112 non-AIDS patients with PBM.” This disease must be routinely sought in any patient with lymphadenopathy because it is so highly prevalent in developing countries, especially among AIDS patients. Tuberculosis is the third most common oppor- tunistic infection among the reported AIDS cases in Brazil, being surpassed in frequency only by candidiasis and I! carinii.‘J8

The two patients reported responded well to anti- fungal treatment, in contrast to the high lethality previ- ously reported for cases of PBM and HIV co-infection. In the cases reported in the literature to date, none of the patients had a concomitant TB infection. Our patients received therapy with amphotericin B (total doses: 30-50 mg/kg), the recommended regimen for treating severe and disseminated PCM, followed by maintenance therapy with TMP/SMX or azole derivatives.7.11,19

As the AIDS epidemic in Brazil matures and spreads throughout the country, from urban to rural regions, there

will likely be increased numbers of cases of “emerging” and “re-emerging” endemic diseases, such as paracoccid- ioidomycosis, tuberculosis, Kala-azar, Chagas disease, and others. Clinicians must be prepared to recognize atypical presentations of common endemic diseases, since early diagnosis and appropriate therapy may result in an improved clinical response, longer survival, and better quality of life for patients.

ACKNOWLEDGMENTS

We thank Dr. Bodo Wanke, Evandro Chagas Hospital, Rio de Janeiro, Brazil, for reviewing the manuscript. We thank Debora McClelland, Kimberley M. Collins, Bertha Carter, Martin Blair, and Theresa O’Brocki, Baltimore, MD, for secretarial support and for proofing the manuscript.

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