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The acute juvenile type is characterized by a rapid course and marked involvement of the reticuloendothelial system (spleen, liver, lymph nodes, and bone marrow). The cell-mediated immune function is severely depressed and runs a rapid course. In the absence of specific therapy, mortality is high.4 This form of the disease is the most severe and has the worst prognosis.2,3,5
Among the laboratory tests performed, the following appear important: hematocrit 30.2%, hemoglobin 9.4% g/dL, white blood cell count 17,000 mm3, 48.5% neutrophils and 40.5% eosinophils, erythrocyte sedimentation rate 120 mm, and hypoalbuminaemia. Hepatic and renal functions were normal, as were stool examinations for enteroparasites. Plasma cortisol (8 h 00) was 21 µg/dL (normal range: 7.9–31.7 (µg/dL). Anti-HIV antibody was negative by enzyme-linked immunosorbent assay. The patient’s hepatitis C serology showed VCH RNA 2.0 (bDNA) using the QUANTIPLEXTEC: 0.816 Meq/mL or million copies/mL (normal range:< 200.000 copies/mL). Lung x-rays were normal (Figure 1a
) and PPD-negative, but lung x-ray repeated 3 weeks later showed minimal trabeculo-nodular lesions, with mild mediastinal widening (Figure 1b). Abdominal CT scan showed hepatosplenomegaly and mesenteric, perihepatic, and celiac adenopathies. Biopsy of the bone marrow (Figure 2a) and the left inguinal node, both stained with hematoxylin and eosin (H&E), revealed granulomas with abundant multiple budding yeasts, typical of P. brasiliensis (Figure 2b). Biopsy of the liver with the application of H&E and the Grocott method showed granulomatous tissue reaction compatible with paracoccidioidomycosis and mild hepatitis C activity, demonstrated by occasional binucleation of hepatocytes, portal inflammation of mononuclear cells with few lymphoid follicles, slight-to-moderate disruption of bile canaliculi with focal alteration of limitant trabecula and sinusoidal congestion, most importantly in mild zonal regions (Figure 2c,d).
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), making necessary thoracotomy and tube drainage. P. brasiliensis was visualized in the pleural liquid. The pleural liquid values were: pH 7.34, glucose 83 mg/dL, protein 6.2 g/dL, LDH 105 UI/L amylase 15 UI/L, positive Rivalta test6 (a qualitative method looking for proteins in exudates of inflammatory origin), cell count 1,400 mm3, 100 polymorphonuclear leukocytes and 1,300 mononuclear leukocytes. AMB administration was increased to 50 mg/day and combined with 400 mg/day of itraconazol. This was continued with a cumulative dose of 2 g AMB for 6 months. The response was favorable, showing a reduction in the number of precipitating lines from four to one. No recurrence of the disease was observed during one-year follow-up. The patient had hepatitis C and showed involvement of the reticuloendothelial system, eosinophilia, blood culture positive for P. brasiliensis, compromise of other systems such as ocular globe, and four bands to P. brasiliensis by the double immunodiffusion test, with an aggressive course of disease. These findings and clinical manifestations support the diagnosis of an atypical acute juvenile form of paracoccidioidomycosis. Even though the onset of an acute form is difficult to predict because of the lack of knowledge about the disease, some of these characteristics may mark the severe course of the disease and serve as prognostic indicators.7
Moreover, paracoccidioidomycosis is quite often associated with other diseases, such as tuberculosis, malaria, Chagas’ disease, leishmaniasis, and malignancies.1,2 In some ways, paracoccidioidomycosis also may be an opportunistic infection but not in the same manner as occurs in industrialized countries. The underlying diseases and debilitating factors there are different from those among rural populations in the tropics, where malnutrition and parasitic diseases with anemia prevail and lead to the opportunistic infections. In this context, as far as we know, this is the first report of paracoccidioidomycosis in association with hepatitis C.
The cellular immune response based on the interplay between CD4 helper cells and CD8 cytotoxic T cells is important in viral clearance. The hepatitis C viral infection is controlled by both cytotoxic T cells and cytokines produced by the T cells, which directly inhibits viral replication. We hypothesize that the simultaneous hepatitis C viral and P. brasiliensis infections in our patient may have compromised the Th1 CD4 response as well as the cytotoxic T-cell response, promoting an immunosuppression status and suppression of cell-mediated immune response, as it is well known in immunosuppressed persons.8 It is worth noting that our patient had hepatitis C, which, added to the risk factors of strong smoking and drinking habits, contributed to the severe manifestation of the disease.
Also, this patient showed 40.5% eosinophils with an absolute value of 6.885 mm3 in peripheral blood. He had no evidence of allergic disease or enteroparasites. There is no satisfactory explanation for the high eosinophilia. Eosinophils have long been associated with defense against parasites, and peripheral blood eosinophilia has been suggested as a prognostic indicator. In paracoccidioidomycosis, eosinophilia has been mainly described in children and other young people.9 In the biopsy of our patient’s bone marrow, granulomatous lesions and abundant fungal elements with the characteristic multiple budding of P. brasiliensis were found. The bone marrow involvement, though unusual, is compatible with the juvenile form of this disease and could explain the high eosinophilic values.
P. brasiliensis was isolated by blood culture, which occurs infrequently and is further evidence of miliary hematogenous dissemination that may affect the course of generalized paracoccidioidomycosis with a bad prognosis.
Furthermore, concerning the retinal hemorrhage of the patient’s right eye, even though no histopathologic or direct examination of the lesion could be performed, its disappearance after onset of treatment with AMB suggests that it was due to ocular involvement with the fungus. Ocular primary lesions are rare.10 Of 50 cases described by Belfort et al., 38% had lid lesions, 24% palpebral-conjunctival involvement, 12% conjunctival, and 4% palpebral-conjunctival-corneal.11 Retinal involvement alone or associated with that of other ocular structures (choroid and uvea) has been described even less frequently.12 All the aforementioned entities confirm the need for routine ophthalmologic examination, including complete fundoscopy, in all patients with paracoccidioidomycosis, as it may indicate the severity of the course of the disease.
Pleural effusion in paracoccidioidomycosis, both acute and chronic, also is uncommon, although some authors have reported a few cases. Concalves et al. found only 1.23% out of 80 patients with acute pleural effusion. Machado and Miranda observed 3.55% out of 338 cases, and Morcelli 3.8% out of 52. Martins observed 2.5% out of 121 patients, Andrade reported 7 out of 55 (13%) and was able to isolate P. brasiliensis in one of them. Valle, after studying 153 chest x-rays of patients with paracoccidioidomycosis, reported four cases with pleural effusion, three unilateral and one bilateral.13–16 The amount of fluid was always small. An exceptionally large pleural effusion was found in our patient. This is, as far as we know, the second reported case of severe juvenile type paracoccidioidomycosis with such an effusion. The presence of several bands by the IDD method is correlated with the severity of the disease. Reduction of the number of precipitating lines during treatment is correlated with the patient’s improvement, giving the test a prognostic value.1,2 Therefore, it is advisable to perform control tests before, during, and after treatment to evaluate the evolution of the disease.
Despite the signs of a poor prognosis, our patient’s clinical response was favorable.
We have observed previously that, as in this case, after the AMB dosage was lowered because of the development of acute anemia and hypokalemia, relapse occurred, with the evolution of the disease worse than the initial state. After increasing the doses of AMB to 50 mg/day again, combined with itraconazole, the outcome was favorable. We do not have a reasonable explanation for this phenomenon. However, we think it is important to maintain the dosage of AMB and, in severe cases like this one, combine it with another antifungal drug like itraconazole, which proved to be very useful in the treatment of paracoccidioidomycosis.
In our experience, itraconazole is the drug of choice for treatment of this disease, and AMB should be used only in immunosuppressed patients or when the patient’s condition is serious enough to require intravenous treatment. Intravenous itraconazole is not available in Venezuela.
Received April 9, 2002. Accepted for publication October 28, 2002.
Acknowledgments: The authors wish to thank the American Committee on Clinical Tropical Medicine and Travelers’ Health (ACCTMTH) for assistance with publication expenses.
Authors’ addresses: Antonella Pellegrino and Israel Montes de Oca, Internal Medicine, Hospital Universitario de Caracas, UCV, Venezuela. Claudia Hartung de Capriles, Sylvia Magaldi, and Celina Pérez, Sección de Micología Médica, Instituto de Medicina Tropical, UCV, Venezuela. Marìa Elena Ruiz, Instituto Anatomía Patológica, UCV, Venezuela. Sofía Mata-Essayag, Apartado Postal 47423, Caracas 1041, Venezuela, Fax: 58-212-662-10-82, E-mail: somae50{at}hotmail.com
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