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Contribution to the Natural History of Paracoccidioidomycosis: Identication of the Primary Pulmonary Infection in the Severe Acute Form of the Disease A Case Report
Gil Benard,1 Jorge Kavakama,3 Maria J. S. Mendes-Giannini,5 Adriana Kono,4 Alberto J. S. Duarte,1 and Maria A. Shikanai-Yasuda2,4 Laboratories of Medical Investigation in 1Dermatology and Immunodeciencies and 2Immunology, and Divisions of 3Radiology and 4Infectious and Parasitic Diseases, University Hospital, Sao Paulo Medical School, Sao Paulo, and 5Department of Clinical Analyses, School of Pharmaceutical Sciences, Sao Paulo State University, Araraquara, Sao Paulo, Brazil

Several aspects of the pathogenesis of paracoccidioidomycosis (PCM) have not yet been fully claried. We describe a patient with an overwhelmingly acute form of PCM who presented with clinically apparent pulmonary infection that spontaneously subsided while yeast cells disseminated systemically. This case may help to explain the paradox of the absence of pulmonary involvement in the acute disseminated form of PCM. Patients with paracoccidioidomycosis (PCM) usually become infected with Paracoccidioides brasiliensis early in life, while living in rural or periurban areas of endemicity. Initially, the infection is apparently subclinical, and individuals may remain infected throughout life without ever developing PCM (i.e., healthy infected persons), or they may develop PCM years or even decades after the acquisition of infection (i.e., patients with the chronic form of PCM) [1]. The portal of entry of P. brasiliensis is the lung, where a self-limited, focal inammatory parenchymal process that results in enlargement of the draining lymph nodes, much like Ghon primary lesion in tuberculosis, is assumed to occur [2]. Thus, although, on the basis of current knowledge regarding
Received 12 August 2004; accepted 6 September 2004; electronically published 6 December 2004. Reprints or correspondence: Dr. Gil Benard, Laboratorio de Investigacao Medica em Dermatologia e Imunodeciencias, Av. Dr. Eneas de Carvalho Aguiar 500, 3 . andar, Sao Paulo, Brazil, CEP: 05403-000 (mahong@usp.br). Clinical Infectious Diseases 2005; 40:e14 2004 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4001-00E1$15.00

the pathogenesis of PCM, one can predict that primary pulmonary lymph node complex or primary pulmonary lesion should occur in patients who develop the acute form of PCM, this clinical scenario has very rarely been reported. One possible reason is that patients generally are seen after the initial focal inammation has resolved and that residual lesions associated with PCM, in contrast to those associated with histoplasmosis or coccidioidomycosis, seldom calcify. Only 3 cases of primary pulmonary complex lesions have been retrospectively diagnosed in older patients on the basis of anatomicopathological ndings [35]. There are also only a few reports of younger individuals who have presented with a pulmonary syndrome resembling a primary pulmonary lymph node complex [6 8]. It has been shown that even patients who have the acute form of PCM with no respiratory symptoms and with normal ndings on chest radiographs may have their lungs colonized with the fungus [9]. Hilar enlargement alone has occasionally been seen on the chest radiographs of patients with the acute form of PCM [10]. Consequently, how the acute form of PCM evolves from putative primary lung lymph node complex to severe disseminated disease that usually spares the lungs remains elusive. The following case report illustrates how the initial pulmonary invasion may evolve and spontaneously regress while the yeast disseminates systemically through the lymphohematogenous route. Case report. At the end of July 2003, a 41-year-old patient complained of experiencing a sudden chest pain, which occurred 1 month after he labored in brushwood where armadillo burrows were located. Bacterial pneumonia was diagnosed at the local health center, and the patient was treated accordingly. The patient experienced no lessening of his pain, and, 1 week after treatment, disseminated cutaneous nodules, fever, weakness, and malaise developed. A biopsy of 1 of the nodules revealed the presence of a granulomatous inammation around typical P. brasiliensis yeast cells. The patient was then referred to our service on 12 September. The 3 chest radiographs that had been obtained initially at the local health center in July were reviewed. The radiograph obtained at the rst visit revealed thickening of the perihilar peribronchovascular interstitium, a gross reticulonodular pulmonary inltrate with the same distribution pattern as that noted for the thickening of the perihilar peribronchovascular interstitium, and bilateral enlarged perihilar lymphadenopathy (gure 1A). The radiograph obtained 1 week after the rst visit revealed the same ndings. The third radiograph, which was obtained 15 days after the second raBRIEF REPORT CID 2005:40 (1 January) e1

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Figure 1. A, Chest radiograph (obtained at the start of development of paracoccidioidomycosis) showing thickening of the perihilar peribronchovascular interstitium, a gross reticulonodular inltrate with the same distribution pattern as that noted for the thickening of the perihilar peribronchovascular interstitium, and bilaterally enlarged perihilar lymphadenopathy. B, Chest radiograph (obtained 3 weeks after the radiograph shown in panel A was obtained) showing persistence of bilaterally perihilar lymphadenopathy but spontaneous and substantial regression of the perihilar peribronchovascular interstitium lines and of the gross reticulonodular inltration. C and E, CT scans of the lung (obtained 1 week after admission of the patient to our service in September 2003) showing thickening of the interlobular septa and peribronchovascular interstitium, as well as a few dispersed nodules (diameter, !0.5 cm). D and F, CT scans (obtained at the same slice level in March 2004) showing disappearance of the abnormalities and no residual brosis.

diograph was obtained, showed that the perihilar lymph nodes were unchanged but the parenchymal changes had signicantly subsided. At the time of admission to our service, the radiological ndingsthat is, prominent lymphadenopathy with practically unaffected parenchymaremained unchanged (gure 1B).
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However, in addition to presenting with cutaneous nodules and other early symptoms, the patient presented with hepatomegaly 5 cm below the costal margin and moderate dyspnea. Treatment with sulfadiazine, 6 g/day, was started. A CT scan revealed severe involvement of the pulmonary lymphatic system, which was characterized by thickening of the

interlobular septa and peribronchovascular interstitium; this contrasted with the relatively mild involvement of the pulmonary parenchyma, which showed only a few, dispersed nodules that were !0.5 cm in diameter (gure 1C and 1E). A small pleural effusion was also noted. CT performed 2 weeks later revealed clearing of the thickened peribronchovascular interstitium and interlobular septa, as well as the development of a massive pleural effusion with passive pulmonary collapse. The scarce parenchyma nodules had completely cleared, but the mediastinal and perihilar lymph nodes remained enlarged. MRI of the abdomen revealed hepatosplenomegaly and disseminated lymphadenopathy, with many lymph nodes demonstrating central necrosis and liquefaction. At the time that MRI was performed, the patient developed severe respiratory failure and required mechanical ventilation in the intensive care unit. Two weeks later, the patients respiratory condition had improved, and CT and MRI were performed again. CT revealed signicant reduction in the severity of perihilar lymphadenopathy and pleural effusion, as well as persistence of some collapsed basal-posterior areas of the parenchyma. MRI showed the same abnormalities that were revealed by the previously performed MRI, in addition to the presence of ascites. On 24 October, the patient was discharged from the hospital while still receiving sulfadiazine therapy, but he now was eupneic and was mostly clear of ascites. His general condition continued to improve, although he was still subject to intermittent bouts of fever. A new CT scan of the lungs revealed absence of pleural effusion and almost complete regression of the lymphadenopathy. The previous pulmonary lymphatic system alterations and the mild parenchymal nodules had disappeared without residual brosis (gure 1D and 1F), which is a common nding in the lungs of patients with the chronic form of PCM [2]. Improvement in the appearance of the abdominal lesions was also noted, but the disease remained active, as supported by the persistence of lymph nodes with central necrosis and hepatosplenomegaly. Up to the time of the last visit, which occurred in July 2004, the patient was still receiving sulfamide therapy. In parallel, the patients wife and 9 other healthy adults, who live very close to him and who have also worked in the local elds, were examined for exposure to P. brasiliensis. Not surprisingly, 7 of the adults had a strong (stimulation index, 110) lymphocyte proliferative response to the main fungusspecic antigen, the 43-kDa glycoprotein, as measured by [3H]-thymidine uptake, and 1 adult had a slight (stimulation index, 3.8) lymphocyte proliferative response to the antigen; only 2 of the 10 adults did not have a lymphocyte proliferative response to the antigen [11]. As expected for healthy infected persons [1], antiP. brasiliensis antibody titers, as determined by ELISA, were below the cutoff value (1:100) for the 9

healthy adults, whereas the patients serum exhibited high titers (1:640). Discussion. The ndings reported here indicate that P. brasiliensis preferentially affects the pulmonary lymphatic system, causing mild and self-limited alterations in the lung parenchyma during the initial phase of PCM, even in the presence of an overwhelming infection with a large fungal burden. The present case report also illustrates that PCM may evolve rapidly (i.e., in a few weeks) in a host who is susceptible to the infection. The patient, who was HIV seronegative and who was in good health until the time that he developed the mycosis, had no history suggestive of immunosuppression. It is likely that the fungus was present in the environment and that the infection consequently was acquired in the neighborhood, because the mononuclear cells of 8 of the 10 healthy people who were living close to the patient (and who had similar habits) responded to the P. brasiliensisspecic antigen. In contrast to the patient, these 8 people developed a cellular immune response that was able to control the infection. We have shown that, unlike healthy infected persons, patients with severe PCM do not have a lymphocyte proliferative response to the specic antigen [11]. The patient described in the present report had respiratory failure, despite the relatively slight initial changes demonstrated by radiography. This was probably the result of the progressive involvement of the pulmonary lymphatic system (as revealed by high-resolution CT), which resulted in thickening of the lymphatic vessels, increased intralumen pressure, and obstruction of the lymphatic ow. Such abnormalities may contribute signicantly to the impairment of gas exchange and to the patients dyspnea, in a fashion similar to the pathogenesis of respiratory failure seen in association with carcinomatous lymphangitis [12]. The increased intralumen pressure was apparently compensated by the development of a large pleural effusion, because the latter coincided with disappearance of the radiological thickening of the peribronchovascular lines. In lesssusceptible individuals with less-severe illnesses, this pulmonary infection is probably subclinical, and the yeast spreads to other organs, leaving the lungs almost unaffected. The involvement of the pulmonary lymphatic system that occurred in the case patient described in the present report was much more prominent than that usually reported among patients with acute PCM, but it tended to remain self-limited. Moreover, the disease process seen in the lungs of patients with the acute form of PCM seemed to be different from that seen in the lungs of patients with the chronic form of PCM. Although the inammatory process almost always subsides in patients with chronic PCM, leaving marked residual brosis, the specic pneumonitis resolved without radiologically apparent sequelae in our case patient. Interestingly, Tuder et al. [13] have shown that, in patients with chronic PCM, pulmonary brosis is associated mainly with
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the progressive cicatrization of the granulomas and, probably, to a lesser degree, with the presence of fungi. More-mature granulomas were associated with dense brosis, whereas lessmature granulomas were associated with peripheral reticulin proliferation. Furthermore, in these patients, the pattern of brosis followed that of the lymphatic distribution, which suggests that it derived from a chronic granulomatous lymphangitis. The early radiographic ndings for the patient described in the present report are compatible with the presence of alveolar foci of inammation and lymphatic involvement. We speculate that these features represent the inammatory foci around the inhaled fungus and their subsequent lymphatic dissemination. Because patients with the acute form of PCM have a profoundly depressed immune response and loose granuloma formation [1], such granulomas would not mature and evolve to dense brosis. This may explain the lack of residual brosis in patients with the acute form of PCM, for whom pulmonary involvement is probably restricted to the initial phase of the disease and remains underdiagnosed because of the absence of clinical or radiological evidence.

Acknowledgments
We thank Soraya Ogusuku for technical assistance and Marcello F. Franco and Ronaldo B. Gryschek for critical advice. Financial support. Larboratorios de Investigacao Medica do Hospital das Clnicas (grant to G.B., A.J.S.D., and M.A.S.-Y.) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (grants #01/11415-0 [to G.B. ` and A.J.S.D.] and #02/07306-3 [to G.B. and M.J.S.M.-G.]). G.B. and A.J.S.D. are senior investigators of the Brazilian Science Research Council. Potential conicts of interest. All authors: no conicts.

2. Londero AT. Paracoccidioidomicose: patogenia, formas clnicas, man ifestacoes pulmonares e diagnostico. Jornal de Pneumologia 1986; 12: 4160. 3. Angulo-Ortega A. Calcications in paracoccidioidomycosis: are they the morphological manifestation of subclinical infections [scientic publication 254]? In: Proceedings of the First Pan American Symposium in Paracoccidioidomycosis (Medellin, Colombia). Washington, DC: Pan American Health Organization, 1972:12933. 4. Severo LC, Geyer GR, Londero AT, Porto NS, Rizzon CF. The primary pulmonary lymph node complex in paracoccidioidomycosis. Mycopathologia 1979; 67:1158. 5. Melo IS, Londero AT. Spontaneously resolving pulmonary lesions in paracoccidioidomycosis: case report and review. Mycopathologia 1983; 82:579. 6. Ramos CD, Londero AT, Gal MC. Pulmonary paracoccidioidomycosis in a nine year old girl. Mycopathologia 1981; 74:158. 7. Wanke B, Andrade EM, Lima Neto JA, Ferreira da Cruz MF. Paracoccidioidomicose pulmonar assintomatica e regressiva, com posterior disseminacao: relato de um caso. Rev Soc Bras Med Trop 1983; 16: 1627. 8. de Campos EP, Bertoli CJ, Barbosa KS. Pulmonary lymph node in acute juvenile paracoccidioidomycosis (a case report) [in Portuguese]. Rev Soc Bras Med Trop 1992; 25:195200. 9. Restrepo A, Trujillo M, Gomez I. Inapparent lung involvement in patients with the subacute juvenile type of paracoccidioidomycosis. Rev Inst Med Trop Sao Paulo 1989; 31:1822. 10. Londero AT, Rios-Goncalves AJ, Terra GMF, Nogueira SA. Paracoc cidioidomycosis in Brazilian children: a critical review (19111994). Arquivos Brasileiros de Medicina 1996; 70:197203. 11. Benard G, Mendes-Giannini MJ, Juvenale M, Miranda ET, Duarte AJ. Immunosuppression in paracoccidioidomycosis: T cell hyporesponsiveness to two Paracoccidioides brasiliensis glycoproteins that elicit strong humoral immune response. J Infect Dis 1997; 175:12637. 12. Fraser RS, Muller NM, Colman N, Pare PD. Secondary neoplams. In: Fraser RS, Muller NM, Colman N, Pare PD, eds. Diagnosis of disease of the chest. 4th ed. Vol II. Philadelphia: W. B. Saunders, 1999: 1381417. 13. Tuder RM, el Ibrahim R, Godoy CE, De Brito T. Pathology of the human pulmonary paracoccidioidomycosis. Mycopathologia 1985; 92: 17988.

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References
1. Franco MF, Mendes RP, Moscardi-Bacchi M, Rezkallah-Iwasso MT, Montenegro MR. Paracoccidioidomycosis. Baillieres Clinical Tropical Medicine and Communicable Diseases 1989; 4:185220.

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