História natural do paracoco primariamente identificado no pulmão - 2005-Benard

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BRIEF REPORT • CID 2005:40 (1 January) • e1

B R I E F R E P O R T

Contribution to the Natural History

of Paracoccidioidomycosis:Identification of the Primary Pulmonary Infection in the SevereAcute 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 Immunodeficiencies

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 paracoccidioidomy-

cosis (PCM) have not yet been fully clarified. 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 sys-

temically. 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 liv-

ing in rural or periurban areas of endemicity. Initially, the in-

fection 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 inflammatory

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 Imunodeficiencias, Av. Dr. Eneas de Carvalho Aguiar 500, 3. andar, S ao Paulo,

Brazil, CEP: 05403-000 ([email protected]).

Clinical Infectious Diseases 2005;40:e1–4

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 pul-

monary 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

inflammation 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 diag-

nosed in older patients on the basis of anatomicopathological

findings [3–5]. 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 acuteform of PCM with no respiratory symptoms and with normal

findings 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 re-

mains elusive. The following case report illustrates how the

initial pulmonary invasion may evolve and spontaneously re-

gress while the yeast disseminates systemically through the

lymphohematogenous route.

Case report. At the end of July 2003, a 41-year-old patientcomplained of experiencing a sudden chest pain, which oc-

curred ∼1 month after he labored in brushwood where ar-

madillo burrows were located. Bacterial pneumonia was di-

agnosed 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 inflammation

around typical P. brasiliensis yeast cells.

The patient was then referred to our service on 12 Septem-

ber. The 3 chest radiographs that had been obtained initially

at the local health center in July were reviewed. The radio-graph obtained at the first visit revealed thickening of the

perihilar peribronchovascular interstitium, a gross reticulo-

nodular pulmonary infiltrate with the same distribution pat-

tern as that noted for the thickening of the perihilar peri-

bronchovascular interstitium, and bilateral enlarged perihilar

lymphadenopathy (figure 1A). The radiograph obtained 1

week after the first visit revealed the same findings. The third

radiograph, which was obtained 15 days after the second ra-



e2 • CID 2005:40 (1 January) • BRIEF REPORT

Figure 1. A, Chest radiograph (obtained at the start of development of paracoccidioidomycosis) showing thickening of the perihilarperibronchovascularinterstitium, a gross reticulonodular infiltrate with the same distribution pattern as that noted for the thickening of the perihilar peribronchovascularinterstitium, and bilaterally enlarged perihilar lymphadenopathy. B, Chest radiograph (obtained 3 weeks after the radiograph shown in panel A wasobtained) showing persistence of bilaterally perihilar lymphadenopathy but spontaneous and substantial regression of the perihilar peribronchovascularinterstitium lines and of the gross reticulonodular infiltration. C and E, CT scans of the lung (obtained 1 week after admission of the patient to ourservice 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 residualfibrosis.

diograph was obtained, showed that the perihilar lymph nodes

were unchanged but the parenchymal changes had signifi-

cantly subsided.

At the time of admission to our service, the radiological

findings—that is, prominent lymphadenopathy with practically

unaffected parenchyma—remained unchanged (figure 1B ).

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



BRIEF REPORT • CID 2005:40 (1 January) • e3

interlobular septa and peribronchovascular interstitium; this

contrasted with the relatively mild involvement of the pul-

monary parenchyma, which showed only a few, dispersed nod-

ules that were !0.5 cm in diameter (figure 1C and 1E ). A small

pleural effusion was also noted. CT performed 2 weeks later

revealed clearing of the thickened peribronchovascular inter-

stitium and interlobular septa, as well as the development of a

massive pleural effusion with passive pulmonary collapse. Thescarce 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 demonstratingcen-

tral necrosis and liquefaction. At the time that MRI was per-

formed, the patient developed severe respiratory failure and

required mechanical ventilation in the intensive care unit.

Two weeks later, the patient’s respiratory condition had im-

proved, and CT and MRI were performed again. CT revealed

significant reduction in the severity of perihilar lymphadenop-

athy and pleural effusion, as well as persistence of some col-lapsed 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 eup-

neic and was mostly clear of ascites. His general condition

continued to improve, although he was still subject to inter-

mittent 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 sys-

tem alterations and the mild parenchymal nodules had dis-

appeared without residual fibrosis (figure 1D and 1F ), which

is a common finding in the lungs of patients with the chronic

form of PCM [2]. Improvement in the appearance of the ab-

dominal 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 patient’s wife and 9 other healthy adults,

who live very close to him and who have also worked in the

local fields, 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 fungus-

specific 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], anti–P. brasiliensis antibody titers, as determined

by ELISA, were below the cutoff value (1:100) for the 9

healthy adults, whereas the patient’s serum exhibited high

titers (1:640).

Discussion. The findings reported here indicate that P.

brasiliensis preferentially affects the pulmonary lymphatic sys-

tem, causing mild and self-limited alterations in the lung pa-

renchyma 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. brasiliensis –specific 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 specific 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 obstruc-

tion of the lymphatic flow. Such abnormalities may contribute

significantly to the impairment of gas exchange and to the

patient’s dyspnea, in a fashion similar to the pathogenesis of

respiratory failure seen in association with carcinomatous lym-phangitis [12]. The increased intralumen pressure was appar-

ently compensated by the development of a large pleural ef-

fusion, because the latter coincided with disappearance of the

radiological thickening of the peribronchovascular lines. In less-

susceptible 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 pa-

tients with acute PCM, but it tended to remain self-limited.

Moreover, the disease process seen in the lungs of patients withthe acute form of PCM seemed to be different from that seen

in the lungs of patients with the chronic form of PCM. Al-

though the inflammatory process almost always subsides in

patients with chronic PCM, leaving marked residual fibrosis,

the specific pneumonitis resolved without radiologically ap-

parent sequelae in our case patient.

Interestingly, Tuder et al. [13] have shown that, in patients

with chronic PCM, pulmonary fibrosis is associated mainly with



e4 • CID 2005:40 (1 January) • BRIEF REPORT

the progressive cicatrization of the granulomas and, probably,

to a lesser degree, with the presence of fungi. More-mature

granulomas were associated with dense fibrosis, whereas less-

mature granulomas were associated with peripheral reticulin

proliferation. Furthermore, in these patients, the pattern of

fibrosis followed that of the lymphatic distribution, which sug-

gests that it derived from a chronic granulomatous lymphan-

gitis. The early radiographic findings for the patient describedin the present report are compatible with the presence of al-

veolar foci of inflammation and lymphatic involvement. We

speculate that these features represent the inflammatory foci

around the inhaled fungus and their subsequent lymphatic dis-

semination. 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 fibrosis. This may explain the lack of residual fibrosis

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 Clınicas (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 conflicts of interest. All authors: no conflicts.

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História natural do paracoco primariamente identificado no pulmão - 2005-Benard