© 2010 ISHAM DOI: 10.3109/13693780903330563

Medical Mycology May 2010, 48, 542–545

Fatal acute respiratory distress syndrome in a patient with paracoccidioidomycosis: fi rst case report

GIL BENARD*, ANDRÉ NATHAN COSTA†, JULIANA RAVANINI‡, SILVIA GOULART§, ELISABETH LIMA NICODEMO§, CARMEN SÍLVIA VALENTE BARBAS † & LUIZ FERNANDO FERRAZ DA SILVA‡

*Laboratory of Dermatology and Immunodefi ciencies, and Laboratory of Medical Mycology, Dermatology Division, Hospital das Clinicas, University of São Paulo Medical School, †Pulmonary Division – Heart Institute (InCor) – University of São Paulo Medical School, ‡Department of Pathology, University of São Paulo Medical School, & §Infectious Diseases Division, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil

Paracoccidioidomycosis is a systemic mycosis that is usually acquired early in life by inhalation of conidia which convert in the lungs into yeast forms; these in turn trig-ger an inflammatory process. This mycosis may appear as an acute/subacute form or a chronic, adult form. Acute/subacute presentations can be observed in children and young adults, with the reticuloendothelial system frequently involved but the lungs are usually spared or present with mild clinical or radiological alterations. Acute respiratory distress syndrome (ARDS), an extensive dysfunction of the lungs alveolar-capillary bar-rier has occasionally been observed in other endemic mycoses such as coccidioidomy-cosis, cryptococcosis, histoplasmosis and blastomycosis. We describe the first patient with acute paracoccidioidomycosis who developed fatal ARDS accompanied by mul-tiple organ injuries. The basis of the rarity of this entity in patients with paracoccidi-oidomycosis, as well as the reasons that may have lead to the development of ARDS in this patient are discussed.

Keywords paracoccidioidomycosis , acute respiratory distress syndrome , respiratory failure , immune dysregulation

affected in the AF, whereas the lungs are the most involved

organ in the CF [ 1 ]. Nevertheless, the Acute Respiratory

Distress Syndrome (ARDS) has never been described in

patients with either form of PCM.

We present an AF PCM case involving a patient with

multiple and severe reticuloendothelial system injuries, but

only slight lung involvement, who developed ARDS. We

discuss the immunological background for this uncommon

but fatal presentation.

Case report

A 22-year-old, white, non-smoker and previously healthy

man, presented with a 5-month history of weakness and

myalgia, adenopathies, night sweats, loss of 7 kg and non-

productive cough that became productive in the last month.

He lived in São Paulo city but regularly visited a nearby

rural area on weekends. A prior investigation at a local

Received 20 July 2009; Received in fi nal revised form 29 August 2009;

Accepted 13 September 2009

Correspondence: Gil Benard, R Dr Eneas de Carvalho August 470,

Instituto de Medicina Tropical (IMT), Cerqueira Cesar, São Paulo,

SP, 05403-903 Brazil. Tel: +55 11 30617457; fax: +55 11 30817190;

Email: mahong@usp.br

Introduction

Paracoccidioidomycosis (PCM) is an endemic systemic

mycosis that is acquired early in life after inhalation of

conidia produced by the fungus Paracoccidioides brasil-iensis . The fungus is probably present in the soil of rural

areas. The disease may develop soon after infection, as an

acute-sub acute form (AF), or many years later, when the

fungus is reactivated from quiescent foci giving rise to the

chronic form (CF) [ 1 ]. Although the lungs are the portal of

entry of the infection, they are either spared or only slightly

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© 2010 ISHAM, Medical Mycology, 48, 542–545

Paracoccidioidomycosis and adult respiratory distress syndrome 543

health service was inconclusive as to the disease’s etiol-

ogy, although an abdominal ultrasonography disclosed a

peripancreatic adenomegaly. On the patient’s first consul-

tation in our service, he was febrile and tachycardic (108

beats per minute), blood pressure was 110/65 mmHg, and

he had generalized superficial adenopathies and hepa-

tosplenomegaly. Lung examination was normal, as was the

X-ray. Chest computed tomography (CT) showed incon-

spicuous diffuse ground glass micronodular infiltrates and

septal thickening, mediastinal and axilar adenomegaly,

and several lytic bone lesions (Fig. 1a,b). In addition,

abdominal CT scan revealed hepatosplenomegaly, multi-

ple adenopathies and lytic bone lesions in L5 vertebra,

ilium and ischium. Laboratory exams revealed mild

leukocytosis with marked eosinophilia (12600/mm3) and

increased IgE. During admittance the patient’s malaise,

fever and abdominal pain persisted. A cervical lymph node

biopsy demonstrated a chronic granulomatous process but

did not reveal any infectious agent on hematoxylin-eosin,

Ziehl-Nielsen, and Groccott stained sections. He then

developed rapidly progressive dyspnea, which progressed

to respiratory insufficiency that required mechanical ven-

tilation. The patient presented a PaO 2 /FIO 2 ratio of 152 at

ICU admission. A chest x-ray at this time showed diffuse

bilateral infiltrates ( Fig. 1c ). Rare P. brasiliensis yeast

cells were then identified in a previously collected sputum

sample. The existence of other infectious agents, including

HIV, and the patient’s use of drugs or gas inhalation were

not found by blood and sputum cultures, serology or ana-

mnesis. The pulmonary artery catheterization ruled out

cardiac dysfunction. The diagnosis of ARDS secondary to

PCM was made, and amphotericin B was initiated. How-

ever, he developed respiratory failure followed by refrac-

tory shock and, despite vasoactive drugs administration

and ventilation protective strategy, he died on the fourth

day of ICU. A complete autopsy was performed and con-

firmed major involvement of reticuloendothelial system,

with vast areas of necrosis and massive infiltration of

P. brasiliensis fungal elements which were identified in HE,

periodic acid-Schiff and Groccott stained material ( Fig.

2a ). Liver histopathology showed granulomatous inflam-

mation mainly in the portal-tract, with the presence of

yeast cells and large areas of necrosis with cellular debris

and a high concentration of inflammatory cells. There was

also bone marrow fungal infiltration with presence of

granulomas. In contrast to the reticuloendothelial system,

there were granulomas in the lungs with scant fungal ele-

ments and a miliary distribution, most circumscribed by a

Fig. 1 CT scan made during initial investigation showing (a) inconspicuous diffuse ground glass micronodular infi ltrate and septal thickening and (b)

mediastinal and axilar adenomegaly (arrows); (c) thoracic X-ray done at admission in the intensive care unit showing diffuse bilateral infi ltrates suggestive

of ARDS.

Fig. 2 Autopsy showing (a) Paracoccidioides brasiliensis yeast cell evidenced by Grocott staining showing multiple sporulation in lymphoid tissue

(1000X); (b) Photomicrograph showing a granulomatous response in lung airway adventitia; (f) Lung with several hyaline membranes within airspaces

and interstitial infl ammation characteristic of ARDS.

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© 2010 ISHAM, Medical Mycology, 48, 542–545

544 Benard et al.

discrete palisade of lymphocytes and eventually eosino-

phils. In addition, there was a diffuse alveolar damage

consisting of edema, intra-alveolar hemorrhage, fibrin

deposition, hyaline membrane formation and diffuse inter-

stitial polimorfonuclear infiltrate and reactive type II

pneumocytes ( Fig. 2b , c ), characteristic of the exudative

phase of ARDS. Foci of bronchopneumonia were absent

and active search for other infectious etiologic agents in

the lung were negative.

Discussion

Acute lung injury (ALI) is characterized by sudden onset

of hypoxemia (PaO2/FIO2 � 300 mm Hg) with bilateral

infiltrates on a frontal chest radiograph which cannot be

explained by the presence of left atrial hypertension [ 2 ].

ALI associated with the most severe hypoxemia (PaO2/FIO2

ratio � 200 mm Hg) is termed acute respiratory distress syn-

drome (ARDS). Various pulmonary and extrapulmonary

insults may lead to ALI/ARDS, most frequently pneumonia

and extrapulmonary sepsis [ 3 ]. Whatever the insult, the pro-

cess involves an excessive amplification of the inflamma-

tory cascade and overproduction of pro-inflammatory

mediators like TNF-α, IL-1β, IL-6, and IL-8, with the con-

sequent uncontrolled activation of the immune system [ 2 ].

ARDS has occasionally been reported in immunoco-

mpetent patients with endemic deep mycoses such as

coccidioidomycosis, blastomycosis, histoplasmosis and

cryptococcosis, with high mortality rates [ 4 – 7 ]. Character-

istically, ARDS developed in the course of a recently acquired

infection, in association with overwhelming pulmonary

involvement, rather than during the chronic phase of the dis-

ease. Moreover, when lung biopsies were available, they

demonstrated massive infiltration by fungal elements.

However, ARDS has never been reported in PCM, even

though the lungs are involved in over 80% of the patients

with its most common chronic presentation. CF results

from reactivation of quiescent foci after long periods (years

to decades) of latency [ 8 ]. Although the lung destruction

usually is extensive in the CF, it evolves gradually, with

areas of fungal invasion and tissue destruction adjacent to

areas where fibrosis and regeneration predominate [ 9 ].

Thus, this allows a certain control of the inflammatory pro-

cess, which probably avoids the unbalance of the immune

response required to trigger ARDS .

In the more severe AF, the inflammatory response is

intense but the lungs are rarely affected [ 1 ]. In these cases,

the cytokine balance is set towards an anti-inflammatory,

Th-2 like, pattern of immune response. There is an over-

production of IL-4 IL-5, IL-10 and TGF- β [ 10 ], the levels

of which decrease during the development of ARDS. This

raises the question of why the infection in our young

patient, with no co-morbidities, developed into a lethal

acute lung injury. The unusual extent and severity of the

necrosis of many reticuloendothelial organs may offer

some hypotheses. Lymph nodes, spleen, liver and bone

marrow were occupied by extensive areas of necrosis,

illustrating the overwhelming, uncontrolled nature of the

inflammatory process. Pathology studies of PCM reveal

that necrosis, when present, is restricted to small areas, the

adjacent areas presenting organized granulomatous

responses with or without caseous necrosis [ 9 ]. Although

the Th-2 pattern of immune response predominates, some

studies show high serum levels of pro-inflammatory cytok-

ines like TNF-α, IL-1 and IL-6 [ 11 ]. In the present case

the extensive necrosis found in the reticuloendothelial sys-

tem can be better explained by an explosion of local pro-

inflammatory cytokines. This uncontrolled cytokine release

would have caused not only the local exacerbated inflam-

matory process, but also, by reaching the circulation, the

inflammatory process of the lungs that resulted in the

development of ARDS. Therefore, considering the contrast

between the massive invasion by P. brasiliensis with its

consequences to the reticuloendothelial system and the

small and apparently controlled inflammatory response to

the scarce fungal elements in the lung, our hypothesis is

that the ARDS was triggered by the systemic inflammatory

response rather than by the lung infection itself, which is

distinct from the ARDS described in other deep endemic

mycoses [ 4 – 7 ]. It would therefore represent the extrapul-

monary model of ALI/ARDS that occurs as a result of

indirect effects on lungs of a systemic inflammatory

response, and not the pulmonary ALI/ARDS, which occurs

due to direct effects on lung cells [ 12 ]. Consistent with this

is the miliary distribution of the granulomas within the

lungs, suggestive of a hematogenic dissemination of the

yeast from primary, extra-pulmonary foci. The diagnosis

of ARDS, sometimes, is not easy to establish, but the

autopsy findings in this fatal case of hyaline membrane and

diffuse alveolar damage associated with the presence of

P. brasiliensis in the lung tissue and the exclusion of other

possible infections or causes of ARDS points out to the

diagnosis of ARDS due to paracoccidioidomycosis.

The question remains as to why such an extensive

necrosis took place in this patient. Recently, a study showed

that mice lacking the effector molecule nitric oxide devel-

oped incipient granulomas with an intense inflammatory

process and necrosis, succumbing to P. brasiliensis infec-

tion. In contrast, normal animals developed typical granu-

lomas and controlled the infection [ 13 ]. In the present

case, the anatomopathological findings of concomitant

overwhelming inflammatory response and high fungal

load also suggest the failure of some effector mechanism

in the patient’s immune response. Unfortunately, no studies

could be performed to determine any putative immuno-

logical defect. Further investigations are needed to better

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© 2010 ISHAM, Medical Mycology, 48, 542–545

Paracoccidioidomycosis and adult respiratory distress syndrome 545

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understand the local and systemic response in severe

and disseminated PCM cases, and the possible correlation

with the inflammatory status that potentially leads to

ALI/ARDS. This would provide means to alert for the

possibility of developing such lethal outcome.

Declaration of interest: None of the authors have any

potential confl ict of interest or fi nancial support in the

subject matter.

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This paper was first published online on Early Online on 11 November 2009.

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