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A 56-Year-Old Honduran Man With Fever, Weight Loss, and Pleuritic Chest Pain

Castro, Dalys E. MD*; Wikenheiser-Brokamp, Kathryn A. MD, PhD; Sinha, Prabhat DO

Infectious Diseases in Clinical Practice: January 2008 - Volume 16 - Issue 1 - p 36-40
doi: 10.1097/ipc.0b013e31815f5261
Radiology in ID

*Neuroradiology and Body Imaging, Cincinnati VA Medical Center and University of Cincinnati; †Pathology and Laboratory Medicine and Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and ‡Division of Pulmonary, Critical Care and Sleep Medicine, Medical Sciences Building, University of Cincinnati Medical Center, Cincinnati, OH.

Address correspondence and reprint requests to Dalys E. Castro, MD, Neuroradiology and Body Imaging, Cincinnati VA Medical Center and University of Cincinnati, 3200 Vine St, Cincinnati, OH 45220. E-mail:

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A 56-year-old man Honduran man presents to a US hospital with a 2-month history of hemoptysis, pleuritic chest pain, night sweats, cough, fever, and back pain associated with a 30-lb weight loss and occasional headaches. He has been in the United States for 20 months and has no knowledge of prior exposure to tuberculosis. On physical examination, he is a cachectic-appearing Hispanic man with a temperature of 37.8°C, a respiratory rate of 20 breaths per minute, and a saturation of 99% on room air. No skin or mucosal lesions were encountered. No organomegaly or adenopathy was noted. Pulmonary examination demonstrated right, lower lobe crackles with decreased breath sounds.

The chest radiograph demonstrated multifocal, nodular airspace disease with foci of cavitation (Figs. 1A, B). Chest computed tomography (CT) confirmed the presence of multiple nodules, some of which were cavitary, irregular foci of airspace disease that appeared more confluent in the lower lobes, and extensive mediastinal and hilar adenopathy (Figs. 2A-C).





The clinical and radiographic manifestations at the time of admission were suggestive of tuberculosis, and the patient was placed in isolation in a negative-pressure room. Multiple sputum samples were negative for acid-fast bacilli. A purified protein derivative (tuberculin) skin test performed in the emergency room showed 2-mm induration. In addition, the patient was negative for cryptococcal antigen and cytomegalovirus early antigen.

Bronchoscopy revealed 3 raised polypoid endobronchial lesions: one along the right lateral trachea, a second in the right mainstem bronchus near the right upper lobe bronchus, and the third at the entrance of the superior segment left lower lobe bronchus (Fig. 3). A biopsy of the lesions in the right upper and left lower lobe bronchi was performed.



Pathological examination of the lung biopsies from the right upper and left lower lobe endobronchial lesions showed similar morphological findings. The biopsies consisted of multiple bronchial wall fragments infiltrated by a mixed acute and chronic inflammatory infiltrate composed of neutrophils, eosinophils, macrophages, and lymphocytes. Collections of histiocytes and multinucleated giant cells were present, forming ill-defined granulomas (Figs. 4A, B). Fragments of pulmonary parenchyma showed focal accumulations of intra-alveolar histiocytes with an associated mild lymphocytic infiltrate. Refractile microorganisms were identified within the macrophages (Figs. 4A, B), which were yeast cells of variable size, spherical to oval, and with thick walls. The yeast forms stained positively with Grocott methenamine-silver (GMS) stain (Fig. 4C) and were negative on mucicarmine stain (Fig. 4D). The GMS stains highlighted budding blastoconidia attached to the yeast cells that had an oval, tubular, or large teardrop configuration. Multiple, variably sized blastoconidia were noted to bud from a single yeast cell focally forming an arrangement resembling a ship's steering wheel. Similar microorganisms were identified in cytological preparations of the bronchoalveolar lavage. Cultures isolated Paracoccidioides brasiliensis from the bronchoalveolar lavage and bronchial washings. Interestingly, the microorganisms did not grow from cultured lung biopsy material despite being present in the histological sections.



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Paracoccidioidomycosis (PCM), commonly called South American blastomycosis, is a systemic granulomatous infection caused by a dimorphic fungus, P. brasiliensis. The disease was first described by Adolpho Lutz in 1908 in Brazil but was frequently confused with coccidioidomycosis until 1930, when Almeida Floriano identified the fungus P. brasiliensis as the causative agent. Among the systemic mycosis, P. brasiliensis is the most prevalent and important fungal infection in Latin and South America, with 80% of reported cases in the world literature coming from Brazil, followed by Colombia and Venezuela. Paracoccidioidomycosis has not been reported in the Caribbean islands, Guyana, Surinam, or Chile. Endemic countries are generally abundant with forests and demonstrate mild temperatures (17°C-24°C), with adequate rainfall (900-1810 mm/y).1,2

All cases that have been reported in the United States and Europe have been imported, meaning the patients have had a positive history of residency or travel to endemic countries. It is important to recognize that in some cases the latency period between departure from the endemic region and the time of clinical manifestation of the disease is prolonged. The dormancy period of PCM has been reported to range from 4 months to 60 years, with an average of 14 years.3,4

The portal of entry of P. brasiliensis is still controversial but is generally believed to enter the human body by inhalation of the conidia produced in the mycelia form of the P. brasiliensis. Upon transformation into the yeast form, a primary pulmonary lymph node complex results in association with parenchymal pulmonary disease. Human-to-human transmission has not been confirmed. Following the primary infection, the P. brasiliensis organism may spread via hematogenous and/or lymphangitic dissemination to the spleen, liver, bone, adrenal glands, genitourinary system, and central nervous system. In a normal host, the primary lesions heal spontaneously or become quiescent.

There are 2 main pulmonary manifestations of PCM which are partially dictated by the immunologic status of the host. An asymptomatic or subclinical infection can be documented by a positive paracoccidioidin skin test.

The second form or symptomatic disease can be divided into 2 clinical presentations. The acute or subacute form (juvenile type) is characterized by a rapid, severe course. The chronic form (adult type) has a more indolent course. In both cases, however, cell-mediated immune functions are abnormal.

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Acute or Subacute Form (Juvenile Type)

This form represents only 3% to 5% of all cases and is characterized by a rapid course (weeks to months) and by marked involvement of the reticuloendothelial system, including the spleen, liver, lymph nodes, gastrointestinal tract, and bone marrow. Cell-mediated immune functions are severely depressed in these patients, most of whom are children and young adults of both sexes. Juvenile type is the most severe form of the disease and also has the worst prognosis. Osteomyelitis and gastrointestinal ulcerative lesions are frequently seen in this type, but involvement of mucous membranes and lungs is rare. Even so, a search for the fungus in pulmonary secretions is usually positive. Biopsies will often show numerous P. brasiliensis microorganisms, but a lack of granuloma formation.1,5-7

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Chronic Form (Adult Type)

The chronic form occurs more commonly (90% of cases) and typically affects adult men aged 30 years or older. The male-to-female ratio is 20:1. When the disease occurs in prepubescent females or postmenopausal patients, there is no sex difference. This male predominance is explained by the protective effect of estrogen. Restrepo et al8 demonstrated in 1984 that estrogens inhibit the mycelium to yeast transformation of P. brasiliensis in vitro.

The adult disease may be localized to the lungs (25% of cases) or disseminated (75% of cases). Patients with localized lung involvement, as in our case, usually present with symptoms of a chronic respiratory infection that may include cough, hemoptysis, dyspnea, thoracic pain, and a low-grade fever. This may be the result of reactivation of a quiescent lesion in the lung. Few studies have been performed to determine the high-resolution CT manifestations of PCM infection in the lungs. The radiographic features of this disease seem to vary according to the time of presentation and response to medical treatment. The most commonly described high-resolution CT findings are symmetric abnormalities involving all lung zones to a similar extent with a slight predilection for the midlung zones and relative sparing of the anterior regions.2,9 In patients who have received no prior medical treatment, the predominant CT findings are areas of ground-glass attenuation, airspace disease, and cavitation. The areas of ground-glass attenuation may exhibit a crescent ring of consolidation (reverse halo sign) in 10% of the cases.10 Small centrilobular nodules as well as large nodules can also be present. Nodules tend to be localized within the periphery of the lungs and show spiculated margins. When the nodules are in proximity to the pleural surface, they may have a pleural tag. Improvement in the radiographic appearance of the pulmonary lesions is noted after 3 to 6 months of treatment. Nodular lesions tend to resolve completely or decrease in size and number during the first 3 months of treatment with no further change thereafter. During this chronic state of infection, the CT findings consist predominantly of parenchymal bands, interlobular septal thickening, and architectural distortion with areas of traction bronchiectasis and paracicatricial emphysema.

The most important considerations in the differential diagnosis of localized pulmonary infections from PCM are tuberculosis and sarcoidosis. Clinically, all 3 conditions present with cough, dyspnea, fatigue, and weight loss; however, patients with sarcoidosis typically have milder symptoms. All 3 conditions may have similar CT and chest radiograph appearances. Although all 3 conditions may present with perilymphatic ground-glass opacities, nodules, and cavitations, the lobar distribution aids in differentiating these entities. Sarcoidosis tends to have an upper lobe predominance, whereas tuberculosis tends to effect the apical posterior segment of the upper lobes and the superior segment of the lower lobes. On the other hand, PCM tends to be bilateral and fairly symmetric and diffusely involve the posterior vertical axis of all lung zones with relative sparing of the anterior zones.

Patients with disseminated PCM classically present with fever, weight loss, and anorexia, as well as a triad of pulmonary, mucosal, and cutaneous lesions. The disease in most patients follows a markedly chronic course. The overall health status of such patients is gradually impaired. They show loss of body weight, asthenia, and exertional dyspnea, with the majority of patients dying of cachexia or respiratory failure. Less than 10% develop secondary lesions: however, when secondary lesions do occur, 70% to 80% are multifocal, starting with mucocutaneous or pulmonary lesions. Oropharyngeal mucosal lesions are frequently painful and appear infiltrative or ulcerative. They may result in destruction of the uvula and extend into the larynx, resulting in destruction of the epiglottis. In such cases, the patient may present with dysphonia, dysphagia, and obstructive dyspnea, and in many cases, the lesions may be indistinguishable from laryngeal carcinoma during laryngoscopy.11 Loss of teeth may result from an ulcerative gingivitis. Skin lesions usually develop after microtrauma and can be extremely pleomorphic. Lesions are frequently located near the mouth and nasal nostrils, resembling American cutaneous leishmaniasis. They can also be found in the anus or genitalia. Cervical, axillary, and mediastinal adenopathy is common and may be complicated by sinus tracts similar to those seen in scrofulodermal tuberculosis. The adrenal glands are involved in 40% of severe cases; however, adrenal insufficiency (Addison disease) does not develop until 90% of the adrenal cortex has been destroyed. In the case of acute adrenal involvement, CT and magnetic resonance imaging (MRI) demonstrate enlargement of the gland with irregular borders. Computed tomography may also demonstrate diffusely decreased density. Magnetic resonance imaging may show diffuse T1 hypointensity and peripheral enhancement consistent with necrosis. In patients who develop Addison disease, CT and MRI demonstrate significant volume loss in the adrenal glands.12

The central nervous system may be involved in 10% to 25.4% of the cases by hematogenous dissemination. Two clinical presentations are described: meningeal and pseudotumoral. The pseudotumoral presentation is the most common (90%-96%), and it is caused by single or multiple granulomas localized to the cerebral hemisphere (67%), brainstem (25%), cerebellum (25%), or spinal cord (4%).13-15 Neuroimaging is helpful but not specific, because images demonstrate features common to all granulomatous diseases ranging from ring enhancing lesions with associated mild perilesional edema with or without calcification to diffuse nodular subarachnoid enhancement. Meningitis is present in 10% to 17% of cases. A definitive diagnosis requires visualization or isolation of the P. brasiliensis microorganisms in a biopsy; however, this is invasive and not always possible. Identifying the fungus in cerebral spinal fluid is time consuming and rarely successful. Cerebral spinal fluid analysis typically reveals increase in total protein and γ-globulin with a normal glucose level.

Other less common sites of infection have been reported, including the testicles, epididymis, prostate, and thyroid gland. The disease is fatal within several years if left untreated. Healing may result in intense fibrosis in the involved organs.

Paracoccidioidomycosis can be associated with other infections. Tuberculosis has been seen in association with PCM in 10% to 12% of cases. Paracoccidioidomycosis has rarely been reported in patients with HIV infection. The rare occurrence of PCM with HIV infection is presumably due to lack of exposure to PCM along with the protective effect of trimethoprim-sulfamethoxazole, which is used as a prophylactic agent against PCP infections but is also very effective against P. brasiliensis. If PCP infection occurs in HIV-infected patients, it behaves similarly to other opportunistic infections and most commonly involves the lymph nodes and lungs.16,17

Treatment of PCM may be difficult and prolonged. Several antimicrobial drugs, including trimethoprim-sulfamethoxazole, imidazoles, and amphotericin B, have been used in the treatment of PCM. In all cases, however, the selection of therapy is based on the clinical course. In adult patients with mild or moderate PCM forms, as in our reported case, imidazoles are preferred. Itraconazole at a dose of 200 mg/d is now considered the drug of choice because of its lower toxicity, less number of relapses (3%-4%), and shorter duration of treatment (3-6 months). In severe cases or in patients with involvement of the central nervous system (neuroparacoccidioidomycosis), a combination of therapy including trimethoprim-sulfamethoxazole and amphotericin B is the treatment of choice, because of better blood-brain barrier penetration as compared with ketoconazole and itraconazole. In current clinical trials, new imidazoles, including fluconazole, voriconazole, and saperconazole, have demonstrated lower toxicity than amphotericin B and better blood-brain barrier penetration than first-generation imidazoles. Although these are promising therapies in cases of neuroparacoccidioidomycosis, more studies are required to confirm the efficacy of these drugs.

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Paracoccidioidomycosis, also known as South American blastomycosis, is a systemic mycosis endemic within Latin America. This disease can be fatal if untreated. Cases too often present a problem to clinicians, particularly in the United States and Europe, because of the long periods of dormancy and the significant gamut of clinical manifestations. Due to the increasing number of immigrants to the United States and frequent travel, it is important for physicians to become familiarized with the clinical and imaging features of this disease. Paracoccidioidomycosis infection should be considered in the differential diagnosis of patients with the appropriate clinical history and previous history of residency or travel to endemic countries.

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