Supported by the Thorax Foundation, Athens, Greece.
A Greek, 38-yr-old male, owner and grill-man in a tavern in an Aegean island (Naxos), with a 40-pack-yrs smoking history, was admitted to the Evangelismos General Hospital of Athens because of chest pain in his left hemithorax, nonproductive cough and fever of 1 month duration. The chest radiograph obtained at that time is shown in figure 1a⇓. The computed tomography (CT) scan is shown in figure 1b⇓. A CT-guided needle biopsy of the lesion was performed a few days before admission, and the histology was pending. Abdomen and brain CT scans performed at that time were negative.
A new chest radiograph, which was obtained on admission, is shown in figure 2⇓. A diagnostic thoracentesis disclosed a bloody exudate, with 75% neutrophils and negative cytology for malignancy. The patient denied previous illness and any other symptoms, including weight loss, haemoptysis and skin rash. He had only fatigue and malaise for 2 months preceding his admission. There was no occupational exposure to asbestos and no drug use. He reported recent agricultural activity (during the last winter) as a pig farmer. He also reported several trips abroad with his wife (every autumn for at least the previous 3 yrs), with a brief visit to various countries of central and south Asia and Africa. In particular, he travelled in Thailand (2-week stay, 3 yrs ago with transit and 1-day stay in Cairo, Egypt), Sri Lanka (2-week stay) and the Maldives (1-week stay) 2 yrs ago. Finally, he travelled in Bali and Singapore for 3 weeks the previous year (5 months before his admission).
On physical examination the patient was apparently in discrete health, with a body temperature of 37.6°C, pulse rate 95 beats·min−1, blood pressure 125 over 80 mmHg, respiration rate 18 breaths·min−1 and oxygen saturation of 95% on room air. Auscultation disclosed diminished breath sounds at the left lower hemithorax. He had no clubbing and a negative tuberculin test.
Laboratory studies demonstrated a white blood cell count of 10.4×109·L−1 (70.6% neutrophils, 21.4% lymphocytes), haematocrit of 0.44 and a platelet count of 330×109·L−1. Serum chemistries, renal and liver function tests were in the normal range. Serology for HIV infection was negative and no other underlying immunosuppressive conditions were disclosed. The histopathology of the pending needle biopsy showed granulomatous inflammation without disclosing specific patterns. Antitubercular treatment (isoniazid, rifampin, and ethambutol) was administered to the patient, but since the whole history was somewhat atypical, and in order to obtain an unequivocal diagnosis, a surgical biopsy was performed. The histology of the specimen and the special stains revealed typical findings (fig. 3a and 3b⇓).
BEFORE TURNING THE PAGE, INTERPRET THE PATIENT'S HISTORY, CHEST RADIOGRAPHS, COMPUTED TOMOGRAPHY SCANS AND HISTOLOGY, AND SUGGEST A DIAGNOSIS.
Chest radiographs and CT scans
The chest radiograph obtained before admission (fig. 1a⇑) shows a relatively well-defined opacity of 5–6 cm in diameter with lobulated boarders. The lesion is located in the left lower lobe since it does not obliterate the left heart boarder.
The CT of the chest at the level of the pulmonary veins (fig. 1b⇑) reveals bilobal soft tissue opacity with marked contrast enhancement and small areas of decreased attenuation, indicating foci of necrosis. There is also a minimal ipsilateral pleural effusion.
The chest radiograph obtained at admission (fig. 2⇑) shows a moderate left-side pleural effusion, obliterating the left costophrenic angle and extending upwards to the lateral hemithorax. No controlateral mediastinal shift is noted despite the size of the pleural effusion, indicating some development of pleural adhesions.
The histopathology of the surgical biopsy, stained with haematoxylin and eosin, revealed granulomatous inflammation with many red-coloured fungal yeasts within multinucleated giant cells or sparse in the tissue, uniform in size and oval in shape (fig. 3a⇑). Grocott's methenamine silver stain showed many round-to-oval yeasts of fairly uniform size of Histoplasma capsulatum (fig. 3b⇑).
Diagnosis: “Acute pulmonary histoplasmosis”.
Treatment and clinical course
After the histological detection of histoplasmosis the antitubercular treatment was discontinued. Itraconazole, 200 mg orally twice daily, was administered for 6 months. This is considered the treatment of choice in immunocompetent patients with mild-to-moderate illness. The patient's course during his hospitalisation was unremarkable, and several months after the treatment completion he remains well with normal chest radiography.
Histoplasmosis is an inhalation-acquired mycosis. The causative agent is H. capsulatum, a dimorphic fungus, whose growth is favoured in warm humid soils containing high concentrations of chicken, pigeon and bat faeces. Histoplasmosis is an endemic mycosis in certain areas of North America (particularly in the regions of the Mississippi and Ohio rivers), Central and South America, East Asia, Oceania, Africa, and in the middle-east (Israel and Egypt). In Europe, sporadic cases that have been reported (Italy, German, France and Switzerland) were mainly imported from the endemic areas, due to travelling and immigration 1. Since this mycosis can be acquired during only a brief stay in an endemic area, it might not be improbable in these days of rapid and frequent travel to discover cases in areas usually considered free of the disease 2. However, autochthonous cases of histoplasmosis have also been reported in the past in Europe, such as those reported in the Po valley of Italy, where the soil is considered as low-endemic pabulum for H. capsulatum 1. Human activities associated with high exposition to histoplasmosis are speleology, mining, building and agriculture occupations.
Histoplasmosis is acquired through inhalation of airborne spores, carried by air currents, and is almost never transmitted from person to person. After inhalation and deposition of conidia within the alveolar spaces, they must convert to the yeast form to become pathogenic, a process completed within several hours to a few days. The pathogenesis is similar to tuberculosis. The granulomatous inflammatory response to H. capsulatum in immunocompetent hosts generally resolves the infection over several weeks 3. The severity of illness varies, depending on the intensity of the exposure and the cellular immunity of the host. Although most patients experience a self-limited disease, those who inhale a large burden of organisms and those who are immunocompromised (e.g. steroid and or cytotoxic therapy, HIV infection) may develop life-threatening pneumonia 4.
The most commonly recognised clinical forms are: 1) acute pulmonary histoplasmosis; 2) chronic pulmonary histoplasmosis; and 3) progressive disseminated pulmonary histoplasmosis. Approximately 90% of the acute pulmonary infections are asymptomatic. Most clinically apparent acute pulmonary infections are mild-to-moderate in severity, with nonspecific symptoms (fever, malaise, headache and nonproductive cough). Chronic pulmonary disease, which often mimics tuberculosis, occurs almost exclusively in patients with underlying severe chronic obstructive pulmonary disease. Progressive disseminated pulmonary histoplasmosis occurs more commonly among infants and immunocompromised adults, and tends to pursue a subacute but relentless course.
Radiological manifestations are usually absent in the normal host, while single or multiple consolidations have been described in severe forms of the disease 5. Hilar lymph node enlargement is common 6, 7. Pleural effusions are rarely observed even in severe forms of the disease 6, 8, 9, and indeed the patient presented only a minimal pleural reaction confined to the boarders of the pulmonary lesion in contact with the pleura, quite undetectable on the chest radiograph. Significant pleural effusion developed only after the thoracentesis and the current authors infer that it was the result of dissemination of the fungi along the needle track. The development of well defined nodular opacities of 3–4 cm in diameter has usually been observed after heavy exposure. These lesions may develop several days after the initiation of symptoms and may resolve within 3–8 months. Calcification, fibrotic foci or complete resolution may be the final result. This pattern of disease is usually associated with hilar lymph node enlargement that may calcify 10. Broncholithiasis with erosion into a bronchus may result in atelectasis and obstructive pneumonitis 6, 7, 11. Finally, after heavy exposure in individuals who react with a vigorous immune response, a miliary pattern may be observed that may resolve or lead to miliary calcifications 12.
Many laboratory methods are available for the diagnosis of histoplasmosis 13. Definitive diagnosis requires growth of the fungus from samples of bloody fluids or tissues. Cultures, fungal stains, serological tests for antibodies and antigen detection are useful for the diagnosis. Yeast forms can be visualised in adequate sections of tissue biopsy when stained with haematoxylin and eosin and/or unequivocally identified with special stains, such as Grocott's methenamine silver or Gomori's stain. Serological tests are important for the diagnosis of histoplasmosis because of the difficulty in detecting the organism by culture or staining in several forms of the disease. Antigen detection in serum and urine with radioimmunoassay is useful in immunocompromised patients with disseminated disease since serological tests may be unreliable 3.
Treatment is usually not indicated in the immunocompetent patient with acute pulmonary infection when the illness is self-limited and associated with minimal morbidity. However, treatment is mandatory in patients with diffuse acute and chronic pulmonary infection, disseminated infection, and mediastinal disease causing stenosis of large vessels or bronchi. Options for therapy include amphotericin B, at a dose of 0.7 mg·kg−1·day−1 (or the lipid formulations), or other antifungal agents, such as ketoconazole, itraconazole and fluconazole 14. The treatment of choice for patients with severe pulmonary involvement is amphotericin, which is highly effective and produces a rapid clinical response. Ketoconazole and itraconazole, both at a dose of 200 mg once or twice daily, are well tolerated and are effective alternatives to amphotericin B for treatment of mild or moderate disease or for use following the initial response to amphotericin B. Fluconazole, at a dosage of 400 mg daily in nonimmunocompromised patients and 800 mg daily in those immunocompromised, is a relatively atoxic agent, effective against H. Capsulatum. However, at least in immunocompromised patients, it is suggested to be used only in those who cannot take itraconazole, because of its inferior activity and the high possibility of an emergence of resistance 15.
The patient presented two different possibilities of acquiring the infection: travelling abroad (the last trip to south Asia a few months before presentation); and work as a pig farmer (which had begun the previous winter). However, no data exist regarding the isolation of Histoplasma capsulatum from soil and animals in Greece. Furthermore, to the best of the current authors' knowledge, no other case of pulmonary histoplasmosis has been described in Greece. For these reasons this case should be considered imported. The differential diagnosis of the bilobal soft tissue mass with central foci of necrosis that the patient presented, excluding malignancy and tuberculosis, should also include Wegener's granulomatosis or other pulmonary mycosis. However, against the diagnosis of Wegener's was the absence of extrapulmonary manifestations, especially those of the upper airways and the kidneys, and against other pulmonary mycosis was the fact that these infections in the Mediterranean area are usually associated with immunocompromisation.
- Received January 21, 2004.
- Accepted April 5, 2004.
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