Fungal Diseases

Histoplasmosis

Histoplasmosis is a respiratory infection caused by inhalation of infectious conidia or mycelia of Histoplasma capsulatum var. capsulatum. In the United States the Mississippi and Ohio River valleys are highly endemic areas. The avian and chiropteran habitats such as chicken coops, roosting shelters, caves, and attics favor the growth and multiplication of Histoplasma in soil enriched with fecal material.

Clinical Features

Almost 75% of infections are asymptomatic and self-limited and heal without treatment. The remaining 25% of patients may develop symptomatic disease manifested as (1) acute pulmonary disease, (2) disseminated disease, (3) chronic pulmonary disease, and (4) fibrosing mediastinitis.

Acute pulmonary disease clinically manifests as fever with cough and chest pain, approximately 1 to 4 weeks after exposure. Symptoms can resolve in a few days to 2 weeks, but may persist up to several months. Disseminated histoplasmosis is seen in patients with impaired cell-mediated immunity, with development of severe systemic symptoms, including weight loss, malaise, hepatosplenomegaly, purpura, and oropharyngeal and intestinal ulcerations. The mortality without antifungal therapy can be as high as 80%. Chronic pulmonary histoplasmosis is primarily a disease of adults with symptoms similar to other chronic progressive pulmonary infections such as tuberculosis.

Fibrosing mediastinitis is a histologically benign disorder caused by proliferation of collagen within the mediastinum as a result of histoplasmosis; however, cases secondary to tuberculosis, zygomycosis, and Langerhans cell histiocytosis are also reported. Most of the patients are young and present with respiratory symptoms. The disease is slowly progressive and may result in extensive fibrosis with entrapment and invasion of structures adjacent to the mediastinal lymph nodes, including the heart, great vessels, and esophagus.

Radiologic Features

In the acute phase, chest radiographs may show hilar lymphadenopathy and a single small area of pulmonary infiltrate forming the primary complex. With disease evolution, chest radiographs may show patchy nodular pulmonary infiltrates and pleural effusion. Four radiologic patterns have been described in chronic pulmonary histoplasmosis: infiltrative, cavitary, fibrosis with emphysema, and residual solitary nodule or histoplasmoma.

Pathologic Features

Gross Findings

In the acute pulmonary disease, patchy bronchopneumonia and hilar lymphadenopathy may be seen. In disseminated histoplasmosis, the lungs may show edema, congestion, and granulomas. Chronic pulmonary histoplasmosis may be seen as diffuse pulmonary infiltrates, frequently apical, but may be bilateral and associated with cavitary lesions, as seen in tuberculosis. Fibrosis may be severe and associated with bronchiectasis. Histoplasmoma, or the “coin” (lesion), may be confused with carcinoma, especially when it is noncalcified. However, histoplasmomas are often rounded, subpleural, and show a concentric calcification pattern, accompanied by enlarged and calcified hilar lymph nodes.

Microscopic Findings

The characteristic histologic lesion of histoplasmosis is a granuloma, with or without central necrosis, surrounded by lymphocytes, macrophages, and multinucleated giant cells. The fungus is an oval, 2- to 5-micron yeast that does not have a capsule and shows narrow-necked budding ( Fig. 12.1 ). The yeast often occurs in clusters, due to its intracellular proliferation in phagocytes. In hematoxylin-eosin–stained sections, the basophilic cytoplasm of the yeast is often retracted from the poorly stained cell wall, creating a false impression of an unstained capsule or a “halo” effect. Poorly formed pseudohyphae consisting of cells attached to each other and germ tubes are often seen in active lesions. The yeast stains strongly with methenamine silver (GMS) stain and may be seen in the central areas of old “coin” lesions. The histoplasmoma consists of a large central zone of caseous necrosis surrounded by a thick fibrous capsule that contains lymphoid aggregates and rare epithelioid and multinucleated giant cells. The central necrotic material may be calcified and may show osseous or myeloid metaplasia.

Prognosis and Therapy

Acute histoplasmosis is usually a benign, self-limited infection that heals without antifungal therapy. However, the progressive pulmonary and disseminated infections require prompt and sometimes prolonged treatment with either amphotericin B or one of its lipid formulations, ketoconazole, itraconazole, or fluconazole. Newer antifungal agents such as triazole and posaconazole are also being used. Fibrosing mediastinitis may require antifungal therapy combined with corticosteroids.

Clinical Features

The disease occurs most frequently in young males and presents either as acute or chronic infection. Pulmonary infection can either remain confined to the lungs or disseminate hematogenously to other organs, and it may be fatal in severe progressive infections. After inhalation of the infectious conidia, patients develop a nonspecific flulike illness progressing to acute pneumonia, with high fever and pleuritic chest pain. Symptoms may persist for a few days to 2 weeks and often result in a self-limited infection. Rarely a more rapid clinical course with development of acute respiratory distress syndrome (ARDS), pulmonary necrosis, and cavitation may be seen. Chronic blastomycosis presents with respiratory symptoms lasting weeks to months, associated with fever, chest pain, weight loss, and night sweats.

Radiologic Features

Acute pulmonary blastomycosis manifests as patchy areas of consolidation, often bilateral, and less commonly associated with pleural effusion and cavitations. The posterior segments of lower lobes are most often involved, but middle and upper lobes may also be affected. A severe infection may result in lobar consolidation and formation of miliary infiltrates. Chronic blastomycosis is associated with linear pulmonary infiltrates, fibronodular densities with cavitations similar to chronic active tuberculosis, and mediastinal lymphadenopathy. Pleural involvement is common.

Pathologic Features

Gross Findings

The lesions of blastomycosis may have a nodular pattern mimicking localized tumors or a miliary pattern. Chronic pulmonary lesions show fibrosis, hyalinization of the nodules, and cavitation, similar to that seen in other granulomatous diseases. A primary pulmonary–lymph node complex is much less frequent than in histoplasmosis. Solitary residual fibrocaseous nodule “coin” lesions are rare, and calcification is even rarer.

Microscopic Findings

B. dermatitidis is a dimorphic fungus that measures 8 to 15 microns in diameter with a thick cell wall and solitary blastoconidia attached by a broad-based septum ( Fig. 12.2 ). The lesions are characterized by abscesslike neutrophil collections, surrounded by epithelioid or palisading macrophages and multinucleated giant cells. The fungus is found usually at the edge of the abscesses, and calcification is not common.

Prognosis and Therapy

Acute primary blastomycosis is often self-limited, and antifungal therapy is not required. However, long-term follow-up is necessary because patients may present with extrapulmonary lesions from months to years after resolution of the primary pulmonary infection. Itraconazole and amphotericin B are the drugs of choice.

Clinical Features

Two clinical forms of cryptococcosis are seen: pulmonary and cerebromeningeal. The pulmonary disease may present in three different forms: (1) transient, asymptomatic colonization of tracheobronchial tree; (2) self-limited or progressive pulmonary disease, with or without extrapulmonary dissemination; and (3) residual pulmonary nodule or “cryptococcoma.” Colonization of the respiratory tract is seen in patients who have preexisting lung disease, such as tuberculosis, chronic bronchitis, asthma, neoplasms, and allergic bronchopulmonary aspergillosis. An invasive infection is not seen in these patients. The majority of immunocompetent people with cryptococcosis have asymptomatic or self-limited pulmonary infections with formation of residual fibrocaseous nodules or cryptococcomas. These nodules are usually subpleural, rounded, 0.2 to 7.0 cm in diameter, and show no calcification. Rarely, a primary pulmonary–lymph node complex may be formed. Progressive pulmonary infection may be asymptomatic or associated with low-grade fever, cough, pleuritic chest pain, and weight loss.

Radiologic Features

Chest radiographs may show interstitial infiltrates, nodules that resemble neoplasms, segmental or lobular consolidation, and, less commonly, hilar lymphadenopathy, pleural effusion, and empyema. The upper lobes are reportedly more frequently involved. Fibrosis and calcification are uncommon. Diffuse interstitial, peribronchial, or miliary infiltrates can develop in profoundly immunodeficient patients.

Pathologic Features

Gross Findings

The severe infection often seen in patients with AIDS presents as diffuse miliary lesions or as areas of patchy consolidation with a mucoid appearance in freshly sectioned lungs. Sometimes cystic lesions composed of densely packed organisms may be seen in immunodeficient patients. In immunocompetent individuals, lesions remain localized and either resolve or become granulomatous with formation of nodules. The firm grayish-white fibrocaseous nodules, “cryptococcomas,” show central necrosis and cavitation, and resemble lesions seen in histoplasmosis and coccidioidomycosis; however, these lesions rarely show calcifications. Smaller satellite nodules may also be present.

Microscopic Findings

In H & E–stained tissue sections, typical cryptococci appear as pleomorphic, eosinophilic, uninucleate, thin-walled, round yeast forms, 2 to 20 microns in diameter, surrounded by a wide, clear polysaccharide capsule ( Fig. 12.3 ). Budding is seen as a single blastoconidium attached to the parent cell by a narrow neck. Active lesions can contain a large number of rapidly dividing cryptococci. The fungi stain with usual fungus stains, as well as with mucin stains such as mucicarmine and alcian blue. Cryptococcus species are the only common pathogenic fungi that produce mucinous capsular material. The host response to C. neoformans depends on the immune status of the host, with immunodeficient patients developing profuse multiplying lakes of cryptococci with little surrounding host response. The cryptococci may appear to fill the alveolar spaces and the thickened alveolar septa and septal capillaries. Immunocompetent individuals and capsule-deficient strains of cryptococci may cause a granulomatous inflammatory response with caseation and fibrosis surrounding the small 2 to 4 micron in diameter capsule-deficient and distorted cryptococci. In these lesions, GMS or modified Fontana-Masson stain can be used to identify the poorly encapsulated cryptococci.

Prognosis and Therapy

Amphotericin B and 5-fluorocytosine is the treatment of choice for progressive pulmonary cryptococcosis and cerebromeningeal cryptococcosis. Maintenance suppressive therapy with fluconazole can be used.