Histoplasma capsulatum, a thermal dimorphic fungus, is the etiologic agent of histoplasmosis. In most endemic areas, H. capsulatum var. capsulatum is the causative agent; in Africa, H. capsulatum var. duboisii is also found. Mycelia—the naturally infectious form of Histoplasma—have a characteristic appearance, with microconidial and macroconidial forms. Microconidia are oval and are small enough (2–4 μm) to reach the terminal bronchioles and alveoli. Shortly after infecting the host, mycelia transform into the yeasts that are found inside macrophages and other phagocytes. The yeast forms are characteristically small (2–5 μm), with occasional narrow budding. In the laboratory, mycelia are best grown at room temperature, whereas yeasts are grown at 37°C on enriched media.
Histoplasmosis is the most prevalent endemic mycosis in North America. Although this fungal disease has been reported throughout the world, its endemicity is particularly notable in certain parts of North, Central, and South America; Africa; and Asia. In the United States, the endemic areas spread over the Ohio and Mississippi river valleys. This pattern is related to the humid and acidic nature of the soil in these areas. Soil enriched with bird or bat droppings promotes the growth and sporulation of Histoplasma. Disruption of soil containing the organism leads to aerosolization of the microconidia and exposure of humans nearby. Activities associated with high-level exposure include spelunking, excavation, cleaning of chicken coops, demolition and remodeling of old buildings, and cutting of dead trees. Most cases seen outside of highly endemic areas represent imported disease—e.g., cases reported in Europe after travel to the Americas, Africa, or Asia.
Pathogenesis and Pathology
Infection follows inhalation of microconidia (Fig. 199-1). Once they reach the alveolar spaces, microconidia are rapidly recognized and engulfed by alveolar macrophages. At this point, the microconidia transform into budding yeasts (Fig. 199-2), a process that is integral to the pathogenesis of histoplasmosis and is dependent on the availability of calcium and iron inside the phagocytes. The yeasts are capable of growing and multiplying inside resting macrophages. Neutrophils and then lymphocytes are attracted to the site of infection. Before the development of cellular immunity, yeasts use the phagosomes as a vehicle for translocation to local draining lymph nodes, whence they spread hematogenously throughout the reticuloendothelial system. Adequate cellular immunity develops ~2 weeks after infection. T cells produce interferon γ to assist the macrophages in killing the organism and controlling the progression of disease. Interleukin 12 and tumor necrosis factor α (TNF-α) play an essential role in cellular immunity to H. capsulatum. In the immunocompetent host, macrophages, lymphocytes, and epithelial cells eventually organize and form granulomas that contain the organisms. These granulomas typically fibrose and calcify; calcified mediastinal lymph nodes and hepatosplenic calcifications are frequently found in healthy individuals from endemic areas. In immunocompetent hosts, infection with H. capsulatum confers some immunity to reinfection. In patients with impaired cellular immunity, the infection is not contained and can disseminate. Progressive disseminated histoplasmosis (PDH) can involve multiple organs, most commonly the bone marrow, spleen, liver (Fig. 199-3), adrenal glands, and mucocutaneous membranes. Unlike latent tuberculosis, latent histoplasmosis rarely reactivates.
Spiked spherical conidia of H. capsulatum (lacto-phenolcotton blue stain).
Small (2–5 μm) narrow budding yeasts of H. capsulatum from bronchoalveolar lavage fluid (Grocott's methenamine silver stain).
Intracellular yeasts (arrows) of H. capsulatum in a liver biopsy specimen (hematoxylin and eosin stain).
Structural lung disease (e.g., emphysema) impairs the clearance of pulmonary histoplasmosis, and chronic pulmonary disease can result. This chronic process is characterized by progressive inflammation, tissue necrosis, and fibrosis mimicking cavitary tuberculosis.
The clinical spectrum of histoplasmosis ranges from asymptomatic infection to life-threatening illness. The attack rate and the extent and severity of the disease depend on the intensity of exposure, the immune status of the exposed individual, and the underlying lung architecture of the host.
In immunocompetent individuals with low-level exposure, most Histoplasma infections are either asymptomatic or mild and self-limited. Of adults residing in endemic areas, 50–80% have skin-test and/or radiographic evidence of previous infection without clinical manifestations. When symptoms do develop, they usually appear 1–4 weeks after exposure. Heavy exposure leads to a flulike illness with fever, chills, sweats, headache, myalgia, anorexia, cough, dyspnea, and chest pain. Chest radiographs usually show signs of pneumonitis with hilar or mediastinal adenopathy. Pulmonary infiltrates may be focal with light exposure or diffuse with heavy exposure. Rheumatologic symptoms of arthralgia or arthritis, often associated with erythema nodosum, occur in 5–10% of patients with acute histoplasmosis. Pericarditis may also develop. These manifestations represent inflammatory responses to the acute infection rather than its direct effects. Hilar or mediastinal lymph nodes may undergo necrosis and coalesce to form large mediastinal masses that can cause compression of great vessels, proximal airways, and the esophagus. These necrotic lymph nodes may also rupture and create fistulas between mediastinal structures (e.g., bronchoesophageal fistulas).
PDH is typically seen in immunocompromised individuals, who account for ~70% of cases. Common risk factors include AIDS (CD4+ T cell count, <200/μL), extremes of age, and the use of immunosuppressive medications such as prednisone, methotrexate, and anti-TNF-α agents. The spectrum of PDH ranges from an acute, rapidly fatal course—with diffuse interstitial or reticulonodular lung infiltrates causing respiratory failure, shock, coagulopathy, and multiorgan failure—to a more subacute course with a focal organ distribution. Common manifestations include fever and weight loss. Hepatosplenomegaly is also common. Other findings may include meningitis or focal brain lesions, ulcerations of the oral mucosa, gastrointestinal ulcerations, and adrenal insufficiency. Prompt recognition of this devastating illness is of paramount importance in patients with more severe manifestations or with underlying immunosuppression, especially AIDS (Chap. 189).
Chronic cavitary histoplasmosis is seen in smokers who have structural lung disease (e.g., bullous emphysema). This chronic illness is characterized by productive cough, dyspnea, low-grade fever, night sweats, and weight loss. Chest radiographs usually show upper-lobe infiltrates, cavitation, and pleural thickening—findings resembling those of tuberculosis. Without treatment, the course is slowly progressive.
Fibrosing mediastinitis is an uncommon and serious complication of histoplasmosis. In certain patients, acute infection is followed for unknown reasons by progressive fibrosis around the hilar and mediastinal lymph nodes. Involvement may be unilateral or bilateral; bilateral involvement carries a worse prognosis. Major manifestations include superior vena cava syndrome, obstruction of pulmonary vessels, and airway obstruction. Patients may experience recurrent pneumonia, hemoptysis, or respiratory failure. Fibrosing mediastinitis is fatal in up to one-third of cases.
In healed histoplasmosis, calcified mediastinal nodes or lung parenchyma may erode through the walls of the airways and cause hemoptysis. This condition is called broncholithiasis.
African histoplasmosis caused by H. capsulatum var. duboisii is clinically distinct and is characterized by frequent skin and bone involvement.
Fungal culture remains the gold standard diagnostic test for histoplasmosis. However, culture results may not be known for up to 1 month, and cultures are often negative in less severe cases. Cultures are positive in ~75% of cases of PDH and chronic pulmonary histoplasmosis. Cultures of bronchoalveolar lavage (BAL) fluid are positive in about half of patients with acute pulmonary histoplasmosis causing diffuse infiltrates with hypoxemia. In PDH, the culture yield is highest for BAL fluid, bone marrow aspirate, and blood. Cultures of sputum or bronchial washings are usually positive in chronic pulmonary histoplasmosis. Cultures are typically negative, however, in other forms of histoplasmosis.
Fungal stains of cytopathology or biopsy materials showing structures resembling Histoplasma yeasts are helpful in the diagnosis of PDH, yielding positive results in about half of cases. Yeasts can be seen in BAL fluid (Fig. 199-2) from patients with diffuse pulmonary infiltrates, in bone marrow biopsy samples, and in biopsy specimens of other involved organs (e.g., the adrenal glands). Occasionally, yeasts are seen in blood smears from patients with severe PDH. However, staining artifacts and other fungal elements may be misidentified as Histoplasma yeasts.
The detection of Histoplasma antigen in body fluids is extremely useful in the diagnosis of PDH and acute diffuse pulmonary histoplasmosis. The sensitivity of this technique is >95% in patients with PDH and ~80% in patients with acute pulmonary histoplasmosis if both urine and serum are tested. Antigen can be detected in cerebrospinal fluid from patients with meningitis and in BAL fluid from those with pneumonia. Cross-reactivity occurs with African histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and Penicillium marneffei infection.
Serologic tests, including immunodiffusion and complement fixation, are especially useful for the diagnosis of self-limited pulmonary histoplasmosis; however, at least 1 month is required for the production of antibodies after acute infection. A fourfold rise in antibody titer may be seen in patients with acute histoplasmosis. Serologic tests are also useful for the diagnosis of chronic pulmonary histoplasmosis. Limitations of serology, however, include insensitivity early in the course of infection and in immunosuppressed patients and the persistence of detectable antibody for several years after infection. Positive results from past infection may lead to a misdiagnosis of active histoplasmosis in a patient with another disease process.
Treatment recommendations for histoplasmosis are summarized in Table 199-1. Treatment is indicated for all patients with PDH or chronic pulmonary histoplasmosis as well as for symptomatic patients with acute pulmonary histoplasmosis causing diffuse infiltrates, especially with hypoxemia. In most cases of pulmonary histoplasmosis, treatment is not recommended because the degree of exposure is not heavy; the infection is asymptomatic or symptoms are mild, subacute, and not progressive; and the illness resolves without therapy.
Table 199-1 Recommendations for the Treatment of Histoplasmosis |Favorite Table|Download (.pdf)
Table 199-1 Recommendations for the Treatment of Histoplasmosis
|Type of Histoplasmosis||Treatment Recommendations||Comments|
|Acute pulmonary, moderate to severe illness with diffuse infiltrates and/or hypoxemia||Lipid AmB (3–5 mg/kg per day) ± glucocorticoids for 1–2 weeks; then itraconazole (200 mg bid) for 12 weeks. Monitor renal and hepatic function.||Patients with mild cases usually recover without therapy, but itraconazole should be considered if the patient's condition has not improved after 1 month.|
|Chronic/cavitary pulmonary||Itraconazole (200 mg qd or bid) for at least 12 months. Monitor hepatic function.||Continue treatment until radiographic findings show no further improvement. Monitor for relapse after treatment is stopped.|
|Progressive disseminated||Lipid AmB (3–5 mg/kg per day) for 1–2 weeks; then itraconazole (200 mg bid) for at least 12 months. Monitor renal and hepatic function.||Liposomal AmB is preferred, but the AmB lipid complex may be used because of cost. Chronic maintenance therapy may be necessary if the degree of immunosuppression cannot be reduced.|
|Central nervous system||Liposomal AmB (5 mg/kg per day) for 4–6 weeks; then itraconazole (200 mg bid or tid) for at least 12 months. Monitor renal and hepatic -function.||A longer course of lipid AmB is recommended because of the high risk of relapse. Itraconazole should be continued until cerebrospinal fluid or CT abnormalities clear.|
The preferred treatments for histoplasmosis include the lipid formulations of amphotericin B in more severe cases and itraconazole in others. Liposomal amphotericin B has been more effective than the deoxycholate formulation for treatment of PDH in patients with AIDS. The deoxycholate formulation of amphotericin B is an alternative to a lipid formulation for patients at low risk for nephrotoxicity. Posaconazole, voriconazole, and fluconazole are alternatives for patients who cannot take itraconazole.
In severe cases requiring hospitalization, a lipid formulation of amphotericin B is followed by itraconazole. In patients with meningitis, a lipid formulation of amphotericin B should be given for 4–6 weeks before the switch to itraconazole. In immunosuppressed patients, the degree of immunosuppression should be reduced if possible, although immune reconstitution inflammatory syndrome (IRIS) may ensue. Antiretroviral treatment improves the outcome of PDH in patients with AIDS and is recommended; however, whether antiretroviral treatment should be delayed to avoid IRIS is unknown.
Blood levels of itraconazole should be monitored to ensure adequate drug exposure, with target concentrations of 2–10 μg/mL. Drug interactions should be carefully assessed: itraconazole not only is cleared by cytochrome P450 metabolism but also inhibits cytochrome P450. This profile causes interactions with many other medications.
The duration of treatment for acute pulmonary histoplasmosis is 6–12 weeks, while that for PDH and chronic pulmonary histoplasmosis is ≥1 year. Antigen levels in urine and serum should be monitored during and for at least 1 year after therapy for PDH. Stable or rising antigen levels suggest treatment failure or relapse.
Previously, lifelong itraconazole maintenance therapy was recommended for patients with AIDS once histoplasmosis was diagnosed. Today, however, maintenance therapy is not required for patients who respond well to antiretroviral therapy, with CD4+ T cell counts of at least 150/μL (preferably >250/μL); who complete at least 1 year of itraconazole therapy; and who exhibit neither clinical evidence of active histoplasmosis nor an antigenuria level of >4 ng/mL. Maintenance therapy also appears to be unnecessary in patients receiving immunosuppressive treatment if the degree of immunosuppression can be reduced through an approach similar to that used for patients with AIDS.
Fibrosing mediastinitis, which represents a chronic fibrotic reaction to past mediastinal histoplasmosis rather than an active infection, does not respond to antifungal therapy. While treatment is often prescribed for patients with pulmonary histoplasmosis who have not recovered within 1 month and for those with persistent mediastinal lymphadenopathy, the effectiveness of antifungal therapy in these situations is unknown.