Essentials of Diagnosis
- Thin-walled oval yeast measuring 2-4 mm in diameter.
- Dimorphic: mycelial in nature, yeast in tissue.
- Endemic within Ohio and Mississippi River Valleys.
- Associated with activities that disturb dust or soil enriched with bird, chicken, and bat excrement.
- Complement fixation antibody titer 1:32 or greater.
- Simultaneous appearance of anti-H and anti-M antibodies.
- Infection most often is asymptomatic or may cause chronic pulmonary infection; less commonly, disseminated infection involving the adrenals, ulcerative gastroenteritis lesions, or central nervous system.
- Recovery of organism from culture of tissue, blood, sputum, or other source.
General Considerations
Epidemiology
Histoplasma capsulatum, the etiologic agent of histoplasmosis, is an endemic, dimorphic fungus that causes a wide spectrum of disease in both immunocompetent and immunocompromised individuals. It is found in temperate zones around the world. In the United States, it is endemic within the Ohio and Mississippi River Valleys. Its natural habitat is soil, especially soil with high organic content such as soil enriched with bird, chicken, and bat excrement. Many types of both occupational and recreational activities (eg, cave exploring, excavation) have resulted in outbreaks of histoplasmosis.
Microbiology
H capsulatum is dimorphic; it grows as a mycelial form outside the human host but converts into its pathogenic yeast form at the body temperature of mammals. The yeast forms seen in tissue are small, thin-walled, oval structures measuring 2-4 mm in diameter.
Pathogenesis
The vast majority of infections caused by H capsulatum are acquired by inhalation and deposition of mycelial fragments into the alveoli. The organism converts into its pathogenic yeast form and is phagocytosed by alveolar macrophages. The yeast forms multiply within the macrophages, eventually causing the destruction of these macrophages. The released yeasts spread to the regional lymph nodes and other organs via the lymphatics and blood. Specific T cell-mediated immunity develops in 2-4 weeks and inhibits the growth of the organisms. Resolution occurs with production of a granulomatous inflammatory response and leads to the formation of granulomas, which may be caseating but usually become calcified. The yeasts persist for prolonged periods within caseating granulomas.
CLINICAL SYNDROMES
A variety of clinical syndromes have been described in association with histoplasmosis (Box 70-1).
PULMONARY INFECTIONS
ACUTE PRIMARY HISTOPLASMOSIS
Clinical Findings
Signs and Symptoms
Among persons with normal cell-mediated immunity, only ~ 1% will develop a mild symptomatic but usually self-limited infection after a low-inoculum exposure to H capsulatum. Fever, malaise, nonproductive cough, chest pain, and fatigue are the most common symptoms.
Imaging
In symptomatic persons, chest roentgenograms show focal infiltrates, hilar or mediastinal lymphadenopathy, or a combination.
Differential Diagnosis
The differential diagnosis of pulmonary histoplasmosis includes tuberculosis, pneumonia caused by other fungi, and bacterial pneumonia.
Complications
Most patients recover fully without treatment but some may experience fatigue and weakness for months. Persons with defects in cell-mediated immunity or persons who have been exposed to a high inoculum of the organisms may develop severe symptomatic infection characterized by severe dyspnea and hypoxemia. Diffuse infiltrates or multiple poorly defined pulmonary nodules are noted on chest roentgenograms. Some may present with disseminated disease.
About 10% of patients develop acute pericarditis. Another 10% experience arthritis with erythema nodosum. These responses are thought to represent immunologic reactions and as such respond to anti-inflammatory therapy and do not usually require antifungal treatment.
CHRONIC PULMONARY HISTOPLASMOSIS
Clinical Findings
Signs and Symptoms
Chronic pulmonary histoplasmosis consists of progressive focal consolidation and cavitation and is most often seen in those with preexisting lung disease such as chronic obstructive pulmonary disease. The main symptoms are productive cough, malaise, fatigue, and weight loss. The lesions are localized in the apical or subapical regions of the lung. The early form of the disease usually presents as interstitial infiltrates but later undergoes necrosis, cavitation, and fibrosis that extend to involve adjacent areas of the lung.
Laboratory Diagnosis
Though anemia and leukocytosis may occasionally be present, routine laboratory studies are usually not helpful to suggest or establish diagnosis.
Differential Diagnosis
Differential diagnosis of chronic histoplasmosis includes tuberculosis and pneumonia caused by other endemic fungi.
Complications
Cavities may extend into adjacent lung tissue. This may undergo fibrosis and contribute to progressive restrictive and obstructive lung disease, which may in turn result in respiratory failure and death.
MEDIASTINAL GRANULOMATOSIS
Signs and Symptoms
After exposure to H capsulatum, the healing process in the lungs is characterized by a granulomatous inflammatory response resulting in the formation of caseated lymph nodes surrounded by fibrosis. Occasionally, these nodes coalesce to form a large lesion in the mediastinum and may attach to adjacent structures such as the bronchi, trachea, and esophagus. Fibrosis of the attached nodes can result in compression of these structures, causing various symptoms such as cough, dysphagia, odynophagia, formation of esophagopulmonary fistula, and development of post-obstructive pneumonia or bronchiectasis.
Laboratory Findings
Thoracoscopy or thoracotomy is required for definitive diagnosis. Necrotizing granulomata are usually found in histological specimens, but the microorganisms themselves may be difficult to stain or recover from cultures.
Complications
Approximately 40% of mediastinal granulomas are asymptomatic, but as many as a third of cases may progress to fibrosing mediastinitis within a 2-year period.
FIBROSING MEDIASTINITIS
In rare instances, the healing process may be complicated by a hyperintense fibrotic reaction culminating in a relentless progressive invasion of mediastinal structures including the esophagus and respiratory and vascular structures. Fibrosing mediastinitis due to histoplasmosis is the most common cause other than malignancy of the superior vena cava syndrome. The intense fibrotic reaction is thought to be caused by continuous antigenic stimulation by the yeast forms that persist within the granuloma.
DISSEMINATED HISTOPLASMOSIS
Signs and Symptoms
Although occasionally seen in normal adults, disseminated histoplasmosis is mainly a disease of infants and adults with defective cell-mediated immunity. It presents as a systemic febrile illness with malaise and weight loss as the main and consistent symptoms. Extrapulmonary involvement is common and may be manifested by hepatosplenomegaly, meningitis or focal central nervous system parenchymal lesions, oral and mucocutaneous lesions, adrenal insufficiency, and endocarditis.
Laboratory Findings
Anemia, leukopenia, thrombocytopenia, and elevation of serum alanine aminotransferase and alkaline phosphatase values are often noted on laboratory evaluation.
Imaging
The most common findings on chest roentgenograms are diffuse infiltrates, but as many as a third of affected individuals may have normal chest x-ray findings.
HISTOPLASMOSIS IN AIDS
Clinical Findings
Signs and Symptoms
Histoplasmosis has been recognized as an opportunistic infection in patients with AIDS since the early days of the HIV epidemic and has been an AIDS-defining illness since 1987. It occurs in ~ 5% of patients residing in areas known to be endemic for H capsulatum. Sporadic cases have also been reported in nonendemic areas, but many of these patients have resided for variable periods of time in or near endemic areas, and their disease likely represents reactivation of infection acquired elsewhere. In the vast majority of cases, infection with H capsulatum in AIDS patients presents as disseminated disease with fever, weight loss, and malaise.
Laboratory Findings
Associated laboratory abnormalities may include a decrease in peripheral blood counts (leukopenia, anemia, thrombocytopenia), hyponatremia, and elevated liver enzymes. Lymphadenopathy and hepatosplenomegaly may be present.
Imaging
Diffuse reticulonodular infiltrates are typically noted on chest roentgenograms. However, as many as one third of patients have normal findings on the initial chest roentgenograms.
Complications
Central nervous system involvement in the form of meningitis, focal brain lesion, or diffuse encephalitis may complicate the course in 10-20% of cases. In 10-20% of cases, histoplasmosis in AIDS patients presents as septic shock, with fever, disseminated intravascular coagulopathy, and multiorgan failure.
Diagnosis
Histoplasmosis can be diagnosed on the basis of serologic testing, antigen detection, histopathological examination, or culture.
Serology
Serologic tests provide important supplemental information in cases where proof of infection cannot be obtained through culture or histopathological examination. Currently, the complement fixation and immunodiffusion tests are the serologic tests that are most commonly employed.
Complement Fixation Test. Complement fixation antibodies may be detected at ~ 3 weeks after acquiring infection and wane over several months. In chronic or disseminated infection, they might remain elevated for years. Titers of 1:32 or greater may be indicative of active infection. Titers of 1:8 or 1:16 should raise suspicion for infection. Cross-reaction may occur with blastomycosis and coccidiomycosis, but in these instances, titers are usually lower.
Immunodiffusion. Immunodiffusion assays detect antibodies to two glycoprotein antigens, designated M and H antigens. Antibodies to M and H antigens appear later in infection than complement fixation antibodies. Anti-M antibodies may persist for years after acute infection. Anti-H antibodies are detected later than antibodies to M antigen and also disappear earlier. Thus they are more specific indicators of active infection. The simultaneous appearance of anti-M and anti-H antibodies occurs in < 20% of patients and is indicative of active infection.
Antigen Detection
A radioimmunoassay that detects a heat-stable H. capsulatum polysaccharide antigen has recently been developed. This assay may be applied to serum, urine, or cerebrospinal fluid and is particularly useful in cases of disseminated infection, where it has a sensitivity of > 90%. The sensitivity of this assay to detect H capsulatum polysaccharide antigen in localized or chronic infection is considerably lower. Recent studies suggest that this test may also have a role in monitoring response to treatment. At present, this test is performed at only one laboratory in the United States.
Histopathological Examination
Histopathological evaluation of tissues can establish the diagnosis of histoplasmosis earlier than can culture. The site most commonly utilized for this purpose is the bone marrow, but other tissues such as lungs, skin, lymph nodes, liver, or respiratory tract secretions or washings can be evaluated. Organisms are identified through the use of special stains such as the Grocott silver methenamine and Wright-Giemsa methods.
Culture
A positive culture from samples of body fluids or tissue specimens is diagnostic. Newly available blood-culturing techniques, such as the lysis-centrifugation blood-culturing method, have greatly enhanced the yield of blood cultures in disseminated histoplasmosis. In AIDS patients with disseminated histoplasmosis, blood cultures are positive in = 90% of cases. The yield is much lower in chronic and localized infection. It may take 2-4 weeks or more of incubation for colonies of H capsulatum to appear on culture media. After initial growth, rapid (within a few hours) identification of the organism may be performed with the aid of nucleic acid probe testing. Another method, the exoantigen test, which utilizes antigen-antibody reaction to identify the mold forms of dimorphic fungi, may be used for this purpose but usually requires a longer period (~ 2 weeks).
Treatment
Amphotericin B is the drug of choice for immunocompromised patients and for patients with life-threatening disease or central nervous system disease (Box 2). For nonmeningeal, non-life-threatening histoplasmosis, the triazole antifungal agent itraconazole has become the preferred agent. It has supplanted the previous azole mainstay of therapy, ketoconazole, because of its lower incidence of side effects and increased efficacy.
Histoplasmosis in AIDS should be treated with an intensive primary or induction therapy followed by lifelong suppressive or maintenance therapy since complete eradication of the organism is impossible. Amphotericin B is the antifungal agent of choice for induction treatment. Itraconazole is preferred for the maintenance phase of therapy. Nonmeningeal and nonseptic cases may be treated with itraconazole in both the initial and chronic phases of treatment. In situations where neither amphotericin B nor itraconazole may be used (because of intolerance, reactions, or allergy), fluconazole is an alternative option.
Prognosis
Prognosis is variable and hard to generalize. Disseminated histoplasmosis, if untreated, especially in immunocompromised patients, will lead invariably to death.
Prevention & Control
Individuals, such as HIV infected persons, who are at increased risk for acquiring serious infection, should be educated to avoid leisure and work activities that may lead to disturbance of potentially histoplasma-contaminated dust or soil (Box 3). At present, the routine use of azoles (eg, itraconazole) for primary prophylaxis of histoplasmosis in HIV-infected persons is not recommended but remains an option in highly endemic areas. HIV-infected persons diagnosed with histoplasmosis should remain on lifelong suppressive therapy with itraconazole to prevent relapse.
BOX 1. Clinical Syndromes in Histoplasmosis
More Common
Acute primary pulmonary histoplasmosis
Less Common
- Disseminated histoplasmosis (in adults with defective cell-mediated immunity)
- Chronic pulmonary histoplasmosis
- Mediastinal granulomatosis
- Fibrosing mediastinitis
BOX 2. Treatment of Histoplasmosis1
Immunocompromised
Patients
Central Nervous
System Disease
Nonmeningeal, Non-
Life-Threatening
Disease
AIDS Patients
First Choice
- Amphotericin B, 0.7-1.0 mg/kg daily for a total of = 35 mg/kg
- Amphotericin B, 0.7-1.0 mg/kg daily for a total of = 35 mg/kg
- Itraconazole, 200-400 mg/daily for 6-12 m
- Amphotericin B, 0.7-1.0mg/kg for 14 d
- Maintenance: itraconazole, 200 mg orally twice per d2
Second Choice
- Itraconazole, 200-400 mg daily PO
- Itraconazole, 200-400 mg daily PO
- Amphotericin B, 0.7 mg-1.0 mg/kg
- Itraconazole, 200-400 mg/daily
- Although data to make firm recommendations are not yet available. in situations in which neither amphotericin B nor intraconazole can be used, high-dose fluconazole (eg, 800 mg daily) may be an option. The efficacy and safety of itraconazole preparations have not been established in children. A few pediatric patients 3-16 years old have been treated with oral itraconazole (100 mg/d) for systemic fungal infections with no serious unexpected adverse effects.
- After 12 weeks of treatment, the dose of itraconazole can be decreased to 200 mg daily.
BOX 3. Control of Histoplasmosis
Precautions
Individuals who are at risk (eg, immunocompromised, HIV-infected) should avoid activities associated with acquiring infection, such as cleaning chicken coops and exploring caves
Prophylaxis
- Prophylaxis with itraconazole may be conisdered for AIDS patients living in endemic areas
- AIDS patients with histoplasmosis who have completed intitial therapy should receive lifelong suppressive treatment with itraconazole.