Histoplasmosis

I. What every physician needs to know.

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum (H. capsulatum) and has a broad clinical spectrum ranging from asymptomatic infection to fulminant, potentially fatal disease. A dimorphic fungus, H. capsulatum, is found in soil with highest concentrations in bird and bat droppings; thus activities such as construction, excavation, and spelunking are associated with increased risk of exposure. Histoplasmosis is the most prevalent endemic mycosis in the United States, predominantly in the Ohio and Mississippi valleys, but can also be found in Asia, Africa, and Central and South America.

Humans are infected via the respiratory tract. After the organism reaches the alveolar space, it replicates in macrophages and spreads in the reticuloendothelial system. Most immunocompetent individuals are asymptomatic or report a mild influenza-like illness, but those with compromised cellular immunity can develop a severe, disseminated disease.

II. Diagnostic Confirmation: Are you sure your patient has histoplasmosis?

No specific clinical criteria are available to confirm the diagnosis, but histopathology including fungal stains, cultures, and antigen detection can aid diagnosis in the appropriate clinical and epidemiologic setting.

A. History Part I: Pattern Recognition:

The clinical manifestations of histoplasmosis vary widely and are often determined by level of exposure, host immune status, and presence of underlying structural lung disease. Over 95% of patients are asymptomatic with low levels exposure. For those that develop symptoms, clinical presentations are divided into three distinct categories: acute pulmonary infection, chronic cavitary pulmonary infection, and progressive disseminated disease.

Acute Pulmonary Infection.

The vast majority of patients with an acute primary infection are undiagnosed because most are asymptomatic or experience a mild influenza-like illness that spontaneously resolves in 1-2 weeks. Symptoms generally occur 1-4 weeks after exposure and include fever, headache, non-productive cough, and retrosternal chest pain (presumably due to lymphadenopathy). For patients who seek medical attention, symptoms are often attributed to an atypical pneumonia rather than histoplasmosis.

During the primary infection, individuals exposed to a large inoculum are at increased risk of developing acute diffuse pulmonary histoplasmosis, particularly if very young (<2 years old), elderly, or immunocompromised. Severe pneumonia manifests by hypoxemia, progressive reticulonodular or miliary pulmonary infiltrates, or in severe cases acute respiratory distress syndrome (ARDS).

Chronic Cavitary Pulmonary Infection.

Chronic pulmonary infection can occur among patients with underlying structural lung disease (such as emphysema). The presentation resembles reactivation of tuberculosis with findings of fever, fatigue, decreased appetite, productive cough, and hemoptysis. Imaging often reveals fibrotic upper lobe infiltrates with cavitation.

Progressive Disseminated Histoplasmosis.

Disseminated infection almost always occurs in the immunocompromised individual and spreads hematogenously. Fever and other systemic findings (chills, anorexia, malaise, diarrhea, weight loss, hepatosplenomegaly, anemia, leukopenia, thrombocytopenia) are characteristic. Sepsis syndrome with ARDS can also be seen. In this setting, diffuse mucosal ulcerations, pancytopenia, increased alkaline phosphatase, and profound elevation of serum ferritin are noted. Hemophagocytic syndrome has been reported. In patients with acquired immunodeficiency syndrome (AIDS), histoplasmosis has been noted to cause fever of unknown origin (FUO) in approximately 7% of patients.

Long-term complications of histoplasmosis include:

a) Mediastinal Granulomas – Occur due to persistently enlarged lymph nodes that may caseate and calcify. The clinical presentation ranges from asymptomatic areas of calcification to obstruction of the vasculature, airway, or esophagus.

b) Fibrosing mediastinitis – A rare but serious complication that consists of a prominent fibrotic response to the organism that is usually unilateral and occurs in young adults. The fibrosis may present as superior vena cava syndrome, respiratory distress, pulmonary emboli, or bronchial constriction.

c) Broncholithiasis – A rare complication where calcified lymph nodes erode into adjacent airways and result in cough, hemoptysis, and purulent sputum.

Other uncommon manifestations seen in less than 10% of patients include pericarditis, arthralgias, erythema nodosum, erythema multiforme, and meningitis.

B. History Part 2: Prevalence:

Histoplasmosis is the most prevalent endemic mycosis in the United States, with an estimated 500,000 new cases each year. It is also the most common cause of hospitalizations among the endemic mycoses. Any activities that cause soil disruption or exposure to bird or bat droppings increase risk of exposure, particularly in the Ohio and Mississippi river valleys. The number of conidia (mold from the soil) inhaled determines the severity of the infection.

Individuals with compromised cell-mediated immunity are at increased risk for disseminated infection. At risk individuals include infants, AIDS (CD4 <150 cells/microliter), systemic steroids, hematologic malignancies, and solid organ transplantation. Also at increased risk are patients receiving anti-tumor necrosis factor (TNF) medications such as etanercept, infliximab, and adalimumab, with infliximab conferring the highest risk. Histoplasmosis, when it occurs, usually presents within 6 months of initiation of therapy.

C. History Part 3: Competing diagnoses that can mimic histoplasmosis.

Atypical pneumonia due to Legionella and Mycoplasma infection

While the clinical presentation may be similar, histoplasmosis and other fungal infections are associated with hilar and mediastinal lymphadenopathy. Histoplasmosis should be considered in the setting of rapidly progressive pneumonia among immunosuppressed patients or immunocompetent patients exposed to a large inoculum (particularly in endemic areas).

Tuberculosis

Histoplasmosis, particularly the chronic pulmonary form, can present with several features that overlap with tuberculosis including mediastinal or hilar lymphadenopathy, cavitary lung disease, and calcified pulmonary granulomas. Thus, work-up for tuberculosis is also indicated for patients with these findings.

Sarcoidosis

Sarcoidosis shares multiple clinical features with histoplasmosis, including pulmonary infiltrates, hilar lymphadenopathy, and non-caseating granulomas, among others. Care should be taken to exclude active histoplasmosis in patients with these findings as empiric treatment with steroids may result in rapid dissemination of histoplasmosis.

D. Physical Examination Findings.

Fever, crackles (which are usually not prominent), and hepatosplenomegaly may be seen during the acute infection.
Mouth ulcers are characteristic in disseminated infection in immunocompromised individuals.

E. What diagnostic tests should be performed?

H. capsulatum serum antibody at presentation and at convalescence.
H. capsulatum urine antigen.
Fungal stains and culture.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Fungal culture remains the gold standard but has a lengthy incubation period. Test characteristics and performance vary with the different clinical syndromes. Histoplasmin skin testing is no longer available.

H. capsulatum serum antibody (complement fixation – CF, immunodiffusion – ID) is more helpful in immunocompetent individuals (a 4-fold increase in titers is noted) and among patients with chronic cavitary and chronic disseminated histoplasmosis. False positive tests can be seen in patients with lymphoma, tuberculosis, sarcoidosis, blastomycosis, and coccidioidomycosis.

H. capsulatum urine antigen by enzyme immuno-assay (EIA). False positives are seen in patients with other fungal infections (the endemic area of blastomycosis overlaps with the one for histoplasmosis). Cross-reactivity does not occur with aspergillosis, candidiasis, or cryptococcosis.

Histopathological exam and culture of fluids and tissues are reserved for critically ill patients or in cases of clinical uncertainty. The 2-4 micrometer oval budding yeasts seen in silver or periodic acid-Schiff staining are characteristic.

Acute Pulmonary Infection.

In localized disease, antibody to H. capsulatum is present in over 90% if both complement fixation and immunodiffusion are used. Serum or urine antigen detection may be as low as 40%. The organism may grow in culture on some lung samples, and sensitivity is improved with antigen testing of bronchoalveolar lavage (BAL) fluid. Histology demonstrates caseating and non-caseating granulomas, with few yeast and giant cells. Fungal burden is higher in acute diffuse disease with antigen and antibody testing conveying the highest sensitivity.

Chronic Cavitary Pulmonary Infection.

Most cases have positive antibody serology, often with high titers. Cultures of sputum or bronchoscopy specimens are positive in 65-85% of patients, and urine antigen sensitivity has been estimated at 87.5%.

Disseminated Histoplasmosis.

Antibody to H. capsulatum is present in 70-90%, and the urine antigen is positive in 75% of immunocompetent and 95% of immunocompromised patients. Serum antigen sensitivity approaches 100%. The organism grows in about half of lung samples, and histology demonstrates diffuse and significant macrophage infiltration and giant cells (the lymphocytic response is limited). Lactate Dehydrogenase (LDH) and ferritin are often markedly elevated in disseminated disease, and other laboratory tests (ex. cytopenias, increased transaminases) can suggest specific organ involvement.

Meningitis.

Cultures of cerebrospinal fluid (CSF) are positive in only 50% of cases, and fungal stains are rarely positive. Antigen testing can also be performed on CSF, but the diagnosis remains difficult and is not excluded by a negative CSF test.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest radiograph shows patchy pneumonitis and hilar adenopathy during acute infection. After the acute infection, calcification of the necrotic tissue and lymph nodes is characteristic – especially if calcifications in other organs are noted (liver, spleen). Imaging in chronic infection may reveal fibrotic upper lobe infiltrates with cavitation.
Computed tomography (CT) of the chest may be helpful if cavitary disease, granulomatous mediastinitis, or fibrosis mediastinitis are suspected.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Polymerase chain reaction (PCR) is not well standardized.

III. Default Management.

Treatment of histoplasmosis varies with each of the clinical syndromes.

Acute Pulmonary Infection:

Mild to moderate – No treatment if symptom duration is less than 4 weeks. If symptoms persist after 4 weeks, itraconazole load (200 milligrams [mg] every 8 hours for 3 days) is recommended followed by 200 mg once to twice daily for 6-12 weeks.
Severe or diffuse disease – intravenous antifungal therapy for 1-2 weeks is recommended followed by itraconazole load and 200 mg twice daily for 12 weeks. Intravenous antifungal options include: Liposomal amphotericin B 3millgrams/kilogram/day (mg/kg/day), amphotericin B lipid complex 5 mg/kg/day, or amphotericin B deoxycholate 0.7-1 mg/kg/day. Additionally, methylprednisolone, 0.5-1 mg/kg/day, is recommended for 1-2 weeks for respiratory complications, such as hypoxemia.

Chronic Cavitary Pulmonary Infection: Itraconazole load, followed by 200 mg once to twice daily for at least 12 months.

Progressive Disseminated Histoplasmosis:

Mild to moderate – itraconazole 200 mg twice daily for at least 12 months.
Severe disease – intravenous antifungal therapy (Liposomal amphotericin B 3 mg/kg/day, amphotericin B lipid complex 5 mg/kg/day, or amphotericin B deoxycholate 0.7-1 mg/kg/day for 1-2 weeks) followed by itraconazole load and 200 mg twice daily for at least 12 months.

Central Nervous System: Treatment is similar to disseminated disease, but a higher dose and duration of intravenous antifungal therapy (Lipsomal amphotericin B 5 mg/kg/day for 4-6 weeks) is recommended.

Fluconazole is a second line agent (responses lower than itraconazole). Ketoconazole should not be used.

A. Immediate management.

None in particular.

B. Physical Examination Tips to Guide Management.

None in particular.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

H. capsulatum urine antigen is used to monitor clinical improvement and detect early relapse.

D. Long-term management.

Long-term management is warranted for patients with severe disease, disseminated infection, immunosuppressed patients, chronic cavitary pneumonia, granulomatous mediastinitis, fibrosing mediastinitis, and meningitis.

Itraconazole serum monitoring is recommended after 2 weeks of treatment (a level of 1 microgram/milliliter is desired).

E. Common Pitfalls and Side-Effects of Management.

Renal dysfunction with the use of amphotericin B, particularly with the deoxycholate formulation.