Pediatrics

Histoplasmosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Histoplasmosis? What are the typical findings for this disease?

The clinical manifestations of histoplasmosis are classified according to site (pulmonary or disseminated), duration (acute or chronic), and pattern (primary or reactivation). Histoplasmosis infections are typically asymptomatic or cause mild symptoms from which patients recover without antifungal or other treatment. Clinical features of acute pulmonary histoplasmosis, the most common form of self-limited infection, include fever, cough, chest pain and fatigue.

Disseminated histoplasmosis may be seen in otherwise normal, healthy infants living in endemic areas or in immunocompromised individuals with a history of living in an endemic area. These patients most frequently present with fever, hepatosplenomegaly, and pancytopenia.

Epidemiology - Histoplasmosis is caused by the dimorphic soil fungus Histoplasma capsulatum. H capsulatum occurs most commonly in North America and Central America, but the organism also exists in many diverse areas around the world. In the United States, infection is common in several regions where the disease is endemic, especially the Ohio and Mississippi River Valleys.

Infections occur sporadically, or in outbreaks when weather conditions predispose to spread of spores. Outbreaks of symptomatic histoplasmosis are associated with point sources, or microfoci, of infection. Microfoci are almost always characterized by contamination with bird or bat manure and include bird roosts, bat caves, old buildings, urban parks, decayed trees, or wood piles, and chicken coops. Spores are spread in dry and windy conditions or when occupational or recreational activities disturb contaminated sites. Infection is acquired when microconidia are inhaled.

Pathogenesis - Virtually all cases of primary histoplasmosis are acquired by inhalation of microconidia from the mycelial phase of the organism. Asymptomatic dissemination of infection beyond the lungs is common and cellular immunity is critical in controlling infection. Reactivation of a silent focus of infection that was acquired years earlier can occur when cellular immunity wanes and is the presumed mechanism for disease recurrence in nonendemic areas.

What other disease/condition shares some of these symptoms?

The differential diagnosis of histoplasmosis depends upon the presentation. Other conditions that can share the symptoms of acute pulmonary histoplasmosis include the following:

Blastomycosis

Coccidioidomycosis

Mycoplasma pneumoniae

Chlamydia pneumoniae

Legionella pneumoniae

Chronic pulmonary histoplasmosis, seen primarily in adults, may be mistaken for the following:

Tuberculosis

Nontuberculous mycobacterial infection

Blastomycosis

Coccidioidomycosis

Sporotrichosis

Paracoccidioidomycosis

Sarcoidosis

Histoplasmosis may present with mediastinal/hilar lymphadenopathy disproportionate to pulmonary infiltrates and must be distinguished from lymphoma.

Differential Diagnosis of Disseminated Histoplasmosis:

Septicemia or reticuloendothelial or primary gastrointestinal tract neoplasm

Differential Diagnosis of Histoplasmosis Pericarditis:

Purulent pericarditis

Rheumatologic conditions

What caused this disease to develop at this time?

Infection with H capsulatum occurs during day-to-day activities in areas where H capsulatum is highly endemic or in the course of occupational and recreational activities that disrupt the soil or accumulated dirt and guano in old buildings, on bridges, and in caves where bats have roosted. The inoculum, strain virulence and immune status of the host affect severity of illness.

Patients who are immunosuppressed and are unable to develop effective cell-mediated immunity against the organism are likely to manifest symptomatic disease during the period of acute dissemination. Patients with primary immunodeficiency disorders (including gamma interferon receptor deficiency), human immunodeficiency virus (HIV) infection, or immunosuppressive therapy (including tumor necrosis factor antagonists) may be predisposed to develop disseminated histoplasmosis.

Otherwise healthy infants and children younger than 2 years of age can also develop disseminated histoplasmosis, presumably because of the immaturity of their cell-mediated immune system.

A person who develops an immunosuppressive condition years after leaving an area of endemicity may reactivate a focus of infection and develop disseminated histoplasmosis.

Clinicians should consider histoplasmosis as a possible cause of acute respiratory or influenza-like illness in travelers returning from areas in which histoplasmosis is endemic.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

In situations where the fungal burden is high, such as acute pulmonary histoplasmosis and progressive disseminated histoplasmosis, culture, histopathology and antigen detection are more useful than serologic tests for antibodies. In milder disease, including subacute pulmonary, rheumatologic, pericarditis and mediastinal syndromes, these tests are infrequently positive, and serologic tests for antibodies are especially useful.

In chronic pulmonary histoplasmosis, cultures of respiratory specimens are usually positive, but may require repeated sampling or bronchoscopy. Culture is the definitive method of diagnosis. H capsulatum from bone marrow, blood, sputum, and tissue specimens grows on standard mycologic media in 1 to 6 weeks. The lysis-centrifugation method is preferred for blood cultures, and a DNA probe for H. capsulatum permits rapid identification.

Tissue should be stained with methenamine silver or periodic acid-Schiff stains to best visualize H. capsulatum. Yeasts are typically found within macrophages but can also be seen free in tissues. In patients with disseminated infection, bone marrow, liver, skin, and mucocutaneous lesions usually reveal organisms. Routine peripheral blood smears will sometimes demonstrate yeasts within neutrophils in severely ill patients with disseminated histoplasmosis (Figure 1). A lung biopsy specimen may reveal organisms in patients severely ill with diffuse pulmonary infiltrates.

Figure 1.

Digitally processed hematoxylin-eosin stain of bone marrow aspirate reveals several histiocytes containing intracellular yeastlike forms (original magnification X 1,000). Reprinted from Arch Pediatr Adolesc Med 2003;157:201-5. Copyright (2003). American Medical Association. All rights reserved.

Tests (quantitative enzyme immunoassay) for antigen are most useful in patients with heavy fungal burden. In this setting they are positive in 80-95% of patients and provide results in 24-48 hours. However, antigen detection can be associated with false-negative and false-positive results. The highest sensitivity is observed in urine specimens, but any body fluid may be tested. Antigen testing in bronchoalveolar lavage fluid may improve the sensitivity for diagnosis in pulmonary histoplamosis. If the result is initially positive, the antigen test is also useful in monitoring treatment response, and after treatment, identifying relapse. Cross-reactions occur in patients with blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and Penicilliummarneffii infection; clinical and epidemiologic factors help in differentiating these infections.

Standard antibody tests are the complement fixation (CF) test that uses yeast and mycelial (histoplasmin) antigens, and the immunodiffusion (ID) test. Diagnosis is based on a fourfold rise in CF antibody titer; a single titer of 1:32 is suggestive, but not diagnostic. The ID assay tests for the presence of M and H precipitin bands. An M band develops with acute infection, is often present in chronic forms of histoplasmosis, and persists for months to years. H bands, although infrequently encountered, are highly suggestive of acute infection. The immunodiffusion test is more specific than the complement fixation test, but the complement fixation test is more sensitive. Cross-reacting antibodies can result from Blastomyces dermatitidis and Coccidioides immitis infections.

Although the histoplasmin skin test reagent was important in defining areas endemic for H capsulatum, it was not a very helpful diagnostic test because of cross-reactions with other fungi, interference with CF antibody assays, and insensitivity in patients with disseminated infection. The skin test reagents are no longer available.

Would imaging studies be helpful? If so, which ones?

Most symptomatic patients have acute pulmonary histoplasmosis, an influenza-like illness with nonpleuritic chest pain, hilar or mediastinal lymphadenopathy and mild pulmonary infitrates on plain chest radiograph. Radiographs of asymptomatic residents of endemic areas can reveal single or multiple calcified nodules in the lungs and hilar lymph nodes, and, occasionally, calcifications in the spleen or liver.

Intense exposure to spores can cause severe respiratory tract symptoms and diffuse nodular pulmonary infiltrates on plain chest radiograph (Figure 2).

Figure 2.

Miliary pulmonary histoplasmosis in an immunologically normal 10-year-old boy from Arkansas. There is a bilateral, diffuse, miliary, pulmonary parenchymal pattern of densities with greater involvement of the lower lobes. No hilar adenopathy or pleural effusion is present. Reprinted from Arch Pediatr Adolesc Med 1994;148:833-4 Copyright (1994). American Medical Association. All rights reserved.

A small proportion of patients with acute pulmonary histoplasmosis develop pericarditis as a complication of infection, which occurs predominantly in younger patients. In such cases, radiographic findings suggesting histoplasmosis include pulmonary infiltrates and/or mediastinal lymphadenopathy in additon to an enlarged cardiac silhouette. Echocardiography will demonstrate the presence of pericardial fluid.

Clinical findings in chronic pulmonary histoplasmosis, which has a predilection for older patients, include cough, low-grade fever, night sweats and weight loss. Chest radiographs show interstitial or consolidative infiltrates associated with cavitation or fluid-filled emphysematous bullae.

The diagnosis of fibrosing mediastinitis, a rare fibrotic reaction to prior histoplasmosis, is usually based on computerized tomographic (CT) findings of a densely calcified mediastinal or hilar mass with narrowing or obstruction of the superior vena cava, pulmonary vessels, esophagus, or airways.

Abdominal CT scans may demonstrate hepatomegaly, splenomegaly, lymphadenopathy or adrenal enlargement in disseminated histoplasmosis.

Small ring-enhancing lesions can frequently be found throughout the brain and spinal cord by magnetic resonance imaging (MRI) scans in the most common central nervous system manifestation of H. capsulatum, chronic meningitis. These occur with meningitis or exist as isolated lesions without meningeal involvement. Larger, more typical brain abscesses can also be found.

If you are able to confirm that the patient has histoplasmosis, what treatment should be initiated?

For moderately severe to severe Acute Pulmonary Histoplasmosis

Amphotericin B deoxycholate (1.0 mg/kg daily intravenously for 1-2 weeks) is usually well tolerated, followed by itraconazole (5-10 mg/kg in 2 divided doses (not to exceed 400 mg daily), generally using the solution formulation, for a total of 12 weeks is recommended. A lipid formulation of amphotericin B (3-5 mg/kg daily) may be substituted if the patient is intolerant of amphotericin B deoxycholate. Methylprednisolone (0.5-1.0) mg/kg daily intravenously during the first 1-2 weeks of antifungal therapy is recommended for patients who develop hypoxemia or significant respiratory distress.

Patients with less severe primary pulmonary infections, who are symptomatic for more than one month, may benefit from oral itraconazole given for 6 to 12 weeks, although the effectiveness of this treatment is not well documented.

For Disseminated Histoplasmosis

Amphotericin B deoxycholate (1.0 mg/kg daily for 4-6 weeks is recommended). A lipid formulation of amphotericin B (3-5 mg/kg daily) may be substituted if the patient is intolerant of amphotericin B deoxycholate. Treatment recommended for disseminated histoplasmosis of infancy does not need to be modified in patients found to have CNS involvement.

Amphotericin B deoxycholate (1.0 mg/kg daily for 2-4 weeks) followed by itraconazole (5-10 mg/kg in 2 divided doses) to complete 3 months of therapy is an alternative.

Longer therapy may be needed for patients with severe disease, immunosuppression, or primary immunodeficiency syndromes.

Lifelong suppressive therapy with itraconazole (5 mg/kg daily, up to 200 mg daily) may be required in immunosuppressed patients if immunosuppresssion cannot be reversed and in patients who experience relapse despite appropriate therapy. Blood levels of itraconazole should be obtained to ensure adequate drug exposure.

Antigen levels should be monitored during therapy and for 12 months after therapy is ended to monitor for relapse.

All children with disseminated histoplasmosis should be screened for HIV infection.

What are the adverse effects associated with each treatment option?

Infusion-related reactions to amphotericin b deoxycholate include fever, chills, and sometimes nausea, vomiting, headache, generalized malaise, hypotension, and arrhythmias. Pretreatment with acetaminophen, alone or combined with diphenhydramine, may alleviate febrile reactions. Hydrocortisone (25-50 mg in adults and older children) also can be added to the infusion to decrease febrile and other systemic reactions. Toxicity from amphotericin B deoxycholate can include nephrotoxicity, hepatotoxicity, thrombophlebitis, anemia, and neurotoxicity. Hypokalemia is common.

Lipid-associated formulations of amphotericin B have a role in some children who are intolerant of or refractory to amphotericin B deoxycholate or can be considered in children who have renal insufficiency or are at risk for significant renal toxicity from concomitant medications.

Azole drugs such as itraconazole are easy to administer and have little toxicity, but their use can be limited by the frequency of their interactions with coadministered drugs. These drug interactions can result in decreased serum concentrations of the azole or unexpected toxicity from the coadministered drug.

What are the possible outcomes of histoplasmosis?

Histoplasmosis infections typically are asymptomatic or cause mild symptoms from which persons recover without antifungal or other treatment. The inoculum size, strain virulence, and immune status of the host affect severity of illness.

Disseminated histoplasmosis in children is fatal if untreated.

Adverse effects of amphotericin B are outlined and preventive strategies explained.

Potential drug interactions of itraconazole should be considered, and concurrent medications should be reviewed to avoid potential adverse clinical outcomes when considering the use of azoles, including itraconazole.

What causes Histoplasmosis and how frequent is it?

Histoplasmosis is caused by the dimorphic fungus, Histoplasma capsulatum, which grows in the environment as a microconidia-bearing mold but converts to the yeast phase at body temperature.

Detailed epidemiology

Histoplasmosis is the most common primary systemic mycosis in the United States. Areas of high incidence include the Ohio and Mississippi River valleys where skin test reactivity has been reported to develop in as many as 80% of residents by 18 years of age. Disseminated histoplasmosis can develop in otherwise healthy infants and children younger than 2 years of age. Chronic pulmonary infection in children has not been described. Among persons with HIV infection residing in areas in which histoplasmosis is endemic, symptomatic disease occurs at an annual incidence approaching 5%.

The fungus grows in soil and its growth is thought to be enhanced by bird and bat excrement. Disruption of soil that contains bird or bat excrement is the primary means of aerosolization and exposure to spores. Spores are spread in dry and windy conditions or when occupational or recreational activities disturb contaminated sites. Infection is acquired when microconidia are inhaled.

Activities associated with H. capsulatum exposure and acquisition through the respiratory route include clearing or cleaning bird roosts and chicken coops, spelunking, construction or excavation, wood gathering or cutting, camping and gardening.

Cellular immune dysfunction caused by primary immunodeficiency disorders (e.g., gamma interferon receptor deficiency and hyper immunoglobulin M syndrome) are risk factors for disseminated histoplasmosis.

How do these pathogens/genes/exposures cause the disease?

Infection with H. capsulatum generally results from inhalation of airborne spores, which germinate into yeast forms within alveoli and bronchioles in 3 to 5 days. Macrophages parasitize the yeast forms in nonimmune individuals, leading to cellular death. Infected macrophages may also effect subclinical dissemination through the lymphatic system to regional lymph nodes, liver and spleen. Healing occurs slowly. Necrotic and caseous pulmonary and lymphatic lesions become encapsulated and calcified over months (children) and years (adults).

Other clinical manifestations that might help with diagnosis and management.

Pericarditis and rheumatologic syndromes occur in 5-15% of patients with symptomatic histoplasmosis and represent an inflammatory or immunological response to the infection. These findings respond to antiinflammatory therapy, and not antifungal therapy. Patients with pericarditis present with typical cardiac signs and symptoms. Patients with the rheumatologic syndrome have joint pain with or without arthritis. Erythema nodosum occurs in about half of these cases.

What complications might you expect from the disease or treatment of the disease?

Adrenal insufficiency, nephrocalcinosis, and hypercalcemia have been associated with disseminated histoplasmosis, and mucous membrane lesions and gastrointestinal tract ulcerations may also be seen. Vertical transmission of histoplasmosis from HIV-infected mothers has been reported on two occasions. Mediastinal fibrosis, or fibrosing mediastinitis, is an uncommon, but frequently lethal complication of pulmonary histoplasmosis. Excessive fibrosis progressively envelops the mediastinal structures, following H. capulsatum infection of mediastinal lymph nodes. Most patients are young adults between the ages of 20 and 40.

Are additional laboratory studies available; even some that are not widely available?

There are several reports of diagnosis of histoplasmosis by polymerase chain reaction (PCR) on tissue specimens or body fluids. The future role of PCR-based methods for the diagnosis of histoplasmosis is not yet clear.

How can histoplasmosis be prevented?

Itraconazole can reduce the frequency of histoplasmosis among adolescents and adults who have advanced HIV infection and who live in areas in which histoplasmosis is highly endemic. However, no survival benefit was observed among persons receiving itraconazole.

Prophylaxis with itraconazole at a dose of 200 mg daily can be considered for patients with CD4 counts less than or equal to 150 cells/ul who are at high risk because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (more than 10 cases/100 patient-years). Primary prophylaxis can be discontinued once peripheral blood CD4 counts are greater than 150 cells/ul for 6 months in patients on highly active antiretroviral therapy. Prophylaxis should be restarted if the CD4 counts fall to less than or equal to 150 cells/ul.

Persons in areas of endemic histoplasmosis who perform certain jobs or activities, such as construction and farming, are at risk for acquiring histoplasmosis. Travel clinics and organizers of group travel to areas of endemic histoplasmosis should be informed about the risk for histoplasmosis among travelers with potential exposure to H. capsulatum. Travelers to areas of endemic histoplasmosis who visit caves or areas with high concentrations of bird or bat excrement, or who perform dust-generating activities, should consider using personal protective equipment (e.g., respirators) and dust-suppression strategies (e.g., keeping surfaces wet) to reduce their potential exposure to H. capsulatum.

Active histoplasmosis during the past 2 years may be a basis for itraconazole prophylaxis during immunosuppression, including tumor necrosis factor blocker therapy. The unexpected finding of histoplasmosis in the explanted tissue of either donor or recipient is mostly found in lung transplant recipients and represents an indication for antifungal prophylaxis.

What is the evidence?

Evidence-based guidelines for the management of patients with histoplasmosis were prepared by an Expert Panel of the Infectious Diseases Society of America (Clin Infect Dis 2007; 45:807-25). These updated guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. In evaluating the evidence regarding the management of histoplasmosis, the panel followed a process, which included a systematic weighting of the quality of the evidence and the grade of recommendation.

Additional references include:

Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. "Red Book: 2009 Report of the Committee on Infectious Diseases". American Academy of Pediatrics. 2009. pp. 373-5.

"Centers for Disease Control and Prevention (Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents)". MMWR. vol. 58. 2009. pp. (50-2).

Kaufman, CA. "Histoplasmosis: a clinical and laboratory update". Clin Mirobiol Rev. vol. 20. 2007. pp. 115-32.

"Centers for Disease Control and Prevention. Outbreak of histoplasmosis among travelers returning from El Salvador-Pennsylvania and Virginia, 2008". MMWR. vol. 57. 2008. pp. 1349-53.

Wheat, LJ. "Histoplasmosis: a review for clinicians from non-endemic areas". Mycoses. vol. 49. 2006. pp. 274-82.

Cuellar-Rodriguez, J, Avery, RK, Lard, M. "Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area". Clin Infect Dis. vol. 49. 2009. pp. 710-6.

Hage, CA, Bowyer, S, Tarvin, SE. "Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy". Clin Infect Dis. vol. 50. 2010. pp. 85-92.

Kleiman, MB, Long, SS, Pickering, LK, Prober, CG. "Principles and Practice of Pediatric Infectious Disease". Churchill Livingstone Elsevier. 2008. pp. 1197-1202.

Ongoing controversies regarding etiology, diagnosis, treatment

Flucconazole is less effective than itraconazole in both patients with, and without, HIV infection, and remains a second-line agent for the treatment of histoplasmosis. Clinical data on the newer azoles, voriconazole and posaconazole, for the treatment of histoplasmosis, are limited. Both agents have activity in vitro against H capsulatum.

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