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Histoplasmosis

Article Last Updated: Jul 2, 2007

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Author:James S Hagood, MD, Director, Pediatric Pulmonary Center, Associate Professor of Pediatrics, Cell Biology and Pathology, Department of Pediatrics, University of Alabama School of Medicine

JamesSHagoodis a member of the following medical societies: American Thoracic Society

Coauthor(s): Asad Ansari, MD, MPH, Pediatric Pulmonary Fellow, Children's Hospital of Alabama, University of Alabama, Birmingham; Gulnur Com, MD, Fellow in Pediatric Pulmonology, Department of Pediatrics, Division of Pulmonary Medicine, University of Alabama School of Medicine

Editors:Glenn J Fennelly, MD, MPH, Director, Division of Pediatric Infectious Diseases, Jacobi Medical Center; Associate Professor, Department of Pediatrics, Albert Einstein College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Larry I Lutwick, MD, Director, Division of Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Professor, Department of Internal Medicine, State University of New York at Downstate; Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Associate Professor, Department of Clinical Pediatrics, State University of New York at Stony Brook; Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Author and Editor Disclosure

Synonyms and related keywords: histoplasmosis, Histoplasma capsulatum, H capsulatum, Histoplasma, fungal pneumonia, tuberculosis, Darling disease, Darling's disease, fibrosing mediastinitis, pulmonary mycosis, systemic mycosis, histoplasmin, chronic pulmonary histoplasmosis, CPH, progressive disseminated histoplasmosis, PDH

INTRODUCTION

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BackgroundHistoplasmosis is a fungal infection caused by the dimorphic fungus Histoplasma capsulatum. The fungus grows saprophytically and develops mycelium with macroconidia and microconidia. The parasitic form is characterized by the production of yeasts 2-4 m in diameter. Histoplasmosis is endemic in the central United States and in other parts of the world with warm humid soil and large populations of migratory birds. It is the most common pulmonary and systemic mycosis of humans. Clinical manifestations vary from a mild flu-like illness that often goes unnoticed to rapidly progressive, often fatal, disseminated disease. The presentation varies depending on the host's immunity and the size of the inoculum.

The principal challenges to the clinician caring for patients with histoplasmosis are to recognize the disease, which can mimic a number of processes, and to rationally use a confusing array of tests for diagnosis and treatment. In 1905, Samuel Darling described histoplasmosis in a patient working in the Panama Canal Zone. As early as the 1940s, Amos Christie, MD, and colleagues used the histoplasmin skin test to demonstrate that numerous patients with abnormal chest radiographs but negative tuberculin results actually had self-limited infection with histoplasmosis.

PathophysiologyFive serotypes of H capsulatum are known, including some avirulent strains. Histoplasma species have a mycelial form at ambient temperatures. The spores of H capsulatum (microconidia) become airborne when soil is disturbed (see Causes).

The initial neutrophil response is ineffective against the yeast form. Macrophages ingest the yeast, but they continue to proliferate. Specific immunity, which occurs 10-21 days after infection, is needed to kill the organisms. Specific helper T cells are able to activate macrophages to form the granulomas that are characteristic of the disease. Natural killer cells mediate extracellular killing, which antibodies enhance.

Pneumonitis, with a predominant mononuclear infiltrate, peaks 2 weeks after infection. Granulomas can form in the pulmonary parenchyma and in the hilar and mediastinal lymph nodes. These lesions can be caseating and may develop calcification and fibrosis over time. In most infections, fungemia likely occurs at some point because splenic granulomas have been observed after asymptomatic infection. In individuals with impaired T cellmediated immunity, other sites of infection include the bone marrow, liver, adrenal glands, CNS, joint spaces, heart valves, and blood vessels.

Reports describe infectious complications in almost every tissue. Reactivation of infection may occur in individuals who become immunosuppressed long after a primary infection; this reactivation accounts for many of the cases observed in nonendemic areas. Reinfection can occur in the setting of heavy conidial burdens, but it is generally mild because of specific immunity.

Recentanimal studies have revealed that IL-1, TNF-alpha, and GR 1(+) cells are important in localizing and controlling Histoplasma infection. YPS3 and cell wall alpha-(1,3)-glucan of Histoplasma are also associated with virulence.

FrequencyUnited States

An estimated 50 million individuals have been infected with H capsulatum. Nationwide, approximately 22% of the population have positive skin-test results for histoplasmin, though the rate may be as high as 80% in endemic areas in the central United States, specifically the Ohio and Mississippi River Valleys (see Image 2). Of the 500,000 individuals who are exposed annually, 50,000-200,000 develop symptoms, and 1500-4000 require hospitalization.

International

Endemic regions for histoplasmosis are found in Central and South America, in the Caribbean, in Africa, and in Asia. However, microfoci are believed to occur anywhere soil conditions are appropriate to support the growth of H capsulatum.Mortality/MorbidityThe overall mortality rate of histoplasmosis is low; most cases spontaneously resolve. In individuals with immunosuppression, progressive disseminated disease has a high mortality rate of 7-23%. Without treatment, disseminated disease is usually fatal. Disseminated infection can localize in any tissue, leading to various complications. Pericarditis and obstruction of mediastinal structures are the principal complications in individuals who are immunocompetent.

RaceNo racial predilection to infection or to disease presentation is apparent.

SexAmong adults, histoplasmosis is described more commonly in men than in women. However, certain clinical manifestations, such as erythema nodosum, are described most commonly in women. These sex differences in infection and disease are not observed in children.

AgeHistoplasmosis occurs at any age. Disseminated disease is more likely to occur in individuals at the extremes of life, unless a person has immunodeficiency. The incidence of disseminated histoplasmosis in children appears to have decreased in the last 30 years. The sex-related differences observed in infection and disease among adults are not observed in children.

CLINICAL

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HistoryClinical presentations vary depending on the size of the inoculum, the host's immune status, and the presence of underlying lung disease. Overt symptoms occur in 5% of individuals after low-level exposure, but the rate of a clinical disease exceeds 75% after heavy exposure in healthy hosts. The incubation time of acute histoplasmosis in previously nonimmune individuals is 9-17 days.

In 80% of patients, symptoms are nonspecific and include fever, chills, myalgias, nonproductive cough, and chest pain. This acute syndrome can range from mild (lasting 1-5 d) to severe (lasting 10-21 d); the latter is associated with weight loss, fatigue, and night sweats. Fatigue may persist for weeks after the acute symptoms resolve.

Syndromes in immunocompetent hosts

Severe acute pulmonary syndrome: After exposure to a large inoculum, patients may develop severe acute pulmonary syndrome, which is characterized by a flulike prodrome with severe fever, chills, fatigue, cough, and chest pain followed by dyspnea and hypoxemia. This hypoxemia may progress to an adult respiratory distress syndrome (ARDS)-like illness (see Image 5).

Histoplasmoma: Histoplasmosis occasionally manifests as a single pulmonary parenchymal nodule, which is observed as a coin lesion on chest radiographs. This nodule is often asymptomatic.

Mediastinal obstructive syndromes (granulomatous mediastinitis)

Mediastinal lymph node enlargementoccurs in most patients with histoplasmosis (see Image 1). In 5-10% of patients with acute pulmonary syndromes, these nodes may be large enough to obstruct contiguous structures, such as airways, esophagus, and large blood vessels. Airway obstruction can lead to a dry or productive cough and dyspnea. In rare cases, erosion of infected nodes into airway walls can lead to hemoptysis, air leak syndromes, broncholithiasis, or lithoptysis.

Esophageal obstruction can cause dysphagia. Airway-esophageal fistulas are reported complications of mediastinal involvement with histoplasmosis. Obstructed pulmonary arteries can produce symptoms of mitral valve obstruction.

Fibrosing mediastinitis is a late complication of mediastinal granuloma, in which sustained and exaggerated fibrosis entraps and impinges on mediastinal structures (see Image 6), which may result in venous obstruction. Fibrosing mediastinitis represents a fibrotic response to a previous episode of histoplasmosis, and some suggest that certain individuals are predisposed to excessive fibrotic responses to Histoplasma antigens. Nonresponses to antifungal treatment and rare isolations of H capsulatum tissue samples indicate that ongoing infection is not likely to play an important role. Presenting symptoms can include cough, dyspnea, wheezing, hemoptysis, dysphagia, and superior vena cava (SVC) obstructive syndrome. In a subset of patients, the process is progressive, leading to death from cor pulmonale or respiratory failure.

Pericarditis: Pericarditis usually results from inflammation in contiguous lymph nodes rather than from fungal infection of the pericardial space and occurs in as m any as 10% of patients with symptomatic acute disease.1 Pericarditis with true infection of the pericardium occasionally occurs in disseminated histoplasmosis.

Rheumatologic syndrome: A syndrome of arthritis, arthralgias, and erythema nodosum is observed in as many as 10% of patients with acute infection. This syndrome is much more common in women than in men. Joint symptoms can persist for months. In an epidemic in the Midwestern United States that occurred in the 1980s, 24 of 381 (6.3%) patients with symptomatic histoplasmosis had rheumatologic symptoms, primarily arthritis or arthralgia.2 Of these, 46% had erythema nodosum.

Syndromes in hosts with an underlying illness or immunodeficiency

Chronic pulmonary histoplasmosis (CPH): CPH most commonly occurs in adults with underlying lung disease (eg, chronic obstructive pulmonary disease [COPD]) and represents 10% of symptomatic cases. Concurrent neoplasia is not uncommon. CPH is rare in children. The presentation of CPH is similar to that of pulmonary tuberculosis. Most patients have productive cough, dyspnea, or chest pain. Systemic symptoms, such as fatigue, fever, and night sweats, are common. The clinical course of untreated CPH is progressive, with spread to contiguous lung. Complications, such as hemoptysis and bronchopleural fistulae, may ensue. Other infections, such as mycobacterial and other fungal infections (eg, aspergillosis), can coexist.

Progressive disseminated histoplasmosis (PDH)

PDH can occur in infants who are immunocompetent but is most likely to affect patients with underlying disorders of cell-mediated immunity. In endemic areas, histoplasmosis accounts for 5% of opportunistic infections among individuals with AIDS and may account for 25% in hyperendemic areas.3 The incidence of histoplasmosis among individuals with AIDS in the United States has declined because of widespread use of antiretroviral therapy. Disseminated histoplasmosis in a patient with HIV can be an AIDS-defining illness. PDH also occurs in individuals with Hodgkin disease or lymphoreticular malignancies or in those receiving immunosuppressive therapy.

In children, the incidence of disseminated histoplasmosis appears to have decreased in the past 3 decades. The onset of PDH can be insidious, with low-grade fever, weight loss, malaise, and oropharyngeal ulcerations. In patients with severely impaired cellular immunity, the presentation of PDH may be acute and rapidly progressive. Presenting symptoms include severe fever, GI symptoms, hepatosplenomegaly, and pancytopenia. In patients with underlying rheumatic disease, this may mimic Felty Syndrome.

Multiorgan system failure and coagulopathy can rapidly ensue. Adrenal involvement is common in PDH (80-90% of patients), and 15% of patients have overt adrenal insufficiency.4 Local manifestations of disseminated disease: Histoplasmosis may include genital ulcers, epididymitis, phimosis, orchitis, cystitis, cholecystitis, pancreatitis, soft-tissue nodules, nodular myositis, panniculitis, carpal tunnel syndrome, osteomyelitis, arthritis, and hypercalcemia. The occurrence of ocular histoplasmosis is controversial because this clinical entity is described in patients who reside exclusively in areas where histoplasmosis in not endemic.

CNS histoplasmosis: Meningitis is a complication in 10% of patients with disseminated disease but occasionally occurs in patients who are immunocompetent.1, 5 Symptoms are usually indolent and chronic; examples include fever, headache, and changes in mental status. Seizures and focal neurologic deficits can occur. Localized lesions in the brain occur in one third of patients with CNS involvement, and isolated spinal cord lesions have been reported.

Adrenal disease may occur as a manifestation of relapsing histoplasmosis several years after the initial episode. Concurrent CNS involvement is common in patients with adrenal involvement. Histoplasmosis should be excluded in all patients with adrenal insufficiency or adrenal masses, and CT scanning to examine the adrenal glands should be considered in patients with disseminated histoplasmosis.

Endocarditis is reported in 4% of patients with disseminated histoplasmosis, and mostly presents with embolic episodes.1Physical Syndromes in immunocompetent hosts

Severe acute pulmonary syndrome: Physical findings are similar to those of diffuse pneumonitis and include increased work of breathing, nasal flaring, accessory muscle use, and diffuse fine crackles. Pleural involvement can present with pleural friction rub or with diminished breath sounds and dullness to percussion.

Mediastinal obstructive syndromes: Obstruction of central airways can produce inspiratory and expiratory wheezes, which may be monophonic and localized. Findings in SVC syndrome include facial swelling, distension of the veins of the neck and upper chest wall, conjunctival injection, and loss of venous pulsations. Pulmonary venous occlusion produces findings consistent with mitral valve stenosis, including a low-pitched diastolic apical murmur.

Pericarditis: Physical findings include chest/abdominal pain, pericardial friction rub, and fever. Signs of hemodynamic compromise can be observed in 40% of patients.1

Rheumatologic syndrome: In a subset of patients, symmetric polyarticular arthritis and erythema nodosum may be seen.

Syndromes in hosts with an underlying illness or immunodeficiency

CPH: Crackles, wheezes, and diminished breath sounds may be heard. Other physical findings are similar to those observed in chronic lung disease. Examples are cyanosis and digital clubbing.

PDH: Patients usually have respiratory distress, inanition, cachexia, pallor, and hepatosplenomegaly. Subcutaneous nodules may be present, as may signs of localized infection in almost any tissue or organ.

Causes The spores of H capsulatum (microconidia) become airborne when soil is disturbed.

High numbers of spores are present in microfoci of soil heavily contaminated with bird or bat droppings, such areas as under bird roosts or in caves (see Image 4).

Urban and suburban outbreaks in endemic areas are often associated with large-scale construction or cleaning projects in which soil is disturbed.

The microconidia (1-5 m in diameter) are easily inhaled and deposited in distal air spaces.

At body temperature, proliferation of the yeast (infective) form of the organism occurs within 3-5 days.

Histoplasmosis can occur in almost all mammals. Although the fungus thrives in bird droppings, birds are not infected. However, bats can be infected with H capsulatum. Direct animal-to-human or human-to-human transmissions are not thought to occur.

DIFFERENTIALS

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BlastomycosisCoccidioidomycosisPneumoniaRespiratory Distress SyndromeSarcoidosisTuberculosisOther Problems to be Considered

Lung abscess Lung cancerLymphoma

WORKUP

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Lab Studies General considerations

The laboratory diagnoses of fungal disease and histoplasmosis are particularly challenging because of the nonspecific clinical findings, the difficulty of culturing organisms, and the confusing array of tests available. MiraVista Diagnostics has established a Web site to assist clinicians.

General laboratory findings in disseminated disease include pancytopenia, elevated liver enzyme levels, hyperbilirubinemia, and elevated serum lactate dehydrogenase (LDH) levels.

Silver stain of tissue sections or Wright stain of smears of peripheral blood or bone marrow aspirates are useful for diagnosing acute disseminated infection or severe pulmonary infection.

Culturing

The criterion standard of diagnosis is culture of the fungus from clinical specimens.

H capsulatum can be recovered from sputum, bronchoalveolar lavage (BAL), skin lesions, blood, or bone marrow on routine fungal cultures, but the organism grows slowly, and plates must be kept as long as 12 weeks. A DNA probe for H capsulatum permits rapid identification.

Blood culture by using the lysis-centrifugation system is somewhat more rapid and increases sensitivity.

Cultures are positive in as many as 85% of patients with PDH or CPH, but they can be falsely negative in about 20% of disseminated cases.

The combination of blood and bone marrow cultures increases the likelihood of positive cultures.

Bronchoscopy is an important diagnostic tool, especially for PDH, with a diagnostic yield of 60% in patients from endemic areas with pulmonary infiltrates and 88% for chronic cavitary histoplasmosis.

Use of several specimens may increase the yield.

Skin testing

Histoplasmin skin testing is not recommended for diagnostic purposes because of the high rate of positive reactions in endemic areas, because of the variable duration of responses to the skin test, and because of skin testing can affect the results of subsequent serologic tests.

Skin testing has been useful as an epidemiologic tool.

Serologic testing

A number of tests have been developed to detect H capsulatum antigen or host antibodies to infection. Tests to detect host antibodies are those more commonly used in the clinical setting. However, test results for antibodies can be falsely negative in patients with disseminated disease because of underlying immunosuppression. On the other hand, patients with disseminated disease have a high fungal burden that enables rapid diagnosis by means of antigen detection. Because of the low fungal burden in patients with mild manifestations, the yield of antigen detection is low.

Antibody levels peak 6 weeks after exposure and decline over 2-5 years. Elevated antihistoplasmal antibody levels might result from a previous infection or after other types of fungal infections.

Antibody testing

The standard serologic tests for histoplasmosis are the immunodiffusion (ID) test and the complement fixation (CF) test.

Histoplasmin, a filtrate of mycelial cultures, is the antigen used in the ID test. Two possible precipitin bands are observed: The H band reflects antibodies formed during active infection and becomes undetectable within 6 months. The M band is present in acute and chronic acute and chronic infection and remains elevated for years. This test is less sensitive than CF and should not be used for screening. M precipitins can be detected in 50-75% of patients with acute histoplasmosis and in almost 80-100% of patients with chronic pulmonary infections.

The CF test uses both mycelial and yeast phase antigens. An antibody to a yeast-phase CF titer of more than 1:32 is consistent with active infection in an endemic area, though an acute titer of more than 1:8 suggests infection, especially in nonendemic areas. CF has higher sensitivity than ID. In acute pulmonary histoplasmosis, the CF result is positive in 90% of patients, whereas the sensitivity of ID is as much as 75%.

A 4-fold rise in titer between acute and convalescent paired sera is diagnostic. Antibodies may clear within months after a brief exposure but might persist for years after a prolonged exposure.

Although CF and ID both are fairly specific, some cross-reactivity with other mycoses occurs.

Radioimmunoassay (RIA) and subsequent enzyme immunoassay (EIA) have been reported to be more sensitive than CF; however, higher background seropositivity in endemic areas and recent studies questioning the sensitivity of these assays compared with CF limit their usefulness.6

Antibody responses can also be measured with enzyme immunoassay or Western blot assay. Although antibodies can be detected faster with these methods than with standard tests, these methods are difficult to standardize and their results are hard to quantitate and interpret.

Antigen testing

Detection of polysaccharide antigen in serum, urine, or BAL of patients with disseminated and acute pulmonary histoplasmosis is a rapid and specific diagnostic method. Urine specimens have high sensitivity, as much as 90% in immunocompetent patients with disseminated or acute pulmonary disease. BAL fluid antigen levels can be higher than those in blood or urine, and matched BAL, urine, and serum specimens have the highest yield.

The recommended approach is first to perform antigen testing with blood and urine from a patient with suspected histoplasmosis. Then, the focus in testing depends on the symptoms. For example, in patients with respiratory symptoms, obtain BAL samples; in those with CNS symptoms, obtain CSF.

Cross-reactivity with other endemic mycoses occurs.

If initial results are positive, the antigen test can be used to monitor the treatment response. Antigen levels decrease with treatment, eventually reaching undetectable levels in patients who are cured or in patients undergoing chronic maintenance treatment. Persistent antigenemia or antigenuria indicates an ongoing infection and supports the continuation of antifungal therapy. Antigen levels rise during relapse, enabling detection in patients whose antifungal treatment has been discontinued.

Recently, Histoplasma antigen detection by means of enzyme-linked immunosorbent assay (ELISA) has become available for different specimens, including serum, urine, BAL, and CSF samples. The sensitivity of this test is reported to be as high as 92% in urine specimens and 82% in serum specimens from patients with disseminated histoplasmosis.1, 7 Although the sensitivity is low in self-limited and CPH, the specificity is as much as 98%.

Molecular diagnostic testing

Preliminary data suggest that polymerase chain reaction (PCR) might improve the accuracy of identifying H capsulatum in tissue specimens.8, 9 DNA probes are also commercially available and are used for definitive identification of positive cultures. DNA probes are also commercially available and are used for confirmation of positive cultures.

A retrospective review of pediatric patients with cancer at St Jude Children's Research Hospital demonstrated that the most rapid and specific tests for histoplasmosis were histopathologic examination of lung biopsy specimens in patients with localized pulmonary infection and Histoplasma-specific antigen detection in the urine of patients with disseminated histoplasmosis.10Imaging Studies Syndromes in immunocompetent hosts

Acute pulmonary syndrome: Plain chest radiography may demonstrate enlarged mediastinal lymph nodes and small reticulonodular infiltrates, with or without small bilateral pleural effusions. More severe acute pulmonary syndromes have more prominent diffuse infiltrates (see Image 5).

Mediastinal obstructive syndromes: Enlarged mediastinal lymph nodes or granulomas, with or without calcification, are often observed on plain chest radiographs (see Image 1). In fibrosing mediastinitis, roentgenographic findings can be subtle and include superior mediastinal widening or carinal splaying (see Image 6). CT demonstrates the extent of mediastinal involvement better than chest radiography. Other studies, such as esophagography, vascular contrast studies, and ventilation-perfusion scanning, can be useful to determine the extent of obstructive involvement of mediastinal structures.

Pericarditis: Echocardiography demonstrates pericardial fluid, but findings are nonspecific.

Syndromes in hosts with an underlying illness or immunodeficiency

CPH: Radiographic manifestations of CPH include apical fibronodular opacities, cavitary lesions, and pleural thickening. CT scanning may be helpful in defining lesions in the context of underlying lung disease.

CNS histoplasmosis: Localized enhancing lesions, single or multiple, can be observed on CT scanning or MRI.

Other Tests Pulmonary function testing may demonstrate fixed or variable airway obstructive patterns in mediastinal obstructive syndromes.

Acute pulmonary disease is most likely to demonstrate a restrictive pattern.

A recent small study found that testing of fecal mucus for Histoplasma was helpful in diagnosing disseminated histoplasmosis in children.

Procedures Pericardiocentesis: Pericarditis may occur in 10% of patients who are symptomatic. Pericardiocentesis yields bloody sterile pericardial fluid.

Bronchoscopy: In acute severe pulmonary syndromes, bronchoscopy with bronchial washing may be indicated to obtain diagnostic material. In chronic pulmonary forms, bronchoscopy with bronchial brushing or transbronchial biopsy may be indicated to obtain samples and to rule out malignancy. Bronchoscopy also may be useful in hemoptysis and broncholithiasis.

Biopsy: Biopsy of the affected tissues can be performed during open procedures or thoracoscopy.

Lumbar puncture: In CNS histoplasmosis, the results of lumbar puncture demonstrate lymphocytic pleocytosis, with elevated protein and normal or low glucose values.

Histologic FindingsPulmonary histoplasmosis has a predominantly mononuclear infiltrate. Multiple granulomas, with multinucleated giant cells, are characteristic findings. Large granulomas are often caseating. The periphery of granulomas may show fibrosis, and calcification of central areas may be present. On hematoxylin and eosin staining, the yeast form of H capsulatum has a false capsule (see Image 3). Special stains, such as Gomori methenamine silver (GMS) or periodic acid-Schiff (PAS), may reveal budding yeast, but the organisms can be mistaken for Pneumocystis carinii and other fungal organisms. In chronic pulmonary forms, in addition to underlying lung disease, vascular involvement, tissue necrosis, and scarring are present. Extensive fibrosis with collagen deposition is observed in fibrosing mediastinitis.

TREATMENT

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Medical CareMost acute forms of histoplasmosis in immunocompetent hosts resolve without specific treatment. Systemic antifungal treatment is indicated for severe acute pulmonary histoplasmosis, CPH, PDH, and any manifestation in an immunocompromised patient. Specific therapy recommendations vary with the presenting syndrome.

Syndromes in immunocompetent hosts

Localized disease: Antifungal therapy is unnecessary in patients with localized disease. However, oral itraconazole is recommended for 6-12 weeks in patients whose symptoms have not improved after 3-4 weeks of observation.

Severe acute pulmonary syndrome: Antifungal therapy (amphotericin B) is indicated for patients presenting with clinically significant dyspnea or hypoxemia. After discharge from the hospital, itraconazole should be used to complete a 12-week course of antifungal therapy. Patients with relatively mild manifestations can be treated with only itraconazole, and treatment should be continued for 3 months. Corticosteroids have also been used for short-term therapy (tapered over 2 wk); however, these agents always should be used with caution in fungal infections because of the risk of impaired cell-mediated immunity with prolonged use.

Mediastinal obstructive syndromes: For patients with clinically significant, symptomatic obstructive symptoms, antifungal treatment should be started. Reports describe successful treatment with oral (eg, itraconazole, ketoconazole) and systemic (amphotericin B) antifungal agents. Surgical resection should be considered for life-threatening obstruction or if a patient's condition fails to improve after 4-6 weeks of antifungal treatment. Surgical interventions do not prevent progression to fibrosing mediastinitis. Although reports mention successful surgical management of fibrosing mediastinitis, the surgical mortality rate is high, and surgeons inexperienced in managing this disorder should not attempt such interventions. Medical management with antifungal agents should be attempted first unless the obstruction is life threatening.

Pericarditis: Anti-inflammatory treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids is the mainstay of management. Progression to constrictive pericarditis is described but rare.

Rheumatologic syndrome: Rheumatologic syndrome often resolves without treatment or with a brief course of NSAIDs.

Syndromes in hosts with an underlying illness or immunodeficiency

CPH: Without antifungal treatment, CPH is progressive, causing loss of pulmonary function in most patients and death in up to half. Amphotericin B has been used most successfully and is effective in 59-100% of cases, but most patients can be treated with itraconazole or ketoconazole for at least 3 months.1 Relapse rates are 10-15% with the last 2 agents; fluconazole is less effective. The preferred treatment is amphotericin B followed by itraconazole for 12-24 months.

PDH

Amphotericin B substantially reduces the mortality rate of PDH. A cumulative dosage of at least 35 mg/kg should be administered to prevent relapse. Liposomal preparations may be substituted to reduce toxicity but may have poor renal penetration.

Many patients have been treated successfully with a change to oral agents after their symptoms initially improve with amphotericin B. Itraconazole is the preferred oral agent, with a 6- to 18-month course of treatment. Patients who cannot tolerate itraconazole should use fluconazole. After an initial 12-week intensive phase with amphotericin B to induce a remission, patients with AIDS require chronic life-long maintenance therapy to prevent relapse. Amphotericin B once or twice a week is effective but inconvenient and not well tolerated.

Azoles are highly effective in most cases, but relapse may occur. Treatment with fluconazole is discouraged because of its reduced efficacy as long-term maintenance therapy for histoplasmosis. Echinocandins should not be used.

Local manifestations of disseminated disease: Endocarditis is very difficult to treat and may require resection of the affected valve and systemic antifungal treatment.

Surgical CareSurgical consultation is indicated for patients with infections complicated by fistulas, hemoptysis, or broncholithiasis. The surgical management of mediastinal obstructive syndromes is somewhat controversial because they may improve with observation or medical therapy. Severe obstruction of the airways or large blood vessels may be life threatening, and immediate intervention may be required.

In general, unroofing and debridement of large granulomas is preferable to excision. Fibrosing mediastinitis is especially difficult to manage because normal structures are encased in collagenous connective tissue. Surgeons in endemic areas often are well versed in the management of these surgically challenging problems.

ConsultationsInfectious disease specialists can assist in the differential diagnosis, in planning appropriate workup, and in choosing therapeutic regimens, particularly for immunocompromised patients.

ActivityBed rest has been recommended for systemic syndromes.

MEDICATION

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Always consult the latest information regarding the drugs of choice (DOCs), the dosages, and the routes of administration. Consultation with infectious diseases specialists can be helpful in choosing appropriate therapy.

Drug Category: Antifungal agentsSystemic antifungal treatment is indicated for severe acute pulmonary histoplasmosis, CPH, PDH, and any manifestation in an immunocompromised patient (see Treatment).

Amphotericin B is the mainstay of therapy for most systemic fungal infections. It is highly effective, but it has potential adverse effects. New lipid formulations of amphotericin B reduce renal toxicity; however, they are expensive and their improvements in efficacy are not proven. A double-blind randomized trial performed to compare liposomal amphotericin B (L-AMB) with the standard formulation (AmB) in patients with AIDS showed that L-AMB was at least as effective as AmB, with marked reduction in renal toxicity.11Echinocandins (eg, caspofungin) should not be used.

Drug NameAmphotericin B (Amphocin, Fungizone)

DescriptionProduced by strain of Streptomyces nodosus. Fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death. DOC for severe or disseminated histoplasmosis.

Adult Dose1 mg IV test dose, then increase by 0.5-1 mg/kg/d; not to exceed 1.5 mg/kg/d; infuse over 2-6 h

Pediatric Dose0.1 mg/kg IV test dose; if tolerated, administer additional 0.4 mg/kg the same day; increase by 0.5-1 mg/kg/d; not to exceed 1.5 mg/kg/d

ContraindicationsDocumented hypersensitivity

InteractionsAntineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; cyclosporine increases risk of renal toxicity

PregnancyB - Usually safe but benefits must outweigh the risks.

PrecautionsCaution in renal impairment; monitor BUN and creatinine qod as dosage increases; patients with renal disease or intolerance of standard preparations may best tolerate lipid or liposomal forms; may offer theoretic advantage of high tissue levels; being compared with standard preparations to treat histoplasmosisMonitor renal function, serum electrolyte (eg, magnesium, potassium levels), liver function, CBCs, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when interrupted for >7 dHypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate amphotericin infusion from leukocyte transfusion); fever and chills not uncommon after first few administrations; rare acute reactions include hypotension, bronchospasm, arrhythmias, and shock

Drug Category: Antifungal agents, azolesThe azole antifungal agents are divided into 2 groups: imidazoles and triazoles. The imidazoles are an older group and include miconazole, ketoconazole, and clotrimazole. The triazoles consist of fluconazole; itraconazole; and the new second-generation azoles ravuconazole (investigational in the United States), voriconazole, and posaconazole.

Itraconazole is more effective than ketoconazole or fluconazole for treatment of histoplasmosis. It is also effective for long-term suppression of histoplasmosis in patients with AIDS.

Voriconazole and posaconazole may be useful in patients who are intolerant of or who fail treatment with AmB or itraconazole. In vitro studies with voriconazole and posaconazole have shown the activity of these agents against H capsulatum, Blastomyces dermatitidis, and Coccidioides immitis. Data from a few animal studies have verified their efficacy in vivo.12, 13Posaconazole is reported to be effective for histoplasmosis in a small number of patients. In a case series, 6 of 7 patients were successfully treated with posaconazole.14 Four of these 6 patients had disseminated infection, and, in all, other therapy failed or was intolerable.

Phase 3 clinical trials for the treatment of invasive fungal infections have been completed, and the US Food and Drug Administration recently approved posaconazole for the prophylaxis of invasive Aspergillus and Candida infections in high-risk, severely immunocompromised patients aged 13 years or older.

Drug NameItraconazole (Sporanox)

DescriptionSynthetic triazole antifungal agent. Can be used in CPH, but relapse rate higher than with amphotericin B.

Adult Dose200 mg PO qd, may increase by increments of 100 mg/d; not to exceed 400 mg/d divided bid

Pediatric DoseNot established, limited data suggest 3-5 mg/kg/d PODisseminated histoplasmosis: 6-8 mg/kg/d POProphylaxis in children with HIV infection: 2-5 mg/kg PO q12-48h

ContraindicationsDocumented hypersensitivity; CNS histoplasmosis

InteractionsInhibits cytochrome P450 (CYP) 3A4; antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses used; rhabdomyolysis may occur with coadministration of beta-hydroxy-beta-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and deathMay increase digoxin levels; coadministration may increase plasma levels of midazolam and triazolam; phenytoin and rifampin may reduce levels (may alter phenytoin metabolism)

PregnancyC - Safety for use during pregnancy has not been established.

PrecautionsCaution in hepatic impairment (monitor liver function); concomitant use of CYP substrates with decreased clearance (eg, cisapride) may result in toxicity

Drug NameKetoconazole (Nizoral)

DescriptionSynthetic imidazole antifungal agent. Can be used for CPH, but relapse rate higher than that of amphotericin B.

Adult Dose200-400 mg PO qd/bid

Pediatric Dose3.3-6.6 mg/kg PO qd

ContraindicationsDocumented hypersensitivity; concomitant use with CYP substrates with decreased clearance (eg, cisapride) may result in toxicity

InteractionsPotent CYP3A inhibitor; isoniazid may decrease bioavailability; coadministration of rifampin decreases effects of both; may increase effect of anticoagulants; may increase toxicity of cyclosporine (adjust dosage) and corticosteroids and other CYP3A substrates; may decrease theophylline levels; administer antacids, anticholinergics, or H2 blockers at least 2 h after ketoconazole dose

PregnancyC - Safety for use during pregnancy has not been established.

PrecautionsEfficacy against H capsulatum less well established than with amphotericin B and itraconazole (use only as alternative to these agents); hepatotoxicity may occur

Drug NameFluconazole (Diflucan)

DescriptionSynthetic triazole antifungal with low plasma protein binding. CNS penetration better than that of imidazoles.

Adult Dose400 mg/d PO/IV for CNS histoplasmosis or for prophylaxis in immunosuppressed patients

Pediatric Dose12 mg/kg/d IV/PO; not to exceed 600 mg/d

ContraindicationsDocumented hypersensitivity

InteractionsInhibits CYP3A4; levels may increase with hydrochlorothiazide; long-term coadministration of rifampin may decrease levels; coadministration may decrease phenytoin clearance; may increase theophylline, tolbutamide, glyburide, and glipizide concentrations; coadministration may increase effects of anticoagulants; may increase cyclosporine concentrations when administered concurrently

PregnancyC - Safety for use during pregnancy has not been established.

PrecautionsDecreased activity against H capsulatum versus other azoles; caution in impaired renal function; periodically monitor liver and renal function

Drug NamePosaconazole (Noxafil)

DescriptionTriazole antifungal agent. Blocks ergosterol synthesis by inhibiting lanosterol 14-alpha-demethylase and the accumulation of sterol precursors. Action disrupts cell membrane. Available as PO susp 200 mg/5 mL. Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Adult Dose200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption

Pediatric Dose13 years: Administer as in adults

ContraindicationsDocumented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine) likely to cause serious toxicities

InteractionsMetabolized by means of uridine diphosphate (UDP) glucuronidation; P-glycoprotein (P-gp) efflux substrate; CYP3A4 inhibitorUDP glucuronidation inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk)Inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)

PregnancyC - Safety for use during pregnancy has not been established.

PrecautionsCommon adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver dysfunction; caution in preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon in package; avoid if breastfeeding

Drug Category: NSAIDsNSAIDs have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions. A brief course of NSAIDs may be required for patients who develop rheumatologic symptoms.

Drug NameNaproxen (Aleve, Naprosyn)

DescriptionFor relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Adult Dose250-500 mg PO bid; may increase to 1.5 g/d for limited periods

Pediatric Dose2 years: 2.5 mg/kg PO q12h; may increase dose, not to exceed 10 mg/kg/d

ContraindicationsDocumented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

InteractionsCoadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase prothrombin time (PT) with anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels when administered concurrently

PregnancyB - Usually safe but benefits must outweigh the risks.

PrecautionsCategory D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion at risk for acute renal failure; leukopenia occurs rarely, is transient, and usually resolves during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and discontinuation may be required

Drug NameIbuprofen (Motrin, Advil, Ibuprin)

DescriptionInhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Adult Dose400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; not to exceed 3.2 g/d

Pediatric Dose20-70 mg/kg/d PO divided tid/qid; start at lower end of dosing range and titrate; not to exceed 2.4 g/d

ContraindicationsDocumented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding

InteractionsCoadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT with anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels when administered concurrently

PregnancyB - Usually safe but benefits must outweigh the risks.

PrecautionsCategory D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

FOLLOW-UP

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Prognosis Most cases of histoplasmosis spontaneously resolve and do not recur.

Reinfection is possible, as is reactivation in individuals from endemic areas who become immunosuppressed.

The mortality rate of disseminated disease even with appropriate treatment is high (7-23%); without treatment it is as high as 80%.

Poor clinical response or relapse may indicate insufficient total dose of antifungal agent, unrecognized immunosuppression, or occult localized infection, such as endocarditis or meningitis.

Relapse occurs in 10-20% of patients with disseminated infection and in as many as 80% of those with AIDS.

Patient Education Prevention of histoplasmosis can be difficult because the source of organisms cannot always be determined, although reports of decontamination of environmental sources have been reported.

Immunocompromised individuals should be counseled to avoid situations in which the likelihood of exposure is high, such as spelunking or outdoor construction projects in endemic areas where significant disturbance of soil occurs.

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS

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Medical/Legal Pitfalls Histoplasmosis has varied and often subtle presentations and has been misdiagnosed as many other entities.

Treating patients who have moved from an endemic area to a nonendemic area and subsequently develop impaired immunity can be challenging for clinicians not familiar with the manifestations of histoplasmosis.

Misdiagnosis as sarcoidosis can be problematic if the patient is treated with systemic corticosteroids or TNF-alpha blocking agents, which may cause progression or dissemination. Fatalities have been described.

MULTIMEDIA

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Media file 1: Hilar lymphadenopathy in an 11-year-old child.

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Media file 2: Map demonstrates the distribution of histoplasmin skin-test positivity by region. Used with permission from the American Thoracic Society.

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Media file 3: Hematoxylin and eosin stain of infected lung tissue. Histoplasma organisms appear to have a false capsule.

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Media file 4: Starling roost in Alabama.

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Media file 5: Acute pulmonary syndrome in a 16-year-old female adolescent.

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Media file 6: Fibrosing mediastinitis with mediastinal widening and tracheal deviation.

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REFERENCES

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