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eMedicine Specialties > Pulmonology > Infectious Lung Diseases

Histoplasmosis

Jazeela Fayyaz, DO, Senior Fellow, Department of Pulmonology, Lenox Hill Hospital
Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Updated: Aug 14, 2009

Introduction

Background

Histoplasma capsulatum is a dimorphic fungus that remains in a mycelial form at ambient temperatures and grows as yeast at body temperature in mammals. Infection causes histoplasmosis. Although the fungus that causes histoplasmosis can be found in temperate climates throughout the world, it is endemic to the Ohio, Missouri, and Mississippi River valleys in the United States. Internationally, the fungus is predominantly found in river valleys in North and Central America, eastern and southern Europe, and parts of Africa, eastern Asia, and Australia. 

The soil in areas endemic for histoplasmosis provides an acidic damp environment with high organic content that is good for mycelial growth. Highly infectious soil is found near areas inhabited by bats and birds. Birds cannot be infected by the fungus and do not transmit the disease; however, bird excretions contaminate the soil, thereby enriching the growth medium for the mycelium. In contrast, bats can become infected, and they transmit histoplasmosis through droppings. Contaminated soil can be potentially infectious for years. Outbreaks of histoplasmosis have been associated with construction and renovation activities that disrupt contaminated soil. In addition, travelers to endemic areas are at risk for histoplasmosis because airborne spores can travel hundreds of feet.[1 ]

Most individuals with histoplasmosis are asymptomatic. Those who develop clinical manifestations are usually immunocompromised or are exposed to a high quantity of inoculum. Histoplasma species may remain latent in healed granulomas and recur, resulting in cell-mediated immunity impairment.

Pathophysiology

H capsulatum in the saprobic state grows in the mycelial form. Macroconidia and microconidia are produced on the hyphae of mycelium and are converted to the yeast form under temperature-controlled regulation.  The aerosolization of conidia and mycelial fragments from contaminated soil results in alveolar deposition via inhalation.

The host defense includes the fungistatic properties of neutrophils and macrophages. T lymphocytes are crucial in limiting the extent of infection. Susceptibility to dissemination is increased markedly with impaired cellular host defenses.

Conversion from the mycelial to the pathogenic yeast form occurs intracellularly. After phagocytosis by macrophages, the yeast replicates in approximately 15-18 hours. Despite fusion with lysosomes, multiplication continues within the phagosomes. Proposed theories suggest that the yeasts may produce proteins that inhibit the activity of lysosomal proteases.

As the host immunity response develops, yeast growth ceases within 1-2 weeks after exposure. Cytokines systemically activate the fungistatic activity of macrophages against intracellular yeasts. With further maturation of the cell-mediated response, delayed-type hypersensitivity to histoplasmal antigens occurs (3-6 wk after exposure). Approximately 85-90% of individuals who are immunocompetent produce a positive response to skin antigen test for Histoplasma species.[2 ]Over weeks to months, the inflammatory response produces calcified fibrinous granulomas with areas of caseous necrosis.

Clinical manifestations of histoplasmosis appear with continued exposure to large inocula. The initial pulmonary infection may disseminate systemically, with hematogenous spread, and produce extrapulmonary manifestations. Hematogenous spread to regional lymph nodes may occur through the lymphatics or the liver and spleen. Progressive disseminated histoplasmosis is rare in adult hosts who are immunocompetent. Systemic spread usually occurs in patients with impaired cellular immunity and typically involves the CNS, liver, spleen, and rheumatologic, ocular, and hematologic systems.

Frequency

United States

Histoplasmosis is the most common endemic fungal infection seen in humans. The central river valleys in the midwestern and south central United States are endemic for histoplasmosis. Approximately 250,000 individuals are infected annually. Clinical manifestations of histoplasmosis occur in less than 5% of the population. Most infections are sporadic, although large outbreaks of histoplasmosis may occur.

Population studies have demonstrated that greater than 80% of young adults from endemic areas (Ohio Valley, Mississippi Valley) have been previously infected with H capsulatum.[3 ]

International

The fungus is predominantly found in river valleys between latitudes 45° north and 30° south in South and Central America.[4 ]

Mortality/Morbidity

Morbidity and mortality are related to the duration and extent of systemic infection.

  • Approximately 90% of patients with acute pulmonary histoplasmosis are asymptomatic. Acute pericarditis can occur in as many as 5% of patients who are symptomatic.[1 ]The pericardial fluid is generally exudative.[4 ] Pleural effusions develop in 40-60% of patients with pericarditis.
  • Chronic pulmonary histoplasmosis occurs in patients with underlying lung disease. Patients develop cavities that may enlarge and result in necrosis. Untreated histoplasmosis may lead to progressive pulmonary fibrosis that results in respiratory and cardiac failure and recurrent infections.
  • Progressive disseminated histoplasmosis occurs in 1 case per 2000 cases in adults who are immunocompetent. Progressive disseminated histoplasmosis occurs in 4-27% of infected children, older individuals, persons who are immunosuppressed. In the subacute form, death occurs within 2-24 months in untreated cases. The acute form, if untreated, results in death within weeks.[3 ]

Sex

The rates of positive results on skin testing for sensitivity to antigens of H capsulatum are similar in males and females. Rheumatologic manifestations tend to occur predominantly in females.[6 ]

Age

Although histoplasmosis can affect individuals of any age, those in extreme age ranges are more prone to developing infection as a result of immature or deteriorated immune defenses.

Clinical

History

A thorough social and occupational history is essential in the initial evaluation of histoplasmosis. Travel or residence in an endemic area or activities involving bats or birds, whether recent or remote, should aid in the differential. Determine if the patient has a drug history or comorbid condition that is contributing to an immunocompromised state. The diagnosis of histoplasmosis should be considered in anyone with an acute febrile respiratory illness who has traveled to an area where histoplasmosis is endemic.[1 ]

  • Acute pulmonary histoplasmosis
    • Approximately 90% of patients are asymptomatic.
    • If symptoms develop, onset occurs 3-14 days after exposure.[6 ]
    • Fever, headache, malaise, myalgia, abdominal pain, and chills are common symptoms; usually, histoplasmosis is self-limited.
    • Individuals exposed to a large inoculum may develop severe dyspnea resulting from diffuse pulmonary involvement.
    • Joint pain and skin lesions occur in 5-6% of patients, mostly in females.[3 ]
    • Enlarged hilar and mediastinal lymph nodes are present in 5-10% of patients.
    • Cough, hemoptysis, dyspnea, and/or chest pain may be present and are related to the degree of compression on the pulmonary airway and circulation. Paratracheal involvement may cause cough or dyspnea because of compression on the trachea or bronchi. Rarely, compression of the esophagus occurs, which causes dysphagia.
  • Chronic pulmonary histoplasmosis
    • This form occurs mostly in older patients with underlying pulmonary disease and is associated with cough, weight loss, fevers, and malaise. 
    • Generally, infection involves the apical segments and occurs near emphysematous bullae. Pleural thickening is often seen.[3 ]
    • If cavitations are present, hemoptysis, sputum production, and increasing dyspnea are common symptoms.
  • Progressive disseminated histoplasmosis
    • This form occurs mostly in hosts who are immunocompromised.
      • Major risk factors include exposure to the fungus as an infant, AIDS with CD4 count of less than 150 cells/µL, use of corticosteroids, hematologic malignancy, and solid organ transplantation.
      • Patients requiring tumor necrosis factor antagonists (eg, etanercept, infliximab) are also an increased risk for disseminated histoplasmosis.[4 ] 
    • After initial exposure, H capsulatum may remain dormant, and reactivation may occur years after initial exposure. The organism may even be transmitted with donated organs.[4 ]
    • Symptoms vary depending on duration of illness. 
      • The acute form may produce fever, worsening cough, weight loss, malaise, and dyspnea. Approximately 5-20% of patients have CNS involvement.
      • The subacute form is associated with a wide spectrum of symptoms that may occur as a result of dissemination and subacute expression in the affected organs. Aside from constitutional symptoms, gastrointestinal involvement may produce diarrhea and abdominal pain. Cardiac involvement resulting in valvular disease, cardiac insufficiency, or vegetations may produce dyspnea, peripheral edema, angina, and fever. CNS involvement may produce headache, visual and gait disturbances, confusion, seizures, altered consciousness, and neck stiffness or pain.
      • The chronic form is associated with constitutional symptoms. Mucous membrane lesions are common in disseminated histoplasmosis.[3 ]
  • Presumed ocular histoplasmosis syndrome
    • Approximately 1-10% of individuals living in endemic areas have ocular involvement that is usually asymptomatic.[6 ]
    • Macula involvement may result in blindness.
  • Mediastinitis
    • Granulomatous mediastinitis may result from enlargement of multiple nodes that undergo necrosis.
    • Fibrosing mediastinitis is an uncommon complication associated with excessive fibrosis that invades the structures of the mediastinum. Most patients are young adults, and women are more commonly affected than men.[3 ]

Physical

Findings on a physical examination are related to the extent and duration of infection.

  • Acute pulmonary histoplasmosis
    • Findings are usually minimal.
    • Approximately 5-6% of patients develop rheumatologic manifestations of erythema multiforme, arthritis, and erythema nodosum.[3 ]
    • Auscultation may rarely reveal rales or wheezes. In cases with high inoculum, individuals may develop severe hypoxemia associated with rales that may mimic acute respiratory distress syndrome. Approximately 10% of patients have asymptomatic pleural effusions.[6 ]
    • In 5% of patients, pericarditis may be present and can be associated with rubs.[7 ]
    • Hepatosplenomegaly may occasionally be present.
  • Chronic pulmonary histoplasmosis: This form may manifest during pulmonary auscultation as nonspecific rales, wheezes, or findings consistent with the extent of underlying pneumonitis, consolidation, or cavitation.
  • Chronic progressive disseminated histoplasmosis: This condition may produce oropharyngeal ulcers involving the buccal mucosa, tongue, gingiva, and larynx. Lesions do not suggest dissemination. Rare cases of isolated lesions have been seen in individuals who are immunocompetent.
  • Subacute progressive disseminated histoplasmosis
    • Gastrointestinal dissemination may result in abdominal mass or intestinal ulcers and lesions. Surgical abdomen may result from intussusception, perforation, or obstruction.
    • CNS dissemination may produce findings associated with possible mass lesions or meningismus, including cranial nerve deficits, muscle weakness, ataxia, altered consciousness, or focal deficits.
    • Cardiac dissemination may result in signs and complications of endocarditis, including murmurs, peripheral edema, pulmonary rales or wheezes, petechia, or skin lesions.
  • Acute progressive disseminated histoplasmosis
    • CNS manifestations that include a mass lesion, encephalopathy, and meningitis (as observed in the subacute form) occur in 5-20% of patients.
    • Hepatosplenomegaly and lymphadenopathy may be present. Superior vena cava (SVC) syndrome may be present with lymphadenopathy severe enough to cause obstruction. The resulting increased venous pressure may manifest as dilatation of collaterals in the neck and thorax; edema of the face, neck, and upper torso; and conjunctiva.
    • Cutaneous lesions are present in 10% of patients. Erythematous maculopapular lesions, ulcerations, purpura, and/or manifestations of endocarditis may be present. Oropharyngeal lesions may also be present.[4 ]
  • Presumed ocular histoplasmosis syndrome
    • Atrophic scars containing foci of lymphocytic cell infiltration termed histo spots may be present and are located posterior to the equator of the eye.
    • If the scars are located on the macula, retinal hemorrhage, detachment, or edema may be present.

Causes

The risk of infection is mostly related to environmental exposure and underlying immune status.

  • Endemic areas: Living in endemic areas with contaminated soil increases the risk of exposure.
  • Inoculum size
    • Individuals who are immunocompetent and exposed to a low inoculum of histoplasmosis are usually asymptomatic.
    • Inhalation of a large inoculum can cause diffuse pulmonary symptoms that may have a protracted course.
  • Immune status and comorbid factors
    • Reactivation, reinfection, or complications of infection usually occur in individuals who are immunocompromised or immunosuppressed.
    • Chronic pulmonary histoplasmosis is more prevalent in patients with underlying emphysema.

Differential Diagnoses

Aspergillosis
Pneumococcal Infections
Blastomycosis
Pneumocystis Carinii Pneumonia
Carcinoid Lung Tumors
Pneumonia, Aspiration
Chlamydial Pneumonias
Pneumonia, Bacterial
Coccidioidomycosis
Pneumonia, Fungal
Legionella pneumonias
Pneumonia, Viral
Lung Cancer, Oat Cell (Small Cell)
Sarcoidosis
Lymphoma, Mediastinal
Tuberculosis
Mediastinal Cysts
Mycoplasma Infections
Pancoast Syndrome

Workup

Laboratory Studies

  • CBC count
    • Mild anemia may be present in chronic pulmonary histoplasmosis.
    • In acute progressive disseminated histoplasmosis, pancytopenia occurs in 70-90% of patients, with a platelet count less than 70,000. Pancytopenia may occur at a lower rate in chronic progressive disseminated histoplasmosis.
  • Alkaline phosphatase: levels are elevated in acute progressive disseminated histoplasmosis and chronic pulmonary histoplasmosis.[8 ]
  • Marked elevations in lactate dehydrogenase levels may be seen in AIDS patients with disseminated histoplasmosis.[9 ]
  • Sputum cultures
    • Positive yields occur in approximately 15% patients with acute pulmonary histoplasmosis.
    • Culture results are positive in 60-85% of specimens from patients with chronic pulmonary histoplasmosis.[8 ]
  • Blood cultures
    • Blood culturing should be performed in all patients, and results are positive in 50-70% of patients with progressive  disseminated histoplasmosis.[8 ]
    • Results are rarely positive in patients with other types of histoplasmosis.
  • Complement-fixing antibodies
    • Titer is considered positive at reciprocal dilutions greater than 1:8. A titer with dilutions greater than 1:32 suggests active histoplasmosis infection. Cross-reactivity with antigens from Blastomyces dermatitidis and Coccidioides immitis may cause a false-positive test result. False positive tests may also occur in persons with lymphoma, tuberculosis,  or sarcoidosis.[4 ]
    • Positive results are expected in 5-15% of cases of acute pulmonary infection 3 weeks after exposure. This figure increases to 75-95% at 6 weeks in cases of symptomatic infection. Test results usually normalize over months, with resolution of infection.
    • Test results may remain positive in 70-90% of cases associated with chronic pulmonary histoplasmosis or chronic progressive disseminated histoplasmosis.[6 ]
  • Immunoprecipitating antibodies
    • This test detects antibodies to 2 glycoproteins, H and M.
    • Anti-M antibody is detected in 50-80% of patients and remains elevated for years.
    • Anti-H antibody is detected in only 10-20% of patients and becomes undetectable within 6 months in the absence of continued infection. Anti-H antibody is more specific for active histoplasmosis.[8 ]
  • Serum and urine antigen detection[10 ]
    • These are useful in individuals who are immunocompromised when antibody production may be impaired.
    • Detection rates in cases of acute progressive disseminated histoplasmosis are 50% with serum assay and 90% with urine assay. Lower detection rates are observed in acute or chronic pulmonary histoplasmosis.[3 ]
    • Cross-reactivity with Blastomyces and Coccidioides species causes false-positive results.
    • Some patients with acute histoplasmosis may have high serum levels of angiotensin-converting enzyme.[11 ]This may cause a diagnostic confusion with sarcoidosis, particularly if the patient with histoplasmosis also has hilar adenopathy.
    • Urine antigen levels may be used to follow the patient's course.[4 ]
    • In making the diagnosis of progressive disseminated histoplasmosis, blood cultures, blood antigen, urine antigen, and Histoplasma immunodiffusion and complement fixation should be obtained.[6 ]

Imaging Studies

  • Chest radiography
    • In acute pulmonary histoplasmosis, findings on chest radiography are usually normal. Occasionally, hilar and mediastinal nodes are enlarged. Patchy infiltrates, predominately in the lower lung fields, may be present. In cases of exposure to high inoculum, diffuse pulmonary involvement correlates with a reticular nodular or miliary pattern on chest radiography. Cavitations are rarely present.
    • Histoplasmomas are healed pulmonary lesions that appear as residual nodules on chest radiography. These coin lesions usually are 1-4 cm in diameter. When yeast forms are present in the core, continued fibrosis in response to the yeast antigens adds to the fibrotic capsule, slowly enlarging the lesions.
    • Hilar lymphadenopathy is rare in chronic pulmonary histoplasmosis, although calcified nodes from prior healed infections may be present. Cavitations, predominantly in the upper lobes, are present in 90% of patients. Underlying emphysematous changes are common. Progressive fibrotic scarring is present in long-standing cases.
    • In chronic progressive disseminated histoplasmosis, chest radiography findings usually do not reveal any active pulmonary disease.
    • In acute progressive disseminated histoplasmosis, hilar lymphadenopathy with diffuse nodular infiltrates is common, occurring in 50% of patients. Findings on chest radiography are normal in 33% of patients initially, but radiographs may reveal pulmonary involvement as the disease progresses.[6 ]
  • CT scanning
    • Head CT scanning is useful in detecting the presence of cerebral histoplasmosis prior to performing a lumbar puncture.
    • Abdominal CT scanning is useful if adrenal involvement is suspected, especially with subacute progressive disseminated histoplasmosis, which results in adrenal infection in 80% of patients. Bilateral adrenal enlargement usually is detectable.[3 ]
  • Echocardiography: Transthoracic or transesophageal echocardiography may be helpful if valvular involvement is suspected; endocarditis with Histoplasma species is rarely associated with positive blood cultures.

Other Tests

  • Pulmonary function testing
    • Determine the extent of pulmonary involvement by evaluating the degree of restrictive defect, the presence of a small airway obstruction, the extent of diffusion impairment, and the presence of hypoxemia.
    • Monitor the progression of pulmonary disease in patients with chronic pulmonary histoplasmosis.

Procedures

  • Lumbar puncture: If CNS involvement is suspected, consider performing a lumbar puncture to evaluate for other possible CNS infections or lesions. Always perform CT scanning prior to lumbar puncture to evaluate for masses or bleeding that may complicate the lumbar procedure.
  • Lavage: Lavage may be required for histiologic evaluation and to obtain cultures to make the diagnosis.
  • Thoracentesis: This procedure may be required if the presence of pleural fluid is causing respiratory distress.
  • Tissue biopsy: Obtaining tissue from pulmonary lesions and lymph nodes by bronchoscopy, percutaneous needle biopsies, or rarely, thoracoscopy may be required to make the diagnosis. Results of biopsy of oropharyngeal ulcers are usually diagnostic.
  • Pericardiocentesis: Cultures of pericardial fluid are rarely diagnostic.

Histologic Findings

Tissue biopsy results may reveal the presence of yeast forms in tissue through hematoxylin and eosin staining. Using the Grocott-Gomori methenamine-silver procedure, yeast may be detected in areas of caseation necrosis from histoplasmomas and calcified lymph nodes. Yeast forms in circulating neutrophils and monocytes are rarely detected using Wright-Giemsa staining. Most biopsies do not reveal organisms.

Treatment

Medical Care

Most infections in individuals who are immunocompetent are self-limiting and do not require therapy. In cases of prolonged infection, cases of systemic infection, or those involving individuals who are immunocompromised, medical treatment is recommended.

  • Acute pulmonary histoplasmosis
    • No treatment is required for individuals who are asymptomatic.
    • Monitor mild symptoms (without treatment).
    • In patients with prolonged symptoms (>4 wk) or those with overwhelming pulmonary involvement, initiate medical therapy with itraconazole for 6-12 weeks.
    • Patients with severe infection should be treated with amphotericin B; once the patient is stable, amphotericin B may be changed to itraconazole and should be continued for 1 year.[12 ]
  • Chronic pulmonary histoplasmosis
    • This often is fatal if not treated; the mortality rate may be as high as 50% without treatment, compared with a mortality rate of 28% with treatment.[3 ]
    • Patients may have a progressive loss of pulmonary function.
    • Patients with cavitary lesions must be treated, in most patients itraconazole is sufficient and should be given for one year.  
    • Persistent cavitations despite multiple courses of medical treatment warrant surgical consideration.
  • Progressive disseminated histoplasmosis and meningitis
    • Initiate medical therapy for all patients with progressive disseminated histoplasmosis and meningitis.
    • Hemodynamic and respiratory compromise from pericardial and pleural involvement warrants immediate procedural intervention. Perform thoracentesis or pericardiocentesis in patients with severe pleural effusions and pericardial tamponade, respectively.
  • Cutaneous and rheumatologic histoplasmosis: Lesions are self-limiting. Therapy is indicated only for prolonged episodes or in individuals who are immunosuppressed.
  • Ocular histoplasmosis: Treat extensive maculopathy in presumed ocular histoplasmosis with steroids.
  • Mediastinal histoplasmosis
    • Treatment for mediastinal granuloma is not recommended in asymptomatic patients; for symptomatic patients, itraconazole may be used for 6-12 weeks, although clinical trials to support this are lacking.[12 ]
    • Antifungal therapy is not effective for fibrosing mediastinitis; corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) also are ineffective. Surgery is not recommended.
    • Antifungals are not recommended for pericarditis because it is an inflammatory reaction.

Surgical Care

Use surgical procedures for diagnostic purposes when other modalities are unrevealing. Intervention is also required when medical therapy is insufficient to alleviate the effects of progressive fibrosis, calcification, and scarring.

  • Thoracic surgery
    • In rare cases when serologic and procedural modalities cannot indicate a definitive diagnosis, consider obtaining sufficient tissue samples using thoracoscopy or by performing an open lung biopsy.
    • Surgical resection of pulmonary cavitary lesions is required when repeated relapses or progressive disease occurs despite repeated intensive medical therapy.
    • Progressive fibrosis of the mediastinum can produce traction or invade into adjacent structures and cause a distorted anatomy. Surgery with spiral vein grafts or vascular stents may be necessary to treat SVC syndrome associated with fibrosing mediastinitis. Surgery may also be required to alleviate scarring, to retain structural integrity, and to alleviate symptoms. The possibility of extensive adhesion and distortion associates surgery with high mortality rates.
    • Mechanical compression by mediastinal and hilar granulomatosis may require surgical excision. However, surgery is risky because of the possibility of spilling necrotic material into the mediastinum and initiating further fibrotic reaction. Patients may develop extensive symptoms from compression of pulmonary, vascular, and rarely, esophageal structures.
  • Cardiac surgery
    • Pericardial window placement may be needed when pericardiocentesis is insufficient to alleviate pericardial tamponade.
    • Endovascular histoplasmosis may result in infected valves and aneurysm formation, which requires surgical excision of infected valves and aneurysm repair. Treating endovascular histoplasmosis with medical therapy alone is rarely curative.
  • Ophthalmologic treatment
    • Laser photocoagulation treatment may be needed in patients with active neovascular membrane formation due to choroiditis.
    • Overgrowth may result in progressive vision loss.

Consultations

Obtain consultations when complications of histoplasmal infection compromise organ systems. Seek out a specialist to perform diagnostic procedures if other modalities do not provide adequate information to make a diagnosis.

  • Pulmonary specialist
    • Bronchoscopy may be needed for diagnostic purposes.
    • Bronchial washings and aspirates are sent for culture and analysis.
    • Transbronchial tissue biopsy provides specimens for histiologic examination.
  • Cardiology specialist: Pericardiocentesis is required to restore hemodynamic stability in patients with pericardial tamponade.
  • Cardiothoracic or ophthalmologic surgeon: Such surgery may be needed if complications arise or if further diagnostic options are required.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antifungals

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.


Fluconazole (Diflucan)

Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tab for oral administration, as powder for oral suspension, and as a sterile sol for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles.

Dosing

Adult

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

Pediatric

12 mg/kg/d IV/PO; not to exceed 600 mg/d

Interactions

CYP450 2C19 and 3A4 inhibitor; levels may increase with hydrochlorothiazide; fluconazole levels may decrease with chronic coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose for renal insufficiency; closely monitor if rashes develop, and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) when taken with underlying medical conditions (eg, AIDS, malignancy) or while taking multiple concomitant medications; not recommended in breastfeeding
Convenience and efficacy of single-dose regimen for treatment of vaginal yeast infections should be weighed against difficulties resulting from higher incidence of adverse reactions reported with oral fluconazole versus intravaginal agents


Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Can be used as substitute for ketoconazole. Indications are similar. Can be used for mildly symptomatic or prolonged acute pulmonary histoplasmosis. Used to treat cutaneous or rheumatologic manifestations in patients who are immunocompromised and in prolonged courses of illness. Can be used as an alternative to amphotericin B in treatment of chronic pulmonary histoplasmosis or chronic and subacute progressive disseminated histoplasmosis. Unlike ketoconazole, can be used as alternate maintenance therapy after induction with amphotericin B in acute progressive disseminated histoplasmosis.

Dosing

Adult

200 mg PO qd; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses)
3- to 6-wk course in acute pulmonary histoplasmosis; 6- to 12-mo course for all other manifestations of histoplasmosis, as indicated
200 mg PO bid as life-long maintenance therapy after amphotericin B in acute progressive disseminated histoplasmosis

Pediatric

Not established; suggested dose of 100 mg/d PO for systemic fungal infections

Interactions

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 are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (ie, lovastatin, simvastatin)
May increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiency


Amphotericin B (Fungizone)

Drug of choice for overwhelming acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, all forms of progressive disseminated histoplasmosis, meningitis, and endovascular histoplasmosis. Can be used as maintenance therapy for acute progressive disseminated histoplasmosis. Treatment with amphotericin alone without surgical intervention in endovascular histoplasmosis rarely is effective. Also used after treatment failure with azoles.

Dosing

Adult

0.7-1 mg/kg/d IV to a total dose of 35 mg/kg; minimum total dose should be 2 g
If life-long antifungal maintenance therapy is desired in acute progressive disseminated histoplasmosis, induce 0.7-1 mg/kg/d IV to total of 20-25 mg/kg; maintenance therapy of 50 mg IV once per wk
Can use itraconazole as alternate maintenance drug
Although unproven, intrathecal or intraventricular injection for severe meningitis is dosed at 0.5-1 mg/5 mL of CSF 3-4 times weekly

Pediatric

Administer as in adults

Interactions

Antineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes such as magnesium and potassium, liver function, CBC, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for > 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)

Nonsteroidal Anti-inflammatory Drugs

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 exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions. Commonly used to alleviate inflammation associated with pericarditis, as in histoplasmal pericarditis.


Ibuprofen (Motrin, Advil)

Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Dosing

Adult

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

Pediatric

20-70 mg/kg/d PO divided tid/qid; start at lower end of dosing range and titrate; not to exceed 2.4 g/d

Interactions

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

Contraindications

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

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.


Prednisone (Sterapred)

Commonly used to decrease hypersensitivity response to histoplasmal infection. High-dose steroids are used in patients with extensive maculopathy.

Dosing

Adult

60-80 mg/d PO; taper over 2-3 wk to treat severe hypersensitivity response in all manifestations of histoplasmosis

Pediatric

4-5 mg/m2/d PO bid/qid; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Follow-up

Further Inpatient Care

  • Acute pulmonary histoplasmosis
    • In rare cases of overwhelming infection, extensive pulmonary involvement may cause severe hypoxemia and acute respiratory distress syndrome.
    • In these instances, initiate antifungal therapy and arrange inpatient supportive respiratory care.[4 ]
  • Chronic pulmonary histoplasmosis
    • Most thin-walled cavities resolve spontaneously.[4 ]
    • Superinfection of cavitations may occasionally require inpatient treatment with appropriate antimicrobials.
  • Progressive disseminated histoplasmosis
    • Chronic infection has a long protracted course over months to years, with long asymptomatic periods. Inpatient care is required when transformation to subacute or acute infection occurs.
    • Subacute infection requires inpatient treatment.
    • Acute infection is life threatening and requires immediate inpatient care. Many of these patients are immunocompromised and have multiorgan involvement. Patients with AIDS usually have other opportunistic infections. Disseminated intravascular coagulation, overwhelming sepsis, and associated gastrointestinal bleeding require ICU monitoring.

Further Outpatient Care

  • To assess resolution of the disease, periodically monitor all patients with histoplasmal infection in an outpatient setting.
  • Chronic pulmonary histoplasmosis
    • Periodically observe thin-walled cavities with chest radiography to monitor for resolution. If symptoms or cavitations persist over a 2- to 4-month period, initiate antimicrobial treatment.
    • All cavitations require close monitoring. The relapse rate for thick-walled cavities is approximately 20%. Patients with progressive disease and those with repeated relapses despite medical therapy need surgical resection. With ongoing infection, pulmonary function progressively declines. Monitor disease progression or resolution with pulmonary function tests.
    • Most relapses occur within 2 years. Chest radiography should be performed every 6 months for the first year and then annually for 4 years to monitor for relapse.[6 ]
  • Progressive disseminated histoplasmosis
    • In chronic and subacute infection, 90% of cases resolve with treatment. Routine examination for relapses is helpful. If relapse occurs, conduct a systemic evaluation for infection by evaluating cardiovascular, neurologic, adrenal, and gastrointestinal systems.
    • Acute infection is associated with a high relapse rate, up to 50% in patients with AIDS. With life-long antifungal maintenance therapy, the relapse rate drops to 10-20%.[13 ]Routine examination is important to monitor for relapses, whether or not maintenance therapy is initiated.[6 ]
  • Presumed ocular histoplasmosis
    • Monitor the progression of maculopathy with routine ophthalmologic evaluations.
    • Consider laser or prednisone treatment for progressive disease.

Inpatient & Outpatient Medications

  • Antifungals
    • The current Infectious Diseases Society of America guidelines recommend itraconazole for mild-to-moderate infection and amphotericin B for severe infection.[12 ]Itraconazole levels should be monitored starting 2 weeks after the start of treatment. The treatment success rate with itraconazole is 80-100%.[6 ]
    • Fluconazole is recommended as a second-line agent. Treatment success is approximately 63% with fluconazole; relapse rates may also be higher.[3 ]Resistance to fluconazole may be seen in AIDS patients with histoplasmosis.
    • Voriconazole and posaconazole are also second-line agents; currently, no clinical trials demonstrate benefit with voriconazole and posaconazole.
    • Ketoconazole is no longer recommended because of its toxicity.
    • Echinocandins are not active against histoplasmosis and should not be used.[12 ]
    • Patients with chronic cavitary pulmonary histoplasmosis should be treated for 1 year.[4 ]
    • Amphotericin B is the drug of choice for treating overwhelming acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, and all forms of progressive disseminated pulmonary histoplasmosis. If using amphotericin B for maintenance therapy for acute progressive disseminated histoplasmosis, continue weekly intravenous treatment in an outpatient setting.
    • Treatment is recommended for at least 1 year; immunosuppressed patients may need a longer duration of treatment.[6 ]
    • Patients with relapse of infection (10-15% of patients) after completion of therapy may require lifelong therapy.[6 ]
    • Also see the guideline summary, Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.[12 ]
  • Anti-inflammatory drugs
    • Use NSAIDs when pericarditis is present.
    • Use steroids to decrease the severe hypersensitivity inflammatory response to histoplasmal antigens. Carefully monitor patients with systemic infections or sepsis and those who are immunosuppressed. Assess for signs of superinfection and worsening sepsis.

Transfer

  • Intensive care monitoring
    • Patients may require inpatient intensive care monitoring, especially those with progressive disseminated histoplasmosis and overwhelming acute progressive histoplasmosis.
    • Respiratory and systemic support is needed for decompensation.
  • Procedural suite
    • If studies are not diagnostic, bronchoscopy may be needed for tissue and lavage samples.
    • Secure facilities for pericardiocentesis in cases of pericardial tamponade.
  • Surgical suite
    • Surgical interventions are rarely needed on an emergency basis.
    • Rarely, a patient with pericardial tamponade that is not amenable to a pericardiocentesis needs placement of a pericardial window.
    • Elective procedures to excise a persistent cavitation, to decompress mediastinal fibrosis or granulomatosis, and to obtain tissue biopsy may be required.

Deterrence/Prevention

  • Most outbreaks are associated with activities that disrupt contaminated soil in endemic areas. Decontaminating infected soil with a 3% formalin solution, with the assistance of local and federal agencies, can prevent aerosolization of conidia and yeast.
  • Educate individuals residing or traveling in endemic areas about exposure risks, including both leisure and work activities. Advance preparation reduces exposure to contaminated soil, bat and bird dwellings, and inoculum.
  • Workers participating in high-risk activities should wear respirators.
  • Itraconazole (200 mg/d) has been shown to be effective in the prevention of histoplasmosis in AIDS patients with CD4 counts of less than 150 cells/µL who are at high risk for infection.[12 ] 
  • Although many exposed immunocompetent individuals from endemic areas do not develop extensive clinical manifestations, reactivation can occur. These individuals, when placed at risk for immunosuppression because of impaired immunity or prolonged drug suppression, may develop active infection from prior lesions. Knowing their history of prior exposures can help to detect and treat subsequent complications.
  • Prior infection does not prevent future reinfection. Individuals should take similar precautions when facing increased exposure risk.

Complications

  • Mediastinal and hilar lymphadenopathies usually resolve. Granulomatous inflammation causes extensive enlargement with caseating necrosis that may fibrose with progressive healing. Occasionally, the lymph nodes may remain enlarged, compressing surrounding structures and distorting anatomic architecture. Postobstructive pneumonia, bronchiectasis, persistent cough, hemoptysis, and/or dysphagia (rarely) are consequences of continued compression. Broncholiths may appear with erosion into a bronchus. Histoplasmal-induced mediastinal fibrosis is the most benign nonmalignant cause of SVC syndrome.
  • Cavitary lesions develop predominantly in chronic pulmonary histoplasmosis.  When persistent or progressive, the cavities are excised surgically. With continued infection, fibrosis and pulmonary scarring continue, causing a progressive deterioration in lung function.
  • Pulmonary lesions heal to become a residual nodule, usually 1-4 cm in diameter. Occasionally, the histoplasmoma may enlarge as an immunologic response to the yeast antigens present within the core. Histoplasmomas are common sites of reactivation.
  • Adrenal insufficiency develops in 5-10% of patients with subacute pulmonary disseminated histoplasmosis, regardless of treatment.[6 ]
  • Overwhelming sepsis with disseminated intravascular coagulation and gastrointestinal bleeding is common with acute progressive disseminated histoplasmosis.
  • Pleural effusions are rare. If present, the effusion is a lymphocytic-predominant exudate. Although not necessary, a pleural biopsy usually reveals noncaseating granulomas. The effusion normally resolves spontaneously over several weeks. No treatment is necessary unless the effusion persists for more than 3-4 weeks or if it occurs in an immunocompromised individual.

Prognosis

  • Acute pulmonary histoplasmosis is associated with a good outcome.
  • Chronic progressive disseminated histoplasmosis has a long-term protracted course, lasting up to years, with long asymptomatic periods.
  • If untreated, subacute progressive disseminated histoplasmosis results in death within 2-24 months.
  • A relapse rate of 50% is associated with acute progressive disseminated histoplasmosis, if treated. The rate decreases to 10-20% with life-long antifungal maintenance. Death is imminent without treatment.[6 ]
  • Cure rates in histoplasmal meningitis with therapy are 50%, with a high rate of relapse.
  • In histoplasmal endocarditis, medical therapy alone rarely is curative.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

  • Histoplasmosis has varied presentations. A thorough evaluation is essential to exclude other etiologies.

Special Concerns

  • Inform travelers to endemic areas how to minimize exposure.
  • Geriatric and pediatric populations without full immunity are at higher risk of infection.
  • Individuals who are immunocompromised from underlying disease, especially AIDS and lymphoma, or from chronic immunosuppression are at higher risk of infection.

References

  1. Outbreak of histoplasmosis among travelers returning from El Salvador--Pennsylvania and Virginia, 2008. MMWR Morb Mortal Wkly Rep. Dec 19 2008;57(50):1349-53. [Medline].

  2. Lowell JR. Diagnosis of histoplasmosis. Ann Intern Med. Feb 1983;98(2):260. [Medline].

  3. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. Jan 2007;20(1):115-32. [Medline].

  4. Kauffman CA. Histoplasmosis. Clin Chest Med. Jun 2009;30(2):217-25, v. [Medline].

  5. Hage CA, Wheat LJ, Loyd J, Allen SD, Blue D, Knox KS. Pulmonary histoplasmosis. Semin Respir Crit Care Med. Apr 2008;29(2):151-65. [Medline].

  6. Picardi JL, Kauffman CA, Schwarz J, Holmes JC, Phair JP, Fowler NO. Pericarditis caused by Histoplasma capsulatum. Am J Cardiol. Jan 1976;37(1):82-8. [Medline].

  7. Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther. Nov 2006;6(11):1207-21. [Medline].

  8. Corcoran GR, Al-Abdely H, Flanders CD, Geimer J, Patterson TF. Markedly elevated serum lactate dehydrogenase levels are a clue to the diagnosis of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis. May 1997;24(5):942-4. [Medline].

  9. Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med. Jan 9 1986;314(2):83-8. [Medline].

  10. Davies SF, Rohrbach MS, Thelen V, et al. Elevated serum angiotensin-converting enzyme (SACE) activity in acute pulmonary histoplasmosis. Chest. Mar 1984;85(3):307-10. [Medline].

  11. [Guideline] Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807-825.

  12. Bennish M, Radkowski MA, Ripon JW. Cavitation in acute histoplasmosis. Chest. Oct 1983;84(4):496-7. [Medline].

  13. Wheat J, Hafner R, Wulfsohn M, et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. Apr 15 1993;118(8):610-6. [Medline].

  14. Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area. Am J Med. Jan 1978;64(1):94-100. [Medline].

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  18. Newman SL, Gootee L, Bucher C, Bullock WE. Inhibition of intracellular growth of Histoplasma capsulatum yeast cells by cytokine-activated human monocytes and macrophages. Infect Immun. Feb 1991;59(2):737-41. [Medline].

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Keywords

histoplasmosis, Histoplasma capsulatum, H capsulatum, Histoplasma species, dimorphic fungus, yeast, bat droppings, bird droppings, acute pulmonary histoplasmosis, pleural effusion, pericarditis, chronic pulmonary histoplasmosis, pulmonary fibrosis, mycelium, macroconidia, microconidia, progressive disseminated histoplasmosis, ocular histoplasmosis syndrome, chronic progressive disseminated histoplasmosis, subacute progressive disseminated histoplasmosis, acute progressive disseminated histoplasmosis

Contributor Information and Disclosures

Author

Jazeela Fayyaz, DO, Senior Fellow, Department of Pulmonology, Lenox Hill Hospital
Jazeela Fayyaz, DO is a member of the following medical societies: American College of Physicians and American Thoracic Society
Disclosure: Nothing to disclose.

Coauthor(s)

Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital
Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Artificial Internal Organs, American Thoracic Society, Physicians for Social Responsibility, and Society of Critical Care Medicine
Disclosure: sepracor None None

Medical Editor

Michael Peterson, MD, Chief of Medicine, Vice-Chair of Medicine, University of California at San Francisco; Endowed Professor of Medicine, University of California at San Francisco-Fresno
Michael Peterson, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H, Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine
Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine
Disclosure: Nothing to disclose.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Ryan C. Chang, MD, and Irawan Susanto, MD, to the development and writing of this article.

Further Reading

Murray & Nadel's Textbook of Respiratory Medicine. 4th ed. 2005. WB Saunders; Philadelphia, Pa. Chapter 34.

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