AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

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. Although the fungus 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 between latitudes 45° north and 30° south in North and Central America.

The soil in endemic areas 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 the fungus through droppings. Contaminated soil can be potentially infectious for years.

Most individuals who are infected 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. Over weeks to months, the inflammatory response produces calcified fibrinous granulomas with areas of caseous necrosis.

Clinical manifestations 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

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 occur in less than 5% of the population.

International

The fungus is predominantly found in river valleys between latitudes 45° north and 30° south in North and Central America.

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 Pleural effusions develop in 40-60% of patients with pericarditis.
• Chronic pulmonary histoplasmosis occurs in patients with underlying lung disease at a rate of 1 case per 100,000 persons per year in endemic areas. Approximately 90% of patients develop cavities that may enlarge and result in necrosis. Untreated cases 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. This form occurs in 4-27% of infected individuals who are immunosuppressed, children, or older individuals. In the subacute form, death occurs within 2-24 months in untreated cases. Approximately 5-10% of patients, treated or not, develop adrenal insufficiency. The acute form, if untreated, results in death within weeks. Approximately 10% of individuals develop hyperacute syndrome, which results in death.

Sex

• The rates of positive results on skin testing for sensitivity to antigens of H capsulatum are similar in males and females.
• Clinical manifestations of disease are more frequent in males than in females, with a male-to-female ratio of 4:1.
• Rheumatologic manifestations tend to occur predominantly in females.

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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

History

A thorough social and occupational history is essential in the initial evaluation. 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.

• Acute pulmonary histoplasmosis
• • Approximately 90% of patients are asymptomatic.
  • If symptoms develop, onset occurs 3-14 days after exposure.
  • Fever, headache, malaise, myalgia, abdominal pain, and chills are common symptoms.
  • 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.
  • Enlarged hilar and mediastinal lymph nodes are present in 5-10% of patients.
  • Occasionally, lymphadenopathy is significant enough to cause local obstructive syndromes. Superior vena cava (SVC) syndrome can occur with compression on the SVC. Significant obstruction of venous drainage may contribute to cerebral symptoms of headache, visual distortion, tinnitus, and altered consciousness.
  • 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 patients with underlying pulmonary disease and is associated with cough, weight loss, fevers, and malaise.
  • 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. Symptoms vary depending on duration of illness.
  • The chronic form is associated with constitutional symptoms. Approximately 50-60% of patients have mouth and gum pain due to mucosal ulcers.
  • 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 acute form may produce fever, worsening cough, weight loss, malaise, and dyspnea. Approximately 5-20% of patients have CNS involvement.
• Presumed ocular histoplasmosis syndrome
• • Approximately 1-10% of individuals living in endemic areas have ocular involvement that is usually asymptomatic.
  • Macula involvement may result in blindness.

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.
  • 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.
  • In 5% of patients, pericarditis may be present and can be associated with rubs.¹ Cardiac tamponade is present in 40% of patients presenting with pericarditis.
  • 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 are present in 30% of patients. 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.
• 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.
  • Approximately 10% of patients have bilateral involvement.
  • 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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Lab 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.
• Sputum cultures
• • Positive yields occur in approximately 10-15% patients with acute pulmonary histoplasmosis.
  • Culture results are positive in 60% of specimens from patients with chronic pulmonary histoplasmosis.
• Blood cultures
• • These findings are positive in 50-90% of patients with acute progressive disseminated histoplasmosis.
  • These findings 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.
  • 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.
• 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.
• Serum and urine antigen detection²
• • 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.
  • 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.³ This may cause a diagnostic confusion with sarcoidosis, particularly if the patient with histoplasmosis also has hilar adenopathy.

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. Pleural effusions are found in fewer than 10% of uncomplicated cases. 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.
• 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.
• 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 tests
• • 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.
  • Cultures are positive in 30-60% of patients with histoplasmal meningitis.
• 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
• • Pericarditis occurs in 10% of patients who are symptomatic. In 40% of these individuals, hemodynamic compromise may occur as a result of cardiac tamponade.
  • 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

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

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.

• Treat acute pulmonary histoplasmosis as follows:
• • No treatment is required for individuals who are asymptomatic.
  • Monitor mild symptoms (without treatment).
  • In patients with prolonged symptoms or overwhelming pulmonary involvement, initiate medical therapy.
• Treat chronic pulmonary histoplasmosis as follows:
• • No treatment is needed for asymptomatic immunocompetent individuals without serious underlying disease.
  • Observe mild interstitial pneumonitis and/or thin-walled (<3 mm) cavities with serial chest radiographs for 2-4 months. If the lesions are persistent, medical treatment is indicated. Patients with cavities with thick walls (>3 mm) or patients who are immunocompromised should receive medical treatment.
  • Persistent cavitations despite multiple courses of medical treatment warrant surgical consideration.
• Initiate medical therapy for all patients with progressive disseminated histoplasmosis and meningitis. In severe cases of CNS infection, administer intrathecal or intraventricular injections in addition to intravenous antifungal therapy.
• Hemodynamic and respiratory compromise from pericardial and pleural involvement warrants immediate procedural intervention. Perform thoracentesis or pericardiocentesis with severe pleural effusions and pericardial tamponade, respectively.
• Cutaneous and rheumatologic lesions are self-limiting. Therapy is indicated only for prolonged episodes or in individuals who are immunosuppressed.
• Treat extensive maculopathy in presumed ocular histoplasmosis with steroids.

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
• • Approximately 10% of symptomatic patients develop pericarditis. Cardiac tamponade occurs in 40% of these individuals.
  • Pericardiocentesis is required to restore hemodynamic stability.
• Cardiothoracic or ophthalmologic surgeon: Such surgery may be needed if complications arise or if further diagnostic options are required.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

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

Drug Category: 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.

Drug Category: 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.

Drug Category: Corticosteroids

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

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

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.
• Chronic pulmonary histoplasmosis
• • Approximately 50% of thin-walled cavities resolve spontaneously.
  • 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. Approximately 80% of patients have adrenal involvement, with 5-10% requiring support for adrenal insufficiency regardless of antimicrobial therapy. Histoplasmal meningitis or mass lesions occur in 10-25% of patients.
  • 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.
• 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%. Routine examination is important to monitor for relapses, whether or not maintenance therapy is initiated.
• Presumed ocular histoplasmosis
• • Monitor the progression of maculopathy with routine ophthalmologic evaluations.
  • Consider laser or prednisone treatment for progressive disease.

In/Out Patient Meds

• Antifungals
• • Ketoconazole is the drug of choice for treating prolonged mildly symptomatic acute pulmonary histoplasmosis. It is administered for 3-6 weeks. Ketoconazole can be used in patients who are immunocompromised with cutaneous or rheumatologic histoplasmal infection or in patients who are immunocompetent with a prolonged course of illness. Use ketoconazole as an alternative to amphotericin B in chronic pulmonary histoplasmosis and chronic/subacute disseminated progressive pulmonary histoplasmosis. Duration of treatment is 6-12 months. Although not routinely prescribed, this antifungal has been used to decrease or halt the progression of enlarging histoplasmomas or granulomatous lymphadenopathy. Therapy may be initiated during hospitalization and continued in an outpatient setting.
  • Itraconazole may be used as an alternative to ketoconazole.⁴ Indications are similar. Itraconazole may additionally be used as an alternative to amphotericin B as antifungal maintenance for acute progressive disseminated histoplasmosis.
  • 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.
• 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.
  • Under the guidance of an ophthalmologist, use high-dose steroids to treat extensive maculopathy.

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.
• 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. Despite treatment, the relapse rate is 20%. 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.
• 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.
• Relapse rate in chronic pulmonary histoplasmosis is 20%.
• 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.
• 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. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Medical/Legal 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.

FURTHER READING

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

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

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

1. 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].
2. 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].
3. Davies SF, Rohrbach MS, Thelen V, Kuritsky J, Gruninger R, Simpson ML, et al. Elevated serum angiotensin-converting enzyme (SACE) activity in acute pulmonary histoplasmosis. Chest. Mar 1984;85(3):307-10. [Medline].
4. Wheat J, Hafner R, Wulfsohn M, Spencer P, Squires K, Powderly W, 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].
5. Bennish M, Radkowski MA, Ripon JW. Cavitation in acute histoplasmosis. Chest. Oct 1983;84(4):496-7. [Medline].
6. 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].
7. Goldman M, Johnson PC, Sarosi GA. Fungal pneumonias. The endemic mycoses. Clin Chest Med. Sep 1999;20(3):507-19. [Medline].
8. Goodwin RA, Alcorn GL. Histoplasmosis with symptomatic lymphadenopathy. Chest. Feb 1980;77(2):213-5. [Medline].
9. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore). Jul 1981;60(4):231-66. [Medline].
10. 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].
11. Paya CV, Roberts GD, Cockerill FR 3rd. Transient fungemia in acute pulmonary histoplasmosis: detection by new blood-culturing techniques. J Infect Dis. Aug 1987;156(2):313-5. [Medline].
12. Salzman SH, Schindel ML, Aranda CP, Smith RL, Lewis ML. The role of bronchoscopy in the diagnosis of pulmonary tuberculosis in patients at risk for HIV infection. Chest. Jul 1992;102(1):143-6. [Medline].
13. Salzman SH, Smith RL, Aranda CP. Histoplasmosis in patients at risk for the acquired immunodeficiency syndrome in a nonendemic setting. Chest. May 1988;93(5):916-21. [Medline].
14. Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore). Sep 1997;76(5):339-54. [Medline].
15. Wheat LJ. Systemic fungal infections: diagnosis and treatment. I. Histoplasmosis. Infect Dis Clin North Am. Dec 1988;2(4):841-59. [Medline].
16. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system. A clinical review. Medicine (Baltimore). Jul 1990;69(4):244-60. [Medline].
17. Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med. Apr 2004;25(2):129-44. [Medline].
18. Wheat LJ, Wass J, Norton J, Kohler RB, French ML. Cavitary histoplasmosis occurring during two large urban outbreaks. Analysis of clinical, epidemiologic, roentgenographic, and laboratory features. Medicine (Baltimore). Jul 1984;63(4):201-9. [Medline].

Article Last Updated: Nov 9, 2007