Histoplasmosis

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, such as caves and chicken coops. Decaying trees and riverbanks also make good habitats for incubations.^[1] 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.^[2]

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.

Clinical presentations include asymptomatic pulmonary histoplasmosis, symptomatic pulmonary histoplasmosis, acute diffuse pulmonary histoplasmosis, chronic pulmonary histoplasmosis, acute respiratory distress syndrome, disseminated histoplasmosis, broncholithiasis, mediastinal granuloma, fibrosing mediastinitis, endobronchial histoplasmosis, and lung nodules.

Combined urine and serum antigen testing have a sensitivity of 90%. Bronchoalveolar lavage antigen testing is more sensitive than urine antigen testing. Fibrosing mediastinitis from histoplasmosis does not require treatment, and hepatosplenic calcifications may be observed. Acute histoplasmosis may not need treatment or may need three months of treatment if symptomatic (itraconazole 200 mg twice daily for 3 months, as compared to 12 months with blastomycosis). Histoplasmosis may mimic lung cancer and sarcoidosis. One of the fastest ways to diagnose histoplasmosis is with a bone marrow biopsy.

A summary of the features of histoplasmosis follows^[3] :

• Location: Midwestern United States, Southeastern United States, Central America, Eastern Canada
• History: Large exposure includes construction sites, birds, caves; low exposure includes living in an endemic area
• Sex/race/ethnicity: No predisposition
• Clinical course: Usually asymptomatic (if symptoms occur they are nonspecific); symptoms < 1 month indicate acute disease; symptoms 1-3 months indicate subacute disease; symptoms >3 months indicate chronic disease
• Acute syndromes: Pneumonia, disseminated disease in immunocompromised persons
• Chronic syndromes: Cavitary pulmonary lung disease, calcified lymph nodes, mediastinal fibrosis
• Physical examination: Uncommon findings include erythema nodosum and erythema multiforme
• CBC count: Thrombocytopenia in disseminated disease
• Serology: Useful in testing immunocompetent individuals with acute or subacute disease.
• Antigen testing: Useful in testing infiltrative or chronic disease in immunosuppressed; urine antigen has ~60% sensitivity; serum antigen has ~60% sensitivity; both combined have >80% sensitivity
• Acute/subacute presentation: Lung infiltrate, lobar pneumonia, micronodular pattern
• Chronic presentation: Cavitary lung lesions
• Immunosuppressed presentation: Diffuse disease.
• Adenopathy: Common, granulomatous mediastinal involvement, can be profound, can calcify
• Extrapulmonary findings: Liver and spleen calcifications, adrenals, oral ulcers, bone marrow
• Differentials: Sarcoidosis and tuberculosis
• Usual treatment: Itraconazole; amphotericin for severe or diffuse disease
• Prognosis: Excellent

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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.^[4] 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.^[5]

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Etiology

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

Living in endemic areas with contaminated soil increases the risk of exposure.

Inoculum size plays a role. Individuals who are immunocompetent and exposed to a low inoculum of histoplasmosis usually are asymptomatic. Inhalation of a large inoculum can cause diffuse pulmonary symptoms that may have a protracted course.

Immune status and comorbid factors affect causation. Reactivation, reinfection, or complications of infection usually occur in individuals who are immunocompromised or immunosuppressed. Cases of histoplasmosis have been reported in patients receiving infliximab. A high index of suspicion should be present in patients on tumor necrosis factor-alpha inhibitors.^[6] Antifungal therapy in these patients is highly effective; however, the safety of restarting tumor necrosis factor inhibitors remains unclear.^[7] Histoplasmosis is rare in solid organ transplant patients; most cases have been reported from the midwest, where it is endemic.^{[5, 8, 9, 10]} Chronic pulmonary histoplasmosis is more prevalent in patients with underlying emphysema.

The risk factors include AIDS, primary immunodeficiencies, drug-induced immunosuppressive states, and the extremes of age.

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Epidemiology

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.^[11]

International

The fungus is predominantly found in river valleys between latitudes 45° north and 30° south in South and Central America.^{[12, 13]}  An outbreak was reported in tunnel workers in the Dominican Republic.^[14]

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.^[15]

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.

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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.^[16]

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.^[15]

Cure rates in histoplasmal meningitis with therapy are 50%, with a high rate of relapse.

In histoplasmal endocarditis, medical therapy alone rarely is curative.

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.^[2] The pericardial fluid is generally exudative.^[12] 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.^[11]

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Patient Education

Inform travelers to endemic areas how to minimize exposure. For patient education resources, see the patient education article Bronchoscopy.

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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.^[17] 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.^[2] Major extrapulmonary manifestations include pericarditis, rheumatologic symptoms, and ocular involvement.

Acute and subacute pulmonary histoplasmosis

Approximately 90% of patients are asymptomatic. If symptoms develop, onset occurs 3-14 days after exposure.^[15] Acute is defined as less than 1 month of symptoms, whereas subacute refers to more than 1 month of symptoms but less than 3 months.^[1] 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.^[11] Enlarged hilar and mediastinal lymph nodes are present in 5-10% of patients. Broncholithiasis can occur if these nodes calcify and erode into the airways, resulting in possible hemoptysis, obstructive pneumonia, and stone expectoration.^[1]

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 of more than 3 months' duration.^[1] Generally, infection involves the apical segments and occurs near emphysematous bullae. Pleural thickening is often seen.^[11] If cavitations are present, hemoptysis, sputum production, and increasing dyspnea are common symptoms. On imaging, upper lobe infiltrates and thick-walled cavities may be seen. Fibrosis and scarring may also be seen.

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.^[12]

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.^[12]

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.^[11]

Presumed ocular histoplasmosis syndrome

Approximately 1-10% of individuals living in endemic areas have ocular involvement that is usually asymptomatic.^[15] 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. It is caused by Histoplasma antigen release. Most patients are young adults, and women are more commonly affected than men.^[11] Associated complications of this condition include pulmonary hypertension, superior vena cava syndrome, airway constriction, and pericarditis with sterile pericardial effusions. Splenic and liver calcifications often help to identify Histoplasma as the causative agent.^[1]

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Physical Examination

Findings on a physical examination are related to the extent and duration of infection. Histoplasmosis may mimic sarcoidosis, and it has been suggested that every patient diagnosed with sarcoidosis should have antigen testing to exclude histoplasmosis.

Acute pulmonary histoplasmosis

Findings are usually minimal. Approximately 5-6% of patients develop rheumatologic manifestations of erythema multiforme, arthritis, and erythema nodosum.^[11] 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.^[15] In 5% of patients, pericarditis may be present and can be associated with rubs.^[18] 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.^[12]

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.

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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.^[15]

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.

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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 and lactate dehydrogenase

Alkaline phosphatase levels are elevated in acute progressive disseminated histoplasmosis and chronic pulmonary histoplasmosis.^[19]

Marked elevations in lactate dehydrogenase levels may be seen in AIDS patients with disseminated histoplasmosis.^{[20, 21]}

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.^[19]

Blood cultures

Blood cultures should be performed in all patients. Results are positive in 50-70% of patients with progressive disseminated histoplasmosis.^[19] 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.^[12]

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.^[15]

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.^[19]

Serum and urine antigen detection ^[22]

These are useful in individuals who are immunocompromised when antibody production may be impaired.

Detection rates in cases of acute progressive disseminated histoplasmosis are 68% with serum assay and 65% with urine assay. With both urine and serum specimens, antigen was detected in 83%. Lower detection rates are observed in acute or chronic pulmonary histoplasmosis.^[11]

Cross-reactivity with Blastomyces and Coccidioides species causes false-positive results. Cross-reactivity may occur in 90% of blastomycosis cases.^[23]

Some patients with acute histoplasmosis may have high serum levels of angiotensin-converting enzyme.^[24] 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.^[12]

In making the diagnosis of progressive disseminated histoplasmosis, blood cultures, blood antigen, urine antigen, and Histoplasma immunodiffusion and complement fixation should be obtained.^[15]

Third-generation antigen assays have increased sensitivity of antigenemia to almost 100% of disseminated histoplasmosis.^[23]

Antigenuria can be detected in as many as 92% of cases with disseminated histoplasmosis, 83% with acute histoplasmosis, 30% with subacute histoplasmosis, and 88% with chronic pulmonary histoplasmosis.^[23]

Negative results do not exclude histoplasmosis, and repeated testing is advised with progressive illness if the initial test results are negative.^[23]

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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.^[15]

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.^[11]

Echocardiography

Transthoracic or transesophageal echocardiography may be helpful if valvular involvement is suspected; endocarditis with Histoplasma species is rarely associated with positive blood cultures.

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Other Tests

Pulmonary function testing

Use pulmonary function testing to 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.

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Procedures

Procedures that may be necessary in the diagnosis of histoplasmosis include the following:

• 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. A 2010 study showed that bronchoalveolar lavage has a sensitivity of 96.8% in detecting antigen for histoplasmosis.^[25]
• 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.^[26]
• Pericardiocentesis: Cultures of pericardial fluid are rarely diagnostic.

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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.

See the images below.

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Thoracic histoplasmosis. Gomori methenamine silver staining performed on lung tissue shows the yeast phase of histoplasmosis.

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Thoracic histoplasmosis. A transbronchial biopsy was performed. Pathologic examination of the specimen revealed multiple noncaseating granulomas prese....

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Thoracic histoplasmosis. Another image of the yeast phase of histoplasmosis.

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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.^[27]

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. Response to therapy should be monitored via chest imaging. Patients should be monitored for several years after treatment for possible relapse.^[27]

Patients with severe infection should be treated with amphotericin B for 1-2 weeks; once the patient is stable, amphotericin B may be changed to itraconazole and should be continued for 1 year.^[28] Patients with acute respiratory distress symptoms may require methylprednisone for 1-2 weeks.^[27]

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.^[11]

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. Relapse may occur in up to 15% of patients.

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.

Broncholithiasis

Antifungal therapy does not play a role. Bronchoscopic or surgical removal may be required.^[27]

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.^[28]

Antifungal therapy is not effective for fibrosing mediastinitis; corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) also are ineffective. Surgery is not recommended. Intravascular stents may be placed to open major vessels compromised by mediastinal fibrosis.

Antifungals are not recommended for pericarditis because it is an inflammatory reaction.

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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.

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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.^[12]

Chronic pulmonary histoplasmosis

Most thin-walled cavities resolve spontaneously.^[12] 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.

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.

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Consultations

Obtain the following 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.

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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. Water sprays should be used during demolition work to decrease dust.^[12]

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.^[28]

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.

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Long-Term Monitoring

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.^[15]

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%.^[29] Routine examination is important to monitor for relapses, whether or not maintenance therapy is initiated.^[15]

Presumed ocular histoplasmosis

Monitor the progression of maculopathy with routine ophthalmologic evaluations. Consider laser or prednisone treatment for progressive disease.

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Amphotericin B is indicated for pregnant women with histoplasmosis who require treatment.

The current Infectious Diseases Society of America guidelines recommend itraconazole for mild-to-moderate infection and amphotericin B for severe infection.^[28] Itraconazole levels should be monitored starting two weeks after the start of treatment. levels greater than 10 mcg/mL should raise concern about toxicity. In addition, hepatic enzymes should be monitored as hepatotoxicity can occur.^[27] The treatment success rate with itraconazole is 80-100%.^[15]

Fluconazole is recommended as a second-line agent. Treatment success is approximately 63% with fluconazole; relapse rates may also be higher.^[11] 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.^[28]

Patients with chronic cavitary pulmonary histoplasmosis should be treated for 1 year.^[12]

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.

Liposomal amphotericin B is preferred over the deoxycholate formulation.

The current Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) guidelines recommend the addition of intravenous methylprednisolone for severe acute pulmonary histoplasmosis.

Treatment is recommended for at least 1 year; immunosuppressed patients may need a longer duration of treatment.^[15]

Patients with relapse of infection (10-15% of patients) after completion of therapy may require lifelong therapy.^[15]

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.

• References

Amphotericin B (Fungizone)

• Dosing, Interactions, etc.

Clinical Context:  Amphotericin B is the drug of choice for overwhelming acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, all forms of progressive disseminated histoplasmosis, meningitis, and endovascular histoplasmosis. It can be used as maintenance therapy for acute progressive disseminated histoplasmosis. Treatment with amphotericin alone without surgical intervention in endovascular histoplasmosis rarely is effective. It is also used after treatment failure with azoles.

• References

Itraconazole (Sporanox, Tolsura)

• Dosing, Interactions, etc.

Clinical Context:  Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Itraconazole can be used as a substitute for ketoconazole. Itraconazole can be used for mildly symptomatic or prolonged acute pulmonary histoplasmosis. It is used to treat cutaneous or rheumatologic manifestations in patients who are immunocompromised and in prolonged courses of illness. It can be used as an alternative to amphotericin B in the treatment of chronic pulmonary histoplasmosis or chronic and subacute progressive disseminated histoplasmosis. Unlike ketoconazole, it can be used as an alternate maintenance therapy after induction with amphotericin B in acute progressive disseminated histoplasmosis.

• References

Voriconazole (Vfend)

• Dosing, Interactions, etc.

Clinical Context:  Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

• References

Posaconazole

• Dosing, Interactions, etc.

Clinical Context:  Posaconazole is a triazole antifungal agent. It blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Posaconazole is available as an oral suspension (200 mg/5 mL). It is indicated for prophylaxis of invasive Aspergillus infections in patients at high risk because of severe immunosuppression.

• References

Fluconazole (Diflucan)

• Dosing, Interactions, etc.

Clinical Context:  Fluconazole is a second-line agent and generally does not have sufficient activity for histoplasmosis. It is a 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. Fluconazole has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. It is available as a tablet for oral administration, as powder for oral suspension, and as a sterile solution for intravenous use. Fluconazole has fewer adverse effects and better tissue distribution than older systemic imidazoles.

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Class Summary

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.

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Ibuprofen (Motrin, Advil)

• Dosing, Interactions, etc.

Clinical Context:  Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

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Class Summary

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. They are commonly used to alleviate inflammation associated with pericarditis, as in histoplasmal pericarditis.

• References

Prednisone (Sterapred)

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is commonly used to decrease the hypersensitivity response to histoplasmal infection. High-dose steroids are used in patients with extensive maculopathy.

• References

Class Summary

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

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