Histoplasmosis

Omar Saeed and J. Jonas Carmichael

The term histoplasmosis refers to any one of a variety of disorders resulting from infection with the thermal dimorphic fungus Histoplasma capsulatum. Pulmonary histoplasmosis is an important cause of morbidity in the United States and Latin America. Up to 50 million people in the United States have been infected by H. capsulatum and up to 500,000 new infections occur each year.

Infections with H. capsulatum are ubiquitous within the major endemic ranges of the Ohio, St. Lawrence, and Mississippi river valleys. The distribution pattern reflects conditions favorable to the organism, such as humidity, moderate climate and soil components. H. capsulatum is fertilized by nitrogen-rich guano from birds or bats. Particularly high guano concentrations occur in areas such as old chicken coops, decayed trees, starling roosts, river or creek banks, and caves with bat colonies. Activities that disturb these sites cause aerosolization of spores and mycelial fragments that can be inhaled. Air currents can carry conidia for miles, exposing distant hosts. Although most cases represent isolated events, numerous epidemics have been traced to activities associated with high-risk exposures creating occupational hazards such as earth moving activities at landfills, construction sites, bird coops, or in caves.

PATHOPHYSIOLOGY

Inhaled spores convert to yeast forms and multiply within airspaces at body temperature. After an ineffective neutrophil response, alveolar macrophages phagocytize the yeast and spread the infection to hilar and mediastinal lymph nodes. The infection spreads hematogeneously and involves distant organs, as evidenced by the calcified granulomas found in the liver and spleen. The severity of the illness depends on the inoculum size as well as the immune status and underlying lung architecture of the host.

Acute Pulmonary Histoplasmosis

The clinical manifestations range from asymptomatic to life-threatening respiratory failure secondary to severe pneumonia. The majority of patients experience an influenza-like syndrome 1 to 2 weeks after infection. Acute pulmonary histoplasmosis is a self-limited condition associated with localized, diffuse or multinodular pulmonary infiltrates. Symptoms usually include fever, chills, headaches, and myalgias. However, if the patient is exposed to a large inoculum (e.g., a closed exposure to a high concentration of bird guano), bilateral infiltrates can progress to respiratory failure requiring mechanical ventilation.

Subacute pulmonary histoplasmosis is characterized by symptomatic illness persisting for more than 1 month, with focal infiltrates and hilar and/or mediastinal lymphadenopathy. Patients develop inflammatory manifestations such as pericarditis, erythema nodosum (in female patients), pleuritis, polyarthiritis, and cystic coalescence of mediastinal lymph nodes known as mediastinal granuloma.

Chronic Pulmonary Histoplasmosis

Infection of distorted lung architecture in an emphysematous lung can cause chronic pulmonary histoplasmosis. Patients have a prolonged duration of symptoms lasting greater than 3 months with cavitary and/or reticulonodular apical infiltrates. Clinical and radiological findings can resemble reactivation tuberculosis with weight loss, dyspnea, productive cough, and hemoptysis.

Progressive Disseminated Histoplasmosis

Acute pulmonary histoplasmosis can be complicated by disseminated infection in patients who have cellular immunodeficiency due to human immunodeficiency virus (HIV) infection, malignancy, immunosuppressive therapy, or advanced age. Besides interstitial pneumonitis, the clinical manifestations are secondary to involvement of spleen, liver, bone marrow, lymph nodes, gastrointestinal tract, adrenal gland, integument, meninges, or heart valves, particularly the aortic valves. Patients often develop hepatosplenomegaly, and 5% to 20% of cases present with focal brain lesions or chronic meningitis.

Other Manifestations

Sites of H. capsulatum infection that heal and condense leading to nodule formation are called histoplasmomas. Typical central and concentric calcification does occur. The time required for a nodule to calcify is unpredictable, which may pose a problem in distinguishing it from malignant growth. Diagnosis can be challenging as some lesions might never calcify and biopsy samples rarely stain positive for the organism. Broncholithiasis occurs when calcified lymph nodes erode into the airway, causing respiratory symptoms. Fibrosing mediastinitis is a reactive, calcified fibrosis which can lead to compression of central vessels and airways. It is considered a late but serious complication of histoplasmosis, especially if it involves both lungs. Approximately 1 in 100,000 infected patients develops this condition, 20% of which will involve both lungs.

IMMUNOCOMPROMISED PATIENTS

Patients with an immunocompromised state, especially T-cell immune deficiencies, are particularly susceptible to histoplasmosis. In its endemic range, histoplasmosis is one of the most prevalent AIDS-defining illnesses. Those coinfected often have untreated severe AIDS with CD4 counts less than 100 cells/μL and high HIV RNA levels. HIV patients not on antiretroviral treatment are much more likely to be symptomatic with primary H. capsulatum infection, and the majority of those patients are found to have progressive disseminated histoplasmosis. Pulmonary involvement without dissemination is uncommon; however, 40% to 50% of patients with progressive disseminated histoplasmosis have pulmonary manifestations. HIV patients with progressive disseminated histoplasmosis manifest the fevers, night sweats, malaise, dyspnea, hepatosplenomegaly, adenopathy, and skin lesions seen in immunocompetent patients but often lack the focal infiltrate seen in acute pulmonary histoplasmosis. Bilateral, diffuse interstitial, or reticulonodular opacities are present in more than half of patients with progressive disseminated histoplasmosis, though the initial imaging may be normal. Other clues of progressive disseminated histoplasmosis include thrombocytopenia, anemia, leukopenia, hepatic enzyme elevation, and adrenal insufficiency. Advanced age, renal insufficiency, fungemia, aspartate aminotransferase (AST) levels greater than 2.5 times the upper limit of normal, and decreased platelet counts have been associated with increased mortality. Severe disease can progress to multiorgan failure or meningitis that carries a mortality approaching 50% even with appropriate antimicrobials.

Cell-mediated immunity is necessary for control of an infection with H. capsulatum. Histoplasmosis is a serious cause of infection in patients taking TNF-α antagonists and has complicated that therapy more than any other endemic mycosis. In a series of 19 patients from an endemic area on TNF-α antagonists who developed histoplasmosis, 17 (89%) patients presented clinically with progressive disseminated histoplasmosis and 15 (79%) had pulmonary involvement. In contrast to HIV patients, radiographic evidence of focal pneumonitis, nodules, or mediastinal lymphadenopathy may predominate, although diffuse, bilateral reticulonodular or military disease is associated with dissemination. The radiographic hallmarks of prior histoplasmosis such as calcified nodules, nodes, or splenic lesions do not portend an increased risk of acute pulmonary histoplasmosis or progressive disseminated histoplasmosis. Etanercept, perhaps by its limited effect on the full array of TNF forms and reduced induction of complement-mediated cell lysis, has been associated with fewer cases of histoplasmosis than infliximab and adalimumab. An immune reconstitution inflammatory syndrome (IRIS) can occur with cessation of TNF-α antagonists following a documented histoplasmosis infection. Although 42% of such patients in one series developed IRIS symptoms, all recovered with antifungals.

Solid organ transplant recipients rarely develop histoplasmosis, even patients with positive pretransplant Histoplasma serologies. A study of transplant recipients performed in an endemic area found no cases of histoplasmosis over 3 years of observation. A previous retrospective study also found it rare in these patients (1 case per 1,000 transplant-person years). If it does occur, unfortunately, it is typically manifested as progressive disseminated histoplasmosis. Cases develop late in comparison to other posttransplant infections, which suggests that the infections are primary rather than reactivation histoplasmosis.

DIAGNOSIS

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