eMedicine Specialties > Pulmonology > Infectious Lung Diseases

Histoplasmosis

Author: Ryan C Chang, MD, Consulting Staff, Department of Internal Medicine, Divisions of Pulmonary and Critical Care, Kaiser Permanente
Coauthor(s): Irawan Susanto, MD, Director of Pulmonary Consultation and Procedures, Associate Professor, Department of Internal Medicine, Divisions of Pulmonary and Critical Care, University of California at Los Angeles School of Medicine
Contributor Information and Disclosures

Updated: Nov 9, 2007

Introduction

Background

Histoplasma capsulatum is a dimorphic fungus that remains in a mycelial form at ambient temperatures and grows as yeast at body temperature in mammals. 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

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.

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