Practice Essentials
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.
Histoplasmosis may mimic lung cancer and sarcoidosis. One of the fastest ways to diagnose histoplasmosis is with a bone marrow biopsy. 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).
Presumed ocular histoplasmosis syndrome (POHS) is a distinct clinical entity being studied as a long-term complication of histoplasmosis although this fungus rarely has been isolated or cultured from an eye. It is characterized by peripheral atrophic chorioretinal scars, peripapillary scarring, and maculopathy. Vitritis typically is absent. [34, 35] Treatment options include intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections or photodynamic therapy (PDT). [33] Because there is no active fungi in the eyes, antifungal medications are not typically recommended as treatment for POHS. [35]
However, conjunctival and scleral involvement, though very rare, has been seen in both immunocompromised and immunocompetent individuals with disseminated histoplasmosis infections. These infections are distinct from POHS and should be treated with antifungal agents. [34]
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]
Presumed ocular histoplasmosis syndrome (POHS)
Following initial infection, hematogenous spread to the eye can occur resulting in the formation of a focal granulomatous choroiditis. This phase seldom is observed in humans. Visual loss in POHS is secondary to the development of macular choroidal neovascularization (CNV). Pigment epithelium derived factor (PEDF) was found to have an inhibitory effect on ocular neovascularization. Another peptide, vascular endothelium growth factor (VEGF), is a well-known ocular angiogenic factor. The balance between antiangiogenic factors (eg, PEDF) and angiogenic factors (eg, VEGF) may determine the growth of CNV. This CNV usually grows in the subretinal space in a sheetlike fashion, not in the sub–retinal pigment epithelium (RPE) space. As the CNV grows, reactive hyperplastic RPE tries to surround and envelop the CNV. If successful, the CNV usually involutes.
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.
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]
Patients in endemic areas receiving TNF-α inhibitors (infliximab, etanercept, adalimumab, certolizumab, golimumab) are at increased risk for histoplasmosis. The incidence of histoplasmosis with infliximab has been estimated to be 18.75 per 100,000 persons, while the incidence with etanercept has been estimated at 2.65 per 100,000 persons. [30]
The incidence rate for POHS was 1.35/100,000, the prevalence rate was 0.064%, and macular neovascularization occurred in 17.4% of eyes in Olmsted county in Minnesota during 2006-2015. Furthermore, 16.8% of the affected eyes had a visual acuity of < 20/40. [32]
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.
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]
Patient Education
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]
Prior infection does not prevent future reinfection. Individuals should take similar precautions when facing increased exposure risk.
For patient education resources, see Histoplasmosis.
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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 present diffusely.
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Thoracic histoplasmosis. Another image of the yeast phase of histoplasmosis.
