Endemic Mycoses

Definition

Blastomycosis (North American blastomycosis) is an endemic mycosis that primarily causes infection of the lungs and skin and, less commonly, infection of the osteoarticular and genitourinary systems ( Table 308-1 ).

The Pathogen

Blastomyces spp. are thermally dimorphic fungi, and numerous new species have been recently identified. In the mold phase in the environment, the organism produces conidia, which when aerosolized and inhaled cause infection. At 37° C on culture media and in tissues, the organism is a distinctive appearing yeast that is 5 to 20 µm in diameter with a thick refractile cell wall, and single broad-based buds ( Fig. 308-1 ).

Epidemiology

Blastomyces spp. exist in diverse geographic areas worldwide, but most cases of blastomycosis are reported from the south central and north central regions of the United States and the Canadian provinces surrounding the Great Lakes. Blastomycosis also occurs in Africa and the Middle East. The natural niche of B. dermatitidis is thought to be soil and decaying vegetation, especially in areas associated with rivers and lakes. Although most cases occur sporadically, several well-described outbreaks have occurred, often in association with activities along waterways. The typical patient with blastomycosis is a middle-aged man who has an outdoor occupation or hobby. Blastomycosis develops in both hunters and their dogs in endemic areas.

Pathobiology

After the inhalation of conidia, B. dermatitidis transforms into the yeast phase and causes pulmonary infection. Although most patients manifest only pulmonary symptoms, others have cutaneous lesions in the absence of other organ involvement or have disseminated infection. It is likely that most patients have asymptomatic hematogenous dissemination after the initial pulmonary infection, so cutaneous lesions should be viewed as a manifestation of hematogenous spread of the organism. Except in rare instances, blastomycosis is not acquired by inoculation. Cellular immunity involving T lymphocytes and macrophages is an important component of the host response to infection with B. dermatitidis , but neutrophils also play a role. Most patients with blastomycosis are healthy. Patients who are immunosuppressed are more likely to have severe disease. Infection in an immunosuppressed host can occur after new exposure to Blastomyces spp. or less often, from reactivation of a latent focus of infection acquired years earlier.

Clinical Manifestations

Disseminated Infection

Cutaneous lesions are the most common manifestation of disseminated blastomycosis. The lesions, which can be single or multiple, are usually well circumscribed and painless ( Fig. 308-2 ). Papules, nodules, plaques, and ulcers can occur; often they are verrucous and develop multiple punctate draining areas in the center. The lesions clinically mimic those associated with non-tuberculous mycobacteria, other fungal infections, or pyoderma gangrenosum ( Table 408-5 ). An uncommon manifestation, seen in immunocompromised patients, is the appearance of pustular lesions that readily reveal the organism when aspirated.

Another manifestation of disseminated blastomycosis is osteoarticular involvement. Osteomyelitis can be associated with contiguous skin lesions or can appear at sites distant from cutaneous lesions. Genitourinary involvement may be asymptomatic or be associated with signs of prostatism and the presence of a nodule on digital examination. Infrequent findings include laryngeal and oropharyngeal nodules; ocular lesions; central nervous system (CNS) involvement with either meningitis or intracerebral mass lesions; and dissemination to the liver, spleen, and lymph nodes.

Diagnosis

The definitive diagnostic test for blastomycosis is growth of the organism from an aspirate, tissue biopsy specimen, sputum, or body fluid. The mold phase takes several weeks to grow at room temperature. Once growth has occurred, the organism can be rapidly identified as Blastomyces spp. with a highly specific and sensitive DNA probe.

In this setting, the distinctive large, thick-walled yeast with a single broad-based bud (see Fig. 308-1 ) may be identified by: histopathologic examination of cutaneous or pulmonary lesions; cytologic examination of sputum, bronchoalveolar lavage fluid, or other tissue fluids; or calcofluor fluorescent staining of sputum or purulent material from pustular lesions. Identification of characteristic organisms on histopathology allows a tentative diagnosis of blastomycosis and initiation of antifungal therapy before culture results are known.

An enzyme immunoassay for B. dermatitidis cell wall antigens is available for use on serum, urine, or bronchial alveolar lavage fluid. The sensitivity of this assay varies with different reports. Because B. dermatitidis and H. capsulatum share many cell wall antigens, this assay is often positive in patients with histoplasmosis, as well as in those with blastomycosis.

It is helpful to obtain a bone scan in all patients with disseminated blastomycosis because of its propensity to infect bone.

Treatment

With the exception of patients who have acute pulmonary blastomycosis that has totally resolved before the diagnosis is established, all patients with blastomycosis should be treated with an antifungal agent. Patients who have mild-to-moderate pulmonary or disseminated blastomycosis should be treated with itraconazole (oral solution or capsules 200 mg three times a day for 3 days then once or twice daily for 6 to 12 months) to achieve mycologic cure and prevent relapse. If itraconazole is not tolerated, voriconazole or posaconazole can be used under expert guidance. The echinocandins are not active against B. dermatitidis and should not be used.

Patients who have severe pulmonary or disseminated blastomycosis, all patients with CNS infection, and most immunosuppressed patients should be treated initially with a lipid formulation of amphotericin B. The dosage is 3 to 5 mg/kg IV daily, except for CNS infection, for which 5 mg/kg IV daily should be used. After clinical improvement has occurred, usually within 1-2 weeks, therapy can be changed to itraconazole (oral solution or capsules, 200 mg three times a day for 3 days then twice daily) for a total of at least 12 months of therapy. For all patients who are treated with itraconazole, serum itraconazole levels should be determined when steady state has been reached after 2 weeks of therapy to ensure adequate absorption. Serum concentrations should be greater than 1 µg/mL.

Corticosteroids have been helpful as adjunctive therapy for patients with blastomycosis-associated acute respiratory distress syndrome (ARDS) ( Chapter 90 ), but this practice remains controversial. In patients who remain seriously hypoxic despite mechanical ventilation, extracorporeal membrane oxygenation may be lifesaving.

Prognosis

The prognosis for patients with pulmonary or disseminated blastomycosis is excellent; more than 90% are cured. Most reported deaths occur in patients with overwhelming pneumonia and ARDS. In patients who require mechanical ventilation, the mortality rate is about 40%.

Definition

Histoplasmosis is the most common endemic mycosis in the United States. Most infections are self-limited, but the organism has the ability to cause acute and chronic pulmonary infections as well as disseminated infection ( Table 308-2 ).

Epidemiology

Histoplasmosis, though found worldwide, is primarily a disease of North and Central America. H. capsulatum is endemic in the Mississippi and Ohio River Valleys, with extension into the St. Lawrence Basin; microfoci exist in discrete isolated areas in several eastern states and may represent novel species. Soil, caves, and abandoned buildings that contain high concentrations of bird or bat guano support growth of the organism. Every year, thousands of individuals who live in areas endemic for H. capsulatum are infected, but infections can occur in persons living in essentially every U.S. state. Most cases are sporadic, and the exact source of exposure is unknown. Point source outbreaks occur in association with disruption of soil; cleaning attics, bridges, or barns; renovating or tearing down old structures laden with guano; and spelunking.

Pathobiology

After inhalation of microconidia into the alveoli, a localized pulmonary infection ensues. Neutrophils and macrophages phagocytize the organism, which is now in the yeast phase. The organism is able to survive and travels within macrophages to the hilar and mediastinal lymph nodes and throughout the reticuloendothelial system by hematogenous dissemination. Such dissemination, which probably occurs in most persons who are infected, is typically asymptomatic in normal hosts. After several weeks, T-cells specifically sensitized by Histoplasma antigens activate macrophages, which are then able to kill the intracellular fungi.

The extent of disease is determined by both the number of conidia inhaled and the immune response of the host. A small inoculum can cause severe infection in immunosuppressed patients. Persons at greatest risk include patients who have acquired immunodeficiency syndrome (AIDS), lymphoma, or are organ transplant recipients, as well as patients who are taking corticosteroids or tumor necrosis factor inhibitors. Reactivation of latent infection occurs in patients who have deficient cell-mediated immunity, as evidenced by the occurrence of histoplasmosis in immunosuppressed persons who grew up in the endemic area but have not returned to that area for years.

Clinical Manifestations