Chapter 296. Blastomycosis

North American blastomycosis is a pulmonary or disseminated fungal infection caused by Blastomyces dermatitidis.1,2 Although rare in children,3 the infection is often difficult to detect unless considered in the differential diagnosis. Blastomyces dermatitidis is a dimorphic fungus that exists as a mold in nature and is generally acquired through the inhalation of spores that transform to yeast in the lungs. Although isolation from natural sources has been very difficult, growth appears to occur in acidic soil in which there is decaying organic matter and high humidity. Cases of blastomycosis are reported from other countries (particularly those in central Africa), but the vast majority of cases have occurred in the Ohio and Mississippi river basins and the southeastern United States. The highest incidence of cases appears to occur in Wisconsin, Minnesota, Mississippi, Kentucky, Tennessee, and Arkansas. In endemic areas, the annual incidence of symptomatic infection is about 1 to 2 per 100,000 population. Pockets of hyperendemic regions exist where the annual incidence of symptomatic infection may approach 40 per 100,000 population.

Although it is clear that asymptomatic infections occur, the distribution and extent have not been determined, because reliable skin tests or seroepidemiologic methods are not available. When careful immunologic studies are performed in reported outbreaks of blastomycosis, as many as 50% of infected individuals are asymptomatic. Most cases of symptomatic blastomycosis occur sporadically, but there are occasional reports of small outbreaks in communities in which as many as 15 individuals may contract infection over a short period of time. The largest reported outbreak involved 46 school-aged children and 2 adults who were infected at a camp in Wisconsin following exposure to a beaver dam and lodge. There is no seasonality to B dermatitidis infections, and infections have been reported in all age groups, including newborns.4 In large surveillance studies of confirmed cases of blastomycosis, pediatric patients age 19 years or less comprise 3% to 11% of all identified cases. However, the typical patient is a male, age 25 to 50 years, who has an outdoor lifestyle. The incubation period from exposure to primary disease is 21 to 106 days (median 45 days). However, latency with eventual reactivation disease is probable with the finding of newly recognized infection in individuals with no exposure to endemic areas for 3 or more years. Human-to-human transmission is rare.

The lungs are the usual portal of entry for B dermatitidis conidia. Inhaled conidia elicit an inflammatory response characterized by polymorphonuclear leukocytes (PMNs). The few conidia that survive the initial PMN phagocytosis transform to yeast, which are more resistant to phagocytosis by PMNs and alveolar macrophages. Response to the replicating yeast cells results in a mononuclear infiltrate with some granulomatous component. Spread of yeast from the lungs, although rare, may seed any body organ. Development of cell-mediated immunity is believed to be the primary mechanism in prevention of progressive blastomycosis, and lymphocyte reactivity is a marker of specific cellular immunity to B dermatitidis. Most symptoms appear to result from progression of the primary infection.

Clinical Manifestations

Pulmonary disease is the most common manifestation of symptomatic blastomycosis. In two 10-year epidemiologic studies of confirmed cases of blastomycosis in Wisconsin and Mississippi (670 and 326 cases, respectively), 75% of the cases were isolated pulmonary disease. Pulmonary plus extrapulmonary disease occurred in 6% to 16%, whereas isolated extrapulmonary infection occurred in 9% to 18% of cases. In clinically apparent primary disease, onset is insidious, resembling a mild respiratory infection accompanied by low-grade fever, chest pain, and nonproductive cough, often with rapid resolution. These patients are usually detected only in an outbreak situation. As the symptoms increase in severity, spiking fevers, productive cough, and pleuritic chest pain develop. Subacute or chronic illness may occur with low-grade fever, productive cough, hemoptysis, weakness, anorexia, and weight loss resembling adult reactivation tuberculosis. Rarely, the illness may be fulminant and resemble adult respiratory distress syndrome. Mortality is such cases may be greater than 50%.

Radiographic studies of the chest vary widely; there is no characteristic feature of blastomycosis that allows easy differentiation from other pulmonary infections. In acute cases, parenchymal infiltrates, lobar or segmental consolidation, and interstitial infiltrates have all been described. Large lobar infiltrates may mimic tumor. In the more chronic form of disease, air-space and interstitial infiltrates are seen, but masslike infiltrates, pulmonary nodules, and cavitation are more common. Pleural effusions and hilar lymphadenitis occur in 10% or less of cases.

Disseminated blastomycosis is caused by hematogenous spread of the infection from the lungs to other areas of the body. Most frequently, the disease involves cutaneous and subcutaneous tissues as well as bone, the central nervous system, and the urogenital tract (only in adults). Cutaneous lesions, the most common extrapulmonary manifestation, initially appear as benign, papulopustular verrucous nodules with a raised irregular border often with crusting and some drainage from an underlying abscess.5 Lesions may also become ulcerative. The borders are usually sharp and heaped up, and the base commonly contains exudate. As the lesion extends peripherally, the central area heals, leaving a soft, atrophic scar. Lytic bone lesions are the second most common extrapulmonary infection. The vertebrae, pelvis, sacrum, skull, ribs, or long bones have been reported most frequently, but essentially any bone may be involved. Granulomatous lesions of the liver and spleen are found in more than 40% of patients with disseminated disease, and the kidneys, prostate, epididymis, bladder, and testes may be involved, causing dysuria, pyuria, and hematuria. Central nervous system involvement may be meningitis, but is more commonly epidural or cranial abscesses. Nearly every body organ has been reported including lymph nodes, eyes, and retropharyngeal soft tissue.

Mortality from blastomycosis is dependent upon age, immune state of the host, and the type of presenting illness. Adults older than age 65 years have a mortality rate from blastomycosis 10 times or more that of children. Although a rare infection in immunocompromised hosts when compared to histoplasmosis, cryptococcosis, and coccidioidomycosis, blastomycosis has been documented to cause severe and often fatal infections in patients with many forms of immune deficiency,6 including those with AIDS, transplants, sarcoidosis, or therapy with corticosteroids. Regardless of the underlying disorder, blastomycosis in immunocompromised hosts is usually an aggressive disease, often presenting with disseminated, multiple-organ involvement and a high, early mortality.

Diagnosis

Although patients may present to a physician early in the course of infection, diagnosis is often delayed more than 30 days. Typically, patients receive one or more courses of antibiotics for bacterial pneumonia before blastomycosis is considered. Clinical diagnosis must be confirmed by laboratory studies, which include microscopic examination of smears, scrapings, aspirates, sputum, and bronchoscopic washings for the characteristic yeast along with fungal culture. In biopsy specimens, caseous necrosis usually is absent. Cutaneous lesions typically reveal pseudoepitheliomatous hyperplasia and budding yeasts in pyogranulomas that are characteristic and pathognomonic. In hematoxylin-and-eosin tissue sections, one often finds the characteristic yeast cells with a thick, double-refractive cell wall, but these may be difficult to see. Therefore, routine use should be made of special stains such as the periodic acid–Schiff and Gomori methenamine silver stain, which may help to differentiate Histoplasma and Cryptococcus. Culture methods can confirm the diagnosis. The infected material should be spread on the surface of Sabouraud dextrose agar slants and incubated at room temperature or 30°C (86°F). The yeast phase may be obtained in culture by inoculating glucose blood agar medium and incubating at 37°C (98.6°F). Growth occurs in 2 to 4 weeks.Because of poor sensitivity and specificity, serologic methods such as complement fixation and enzyme-linked immunosorbent assay (EIA) usually are not helpful. Newer EIA tests, using more purified antigens, show sensitivities of 80% to 88% and specificities of 98% to 100% in proven blastomycosis. EIA titers greater than or equal to 1:32 support the diagnosis of blastomycosis. Cross-reactivity with antigens of other fungi, particularly Histoplasma, makes low titers of these serologic tests difficult to interpret. Until specific antigen or polymerase chain reaction methods are introduced, definitive diagnosis of blastomycosis will depend on finding the organism in tissue, body fluids, or culture.

Treatment

The prognosis for pulmonary or disseminated disease is generally good with appropriate therapy. Untreated, widely disseminated disease always has a poor prognosis. The treatment of choice for life-threatening or severe disease is amphotericin B.7 Ketoconazole and itraconazole are very effective in less severe infections in adults, but the data on pharmacokinetics, safety, and efficacy of these drugs for children are insufficient. Itraconazole has fewer side effects than ketoconazole and is probably the preferred option. Small numbers of children have been treated for 6 months with a 5 to 10 mg/kg daily dose of itraconazole. However, until more data are available, patients treated with itraconazole who fail to respond within 2 to 4 weeks, who have inadequate serum concentrations, or who develop clinical deterioration, should be switched to amphotericin B.