Blastomycosis (Blastomyces dermatitidis)

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Chapter 231 Blastomycosis (Blastomyces dermatitidis)

Gregory M. Gauthier, Bruce S. Klein

Etiology

Blastomyces dermatitidis belongs to a group of fungi that exhibit thermal dimorphism. In the soil, these fungi grow as mold and produce spores, which are the infectious particles. When inhaled into the lungs, the spores convert into pathogenic yeast and cause infection.

Epidemiology

B. dermatitidis causes disease in immunocompetent and immunocompromised children. Only 2-13% of blastomycosis cases occur in patients <18 yr of age. Neonatal blastomycosis is rare and can be transmitted through the placenta to the fetus. In North America, the geographic distribution of blastomycosis cases is restricted to the Midwest, south-central, and southeastern USA and parts of Canada bordering the Great Lakes and Saint Lawrence River Valley. Infections have also been reported from Africa, India, the Middle East, and Central and South America. B. dermatitidis grows in sandy soils that have decaying vegetation and are near water. Most infections with B. dermatitidis are sporadic; however, outbreaks have been well described. The severity of infection is influenced by the size of the inhaled inoculum and the integrity of the patient’s immune system.

Pathogenesis

The ability to convert from spores to yeast in the lung is a crucial event in the pathogenesis of infection with B. dermatitidis and other dimorphic fungi. This phase transition enables B. dermatitidis to evade the host immune system and establish infection. In the yeast form, B. dermatitidis produces BAD-1 (Blastomyces adhesin-1; formerly WI-1), an essential virulence factor that is displayed on the cell wall and secreted. BAD-1 promotes binding of yeast to macrophages in lung alveoli, blocks the deposition of complement on the yeast surface, binds calcium, and suppresses the production of pro-inflammatory cytokines in the host.

The phase transition from mold to yeast is a complex event that involves alteration in cell wall composition, metabolism, intracellular signaling, and gene expression. In B. dermatitidis, this transition is regulated, in part, by a histidine kinase known as DRK1 (dimorphism regulating kinase-1). This sensor kinase controls not only the conversion of mold to yeast but also spore production, cell wall composition, and BAD-1 expression; the loss of DRK1 expression through gene disruption renders B. dermatitidis avirulent in a murine model of blastomycosis.

Clinical Manifestations

The clinical manifestations of blastomycosis are heterogeneous and include subclinical infection, symptomatic pneumonia, and disseminated disease. Clinical disease develops 3 wk to 3 mo following exposure to B. dermatitidis. Asymptomatic or subclinical infections are estimated to occur in 50% of patients.

The most common clinical manifestation of blastomycosis is acute pneumonia. Symptoms include fever, dyspnea, cough, and malaise. Respiratory failure can occur in patients with severe pulmonary disease. Chest imaging typically demonstrates airspace consolidation, which can involve the upper or lower lobes. Other radiographic features include nodular, reticulonodular, and miliary patterns. Hilar adenopathy and pleural effusions are uncommon. Because the clinical and radiographic features can mimic bacterial pneumonia, patients can be mistakenly treated with antibiotics, resulting in disease progression. Patients with chronic pneumonia present with fevers, chills, night sweats, cough, weight loss, hemoptysis, dyspnea, and chest pain. Airspace consolidation, masslike lesions, or cavitary disease can be present on chest roetenography. These features can mimic tuberculosis or malignancy.

Extrapulmonary blastomycosis most often affects the skin or bone, but can involve almost any organ. The incidence of extrapulmonary disease in children is not well defined; the rate of disseminated disease is thought to be similar to the rate in adults (25-40%). The skin is the most common site for extrapulmonary blastomycosis, which is usually the result of hematogenous dissemination. Direct inoculation of B. dermatitidis into the skin from trauma or a laboratory accident can result in primary cutaneous blastomycosis. Skin manifestations include plaques, papules, ulcers, nodules, and verrucous lesions. The bone is the second most common site of extrapulmonary involvement, including the ribs, skull, spine, and long bones. Clinical symptoms of bone involvement include bone pain, soft tissue swelling, sinus formation, and ulceration. Patients with osteomyelitis often have pulmonary or cutaneous manifestations of blastomycosis. Complications include paraspinal abscess, vertebral collapse, and septic arthritis. Genitourinary blastomycosis occurs in 10-30% of adults but is rare in children.

Blastomycosis of the central nervous system (CNS) occurs in <5-10% of immunocompetent patients and can result in brain abscess or meningitis. Some patients with CNS blastomycosis have widely disseminated disease. Symptoms include headache, altered mental status, memory loss, seizure, cranial nerve deficits, and focal neurologic deficits. Lumbar puncture demonstrates leukocytosis with a lymphocyte predominance, elevated protein, and low glucose. Growth of B. dermatitidis in culture from cerebral spinal fluid is uncommon.

Diagnosis

The diagnosis of blastomycosis requires a high index of suspicion, because the clinical and radiographic manifestations can mimic other diseases. Blastomycosis should be included in the differential diagnosis for patients with pneumonia who live in or visit areas in which this pathogen is endemic, fail to respond to antibiotics, or have chronic skin lesions or osteomyelitis. Growth of B. dermatitidis in culture from sputum, skin, bone, or other clinical specimens provides a definitive diagnosis. Sputum specimens should be stained with 10% potassium hydroxide or calcofluor white. Histopathology shows neutrophilic infiltration with noncaseating granulomas (pyogranulomas). B. dermatitidis yeast in tissue samples can be visualized using Gomori methenamine silver (GMS) or periodic acid–Schiff (PAS) stains. Yeast are 8-20 µm in size, have a double refractile cell wall, and display broad-based budding.

Serologic methods including complement fixation and immunodiffusion suffer from poor sensitivity. In contrast, the Blastomyces urine antigen test has a sensitivity of 92.9%; however, it cross-reacts upon infection with other dimorphic fungi, reducing its specificity.

Treatment

Antifungal therapy is influenced by the severity of the infection, involvement of the central nervous system, and the integrity of the host’s immune system. Newborns with blastomycosis should be treated with amphotericin B deoxycholate 1 mg/kg/day. Children with mild to moderately severe infection can be treated with itraconazole 10 mg/kg/day (maximum 400 mg/day) for 6-12 mo. Children with severe disease or underlying immunocompromise should be treated with amphotericin B deoxycholate 0.7-1.0 mg/kg/day, or lipid formulation 3-5 mg/kg/day, until there is clinical improvement, generally 7-14 days, and then itraconazole 10 mg/kg/day (maximum 400 mg/day) for a total of 12 mo. CNS blastomycosis requires therapy with a lipid formulation of amphotericin B at 5 mg/kg/day for 4-6 wk followed by itraconazole, fluconazole, or voriconazole for ≥12 mo.

For patients receiving itraconazole, the oral antifungal of choice, serum drug levels need to be measured 14 days into therapy (goal ≥1 µg/mL) and liver function tests should be monitored periodically. The newest azole antifungal drugs, voriconazole and posaconazole, have activity against B. dermatitidis; however, clinical experience with these drugs remains limited. The echinocandins (caspofungin, micafungin, and anidulofungin) should not be used to treat blastomycosis. Serial measurement of urine antigen levels to assess response to therapy appears promising, but the clinical usefulness of this strategy remains to be determined.

Bibliography

Brandhorst TT, Gauthier GM, Stein RA, et al. Calcium binding by the essential virulence factor BAD-1 of Blastomyces dermatitidis. J Biol Chem. 2005;280:42156-42163.

Chapman SW, Dismukes WE, Proia L, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:1801-1812.

Durkin M, Witt J, Lemonte A, et al. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol. 2004;42:4873-4875.

Fang W, Washington L, Kumar N. Imaging manifestations of blastomycosis: a pulmonary infection with potential dissemination. Radiographics. 2007;27:641-655.

Freifeld A, Proia L, Andes D, et al. Voriconazole use for endemic fungal infections. Antimicrob Agents Chemother. 2009;53:1648-1651.

Gauthier GM, Klein BS. Insights into fungal morphogenesis and immune evasion. Microbe. 2008;3:416-423.

Klein BS, Vergeront JM, Weeks RJ, et al. Isolation of Blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in Wisconsin. N Engl J Med. 1986;314:529-534.

Mongkolrattanothai K, Peev M, Wheat JL, et al. Urine antigen detection of blastomycosis in pediatric patients. Pediatr Infect Dis J. 2006;25:1076-1078.

Morris SK, Brophy J, Richardson SE, et al. Blastomycosis in Ontario, 1994-2003. Emerg Infect Dis. 2006;12:274-279.

Nemecek JC, Wuthrich M, Klein BS. Global control of dimorphism and virulence in fungi. Science. 2006;28(312):583-588.

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