Disseminated Blastomycosis: A Case of Multisite Infection in an Immunocompetent Patient

Introduction

Blastomycosis is a serious and potentially fatal systemic fungal infection caused by Blastomyces dermatitidis and Blastomyces gilchristii. These dimorphic fungi are endemic to specific regions of North America, including parts of Canada. Among these areas, the upper Midwest and Great Lakes region experiences a notably higher incidence, with Wisconsin standing out as one of the most affected states, where cases range from approximately 10 to 40 per 100 000 people – significantly exceeding the national average of around 2 per 100 000 [1–3].

Infection typically begins with the inhalation of fungal conidia, making the lungs the primary site of disease. Construction and outdoor activities such as farming, hunting, and canoeing, are key risk factors for environmental exposure to fungal conidia, which are present in the soil and decaying wood. Pulmonary blastomycosis often presents with cough and dyspnea, and can mimic bacterial pneumonia [3]. The infection can progress to a disseminated form when it spreads to other organ systems [3–5]. Dissemination in blastomycosis can involve the skin, bones, central nervous system, or genitourinary tract [5]. Clinical presentations are highly variable, often making diagnosis difficult. If left undetected, the infection can disseminate or progress to severe disease. The estimated annual mortality rate of 8–10% among hospitalized patients highlights the need for prompt recognition and treatment [1].

While blastomycosis is more frequently reported in individuals with immunosuppression, it is unique among endemic mycoses for its ability to disseminate in immunocompetent hosts. This contrasts with other endemic fungal infections such as histoplasmosis and coccidioidomycosis, which typically disseminate only in the context of immunosuppression [5,6].

Case Report

A previously healthy 54-year-old man presented to the emergency department with persistent pain and erythema of the right foot for 2 weeks (Figures 1, 2). He reported the onset of symptoms following a spontaneously draining ulcer on the right buttock that had developed 1–2 months prior. The ulcer had been diagnosed as a soft tissue abscess by his primary care provider and treated empirically with doxycycline 100 mg orally twice daily, leading to partial improvement. No culture or incision and drainage were performed at that time. While still on doxycycline, the patient developed new erythema and pain over the dorsum of the right foot. Cephalexin 500 mg twice daily orally was added, but symptoms progressed. A venous Doppler ultrasound ruled out deep vein thrombosis but revealed hematoma. He denied trauma and was not on anticoagulation. Intermittent chills were reported, but no other systemic symptoms. The patient had no known allergies and was not taking other medications. He had quit chewing tobacco a year prior, consumed alcohol occasionally, and denied recent travel outside Wisconsin or known sick contacts. He worked for the local school district, hiked regularly, and had an outdoor dog.

Due to treatment failure and diagnostic uncertainty, he was admitted. Vitals were notable for tachycardia (HR 105 bpm), but otherwise within normal limits. Examination revealed a 2×2 cm draining ulcer near the anal region, a small erythematous area on the medial thigh, and erythema with mild edema and blistering from the toes to midfoot on the right foot. Empiric IV vancomycin (1.5 g twice daily) was initiated for presumed cellulitis, and consultations were obtained with the Infectious Disease, Podiatry, and General Surgery departments. Ceftriaxone IV was added for Gram-negative coverage. Vancomycin was later replaced with daptomycin IV 750 mg daily due to infusion-related rash. Blood cultures were negative. Cultures from the buttock ulcer grew skin flora and were deemed contaminants.

On day 2, surgical aspiration of the medial thigh yielded bloody, yellowish fluid; cultures remained sterile. MRI of the right foot showed acute osteomyelitis of the second proximal phalanx with a 2.9×0.9×1.7 cm abscess adjacent to the metatarsophalangeal joint (Figures 3, 4). The patient underwent second toe amputation and debridement. Intraoperative cultures and broad-range PCR were negative. Transthoracic echocardiogram ruled out endocarditis.

Despite antimicrobial therapy, leukocytosis persisted, and purulence recurred. Ceftriaxone was replaced by ampicillin-sulbactam 3 g IV every 6 hours. On day 5, the patient underwent repeat debridement for wound dehiscence, hematoma, and recurrent abscess (Figure 5). Incision and drainage of the thigh yielded minimal purulence (Figure 6); the buttock ulcer showed healthy granulation and required no intervention. Histopathology from the amputated toe revealed acute osteomyelitis with thick-walled, broad-based budding yeast forms, consistent with Blastomyces species (Figures 7, 8). Cultures from multiple sites, including bone, confirmed Blastomyces dermatitidis/gilchristii. Serologic and urinary antigen testing supported the diagnosis. Chest CT showed diffuse pulmonary nodules, although the patient remained asymptomatic. Head CT was normal. He was diagnosed with disseminated blastomycosis involving bone, soft tissue, and lungs. He later disclosed prolonged soil exposure while working near a swamp.

Antibacterial agents were discontinued. Oral itraconazole (200 mg 3 times per day for 3 days, then twice per day) was initiated and well tolerated. Cellulitis improved, and no further purulence developed. Wound vacuum-assisted closure devices were placed on the foot and thigh. The patient was discharged to complete 12 months of continued itraconazole therapy. Follow-up included liver function monitoring, itraconazole levels, electrocardiogram for corrected QT interval, and a repeat chest CT. The patient tolerated the treatment well, with complete resolution of all of his symptoms and radiological resolution of his lung lesions (Figures 9, 10).

Discussion

Blastomyces species primarily infect humans via inhalation of spores from contaminated soil. Once inside the host, the organism undergoes thermal dimorphism, converting to a pathogenic yeast at body temperature – driving the diverse clinical manifestations of blastomycosis [3]. Our patient likely acquired the infection while residing near a swamp and working outdoors in construction over several months. Blastomycosis can be transmitted from animals, particularly dogs, to humans through bites, placing veterinarians at increased risk [1].

Increased susceptibility among certain ethnic groups – particularly African Americans and Hmong Asians – suggests a potential genetic predisposition. The Hmong, originally from Southeast Asia, resettled in the U.S. post-Vietnam War, primarily in north-central Wisconsin. A 2010 outbreak among this population displayed significant household clustering, raising concerns of inherited vulnerability [7]. Subsequent genomic analyses revealed polymorphisms in Hmong individuals associated with diminished IL-6 and IL-17 cytokine production, impairing immune defense against Blastomyces [8]. Our patient, however, a White American, did not have this ancestry.

Blastomycosis exhibits a wide clinical spectrum. Disseminated disease is defined by multi-organ or extrapulmonary involvement. Pulmonary infection is most prevalent, typically developing after a 2–6-week incubation with presentations ranging from asymptomatic to fulminant acute respiratory distress syndrome [5]. Persistent symptoms despite antibiotics in endemic regions should raise suspicion. Without treatment, the disease may progress to chronic pulmonary infection or disseminate. Risk factors for severe pulmonary disease in otherwise healthy individuals include morbid obesity and vitamin D deficiency [9].

Extrapulmonary spread via hematogenous dissemination most frequently affects the skin (60%), bones/joints (25%), genitourinary system, and central nervous system (CNS) (5–10%), though virtually any organ can be involved [5]. Cutaneous lesions – verrucous or ulcerative – commonly appear on exposed skin. A Wisconsin review revealed that 50% of patients with skin involvement lacked pulmonary disease, and 75% were immunocompetent [2]. Osteoarticular blastomycosis often targets long bones near the knee and the spine, with symptoms developing insidiously as localized pain, warmth, erythema, abscesses, or draining sinus tracts [10]. Vertebral involvement may lead to epidural or psoas abscesses, potentially causing spinal cord compression. Genitourinary blastomycosis occurs more frequently in men, with the prostate, epididymis, and testes being common sites. Patients may experience dysuria, pelvic discomfort, or urinary obstruction [5,11]. Though rare, uterine and tubo-ovarian abscesses have been reported in women. CNS involvement is infrequent but serious, manifesting as meningitis or intracranial abscesses [5].

Due to its protean manifestations, blastomycosis may mimic malignancy, sarcoidosis, tuberculosis, or other fungal infections such as histoplasmosis, coccidioidomycosis, or cryptococcosis [12–15]. Lung or skin lesions may appear granulomatous or tumor-like, further complicating diagnosis. Definitive diagnosis requires identification of broad-based budding yeast via microscopy or fungal culture. In a 12-year retrospective study of 106 patients, microscopy detected yeast in 81.8% of cases, while cultures confirmed Blastomyces in all remaining patients [3]. This underscores the necessity of combining culture with non-culture diagnostics. Antigen testing, though useful, cross-reacts with other endemic fungi, reducing specificity. PCR assays are rapid but variable in performance, limiting reliability.

First-line treatment includes amphotericin B (preferably lipid formulations) for severe or CNS disease, followed by prolonged azole therapy (itraconazole, posaconazole, voriconazole, isavuconazole) for 6–12 months, depending on severity and organ involvement [3]. As our patient had moderate disseminated blastomycosis without CNS involvement, itraconazole was deemed sufficient, eliminating the need for amphotericin B. Comparative studies show immunocompromised patients experience more severe disease, respiratory failure, and higher mortality. Interestingly, dissemination rates are similar between immunocompromised and immunocompetent hosts, suggesting fungal virulence and exposure burden may outweigh host immunity in driving dissemination – a distinction from other mycoses like coccidioidomycosis and histoplasmosis [3]. Outcomes are more favorable in immunocompetent individuals. However, delayed diagnosis contributes significantly to poor prognosis. In our case, symptom onset preceded diagnosis by over 7 weeks. This highlights the diagnostic complexity of blastomycosis, even in endemic regions with experienced clinicians.

Conclusions

Disseminated blastomycosis can occur in immunocompetent individuals. It appears to be pathogen specific. A high index of suspicion remains crucial, especially in patients originating from endemic areas whose clinical course is not improving with antibacterial treatment. Tissue culture remains the gold standard for diagnosis.