Central nervous system blastomycosis in an immunocompetent child

Key points

• Blastomyces dermatitidis and Blastomyces gilchristii, the causative agents of blastomycosis, are dimorphic fungi endemic to certain regions of Canada, especially Ontario, Quebec, Manitoba, and Saskatchewan.

• Blastomycosis should be considered in the differential diagnosis of rapidly evolving skin lesions with purulence when bacterial cultures are negative or when such lesions are not responsive to standard antibiotic therapy.

• Brain imaging should be considered as a part of the workup for disseminated blastomycosis, even in the absence of neurologic signs or symptoms.

• After an initial 4–6 weeks of intravenous amphotericin B, transition to an oral azole agent to complete a minimum of 12 months of therapy is recommended, with voriconazole the preferred option for blastomycosis involving the central nervous system.

A 5-year-old boy from rural east-central Ontario was referred to the urgent dermatology service with tender papulopustular and nodular lesions on the trunk, limbs, and face, which had developed over 9 days. The 7 lesions began as small papules that gradually enlarged and developed purulent discharge. At the time of presentation, the largest lesion was a nodule (around 2 cm) with a central depression (Figure 1A), while other lesions were smaller (0.5–1.5 cm), and some were actively draining pus (Figure 1B).

Figure 1:

(A) An eroded nodule with superficial pustules on the left elbow and (B) an ulcerated, pus-draining nodule on the anterior central chest of a 5-year-old boy with blastomycosis.

The patient had a 1-month history of a nonresolving cough, 2 brief febrile episodes, and mild lethargy. Three weeks before the skin lesions appeared, he had received 2 doses of oral dexamethasone for suspected croup, without improvement. Two days after the skin lesions appeared, he was started on azithromycin for clinical suspicion of pneumonia. Two days later, his treatment was changed to oral amoxicillin–clavulanic acid, given the pustular nature of the skin lesions. Six days after onset of the skin lesions, a chest radiograph showed left lower lobe infiltrate and a small pleural effusion. A complete blood count obtained at the same time revealed a leukocyte count of 10.1 (normal 5–13.2) × 10⁹/L with normal differential, a platelet count of 457 (normal 197–382) × 10⁹/L, and a hemoglobin of 125 (normal 96–128) g/L. His C-reactive protein was mildly elevated at 14.4 (normal < 5) mg/L. He completed a 7-day course of amoxicillin–clavulanic acid, which had no effect on the skin lesions.

The patient’s medical history was notable for reactive airway disease managed with fluticasone (250 μg, 2 puffs twice daily). There was no history of recurrent or severe infections, and he was immunized according to the standard schedule. He had no recent travel, ill contacts, or symptomatic family members. Aside from the family owning 2 healthy dogs, he had no other contact with animals. The family had regraded the front yard of their home around 3 months before the onset of the skin lesions.

After 5 days of amoxicillin–clavulanic acid treatment, the patient was seen in our dermatology clinic, where he was assessed by the dermatology and infectious diseases teams. A punch biopsy of the elbow lesion was performed. Four days after the biopsy, the histopathology results showed the presence of broad-based budding yeast (diameter 10–12 μm) with double-contoured walls, consistent with Blastomyces infection (Figure 2), along with a prominent acute inflammatory infiltrate.

Figure 2:

Skin biopsy slide with Grocott methanamine silver staining (magnification ×1000), showing round-to-oval, broad-base budding yeast measuring 8–15 μm in diameter, with double-contoured walls.

Fungal culture of the skin lesion grew a white-beige fungus after 5 days of incubation. Given the histopathology result and the growth characteristics of the fungus, the isolate was forwarded to our provincial laboratory as a risk group 3 pathogen. The fungus was later confirmed to be Blastomyces dermatitidis or Blastomyces gilchristii according to phenotypic and molecular methods. Bacterial and mycobacterial cultures were negative.

With the preliminary histopathologic results, the patient was admitted to our pediatric ward and started on intravenous liposomal amphotericin B (L-AmB) at 5 mg/kg every 24 hours. Despite the absence of neurologic symptoms or positive findings on neurologic and musculoskeletal examination, we ordered brain and spine magnetic resonance imaging (MRI). Multiple bilateral small foci of hyperintensity were identified in the white matter on fluid-attenuated inversion recovery T₂-weighted images (Figure 3), presumed to be related to disseminated blastomycosis. We did not observe any radiologic evidence of spine involvement. Additional workup for disseminated blastomycosis, including an ophthalmologic exam and abdominal ultrasonography, was normal. Serum immunoglobulin levels, the neutrophil oxidative burst index, and flow cytometry (T cells, B cells, natural killer cells) were normal.

Figure 3:

Axial T₂-weighted fluid-attenuated inversion recovery magnetic resonance imaging the brain showing multiple hyperintensities in the (A) right occipital lobe and left internal capsule; (B) the right pons; (C) the right parietal, right frontal, and bilateral occipital lobes; and (D) the bilateral cerebellum.

We discharged the patient to continue intravenous L-AmB treatment at home, with twice-weekly monitoring of his electrolytes at a nearby community hospital. After 6 weeks of L-AmB, the skin lesions showed notable regression (Figure 4), and he was transitioned to oral voriconazole (9 mg/kg every 12 h). Therapeutic voriconazole levels were confirmed by therapeutic drug monitoring. The family was counselled about the potential adverse effects of voriconazole, including skin photosensitivity, visual disturbances, and liver function test abnormalities.

Figure 4:

Progression of lesion at the patient’s left elbow (A) 3 days before initial dermatology assessment, (B) at presentation, (C) before treatment with liposomal amphotericin B (3 days after presentation), and (D) after 2 months of treatment, demonstrating clinical improvement of the draining nodule.

Follow-up chest radiography after 2 months of therapy showed radiologic improvement. The patient’s cough had resolved, and his neurological exam remained normal, with no evidence of clinical seizures. No additional skin lesions were noted. One year after treatment initiation, follow-up brain MRI showed complete resolution of the brain lesions. He completed a 13-month course of antifungal therapy.

Discussion

Blastomyces dermatitidis and B. gilchristii are dimorphic fungi endemic to certain regions of Canada, especially Ontario, Quebec, Manitoba, and Saskatchewan. Infection is hyperendemic in the northwestern area of Ontario, with an annual incidence of 0.45–0.8 per 100 000 population, with a trend toward increasing numbers of cases in recent years,¹ and an expanding geographic distribution beyond its historic range, extending further west in the United States and Canada.² The total reported mortality among children with blastomycosis ranges from 0% to 4.4%.^3,4

Infection is usually acquired through inhalation of spores that have been liberated from disturbed soil. Risk factors include residence in endemic regions and activities that increase exposure risk, such as camping, construction work, or other situations associated with exposure to disturbed soil.⁵ In the case of our patient, outdoor construction near the home and the history of him frequently playing in this area in the months preceding symptom onset was the most likely source of his infection.

The classic clinical scenario of blastomycosis is a school-aged child or young adult with nonresolving pneumonia or a cough that does not respond to standard antibiotic therapy or asthma management. Symptoms often overlap with those of other infections, including bacterial infections, tuberculosis, and other dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Less commonly, localized cutaneous disease can occur following direct skin inoculation.^5,6 Cutaneous blastomycosis usually starts as a papule that grows into a wart-like or ulcerative lesion. Wart-like lesions have raised, well-demarcated borders with crusting, while ulcers display a moist base and raised edges.⁵ A noninfectious etiology of cutaneous lesions that resemble those caused by blastomycosis is acute febrile neutrophilic dermatosis (Sweet syndrome), characterized by painful pustular lesions on the face, neck, or trunk, often associated with fever and elevated inflammatory markers.⁵ Erythema nodosum, which may coexist with infectious and noninfectious lung pathologies, can also present with cutaneous nodules; however, these do not usually ulcerate or discharge pus.⁵

Disseminated (extrapulmonary) infections accounted for 30% of blastomycosis cases in a large retrospective review involving 143 patients aged 0–79 years.⁷ In a pediatric study involving 114 children, 21% had extrapulmonary disease.⁴ The most commonly involved extrapulmonary sites were skin, bone, the genitourinary tract, and the central nervous system (CNS).⁵ Our patient had a respiratory prodrome starting 1 month before the onset of skin lesions, suggesting that he had primary pulmonary blastomycosis that later disseminated. This is consistent with previous reports demonstrating that prolonged duration of respiratory symptoms before diagnosis is associated with a higher risk of disseminated disease.⁷ Additional factors that may predispose to dissemination include diabetes mellitus and immunodeficiency states such as advanced HIV infection, organ transplantation, chemotherapy, or receipt of immunosuppressive medications such as tumour necrosis factor-α inhibitors or high-dose corticosteroids.⁵

Clinical manifestations of CNS disease are nonspecific and may include headache, nuchal rigidity, altered mental status, focal neurologic deficits, and seizures.^3,5 As illustrated by our case, CNS involvement can be asymptomatic. Rates of CNS involvement among patients with disseminated disease range from 1.4% to 30%.^3,4,7

A preliminary diagnosis of blastomycosis can be made by direct microscopic examination of clinical specimens. Fungal culture remains the gold standard for confirming the diagnosis and can be performed on sputum samples, bronchioalveolar lavage samples, or material from fine needle aspirates, as well as fresh-tissue biopsies.⁶ Antigen detection in urine has a reported sensitivity of 84%–93%^4,6 but is limited by cross-reactivity with other fungal infections such as histoplasmosis, paracoccidioidomycosis, talaromycosis, cryptococcosis, and aspergillosis.^5,6 Serologic testing is of limited utility, given its low sensitivity (65%–80%).⁶

We treated our patient according to the Infectious Diseases Society of America’s recommendations for CNS blastomycosis, with an initial 6-week course of intravenous L-AmB, followed by an oral azole for a total treatment duration of 13 months.⁸ We selected voriconazole because of its effective CNS penetration, the availability of voriconazole therapeutic drug monitoring at our facility allowing for real-time dose optimization, and reports in the literature favouring voriconazole over other azoles in the treatment of CNS blastomycosis.^9,10 Alternatives to voriconazole include fluconazole, itraconazole,⁸ or isavuconazole.¹¹

This case underscores the importance of maintaining a high index of suspicion for blastomycosis to ensure early diagnosis, timely treatment, and prevention of the sequelae of dissemination. Important clues to the diagnosis of disseminated blastomycosis included the rapidly evolving skin lesions, negative bacterial cultures from the biopsy samples, and failure of the cutaneous lesions and pneumonia to respond to typical anti-biotic therapy. As this case illustrates, CNS involvement may be present despite the absence of neurologic symptoms or signs.⁵ Therefore, strong consideration should be given to CNS imaging in all cases of disseminated blastomycosis.

The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition follows (1000 words maximum). Visual elements (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca.