A Healthy Adult With Tibial Swelling and Pain

A 64-year-old man noticed an insidious onset of throbbing pain in his right leg, just below the knee. He did not recall trauma, but he enjoyed playing pickle ball and kayaking. He did not have immunocompromising conditions, and he had no history of leg surgery or therapeutic injection in the knee. In the beginning, his pain was more prominent after games at night. It gradually became worse, and he had difficulty moving his knee joint and ambulating. Three months later, he noticed a painful swelling in the anteromedial aspect of his leg below the knee (Figure 1A). The swelling was slightly warm to the touch, but there was no erythema or fluctuance. The patient also reported occasional night sweats but no fever or other systemic symptoms. A, Diffuse swelling (arrow) in the upper part of the right leg, inferomedial to the knee. B, Magnetic resonance image showing right tibial lesion (arrow) eroding into the soft tissue. Radiography of the patient’s right leg performed about 4 months after symptom onset showed a multiloculated lucency in the proximal tibia. Subsequent magnetic resonance imaging confirmed a 6 × 4 × 3-cm cystic lesion within the proximal metaphysis of the tibia, with extension through the bone cortex into the soft tissue (Figure 1B). The erythrocyte sedimentation rate and C-reactive protein level, mg/dL were elevated, at 59 mm/h (normal, <15 mm/h) and 13.2 (normal, <0.5) respectively, and the peripheral blood cell counts were normal. Human immunodeficiency virus antibody/antigen test results was negative. The patient eventually underwent debridement with saucerization of right tibia, 5 months after symptom onset. There was copious purulent material in the affected bone. The histopathologic appearance of the tibial bone is shown in Figure 2. Figures 3 and 4 show the culture plate and the lactophenol cotton blue stain of the culture isolate. respectively. Hematoxylin-eosin stain of tibial bone biopsy specimen (original magnification ×20). Culture on Sabouraud dextrose agar. Note the brown–black velvety appearance of the isolate. The reverse was black (not shown). Lactophenol cotton blue stain of the culture isolate (original magnification ×1000). What is your diagnosis? Answer to Photo Quiz: Cladophialophora bantiana osteomyelitis Hematoxylin-eosin stain of the tibial bone showed septate, branching, irregularly shaped, bullous hyphae in the background of acute nonnecrotizing granulomatous inflammation (Figure 5). The brownish color of the hyphae on hematoxylin-eosin stain is characteristic of dematiaceous molds and is attributed to melanin in the fungal cell wall. The irregular contour of the hyphae was also well visualized with Grocott methamine silver stain (Figure 6). The Gram stain was negative, but bacterial culture of the tibial bone grew black colored mold. Subculture of the black mold from routine bacteriologic media to the fungus-specific medium, Sabouraud dextrose agar, demonstrated a brown-black velvety mycelium (Figure 3). The reverse was black in color (not shown). A tape preparation of the mold was stained with lactophenol cotton blue stain and examined microscopically to observe morphologic structures. Culture on Sabouraud dextrose agar. Note the brown–black velvety appearance of the isolate. The reverse was black (not shown). Lactophenol cotton blue stain of the culture isolate (original magnification ×1000). Branching, irregularly shaped, bullous hyphae with giant cells in the background of acute nonnecrotizing granulomatous inflammation (hematoxylin-eosin stain; original magnification ×20). The brown color of the hyphae is indicative of the presence of melanin in the cell wall. Arrowheads indicate some of the branching, irregularly shaped, bullous fungal hyphae. Branching fungal hyphae seen with on Grocott methamine silver stain (original magnification ×20). The isolate demonstrated long, sparsely branched, wavy chains of smooth oval conidia consistent with Cladophialophora bantiana (Figure 4). Conidiophores were not observed. Antifungal susceptibility showed minimal inhibitory concentrations (MICs) of ≤0.03 against voriconazole and posaconazole, 0.03 against caspofungin, and 0.5 against amphotericin B. The serum Aspergillus galactomannan result was negative, but the serum 1,3-β-D-glucan level was elevated, at 347 pg/mL (normal, <80 pg/mL). There was no evidence of disseminated infection, with negative findings of chest computed tomography and brain magnetic resonance imaging. The patient was treated with voriconazole for 8 weeks, followed by posaconazole with a good response. The plan is to treat his infection for a total of 6 months. Cladophialophora is a dematiaceous mold, characterized by dark-walled cells owing to the presence of melanin. Dematiaceous molds are ubiquitous in the environment and can cause a wide range of infections (loosely termed phaeohyphomycosis) from skin abscesses to central nervous system (CNS) lesions. In addition, they can cause eumycetoma and chromoblastomycosis. C. bantiana is the most common Cladophialophora species implicated in human infections. These infections are rare, but their incidence seems to be increasing [1]. C. bantiana comprised only 5 of 33 fungal brain abscess cases (15%) over a 10-year period in one center [1]. In an analysis of 72 clinically significant specimens of dematiaceous mold over a 4-year period from 19 centers in India, only 7 specimens were Cladophialophora (including 6 cases with C. bantiana) [2]. C. bantiana is neurotropic and primarily causes CNS infections, especially brain abscesses. Meningitis alone is uncommon [1, 3]. In a study of 101 cases of primary CNS phaeohyphomycosis, C. bantiana was the most common etiologic agent, accounting for 48% of cases [4]. It can affect both immunocompetent and immunocompromised patients [1, 3]. Most cases of C. bantiana brain abscesses have been reported from India; they are more common in rural areas and show a male predominance [1, 3]. The presenting clinical features can be nonspecific, and the diagnosis can be delayed, with a mean delay of 115 days [1]. C. bantiana hardly ever causes infection outside the CNS. Among 112 patients with CNS C. bantiana infection, only 8 (7%) had disseminated infection [1]. A review of C. bantiana infections between 1912 and 2015 disclosed only 27 cases of non-CNS C. bantiana infection [3]. Five of these cases had concomitant brain abscesses, but most involved cutaneous lesions. Traumatic inoculation at non-CNS sites hardly ever causes disseminated infection [3]. Infections caused by Cladophialophora species other than bantiana are less commonly reported but have included both CNS and non-CNS infections [3]. Cladophialophora osteoarticular infection is even more uncommon and can occur as an isolated finding or as a part of disseminated infection in both immunocompetent and immunocompromised patients [5–10]. In a study from India, among 70 patients with dematiaceous mold infection over a 4-year period, there were only 3 cases of osteomyelitis, 2 caused by C. bantiana [2]. The clinical course can be indolent [8, 10]. The mode of acquisition of infection is often unclear but can be related to remote trauma resulting in localized osteomyelitis [10]. Hematogenous dissemination may play a role in disseminated infection, but the portal of entry is not obvious in the vast majority of Cladophialophora infections (especially in brain abscesses) [3]. Itraconazole, voriconazole, posaconazole, isavuconazole, and amphotericin B exhibit low in vitro MICs against C. bantiana, whereas echinocandins demonstrate variable MICs and fluconazole a high MIC [1, 3]. In Cladophialophora brain abscess, the overall mortality rate is high but seems to be lower with a combination of antifungal treatment and surgical excision or debridement [1, 3]. The duration of antifungal treatment is not well defined for brain abscesses or osteoarticular infection, but a prolonged course of treatment is likely needed. Our patient likely had occult trauma in his leg leading to inoculation of fungal spores. As with other Cladophialophora infections, he had an indolent course with a 5-month delay in diagnosis. However, he responded well to a combination of surgical debridement and antifungal treatment. Potential conflicts of interest. G. A. C. is on the speakers bureau for BioFire Diagnostics and is on the speakers bureau and scientific advisory board and provides research support for Quidel Diagnostics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.