Scedosporium infection disseminated “from toe to head” in ...

The patient is a 65-year-old female who was diagnosed with unfavorable risk AML [with TP53 mutation and del(5q)] in April 2022. She was refractory to standard induction therapy but responded to a combination of a hypomethylating agent and venetoclax (3 cycles). She remained neutropenic throughout and after treatment, and received prophylaxis with fluconazole 400 mg daily for 3 months until her transplant, due to concern for elevated liver enzymes previously with posaconazole. She was neutropenic upon admission for alloHCT [white blood cells (WBC) 0.81 × 10⁹/L and absolute neutrophil count (ANC) 0.62 × 10⁹/L]. Her pre-transplant chest computerized tomography (CT) revealed irregular nodular opacities, therefore posaconazole 300 mg daily was re-challenged on admission (day -6). On day + 5, she was switched to micafungin 150 mg daily with concern for transaminitis. On day + 6, she developed hypoxemia, and had a worsening RUL nodular opacity on chest CT (Fig. 1A, B). Bronchioalveolar lavage (BAL) was performed with negative BAL galactomannan and cultures. Serum β-D-Glucan (Fungitell™ assay) was positive (180 pg/mL, reference range < 60 pg/mL). Her hypoxia resolved with diuresis, and posaconazole was resumed day + 8. On day + 15, neutrophil engraftment was noted and was associated with hypoxia, fevers, and diarrhea. Methylprednisolone (1 mg/kg daily) started on day + 16 for engraftment syndrome led to improvement.

At the same time, she was noted to have right toe swelling and erythema, initially thought to be traumatic and improved without intervention (Fig. 2A). Onychomycosis was presumed due to the appearance of the nailbed, and topical ketoconazole 2% ointment was applied for the duration of her treatment course. Her performance status declined significantly, and she became more lethargic and less responsive to verbal or non-verbal stimuli. Viral studies including serum human herpesvirus 6 (HHV6), adenovirus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and blood cultures, were unrevealing. CT of the brain was negative for bleeding or any new abnormality to explain the clinical picture. Psychiatry and neurology evaluations suggested hypoactive delirium and medications were adjusted to account for possible psychogenic side effects. On day + 26, with no improvement in her mental status, brain magnetic resonance imaging (MRI) showed a rim-enhancing lesion in the periventricular right frontoparietal region, concerning for abscess (Fig. 3A). Cerebral spinal fluid (CSF) PCR studies for CMV, Herpes simplex, HHV6, adenovirus, EBV, Cryptococcus, and fungal and bacterial cultures were negative, though protein and glucose were elevated. CT chest was suggestive of persistent but improved nodular opacities. Dual antifungal therapy comprising liposomal amphotericin B 3 mg/kg daily and voriconazole 350 mg BID was started. Repeat imaging a week later revealed an increase in size of the abscess with interval new lesions (Fig. 3B). The liposomal amphotericin B dose was increased to 5 mg/kg daily while voriconazole level was therapeutic at 2.8 µg/mL. Her level of alertness waxed and waned; however, she remained bedbound and required enteral nutrition. With no clear improvement, CSF analysis was repeated and remained negative for all pathologic microbiologic agents (repeated as above). Brain biopsy was deferred due to high risk for complications. Her right toe exam was concerning for worsening paronychia. Podiatry noted a positive probe-to-bone test, a finding with greater than 90% positive predictive value for osteomyelitis in high-risk patients, but lower in immunocompetent patients [5]. This finding was further supported by decreased T1 marrow signal intensity on MRI (Fig. 2B), a test with a lower positive predictive value approaching 80% [6]. The probed tissue was cultured, and initially grew coagulase-negative Staphylococcus and diptheroids. She received doxycycline 100 mg BID for 4 weeks.

After 5 weeks of aggressive antifungal therapy (day + 58), MRI imaging finally showed significant improvement in the brain abscess. On day + 60, fungal cultures from the right hallux grew Scedosporium apiospermum, 7 days after specimen collection. Culture media included Sabouraud Dextrose with brain–heart infusion agar, inhibitory mold agar, and brain–heart infusion agar with sheep blood, chloramphenicol, and gentamycin. Laboratory identification was performed at the University of Texas Health Science Center fungus testing laboratory, based on sequencing of internal transcribed spacer, beta-tubulin, and calmodulin loci. Antifungal susceptibilities (using CLSI M38-A2 standard) showed voriconazole minimum inhibitory concentrations (MIC) = 1 µg/ml, posaconazole MIC = 1 µg/mL, amphotericin B MIC = 1 µg/ml and isavuconazole MIC = 8 µg/ml. It should be noted that despite the low MIC, liposomal amphotericin B clinically performs poorly against Scedosporium spp. regardless of the MIC range [7]. Liposomal amphotericin B was discontinued and voriconazole continued as monotherapy. At day + 76, her poor performance status remained unchanged despite improvement in her imaging and otherwise excellent organ and graft function, and she was transferred to a rehabilitation facility. A repeat MRI brain on day + 83, after 8 weeks of treatment, showed significant decrease in the size of the lesion (Fig. 3C). Her mental status and cognitive functions eventually returned to baseline during her rehabilitation course. However, she developed failure to thrive due to other non-infectious HCT complications, and opted to transition to comfort care. She ultimately passed away 6 months after her HCT. See Fig. 4 for a timeline of the patient's clinical course and interventions.