Endophthalmitis, Cutaneous Nodules, and Brain Lesions in Stem Cell Transplant Recipient

A 46-year-old man with relapsed acute myeloid leukemia underwent his second matched related donor stem cell transplant (SCT), after fludarabine and melphalan conditioning followed by post-transplant cyclophosphamide. He engrafted on day +20. On day +27, he developed fever, sinusitis, left eyelid swelling, and right eye subconjunctival swelling (Figure 1A). He required an urgent right vitrectomy for endophthalmitis. Seven days later, he developed skin nodules on his upper and lower extremities which progressively enlarged and became more diffuse (Figure 1Band 1C). Laboratory tests showed leukopenia (white blood cell count 3.1 × 10⁹/L), anemia (Hb 7.2 g/dL), and severe thrombocytopenia (25 × 10⁹/L) with normal electrolytes, and normal renal and hepatic function. Blood, urine, and sputum cultures were no growth, and infectious serologies, nucleic acid, and antigen tests were negative, including for human immunodeficiency virus, syphilis, Toxoplasma, tuberculosis, cytomegalovirus, and Strongyloides. Nasal endoscopy did not demonstrate necrosis of sinus tissue, and sinus swab cultures did not grow any organisms of clinical significance. Wide excisional skin biopsies of skin lesions demonstrated a lymphohistiocytic infiltrate and panniculitis (Figure 2A) and circular structures (Figure 2B). Vitrectomy was performed for endophthalmitis, and vitreous fluid cultures had no growth. Positron emission tomography (PET) demonstrated diffuse subcutaneous foci most numerous of the lower extremities, and a left occipitotemporal focus (Figure 3A). Shortly thereafter, he developed acute encephalopathy, drowsiness, and rhythmic movements of his right arm concerning for seizures. Brain magnetic resonance imaging (MRI) demonstrated abnormalities of the left frontal gyrus, occipital lobe, parieto-occipital sulcus, and cerebellum, concerning for embolic strokes (Figure 3B). He continued to have fever and progression of skin lesions despite treatment with meropenem, vancomycin, minocycline, and amphotericin. What is the likely diagnosis?

Figure 1.

A, Left peri-orbital cellulitis and edema and right subconjunctival edema; diffuse subcutaneous nodules of (B) upper and (C) lower extremities.

Figure 2.

Skin biopsy of subcutaneous nodule: (A) Hematoxylin and Eosin ×600. (B) Periodic acid–Schiff (PAS) × 600.

Figure 3.

A, Positron emission tomography with diffuse cutaneous and subcutaneous foci, most numerous of the lower extremities, and a left occipitotemporal focus. B, MRI brain with T2 hypointense lesion of the left parieto-occipital sulcus with vasogenic edema. Abbreviation: MRI, magnetic resonance imaging.

Diagnosis: Disseminated Acanthamoebiasis with Granulomatous Amebic Encephalitis.

We conducted multidisciplinary discussions among specialists in infectious diseases, clinical microbiology, pathology, and hematology/oncology for comprehensive evaluation of this complex case. Our differential diagnosis for culture-negative disseminated infection with persistent fevers and prominent subcutaneous nodules despite broad empiric antimicrobial therapy included non-tuberculous mycobacteria, mold, amoeba, and Nocardia. Further examination of skin lesion hematoxylin and eosin (H&E) stain demonstrated polygonal cells with finely vacuolated cytoplasm, perinuclear pallor, nuclei, and variable prominent nucleoli/karyosomes compatible with amoebic trophozoites (Figure 4A). A periodic acid–Schiff (PAS) stain of the skin lesion biopsy demonstrated circular structures with PAS-positive refractile walls compatible with amoebic cysts (Figure 4B). Indirect immunofluorescence demonstrated Acanthamoeba trophozoites surrounding blood vessels (Figure 4C). Acanthamoeba polymerase chain reaction (PCR) was positive from both the skin lesion tissue and vitreous fluid. The patient was started on the combination therapy regimen suggested by the Centers of Disease Control and Prevention with pentamidine, sulfadiazine, flucytosine, fluconazole, and miltefosine [1]. Following treatment, the patient had improvement of his skin but progressive worsening of brain lesions, and he ultimately died 64 days after initially developing symptoms.

Figure 4.

A, Arrows indicate polygonal cells with finely vacuolated cytoplasm, perinuclear pallor, nuclei, and nucleoli compatible with amoebic trophozoites. B, Arrow indicates circular structure with PAS-positive refractile wall compatible with amoebic cysts. C, Indirect immunofluorescence using rabbit anti-Acanthamoeba sera ×100 with trophozoites surrounding blood vessels (BV) indicated by arrows.

Acanthamoeba are eukaryotic protists, categorized as free-living amoeba (FLA) that are opportunistic parasites to humans and animals. The 3 most common genera of FLA that cause infections in humans are Acanthamoeba, Balamuthia, and Naegleria [2]. Acanthamoeba have been found throughout the natural environment in both soil and waterways and have also been detected in tap water, swimming pools, and indoor ventilation systems [2], as well as in healthy people without signs of infection [3]. Immunocompromised patients are at risk for invasive Acanthamoeba infections, including rhinosinusitis, cutaneous disease, granulomatous amebic encephalitis (GAE), and other disseminated infections. Acanthamoeba are thought to be acquired through direct contact with nasal passages, the respiratory system, or broken skin and invade local blood vessels (Figure 3C) to subsequently cause these manifestations. Due to the ubiquitous presence of Acanthamoeba and our patient's self-imposed activity limitation due to his medical conditions, it is difficulty to identify the source of Acanthamoeba acquisition. However, the patient did state that he had visited a “dusty” farm in rural Texas in the months preceding his hospitalization. Invasive Acanthamoeba infections were initially reported in the literature as opportunistic infections in people with AIDS [4] and now have been reported in solid organ [5] and stem cell [6] transplant recipients, and in patients with autoimmune conditions on immunosuppressant medications [7]. Due to the rarity of invasive acanthamoebiasis and the non-specific and variable nature of symptoms, most cases are diagnosed post mortem [8]. Skin lesions, which can precede neurological symptoms, offer an opportunity for antemortem diagnosis and treatment. Amebic subcutaneous lesions in the presented case demonstrated ¹⁸F-fluorodeoxyglucose uptake on PET, which has not been previously described, and provided early evidence of disseminated infection. Skin histopathology frequently demonstrates neutrophilic or lymphocytic inflammation, necrotizing granulomata, and panniculitis [9]. Trophozoites can be visualized on tissue H&E; however, these can be mistaken for tissue histiocytes [5]. Diagnosis should be confirmed by submission of infected tissue or fluid for Acanthamoeba PCR [10]. Cases of invasive acanthamoebiasis have been reported in hematological malignancy SCT recipients for the past 30 years [11]. Few published cases of patients [6, 12] have been diagnosed antemortem with invasive Acanthamoeba infections and subsequently received treatment. Antemortem diagnosis of this difficult-to-recognize and rare disease will allow for prompt treatment and offers the best opportunity for survival.

Notes

Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention.

Financial support. This work was supported by the National Institutes of Health Loan Repayment Program (award number L30AI154520) to D. B. A.