SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 700 BRIEF ARTICLE Cutaneous Acanthamoeba Infection Presenting with Granulomatous Vasculitis Meredith Park, BS1, Paul B. Googe, MD2, Vimal K. Derebail, MD, MPH3, Manish K. Saha, MD3, Eduard Matkovic, MD4,5, Jennifer R. Cope, MD, MPH4, Ibne Karim M. Ali, MS, PhD4, Carolyn Ziemer, MD, MPH2, Sam Wu, MD2 1 School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 2 Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 3 Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 4 National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 5 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI Free-living amebae from the Acanthamoeba genus are common in soil, water and dust. They exist as trophozoites in favorable conditions and as cysts in nutrient poor conditions.1 Cutaneous acanthamoebiasis due to Acanthamoeba is extremely rare, predominantly occurring in immunosuppressed individuals.2 Disseminated Acanthamoeba infection carries a poor prognosis, with mortality over 70%, and 100% in patients with central nervous system (CNS) involvement.2 CNS involvement is thought to occur from hematogenous spread after cutaneous or nasal exposure.1 Therapeutics for Acanthamoeba infection are poorly studied and numerous antimicrobial agents have been employed with varying response.2,3 We describe a fatal case of invasive Acanthamoeba infection. ABSTRACT Cutaneous acanthamoebiasis is a rare diagnosis that carries a mortality rate of over 70%.2 This disease predominantly affects immunocompromised individuals, though infections have been reported in immunocompetent individuals.2 We report a fatal case of cutaneous Acanthamoeba infection in a patient with granulomatous vasculitis on biopsy, initially thought to be antineutrophil cytoplasmic antibody (ANCA)-negative vasculitis. The patient primarily presented with ulcerating nasal lesions, which subsequently developed into widespread cutaneous lesions. Diagnosis was made months after presentation when amebae were identified during histopathological examination of biopsies obtained repeatedly after the patient failed to improve on standard therapies for ANCA-negative vasculitis. Treatment was unsuccessful, and the patient died due to complications of widespread Acanthamoeba infection. Cutaneous acanthamoebiasis should be considered in the differential diagnosis of granulomatous vasculitis that fails to improve on standard therapies. Early detection and treatment may improve outcomes and reduce mortality in this highly fatal infection. INTRODUCTION SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 701 A 52-year-old woman with type 2 diabetes mellitus and recurrent marginal zone lymphoma in remission presented with erythematous and subcutaneous nodules on her right upper arm and both legs. Her lymphoma diagnosis was 25 years prior to her skin lesions and recurred five and 17 years after her diagnosis. She initially received radiation, then 6 cycles of cyclophosphamide, vincristine and prednisolone for her first recurrence, and 6 cycles of rituximab with bendamustine (R- bendamustine) for her second recurrence. Biopsy of the nodules showed granulomatous dermatitis, concerning for sarcoidosis, without identifiable organisms. Blood counts, electrolytes and inflammatory markers a few months earlier were unremarkable. Full body computed tomography one year prior showed no hilar adenopathy. Concurrently, she was treated by otolaryngology for nasal septal abscesses with Aspergillus and septal perforation. After seven months, she developed an erythematous infiltrative plaque with overlying yellow crust on the nose encompassing nasal tip, nasal side walls, right medial cheek, and right upper cutaneous lip (Figure 1). Both lower extremities had violaceous, indurated nodules and plaques. She received intralesional triamcinolone and oral minocycline. A month later, due to lesion progression and concern for vasculitis, she was started on hydroxychloroquine and methotrexate. Within three weeks the nasal lesion extended to the medial cheeks bilaterally and upper cutaneous lip. Two lesions on her lower extremities became ulcerated with gray borders. She was admitted and treated with prednisone and an increased dose of methotrexate. Figure 1. Erythematous infiltrative plaque with overlying yellow crust on the nose and upper lip. Shortly after discharge, she required another admission after the lesion progressed to erosions with plaques of thick yellow-brown crust encompassing the entire nose, medial cheeks, upper cutaneous and mucosal lip. She received pulse-dose steroids and intravenous cyclophosphamide. One month later was re-admitted when the lesion coalesced, creating a dry, brown plaque of the central face with necrotic nasal cartilage. She received oral cyclophosphamide and prednisone. Repeat testing for HIV, tuberculosis, antinuclear antibodies, antineutrophil cytoplasmic antibody (ANCA), acid-fast bacterial culture and smear, and fungal studies were negative. Repeat biopsies showed small vessel vasculitis with necrosis, granulomatous inflammation, and arteritis which continued to be interpreted as ANCA-negative granulomatosis with polyangiitis. Tissue cultures grew pan- sensitive methicillin-susceptible Staphylococcus aureus, subsequently treated with intravenous vancomycin. She received intravenous immunoglobulin intermittently for low immunoglobulin levels, initially concerning for common variable immunodeficiency, though later thought CASE REPORT SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 702 unlikely. Despite continued treatment with pulse-dose steroids and cyclophosphamide, a month later her facial lesion evolved to a dry necrotic eschar replacing the entire nose and medial cheeks. Her upper lip was mostly lost with underlying dental structures exposed (Figure 2). Scattered nodules with eschar and deep ulceration developed on her chest and extremities. Figure 2. Dry necrotic eschar encompassing the nose, medial cheeks, and upper lip. The patient became febrile, tachycardic and was treated for presumed sepsis. Repeat deep tissue biopsy and review of previous biopsies showed very rare, large, rounded mononucleated cells with vacuolated cytoplasm and centrally located nuclei with a dense, slightly eosinophilic structure in the nucleoplasm suspicious for trophozoites. These findings suggested tissue invasive acanthamoebiasis, confirmed by the Centers for Disease Control and Prevention (CDC) via immunohistochemistry assay to be Acanthamoeba species (Figure 3). Brain imaging showed no evidence of CNS involvement. Immunosuppressive medications and antibiotics were stopped. Despite treatment with miltefosine, fluconazole, oral and topical sulfadiazine, pentamidine, flucytosine, and topical ketoconazole, the patient developed sepsis, kidney failure, and respiratory failure and died 15 months after initial presentation. Figure 3. Large, rounded mononucleated cells with vacuolated cytoplasm and centrally located nuclei with a dense, slightly eosinophilic structure in the nucleoplasm suspicious for trophozoites. The diagnosis of acanthamoebiasis requires a high index of suspicion, given its rarity and ability to mimic other pathologies.1,2,4 Lesions of Acanthamoeba infection are usually described as erythematous or violaceous intradermal or subcutaneous nodules.2 These lesions typically enlarge, ulcerate, developing into necrotic eschar, as illustrated here. Pathology often shows nonspecific granulomatous inflammation and previously reported cases were initially mistaken for DISCUSSION SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 703 fungal infections and vasculitides.1,2,4 Acanthamoeba species may infect the CNS causing granulomatous amoebic encephalitis, which shows necrotizing or granulomatous response on pathologic examination.5 Granulomatous vasculitis is often associated with ANCA vasculitis, and less commonly other etiologies such as lymphomatoid granulomatosis, rheumatoid vasculitis, or herpes simplex virus.7 Given the severity of Acanthamoeba infection, cutaneous acanthamoebiasis should be considered in the differential diagnosis of granulomatous vasculitis that fails to improve on standard therapies and with clinical history suggestive of exposure. While histopathology is crucial to diagnosis, more sensitive molecular analysis of tissue with polymerase chain reaction (PCR) (available through the CDC or Mayo Medical Laboratories), may allow earlier detection.3,8,9 This real-time PCR assay is able to detect one amoeba per sample.10 Early diagnosis of Acanthamoeba infection is essential for appropriate management that may reduce likelihood of death.4,8 Historically, cutaneous Acanthamoeba infections have almost exclusively been seen in immunocompromised individuals.2,11 While this patient was not on immunosuppression initially, she had diabetes mellitus which increases the risk of skin infections.12 The patient’s exposure was thought to be from swimming in a fresh water lake or through nasal lavage with well water. Management of cutaneous Acanthamoeba infection is not well studied and no consensus on optimal pharmacologic therapy exists.2,4 Previously reported cases were treated with various antimicrobial agents with variable effect.2– 4,8,9,11 Treatment with flucytosine and miltefosine has been associated with better responses, although rarely curative.2,3 As illustrated here, the toxic effects of these antimicrobial agents must be considered during treatment. Acanthamoeba infection is a rare cause of cutaneous lesions that may mimic granulomatous inflammatory diseases including vasculitis. Given its high potential mortality, patients with worsening lesions despite conventional therapies and granulomatous vasculitis on pathology should be further evaluated for amoebiasis either by meticulous histopathology or by PCR. 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. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Meredith Park, BS University of North Carolina at Chapel Hill School of Medicine 321 S Columbia St. Chapel Hill, NC 27599 Email: Meredith_park@med.unc.edu References: 1. Murakawa GJ, Mccalmont T, Altman J, Telang GH, Kantor GR, Berger TG. Acanthamebiasis With. Published online 2015:2-7. 2. Paltiel M, Powell E, Lynch J, Baranowski B, Martins C. Disseminated cutaneous acanthamebiasis: A case report and review of the literature. Cutis. 2004;73(4):241-248. 3. Aichelburg AC, Walochnik J, Assadian O, et al. Successful Treatment of Disseminated Acanthamoeba sp. Infection with Miltefosine. Emerg Infect Dis • www.cdc.gov/eid •. 2008;14(11). doi:10.3201/eid1411.070854 4. Steinberg JP, Galindo RL, Kraus ES, Ghanem KG. Disseminated acanthamebiasis in a renal transplant recipient with CONCLUSION SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 704 osteomyelitis and cutaneous lesions: case report and literature review. Clin Infect Dis. 2002;35(5):43-49. doi:10.1086/341973 5. Wiley CA, Safrin RE, Davis CE, et al. Acanthamoeba Meningoencephalitis in a Patient with AIDS. Source J Infect Dis. 1987;155(1):130-133. Accessed May 15, 2022. https://about.jstor.org/terms 6. Schuster FL, Guglielmo BJ, Visvesvara GS. In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol. 2006;53(2):121-126. doi:10.1111/J.1550-7408.2005.00082.X 7. Pagnoux C, Bienvenu B, Guillevin L. The spectrum of granulomatous vasculitides. Futur Rheumatol. 2006;(6):729-750. doi:10.2217/17460816.1.6.729 8. Morrison AO, Morris R, Shannon A, Lauer SR, Guarner J, Kraft CS. Disseminated acanthamoeba infection presenting with cutaneous lesions in an immunocompromised patient: A case report, review of histomorphologic findings, and potential diagnostic pitfalls. Am J Clin Pathol. 2016;145(2):266-270. doi:10.1093/AJCP/AQV081 9. Afshar K, Boydking A, Ganesh S, Herrington C, Michael McFadden P. Rapidly fatal disseminated acanthamoebiasis in a single lung transplant recipient. Ann Transplant. 2013;18(1):108-111. doi:10.12659/AOT.883846 10. Qvarnstrom Y, Visvesvara GS, Sriram R, Da Silva AJ. Multiplex real-time PCR assay for simultaneous detection of Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri. J Clin Microbiol. 2006;44(10):3589- 3595. doi:10.1128/JCM.00875-06 11. Galarza C, Ramos W, Gutierrez EL, et al. Cutaneous acanthamebiasis infection in immunocompetent and immunocompromised patients. Int J Dermatol. 2009;48(12):1324- 1329. doi:10.1111/J.1365- 4632.2008.03786.X 12. Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. SCIENCE BENTHAM. Type 2 Diabetes and its Impact on the Immune System. Curr Diabetes Rev. 2020;16:442- 449. doi:10.2174/1573399815666191024085838