Balamuthia mandrillaris infection with cutaneous nodules as the first presentation

Balamuthia mandrillaris, belonging to the family Acanthamoebidae, primarily causes skin and central nervous system (CNS) disease. To date, over 200 cases have been reported worldwide, predominantly in warmer regions [1]. In China, most cases present with cutaneous infections as the initial symptom, followed by neurological manifestations several months or years later. Balamuthia mandrillaris encephalitis is characterized by rapid progression, high misdiagnosis rates, and high morbidity and mortality, highlighting the importance of early diagnosis and treatment [2]. This article reports a case of Balamuthia mandrillaris infection in an elderly Chinese female who developed recurrent red infiltrative plaques on her left hand, which eventually progressed to fatal encephalitis. The patient died despite resuscitation attempts. The authors reviewed relevant literature, summarized clinical manifestations, and provided insights for early diagnosis and treatment.

Balamuthia mandrillaris is an aerobic, free-living amoeba found in soil and water. It can infect various animals, including orangutans, bats, horses, and dogs [3-5]. Transmission occurs via inhalation, inoculation through broken skin, or hematogenous spread to the brain and other organs [6]. The first case of Balamuthia mandrillaris encephalitis was reported in 1986 when it was isolated from the brain tissue of a baboon that died of meningoencephalitis at the San Diego Zoo [7]. Balamuthia mandrillaris encephalitis is a rare, fatal CNS infectious disease with an unclear pathogenesis, posing challenges in diagnosis and treatment. This case report highlights dermatologic lesions as the initial presentation.

Case Presentation A 65-year-old woman presented with a three-year history of skin lesions on her left upper extremity. Initially, a subcutaneous nodule appeared on the dorsum of her left hand, accompanied by itching. It was surgically excised at a local hospital. One month later, another subcutaneous nodule reappeared and was excised again. Subsequently, erythema developed at the surgical site, gradually forming a plaque protruding from the skin surface, accompanied by itching. One year prior to presentation, a subcutaneous nodule developed on the flexor side of her left forearm, which was excised along with a biopsy of the dorsum plaque. Histopathology revealed mild epidermal hyperplasia and diffuse dermal infiltration of histiocytes, lymphocytes, neutrophils, plasma cells, and multinucleated giant cells. The lesions recurred post-surgery, enlarging over time. After self-treatment with herbal wet compresses, the lesions eroded, prompting her to seek dermatological care at Sichuan Provincial People’s Hospital. She resided in a rural area, denied trauma history, and underwent dermatologic examination. Findings included an infiltrative red plaque covering the dorsum of her left hand with clear borders and an egg-sized, slightly hard, movable mass on her left forearm, which was painless. (Figure 1) After admission, relevant examinations, including chest and abdominal CT, blood routine, and tuberculosis T-cell testing, revealed no abnormalities. Cranial CT showed a few speckled low-density shadows in the left basal ganglia region, suggestive of cavity infarcts. A skin biopsy from the left forearm lesion showed granulomatous inflammation in the dermis (Figure 2). Tests for TB-PCR, deep fungal culture, PAS, silver hexammonium, and acid-fast staining were negative. Next-generation sequencing (NGS) of the forearm lesion identified Balamuthia mandrillaris with 2216 sequences and a relative abundance of 80.3% (Figure 3). The diagnosis of Balamuthia mandrillaris skin infection was confirmed on the seventh day of admission. The patient was treated with hydroxychloroquine (200 mg/day), clarithromycin (0.5 g/day), metronidazole (0.6 g/day), and itraconazole (0.2 g/day) and discharged with the medications. Forty days later, she developed high fever and blurred consciousness. Cranial MRI at an outside hospital revealed multiple bilateral brain lesions, suggestive of metastatic brain tumors. Her condition deteriorated, and she died 43 days post-discharge despite resuscitation attempts. Histopathological Histopathology is used to observe cellular structure and morphological changes in the skin and to try to find trophozoites. MRI MRI shows the brain structures clearly and reveal the shape, size and location of the lesion, as well as the invasion of surrounding tissues. NGS NGS is used to rapidly detect viruses, bacteria and eukaryotic parasites in clinical samples, helping physicians improve the accuracy of diagnosing diseases, especially for rare and difficult cases.

Histopathological findings on skin biopsy showed granulomatous inflammation and no amoebic trophozoites were detected.MRI findings at the time of the patient’s onset of hyperthermia and unconsciousness demonstrated multiple lesions in the brain bilaterally, and metastatic brain occupations were considered.NGS examination of a skin lesion on the left forearm revealed 2216 Balamuthia mandrillaris sequences with a relative abundance of 80.3%.

Free-living amoebas are ubiquitous environmental protozoa that infect humans and animals without requiring a vector. Balamuthia mandrillaris is most commonly isolated from soil [8], with infections linked to agricultural activities, motorcycling, swimming, and gardening [9]. The disease affects both immunocompetent and immunosuppressed individuals. This patient’s long-term rural residence and farming work likely exposed her to the parasite. Three clinical patterns exist: (1) initial skin lesions followed by neurological symptoms, predominantly in China and Peru; (2) isolated neurological involvement, mainly in the United States; and (3) pure cutaneous infection [10]. Cutaneous involvement typically manifests as nonulcerative plaques, often asymptomatic and occasionally with satellite foci [12-14]. Neurologic symptoms result from thrombophlebitis-induced hemorrhage, infarction, and necrosis [15]. Common initial signs include headache, cervical rigidity, fever, nausea, and seizures, often followed by progressive loss of consciousness. The nonspecific clinical presentation frequently leads to misdiagnosis. Early recognition of midface lesions facilitates diagnosis, but lesions outside this area require heightened suspicion. Typical histopathologic features include diffuse granulomatous reactions with ill-defined granulomas, lymphocyte-rich peripheral infiltrates, and multinucleated giant cells. Definitive diagnosis relies on identifying trophozoites. Neurological involvement poses diagnostic challenges due to broad differentials. NGS is a rapid and accurate tool for identifying rare pathogens, as shown in this case, where it facilitated early diagnosis of unexplained granulomatous lesions. Treatment remains unclear due to limited case reports. The CDC recommends combination therapy with sulfadiazine, pentamidine, flucytosine, fluconazole, clarithromycin or azithromycin, and miltefosine [17]. However, outcomes are often suboptimal. Recent studies suggest that quinoline nitroxoline may be superior to current recommendations [18]. A patient with Balamuthia mandrillaris encephalitis showed clinical remission after adding quinoline nitroxoline to their regimen [19,20]. However, treatment efficacy varies, and the lack of certain drugs in China may have contributed to this patient’s poor outcome.

In conclusion, Balamuthia mandrillaris infection poses diagnostic and therapeutic challenges. Clinicians should maintain high suspicion for unexplained granulomatous lesions and utilize advanced diagnostic methods like NGS for pathogen identification. Early recognition and treatment may improve survival rates, underscoring the importance of clinician awareness to prevent misdiagnosis and ensure timely management. Ackonwledgement No acknowledgements.

[1]Diaz JH. The public health threat from Balamuthia mandrillaris in the southern United States. J La State Med Soc. 2011;163(4):197-204. [2]Wang L, Cheng W, Li B, et al. Balamuthia mandrillaris infection in China: a retrospective report of 28 cases. Emerg Microbes Infect. 2020;9(1):2348-2357. doi:10.1080/22221751.2020.1835447. [3] Finnin PJ, Visvesvara GS, Campbell BE, Fry DR, Gasser RB. Multifocal Balamuthia mandrillaris infection in a dog in Australia. Parasitol Res. 2007;100(2):423-426. doi:10.1007/s00436-006-0302-0. [4]Kinde H, Visvesvara GS, Barr BC, Nordhausen RW, Chiu PH. Amebic meningoencephalitis caused by Balamuthia mandrillaris (leptomyxid ameba) in a horse. J Vet Diagn Invest. 1998;10(4):378-381. doi:10.1177/104063879801000416. [5]Retana-Moreira L, Abrahams-Sandí E, Cabello-Vílchez AM, et al. Isolation and molecular characterization of Acanthamoeba and Balamuthia mandrillaris from combination shower units in Costa Rica. Parasitol Res. 2014;113(11):4117-4122. doi:10.1007/s00436-014-4083-6. [6]Zhang Z, Liang J, Wei R, et al. Facial Balamuthia mandrillaris infection with neurological involvement in an immunocompetent child. Lancet Infect Dis. 2022;22(3):e93-e100. doi:10.1016/S1473-3099(21)00334-0. [7]Visvesvara GS, Martinez AJ, Schuster FL, et al. Leptomyxid ameba, a new agent of amebic meningoencephalitis in humans and animals. J Clin Microbiol. 1990;28(12):2750-2756. doi:10.1128/jcm.28.12.2750-2756.1990. [8]Dunnebacke TH, Schuster FL, Yagi S, Booton GC. Balamuthia mandrillaris from soil samples. Microbiology (Reading). 2004;150(Pt 9):2837-2842. doi:10.1099/mic.0.27218-0. [9]Diaz JH. The public health threat from Balamuthia mandrillaris in the southern United States. J La State Med Soc. 2011;163(4):197-204. [10]The Epidemiology and Clinical Features of Balamuthia mandrillaris Disease in the United States, 1974-2016. [11]Chang OH, Liu F, Knopp E, et al. Centrofacial Balamuthiasis: case report of a rare cutaneous amebic infection. J Cutan Pathol. 2016;43(10):892-897. doi:10.1111/cup.12748. [12]Reed RP, Cooke-Yarborough CM, Jaquiery AL, et al. Fatal granulomatous amoebic encephalitis caused by Balamuthia mandrillaris. Med J Aust. 1997;167(2):82-84. doi:10.5694/j.1326-5377.1997.tb138785.x. [13]Sangruchi T, Martinez AJ, Visvesvara GS. Spontaneous granulomatous amebic encephalitis: report of four cases from Thailand. Southeast Asian J Trop Med Public Health. 1994;25(2):309-313. [14]Pritzker AS, Kim BK, Agrawal D, Southern PM Jr, Pandya AG. Fatal granulomatous amebic encephalitis caused by Balamuthia mandrillaris presenting as a skin lesion. J Am Acad Dermatol. 2004;50(2 Suppl):S38-S41. doi:10.1016/s0190-9622(03)02090-5. [15]Recavarren-Arce S, Velarde C, Gotuzzo E, Cabrera J. Amoeba angeitic lesions of the central nervous system in Balamuthia mandrilaris amoebiasis. Hum Pathol. 1999;30(3):269-273. doi:10.1016/s0046-8177(99)90004-7. [16]Vargas-Zepeda J, Gómez-Alcalá AV, Vásquez-Morales JA, Licea-Amaya L, De Jonckheere JF, Lares-Villa F. Successful treatment of Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin. Arch Med Res. 2005;36(1):83-86. doi:10.1016/j.arcmed.2004.11.003. [17]Centers for Disease Control and Prevention.Parasites-Balamuthia mandrillaris-Granulomatous Amebic Encephalitis(GAE)[EB/OL]. (2019-09-05)[2023-11-15]. https://www.cdc.gov/parasites/balamuthia/treatment.html. [18]Laurie MT, White CV, Retallack H, et al. Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen Balamuthia mandrillaris. mBio. 2018;9(5):e02051-18. Published 2018 Oct 30. doi:10.1128/mBio.02051-18. [19]Spottiswoode N, Pet D, Kim A, et al. Successful Treatment of Balamuthia mandrillaris Granulomatous Amebic Encephalitis with Nitroxoline. Emerg Infect Dis. 2023;29(1):197-201. doi:10.3201/eid2901.221531. [20]Spottiswoode N, Haston JC, Hanners NW, et al. Challenges and advances in the medical treatment of granulomatous amebic encephalitis. Ther Adv Infect Dis. 2024;11:20499361241228340.Published 2024 Feb 2.doi:10.1177/20499361241228340 Figure 1. The patient’s skin lesions observed on the day of admission: A clearly demarcated infiltrative red plaque covered the entire dorsum of the left hand. Additionally, an egg-sized mass was noted on the left forearm. Figure 2. Histopathological examination of the left forearm reveals granulomatous inflammation. (A: Hematoxylin-eosin stain, ×20; B: Hematoxylin-eosin stain, ×40) | Genus | Species | | Name sequence number | Name sequence number Relative abundance | | Balamuthia 2216 | Balamuthia mandrillaris 2216 80.83% | Figure 3. Next-generation sequencing of the skin tissue identified 2,216 sequences of Balamuthia mandrillaris. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 226views 133downloads Citations Download citation Huiyun Fan, Yangying Liu, Siyu Wang, et al. Balamuthia mandrillaris infection with cutaneous nodules as the first presentation. Authorea. 17 January 2025. DOI: https://doi.org/10.22541/au.173708535.54706718/v1 DOI: https://doi.org/10.22541/au.173708535.54706718/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.