A 73-year-old Japanese Woman With Rheumatoid Arthritis and Exposure to Water From a Well

A 73-year-old woman with type 2 diabetes mellitus and rheumatoid arthritis (RA) for 14 years was admitted to hospital with fever, generalized pain, muscle weakness, and loss of appetite for 3 weeks. Her RA was stable on prednisolone and methotrexate. She used water from a well for domestic use, including as drinking water. On admission, she had an elevated serum creatinine kinase level of 605 U/mL (reference range 45–153). Initially, methotrexate was discontinued, prednisolone was gradually reduced, and antibacterial therapy was initiated. On day 6 of admission, she was treated with 3 days of methylprednisolone and empiric liposomal amphotericin was added to the regimen. This led to an improvement in the fever. However, by day 47, there was persistent fever, weakness, and atrophy in the proximal limb muscles and unsteady gait. There was no sensory loss, dysarthria, or dysphagia. Needle electromyography from the biceps brachii and vastus lateralis showed myopathic changes. A left biceps brachii muscle biopsy was performed on day 51. On histopathology (Figure 1A), there was moderate to marked fiber size variation, with internalized nuclei in scattered fibers, and clusters of necrotic fibers undergoing phagocytosis. There were also numerous 3 × 4 μm ovoid spores in the cytoplasm (Figure 1A and 1B). The spores were too small for Cryptococcus spp. and lacked a thick capsule (Figure 1B). On immunohistochemistry, numerous CD68-positive cells, indicative of macrophages, were seen with numerous ovoid spores in the cytoplasm (Figure 1C). On electron microscopy, mature spores with 9–10 polar tubule coils were present (Figure 1D). Muscle magnetic resonance imaging (MRI) performed at the muscle biopsy showed edematous lesions within the muscles, particularly around the intramuscular vessels (Figure 2). Brain MRI revealed no abnormalities. Histochemical and electromicroscopic findings in biceps brachii muscle. A, B, Modified Gomori-Trichrome staining before albendazole treatment. A, Massive necrotic fibers with phagocytosis, containing numerous ovoid spores (arrowhead) in the cytoplasm, are seen regionally: bar = 20 μm. B, Scattered fibers have cytoplasmic capsular infiltration: bar = 10 μm. C, Numerous CD68-positive histiocytes, which contain many capsular infiltration (arrowheads) are seen: bar = 20 μm. D, On electron microscopy, spores had an electron-dense exospore, an electron-lucent endospore, and a polar tubule arising from the anchoring plate, with 9–10 coils arranged in a single row: bar = 0.2 μm. Myoedema on skeletal muscle imaging. Short tau inversion recovery (STIR) image in right thigh. Vastus lateralis shows clustered high intensity around blood vessels (arrowheads). What is your diagnosis? Diagnosis: infectious myositis caused by the microporidian, Anncaliia algerae. The diagnosis of Anncaliia algerae myositis was confirmed on polymerase chain reaction (PCR) and sequence analysis, using published primer sets, on DNA extracted from frozen muscle biopsy specimens [1, 2]. PCR was negative on DNA extracted from the cerebrospinal fluid, alveolar lavage fluid, urine, serum. and the well water, which was used daily by the residents of the house. Albendazole (600 mg 1×/day orally) therapy was initiated on day 114 and continued for 28 days. Her muscle strength improved, and she was able to mobilize using a walker. A repeat left biceps brachii muscle biopsy was performed on day 149. On histopathology, there were some necrotic and regenerating muscle fibers with mild mononuclear cell infiltration, primarily composed of macrophages containing vacuolar structures. There were no spores visible. On day 158 of admission, she was discharged and able to walk without any assistance. She has remained in remission for more than 1 year after treatment. A. algerae can cause localized infection, including keratitis, and a potentially fatal systemic infection that presents most commonly as a myositis [2, 3]. The first report of myositis was in 2004, in a woman from Pennsylvania with RA and type 2 diabetes mellitus [4]. A total of 11 cases of systemic infection have been reported with 7 fatalities: 2 from the United States, 1 from Canada, 6 from Australia, 1 from New Zealand, and 1 from China [2–9]. These cases have been associated with immunosuppressive therapy due to rheumatoid arthritis, psoriatic arthritis, hematological malignancies, and stem cell and solid organ transplantation [2–9]. The basis for the recent emergence of the infection remains unclear, and in this case, the patient was taking standard treatment for rheumatoid arthritis [2]. A. algerae is a micropordian that infects a broad range of environmental hosts, including mosquitoes and other insects. One means of transmission to humans may be through contact with untreated water that contained infected insects [2, 9]. Although infection of the cornea may be related to direct contact with water containing spores, systemic infection is indicative of intravascular spread [2, 9, 10]. Previous reports of systemic infection noted that patients have ingested or inhaled water from untreated sources, or lived in areas near bodies of water with abundant mosquitoes [2, 3, 5, 9]. Although there is advice that immunosuppressed persons should avoid or boil untreated water, levels of patient and clinician awareness are unknown [9]. In this case, the patient regularly consumed water from a well, and the negative water testing result may have been related to sampling or other pre-analytical factors limiting the test sensitivity. As the symptoms of A. algerae myositis are non-specific, they may be misdiagnosed as an automimmune complication and treated with an increased amount of immunosuppressive therapy. In this situation, the disease will worsen, sometimes after a brief period of improvement. It is essential to perform a muscle biopsy to clarify the diagnosis of Anncaliia infection, considering the need for specific therapy to prevent fatality. The histopathological appearance of the spores on biopsy can be confused with the yeast form of fungus, which can lead to inappropriate treatment with an antifungal and delays in directed therapy [2]. Electron microscopy will assist with the diagnosis of Anncaliia, as mature spores have a dense exospore coat, a pale endospore, and single rows of 8–11 polar tubule coils (Figure 1D) [2]. PCR and sequence analysis from biopsy material allowed confirmation of the species [1, 2]. The MRI findings (Figure 2) demonstrated myositis, with high signal surrounding blood vessels suggestive of intravascular dissemination. The normal findings on brain MRI were consistent with the negative cerebrospinal fluid PCR and no symptoms of meningo-encephalitis. The effectiveness of albendazole and a reduction in immunosuppressive therapy was cofirmed by clinical improvement without relapse and the clearance of the spores on repeat muscle biopsy. Fumagillin has been added to albendazole to successfully treat infection [6]. Patients need to be monitored closely for signs of bulbar muscle weakness and aspiration pneumonia, as this can be a fatal complication [2]. In this case, the absence of clinically evident bulbar muscle weakness may indicate less extensive disease that contributed to the patient's survival. A. algerae infection should be considered in patients with RA and other immunosuppressive conditions who present with muscle weakness, fever, and myalgia. A biopsy is needed to confirm the diagnosis and allow the urgent commencement of directed therapy. Immunosuppressed patients who are exposed to untreated water should be educated about precautions and the options for water treatment. Acknowledgments. The authors thank Ms Kaoru Tatezawa, Ms Kazu Iwasawa, Ms Fumi Katahira, Ms Hiroko Koyama, Mr Ichiro Takahashi, and Mr Hisayoshi Nakamura of Medical genome center, National Center of Neurology and Psychiatry (NCNP), for their technical assistance. They also thank Prof Kum Thong Wong, Department of Pathology, University of Malaya, Kuala Lumpur, Malayasia for his critical comments, Prof Jantima Tanboon, Department of Pathology, Siriraj Hospital, Mahidold University, Bangkok, Thailand for her advice, and Prof Louis M. Weiss, Division of Parasitology and Tropical Medicine, Albert Einstein College of Medicine, New York, United States, for providing technical information. Ethical approval. This study was approved by the ethics committee of the National Center of Neurology and Psychiatry (NCNP) in Japan (A2019-123). Financial support. This study was supported partly by Intramural Research Grant (grant numbers 2-5 and 5-6) for neurological and psychiatric disorders of NCNP.

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