To the Editor: A 13-year-old girl with Crohn disease (CD) from Shandong Province transferred to our inflammatory bowel disease (IBD) center during April 2013. Three months previously, the patient presented with hematochezia and fever, but antibiotic treatment was unsuccessful. After admission, a colonoscopy indicated manifestations of segmental lesions, cobble stoning, and stricture [Figure 1A]. Cytomegalovirus, Epstein-Barr virus, Clostridium difficile, and amoebae were excluded as possible causes. There were also no indications of Behcet disease, systemic vasculitis, or other autoimmune diseases. Our initial diagnosis was active severe CD (Vienna typing, A1L3B2). This study was approved by the Ethical Committee of First Hospital of Peking University (No. 2019153). An appropriate signed patient consent form was obtained.
Because intestinal tuberculosis could not be easily excluded, we initially administered a glucocorticoid to induce remission with antituberculosis therapy. However, there was no response, so we switched to infliximab. After three doses of infliximab (weeks 0, 2, and 6), we performed another colonoscopy [Figure 1B] and found that infliximab failed to improve the lesion. A biopsy was sent for culture to exclude specific infections, but the culture was positive for fungus [Figure 1C and 1D]. The fungus was subsequently identified as Trichosporon montevideense based on sequence analysis of internal transcriber spacers and intergenic spacer regions (Supplementary Material for the method, http://links.lww.com/CM9/A219). However, we considered T. montevideense colonization to be unrelated to the symptoms because this genus is common in the microbiota of normal intestines.
After 3 months of infliximab therapy, abdominal pain and general well-being showed no improvement. Then, the patient suddenly underwent emergency surgery for intestinal bleeding, which included total colectomy and ileostomy. After the operation, the patient developed high fever (39°C). Considering the long duration of glucocorticoid and infliximab treatments, we treated the patient with an antibiotic combination (meropenem, teicoplanin, and caspofungin acetate), but her temperature remained elevated after 72 h. There were no pathogens in a blood culture or a peritoneal lavage culture, and the (1, 3)-β-D glucan test and galactomannan test were negative. Continuation of the high fever would place the patient in extreme danger.
The vast majority of yeast isolated from our intensive care units were from the genus Candida. Rare pathogenic fungi, such as Cryptococcus and Trichosporon, have also emerged (unpublished data). However, our center did not find Candida species that were caspofungin resistant (unpublished data). Therefore, we speculated that Trichosporon sp. may be the cause of her symptoms for several reasons. T. montevideense was previously cultured from her colon mucosa, Trichosporon sp. is considered the second most common cause of basidiomycetous yeast infections in humans, and gut translocation is considered the major source of infection. Moreover, Trichosporon sp. is naturally resistant to caspofungin acetate. Thus, we initiated treatment with voriconazole, to which Trichosporon sp. is susceptible. Encouragingly, the patient's temperature began to decrease after 24 h, and it returned to near normal after 3 days. Three months later, the patient recovered enough to be discharged home. Additionally, we found yeast in colon tissue by immunofluorescence [Figure 1E; Supplementary Material for method, http://links.lww.com/CM9/A219], so it is likely that the pathogen causing the fever was Trichosporon sp.
The role of T. montevideense in colitis is still unclear, although there is a close association between gut mycobiota and inflammatory bowel disease. For example, Candida albicans and Malassezia spp. can aggravate colitis, whereas Saccharomyces boulardii can alleviate colitis.[1,3] The presence of antibodies against Saccharomyces cerevisiae is a marker for susceptibility to IBD. Caspase recruitment domain 9 (Card9) is a key regulator of immunity to fungi, and certain Card9 polymorphisms are associated with IBD.
A previous study reported the presence of Trichosporon spp. in the intestinal mucosa of patients with CD. Iliev et al found increased amounts of Trichosporon spp. during colitis in mice, suggesting that these fungi may be adapted to the inflammatory environment. Thus, we examined the effect of our clinical isolate of T. montevideense (BMU 07526) in a mouse model of colitis, in which disease was induced by dextran sodium sulfate (DSS). These experiments were approved by the Peking University First Hospital Laboratory Animal Welfare and Ethics Committee (No. 201913). The experimental mice received a gavage with 108T. montevideense cells each day. The results indicated that T. montevideense had no effect on the control (non-colitis) group but exacerbated colitis in the DSS group. Moreover, relative to control mice, mice treated with yeast had greater weight loss, shorter colon lengths, higher disease activity scores, and higher histopathology scores [Figure 1 F–H, J; Supplementary Material for method, http://links.lww.com/CM9/A219]. Moreover, we detected by polymerase chain reaction the Trichosporon spp. from the colon mucosa of mice that received the yeast gavage [Figure I; Supplementary Material for method, http://links.lww.com/CM9/A219].
These results indicated that Trichosporon spp. are capable of gut colonization, can cause invasive infections, and can exacerbate the symptoms of colitis. We suggest that clinicians consider intestinal colonization by fungi, especially Trichosporon spp., in patients with CD who present with fever, hematochezia, and colon biopsy cultures that are positive for fungi.
Conflicts of interest
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