Sclerosing Cholangitis Associated With Trichosporon Infection and Natural Killer Cell Deficiency In An 8-Year-Old Girl:

Abstract

Trichosporon is a basidiomycete yeast responsible for white piedra, an asymptomatic infection of the hair shaft and follicle. Invasive trichosporonosis is uncommon and affects immunocompromised patients (1). We report a case of invasive trichosporonosis in a previously healthy child with selective natural killer cell deficiency. CASE REPORT An 8-year-old previously healthy white girl presented with abdominal pain and vomiting of a month's duration with recent weight loss and jaundice. She was the product of first-degree consanguinity. Family history was non-contributory. Physical examination revealed a thin, jaundiced child. A firm, non-tender liver edge was noted two centimeters below the right costal margin. Laboratory tests, summarized in Table 1, were consistent with a biliary disorder.TABLE 1: Laboratory tests on admissionComputerized abdominal tomography demonstrated multiple gallstones. Endoscopic retrograde cholangiopancreatography (ERCP) revealed multiple stenotic lesions in the distal biliary tree without evidence of ductal stones. Colonoscopy to the ileum was normal. A cholecystectomy was performed, during which a 1.5 cm stone and exudate were found in the cystic duct. A liver biopsy was also performed at that time. Pathologic examination of the gallbladder and cystic duct demonstrated granulomatous inflammation with eosinophilia as well as necrotic foci with giant cells and yeast-like forms in the lamina propria and serosa (Fig. 1). The liver histology was consistent with cholangitis. Gallbladder cultures grew Trichosporon beigelii (asahii).FIG. 1.: A) Section of the gallbladder showing a subepithelial granuloma (HE X 75). B) Numerous yeast and hyphal forms are highlighted by silver stain i.e., appear dark (GMS X 200).The patient was treated with a low fat diet, parenteral nutrition, ursodiol, and a two week course of intravenous amphoterocin B. Follow-up ERCP continued to demonstrate multiple, segmental irregularities of the main cystic and hepatic ducts (Fig. 2). A stent was placed to allow for biliary drainage. Her symptoms diminished, her laboratory values normalized, and she was discharged on itraconazole to be taken by mouth for one year.FIG. 2.: A) Selective intubation of the right hepatic duct distal to stenosis of the common hepatic duct early in the course of the disease. B) Contrast delineating the hepatic ducts late in the course of the disease demonstrating marked improvement.Further evaluation included an immunologic profile (Table 2). The patient was deficient in suppressor/cytotoxic T (CD8) cells and natural killer (NK) cells (CD16+CD56). Cytotoxic testing of NK cell lytic activity showed complete absence of NK cell function. A quantitative immunoglobulin (Ig) panel showed elevation of IgE. Lymphocyte and neutrophil function, leukocyte adhesion, and complement studies were all normal. Autoimmune antibody titer for anti-saccaromyces cerevisiae antibody, anti-neutrophilic cytoplasmic antibody, and anti-nuclear antibody were negative. Smooth-muscle antibody was minimally elevated with a titer of 40 (normal titer <20). Genetic testing was negative for chromosomal deletions, duplications, or translocations. Evaluations for human immunodeficiency virus, histoplasmosis, blastomycosis, leptospirosis, Epstein-Barr Virus, Hepatitis Virus A, B, and C, and tuberculosis were negative.TABLE 2: Immunodeficiency profileIn the year after diagnosis, she underwent multiple ERCPs, largely for stent blockage and maintenance. The irregularities of the pancreatic duct and biliary tree slowly improved. Biopsy and cytologic specimens were obtained and cultured at each subsequent ERCP. Specimens became negative for trichosporon four months after initial presentation. The bile duct irregularities gradually improved but were still apparent at the last ERCP. Eighteen months after initial presentation, the patient was free of symptoms. She was thriving and had normal serum tests of liver and biliary function. DISCUSSION Trichosporon, a basidiomycete characterized by a spore-bearing organ, was first described by Beigel in 1865, who identified it as the cause of white piedra, a disease of the hair follicle and shaft, which manifests as soft, mucilaginous, white to light brown hair nodules. The infection may cause the hair shaft to break but produces no other signs or symptoms. The genus was further delineated in 1890 by Behrend, who recognized two pathogenic species which he named T. cutaneum and T. capitatum. In 1902, Vuillemin renamed the former T. beigelii (2). Significant revisions were proposed in 1992 when Gueho et al. reported that the species that cause deep-seated and disseminated infections, are distinct from the agents of superficial infections. Sugita et al. proposed in 1999 six pathogenic Trichosporon species:T. asahii and T. mucoides, responsible for deep-seated and disseminated infections, T. asteroids and T. cutaneum for superficial infections, and T. ovoides and T. inkin for white piedra (3–4). In the present case the pathogen was T. beigelii, which under the new classification corresponds to T. asahii. Disseminated infection has been reported in both adults and children, and more recently in premature neonates (5). The infection may involve the meninges, lungs, heart, esophagus, liver, biliary tree, urinary tract, peritoneum, and uterus (2,6–12). Most patients have an underlying immunodeficiency, and the infection commonly occurs after surgical intervention, such as the placement of an indwelling prosthesis. Our patient was not neutropenic or on immunosuppressive medication and was thought to be healthy. The role of the NK cell deficiency and dysfunction in her infection is not clear. NK cells appear to play a role in the control of tumor growth and are fundamental in defense against some cytopathic viruses, but there is no evidence that NK cells provide protection against fungal infections (13). NK cell dysfunction is associated with some genetic syndromes, particularly Chediak-Higashi and Griscelli, both of which are autosomal recessive. Some studies indicate that lower NK cell function can be inherited as a recessive trait (14). NK cell dysfunction is also associated with illnesses such as systemic lupus erythematosus, lymphoproliferative disorders, malignancies, sclerosing cholangitis (SC), and hepatitis (15–16), and has been reported in association with postoperative bacterial wound infection and sepsis, and with mycobacterial and aspergillos infections (17–19). Debray et al. reported 56 children with SC. Thirty-one (55%) of the children had an associated condition (e.g. histiocytosis X, IBD, psoriasis). An immunodeficiency syndrome (most frequently combined humoral and cellular deficiency) was present in 8 (14%); consanguinity was reported in 13 (23%) (20). NK cell dysfunction has not been reported in association with SC. A few reports traced found Trichosporon infection to be nosocomial. These cases involved multiple individuals, and the infective strain was shown to be the same, using random amplified polymorphic DNA (RAPD) and amplified fragment length polymorphism (AFLP) (2,21–22). Our patient's presentation was initially suggestive of cholelithiasis. An ERCP yielded findings consistent with SC, and a colonoscopy was performed to rule out inflammatory bowel disease. Nosocomial infection seems unlikely in our patient because she was the only person infected and the ductal lesions were very severe, especially when considering the time frame between the initial and follow-up ERCPs. We speculate that the pathway of infection was ascending since the infection was localized in the biliary tract without significant liver pathology. Treatment of her infection with surgery, medication, and procedural drainage cleared the biliary tree of the pathogen within three months; however, mild sclerosis persisted at her last follow-up Infections have been implicated previously in the development of sclerosing cholangitis. Bucuvalas et al. described a case of cholangitis associated with Cryptococcus neoformans in an otherwise healthy 15-year-old girl. At presentation, ascitis and splenomegaly were present, and despite aggressive therapy and intensive support, the patient died 16 days after admission. At autopsy, active sclerosing granulomatous cholangitis involved the common bile duct and common hepatic duct, but not the gallbladder and cystic duct. The liver was cirrhotic. The authors concluded that the young woman developed cryptogenic cirrhosis with superimposed infectious cholangitis (23). There are other reported cases of biliary tree fungal infections with Candida, Histoplasma, Aspergillus and Blastomyces (24–27). Most of these infections also developed in immunodeficient hosts. The reports collectively conclude that fungal cholangitis carries a poor prognosis, especially in patients who are either immunocompromised or have a second, underlying condition (e.g. cancer, diabetes). We suggest that our patient's ascending infection resulted in inflammation and sclerosis of the biliary tree. Medical treatment with amphotericin B and an oral azole agent, and bile duct stenting, were successful in clearing the infection and restoring normal bile flow. In conclusion, trichosporon infections appear to affect mostly immunocompromised patients but can occur in clinically healthy hosts as well. We report successful treatment of sclerosing cholangitis associated with trichosporon infection, and complicated by immunodeficiency in an otherwise healthy 8-year-old girl.