Herbst Martin, Gazendam Roel, Reimnitz Denise, Sawalle-Belohradsky Julie, Groll Andreas, Schlegel Paul-Gerhardt, Belohradsky Bernd, Renner Ellen, Klepper Jörg, Grimbacher Bodo, Kuijpers Taco, Liese Johannes
From the *Department of Pediatrics, Pediatric Infectious Diseases and Immunology, University of Wuerzburg, Germany; †Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, Amsterdam, The Netherlands; ‡Department of Pediatrics, Hospital Aschaffenburg, Germany; §University Children's Hospital at Dr. von Haunersches Kinderspital, Ludwig Maximilians University, Munich, Germany; ¶Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany; ‖Center for Chronic Immunodeficiency, University of Freiburg, Germany; and **Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Pediatr Infect Dis J. 2015 Sep;34(9):999-1002. doi: 10.1097/INF.0000000000000736.
A 4-year-old Turkish girl of consanguineous parents was hospitalized for the evaluation of headaches and recurrent febrile episodes of unknown origin. Her medical history was unremarkable except for a few episodes of uncomplicated oral thrush. Meningitis was diagnosed, and Candida albicans was the only pathogen identified by polymerase chain reaction and culture. Despite systemic antifungal multidrug therapy, a prolonged course of 16 months of therapy was necessary to clear C. albicans from the cerebrospinal fluid. Molecular genetic analysis revealed a homozygous caspase recruitment domain 9 (CARD9) mutation (Q295X), which was reported to predispose to chronic mucocutaneous candidiasis. Immunologic workup excluded predisposing B-cell and T-cell defects. In addition, T cells producing interleukin-17 were repeatedly measured within the normal range. Analyses of neutrophils demonstrated normal nicotinamide adenine dinucleotide phosphate oxidase activity in response to various stimuli including Staphylococcus aureus and C. albicans. Additional neutrophilic functional testing, however, showed a decreased cytotoxicity to nonopsonized C. albicans, indicating an impaired killing mechanism against Candida spp. independent from the production of reactive oxygen species by the nicotinamide adenine dinucleotide phosphate oxidase system. Because this defect was only demonstrated in the absence of opsonins, it might especially predispose to chronic C. albicans infections in the central nervous system where opsonin concentrations are usually low. We, therefore, suggest that due to an additional neutrophil dependent defect CARD9 deficiency predisposes not only to chronic mucocutaneous candidiasis, but also to invasive chronic Candida infections, especially of the central nervous system.
一名父母近亲结婚的4岁土耳其女孩因不明原因的头痛和反复发热发作入院接受评估。除了几次单纯性口腔念珠菌感染外，她的病史并无异常。诊断为脑膜炎，聚合酶链反应和培养仅鉴定出白色念珠菌这一病原体。尽管进行了全身性抗真菌多药治疗，但仍需要16个月的长期治疗才能使脑脊液中的白色念珠菌清除。分子遗传学分析发现了一个纯合的半胱天冬酶募集结构域9（CARD9）突变（Q295X），据报道该突变易导致慢性黏膜皮肤念珠菌病。免疫检查排除了易患的B细胞和T细胞缺陷。此外，产生白细胞介素-17的T细胞多次测量均在正常范围内。对中性粒细胞的分析表明，其对包括金黄色葡萄球菌和白色念珠菌在内的各种刺激的烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性正常。然而，额外的中性粒细胞功能测试显示，对未调理的白色念珠菌的细胞毒性降低，表明对念珠菌属的杀伤机制受损，这与烟酰胺腺嘌呤二核苷酸磷酸氧化酶系统产生活性氧无关。由于这种缺陷仅在没有调理素的情况下才表现出来，因此它可能特别易导致中枢神经系统慢性白色念珠菌感染，因为中枢神经系统中调理素的浓度通常较低。因此，我们认为，由于存在额外的中性粒细胞依赖性缺陷，CARD9缺乏不仅易导致慢性黏膜皮肤念珠菌病，还易导致侵袭性慢性念珠菌感染，尤其是中枢神经系统感染。
