Chronic Candida albicans Meningitis in a 4-Year-Old Girl with a Homozygous Mutation in the CARD9 Gene (Q295X).
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.
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.
Martin
M
Herbst
Roel
R
Gazendam
Denise
D
Reimnitz
Julie
J
Sawalle-Belohradsky
Andreas
A
Groll
Paul-Gerhardt
PG
Schlegel
Bernd
B
Belohradsky
Ellen
E
Renner
Jörg
J
Klepper
Bodo
B
Grimbacher
Taco
T
Kuijpers
Johannes
J
Liese
D000935:Antifungal Agents / Q000008:administration & dosage; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency* / Q000235:genetics; D002176:Candida albicans / Q000302:isolation & purification*; D002177:Candidiasis / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006720:Homozygote; D006801:Humans; D016921:Meningitis, Fungal / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D020125:Mutation, Missense; D016896:Treatment Outcome; D014421:Turkey
D000935:Antifungal Agents; D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human