title: ExtrapulmonaryAspergillusinfection in patients with CARD9 deficiency.
abstract: Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developedAspergillusinfection of the lungs. One patient had homozygous M1ICARD9(caspase recruitment domain family member 9) mutation, while the other had homozygous Q295XCARD9mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst againstAspergillus fumigatuswere intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonaryAspergillusinfection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.
authors: Infectious Diseases and Immunology, Department of Pediatrics I, University of Tübingen, Germany.|Department of Pediatrics, Munich Schwabing Hospital, Munich Technical University, Munich, Germany.
authors: Nikolaus
authors: N
authors: Rieber
authors: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Roel P
authors: RP
authors: Gazendam
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Alexandra F
authors: AF
authors: Freeman
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Amy P
authors: AP
authors: Hsu
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Amanda L
authors: AL
authors: Collar
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Janyce A
authors: JA
authors: Sugui
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Rebecca A
authors: RA
authors: Drummond
authors: Wayne State University and Children's Hospital of Michigan, Detroit, Michigan, USA.
authors: Chokechai
authors: C
authors: Rongkavilit
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Kevin
authors: K
authors: Hoffman
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Carolyn
authors: C
authors: Henderson
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Lily
authors: L
authors: Clark
authors: Infectious Diseases and Immunology, Department of Pediatrics I, University of Tübingen, Germany.
authors: Markus
authors: M
authors: Mezger
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Muthulekha
authors: M
authors: Swamydas
authors: Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, Tübingen, Germany.
authors: Maik
authors: M
authors: Engeholm
authors: Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, Tübingen, Germany.
authors: Rebecca
authors: R
authors: Schüle
authors: Institute of Pathology, University of Tübingen, Tübingen, Germany.
authors: Bettina
authors: B
authors: Neumayer
authors: Max-von-Pettenkofer-Institute, Ludwig-Maximilians-University, Munich, Germany.
authors: Frank
authors: F
authors: Ebel
authors: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors: Constantinos M
authors: CM
authors: Mikelis
authors: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors: Stefania
authors: S
authors: Pittaluga
authors: Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina, USA.
authors: Vinod K
authors: VK
authors: Prasad
authors: Infectious Diseases and Immunology, Department of Pediatrics I, University of Tübingen, Germany.
authors: Anurag
authors: A
authors: Singh
authors: Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Joshua D
authors: JD
authors: Milner
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Kelli W
authors: KW
authors: Williams
authors: Wayne State University and Children's Hospital of Michigan, Detroit, Michigan, USA.
authors: Jean K
authors: JK
authors: Lim
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Kyung J
authors: KJ
authors: Kwon-Chung
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Steven M
authors: SM
authors: Holland
authors: Infectious Diseases and Immunology, Department of Pediatrics I, University of Tübingen, Germany.
authors: Dominik
authors: D
authors: Hartl
authors: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Taco W
authors: TW
authors: Kuijpers
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Michail S
authors: MS
authors: Lionakis
mesh_terms: D000293:Adolescent; D000328:Adult; D001228:Aspergillosis / Q000235:genetics / Q000276:immunology*; D001232:Aspergillus fumigatus; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency* / Q000235:genetics; D002648:Child; D006720:Homozygote; D006801:Humans; D008168:Lung; D008297:Male; D009154:Mutation; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human