Laura Perez1, Fernando Messina2, Ricardo Negroni2, Alicia Arechavala2, Jacinta Bustamante3,4,5,6, Matías Oleastro7, Mélanie Migaud3,4, Jean-Laurent Casanova3,4,5,8,9, Anne Puel3,4,5, Gabriela Santiso2. 1. Department of Immunology and Rheumatology, "J. P. Garrahan" National Hospital of Pediatrics, Combate de los Pozos No 1881, C1245AAM, Buenos Aires, Argentina. leperez77@gmail.com. 2. Mycology Unit of the Infectious Diseases Hospital F.J. Muñiz, Reference Center of Mycology of Buenos Aires City, Buenos Aires, Argentina. 3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker, Hospital for Sick Children, Paris, EU, France. 4. Paris University, Imagine Institute, Paris, EU, France. 5. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 6. Center for the Study of Primary Immunodeficiencies Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, EU, France. 7. Department of Immunology and Rheumatology, "J. P. Garrahan" National Hospital of Pediatrics, Combate de los Pozos No 1881, C1245AAM, Buenos Aires, Argentina. 8. Howard Hughes Medical Institute, New York, NY, USA. 9. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, EU, France.
Abstract
PURPOSE: Caspase-associated recruitment domain-9 (CARD9) deficiency is an inborn error of immunity that typically predisposes otherwise healthy patients to single fungal infections and the occurrence of multiple invasive fungal infections is rare. It has been described as the first known condition that predisposes to extrapulmonary Aspergillus infection with preserved lungs. We present a patient that expands the clinical variability of CARD9 deficiency. MATERIALS AND METHODS: Genetic analysis was performed by Sanger sequencing. Neutrophils and mononuclear phagocyte response to fungal stimulation were evaluated through luminol-enhanced chemiluminescence and whole blood production of the proinflammatory mediator interleukin (IL)-6, respectively. RESULTS: We report a 56-year-old Argentinean woman, whose invasive Exophiala spinifera infection at the age of 32 years was unexplained and reported in year 2004. At the age of 49 years, she presented with chronic pulmonary disease due to Aspergillus nomius. After partial improvement following treatment with caspofungin and posaconazole, right pulmonary bilobectomy was performed. Despite administration of multiple courses of antifungals, sustained clinical remission could not be achieved. We recently found that the patient's blood showed an impaired production of IL-6 when stimulated with zymosan. We also found that she is homozygous for a previously reported CARD9 loss-of-function mutation (Q289*). CONCLUSIONS: This is the first report of a patient with inherited CARD9 deficiency and chronic invasive pulmonary aspergillosis (IPA) due to A. nomius. Inherited CARD9 deficiency should be considered in otherwise healthy children and adults with one or more invasive fungal diseases.
PURPOSE:Caspase-associated recruitment domain-9 (CARD9) deficiency is an inborn error of immunity that typically predisposes otherwise healthy patients to single fungal infections and the occurrence of multiple invasive fungal infections is rare. It has been described as the first known condition that predisposes to extrapulmonary Aspergillus infection with preserved lungs. We present a patient that expands the clinical variability of CARD9 deficiency. MATERIALS AND METHODS: Genetic analysis was performed by Sanger sequencing. Neutrophils and mononuclear phagocyte response to fungal stimulation were evaluated through luminol-enhanced chemiluminescence and whole blood production of the proinflammatory mediator interleukin (IL)-6, respectively. RESULTS: We report a 56-year-old Argentinean woman, whose invasive Exophiala spinifera infection at the age of 32 years was unexplained and reported in year 2004. At the age of 49 years, she presented with chronic pulmonary disease due to Aspergillus nomius. After partial improvement following treatment with caspofungin and posaconazole, right pulmonary bilobectomy was performed. Despite administration of multiple courses of antifungals, sustained clinical remission could not be achieved. We recently found that the patient's blood showed an impaired production of IL-6 when stimulated with zymosan. We also found that she is homozygous for a previously reported CARD9 loss-of-function mutation (Q289*). CONCLUSIONS: This is the first report of a patient with inherited CARD9 deficiency and chronic invasive pulmonary aspergillosis (IPA) due to A. nomius. Inherited CARD9 deficiency should be considered in otherwise healthy children and adults with one or more invasive fungal diseases.
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