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Inherited CARD9 Deficiency in a Patient with Both Exophiala spinifera and Aspergillus nomius Severe Infections

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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.

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Acknowledgments

We would like to thank the patient’s family for consenting to this publication.

Funding

The Laboratory of Human Genetics of Infectious Diseases is supported in part by institutional grants from INSERM, Paris Descartes University, The Rockefeller University and the St. Giles Foundation, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health grant # R01AI127564, and grants from the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01) and ANR-HGDIFD (ANR-14-CE15-006-01 for AP).

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Authors and Affiliations

  1. Department of Immunology and Rheumatology, “J. P. Garrahan” National Hospital of Pediatrics, Combate de los Pozos No 1881, C1245AAM, Buenos Aires, Argentina

    Laura Perez & Matías Oleastro

  2. Mycology Unit of the Infectious Diseases Hospital F.J. Muñiz, Reference Center of Mycology of Buenos Aires City, Buenos Aires, Argentina

    Fernando Messina, Ricardo Negroni, Alicia Arechavala & Gabriela Santiso

  3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker, Hospital for Sick Children, Paris, EU, France

    Jacinta Bustamante, Mélanie Migaud, Jean-Laurent Casanova & Anne Puel

  4. Paris University, Imagine Institute, Paris, EU, France

    Jacinta Bustamante, Mélanie Migaud, Jean-Laurent Casanova & Anne Puel

  5. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Jacinta Bustamante, Jean-Laurent Casanova & Anne Puel

  6. Center for the Study of Primary Immunodeficiencies Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, EU, France

    Jacinta Bustamante

  7. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  8. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, EU, France

    Jean-Laurent Casanova

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  1. Laura Perez
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  2. Fernando Messina
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  3. Ricardo Negroni
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  8. Jean-Laurent Casanova
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  9. Anne Puel
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  10. Gabriela Santiso
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Corresponding author

Correspondence to Laura Perez.

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Research Involving Human Participants

Informed consent for participation in this study was obtained in accordance with local regulations, with approval from the IRB. The experiments described here were performed in Argentina and in France, in accordance with local regulations, and with the approval of the IRB of Necker Hospital for Sick Children, France.

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Written informed consent was obtained from the patient’s family.

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Perez, L., Messina, F., Negroni, R. et al. Inherited CARD9 Deficiency in a Patient with Both Exophiala spinifera and Aspergillus nomius Severe Infections. J Clin Immunol 40, 359–366 (2020). https://doi.org/10.1007/s10875-019-00740-2

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  • DOI: https://doi.org/10.1007/s10875-019-00740-2

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