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Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency

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Abstract

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell–depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

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Authorship Contributions

FQT and ASG were involved in all steps of the report; TM, JM, RMNCS, RS, FH, JFM, PFH, GLC, JBF, and NARF were involved in the patients’ care and immunologic evaluation before and after HSCT; TM, JM, CBSS, and CB were responsible for HSCT; FH, JFM, and PFH performed the microbiologic and molecular identification of the isolates; OL, FL, JLC, and AP were responsible for critical revision and previous discussion about the directions for therapy. All the authors revised the manuscript and agreed before submitting to the journal.

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Authors and Affiliations

  1. Department of Public Health, Federal University of Parana, Curitiba, Brazil

    F. Queiroz-Telles

  2. Department of Haematology, University Hospitals Leuven, Leuven, Belgium

    T. Mercier, J. Maertens & R. Schrijvers

  3. Bone Marrow Transplant Unit, Hospital de Clinicas, Federal University of Parana, Curitiba, Brazil

    C. B. S. Sola & C. Bonfim

  4. Imagine Institute, Paris Descartes University, 75015, Paris, France

    O. Lortholary, J. L. Casanova & A. Puel

  5. Clinical Immunology, Faculdade de Medicina ABC, Av Lauro Gomes 2000, Santo Andre, Sao Paulo, 09060-870, Brazil

    R. M. N. Constantino-Silva & Anete S. Grumach

  6. Department of Medical Mycology, Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands

    F. Hagen

  7. Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands

    F. Hagen & J. F. Meis

  8. Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands

    J. F. Meis

  9. Carlos Chagas Institute, Oswaldo Cruz Foundation(Fiocruz), Curitiba, Brazil

    P. F. Herkert

  10. National Institute of Science and Technology (INCT) of Inovation in Neglected Diseases, Curitiba, Brazil

    P. F. Herkert

  11. Infectious Diseases Unit, Hospital de Clinicas, Federal University of Parana, Curitiba, Brazil

    F. Queiroz-Telles, G. L. Breda & J. B. França

  12. Department of Pediatrics, Federal University of Parana, Curitiba, Brazil

    N. A. Rosario Filho

  13. Unite de Mycologie Moleculaire, Institut Pasteur, CNRS URA3012, Paris, France

    F. Lanternier

  14. Centre National de Référence Mycoses invasives et Antifongiques, Institut Pasteur, Paris, France

    F. Lanternier

  15. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015, Paris, France

    F. Lanternier, J. L. Casanova & A. Puel

  16. Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France

    J. L. Casanova

  17. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA

    J. L. Casanova & A. Puel

  18. Howard Hughes Medical Institute, New York, NY, 10065, USA

    J. L. Casanova

Authors
  1. F. Queiroz-Telles
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  2. T. Mercier
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  3. J. Maertens
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  4. C. B. S. Sola
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  5. C. Bonfim
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  6. O. Lortholary
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  7. R. M. N. Constantino-Silva
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  8. R. Schrijvers
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  9. F. Hagen
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  10. J. F. Meis
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  11. P. F. Herkert
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  12. G. L. Breda
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  13. J. B. França
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  14. N. A. Rosario Filho
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  15. F. Lanternier
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  16. J. L. Casanova
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  17. A. Puel
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  18. Anete S. Grumach
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Corresponding author

Correspondence to Anete S. Grumach.

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Key Points

• Allogenic stem cell transplantation is a therapeutic option for CARD9 deficient patients.

• Our observation supports the role of hematopoietic cells in the pathogenesis of fungal infections in patients with CARD9 deficiency.

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Queiroz-Telles, F., Mercier, T., Maertens, J. et al. Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency. J Clin Immunol 39, 462–469 (2019). https://doi.org/10.1007/s10875-019-00662-z

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  • DOI: https://doi.org/10.1007/s10875-019-00662-z

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