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

J Clin Immunol. 2020 Feb;40(2):359-366. doi: 10.1007/s10875-019-00740-2. Epub 2020 Jan 15.


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.

Keywords: Aspergillus nomius; Chronic invasive pulmonary aspergillosis; Exophiala spinifera; Inherited CARD9 deficiency; Phaeohyphomycosis.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspergillus / physiology*
  • CARD Signaling Adaptor Proteins / genetics*
  • Candidiasis, Chronic Mucocutaneous / diagnosis*
  • Candidiasis, Chronic Mucocutaneous / genetics
  • Cells, Cultured
  • Exophiala / physiology*
  • Female
  • Humans
  • Interleukin-6 / metabolism
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Phaeohyphomycosis / diagnosis*
  • Phaeohyphomycosis / genetics
  • Pneumonectomy
  • Pulmonary Aspergillosis / diagnosis*
  • Pulmonary Aspergillosis / genetics


  • CARD Signaling Adaptor Proteins
  • CARD9 protein, human
  • Interleukin-6

Supplementary concepts

  • Aspergillus nomius
  • Candidiasis familial chronic mucocutaneous, autosomal recessive
  • Exophiala spinifera