Complete clinical remission of invasive Candida infection with CARD9 deficiency after G-CSF treatment

Highlights

• CARD9 deficiency is an autosomal-recessive primary immunodeficiency characterized by susceptibility to recurrent Candida infections.

• A homozygous mutation in CARD9 (c.819-820insG) was identified.

• The combination of G-CSF and antifungal agents was suitable for Children cases with CARD9 immunodeficiency.

Abstract

Caspase-associated recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency characterized by susceptibility to recurrent Candida infections, and its diagnosis and treatment is challenging. The present study aims to investigate the genetic characteristic and treatment strategy of a Chinese pediatric patient with CARD9 deficiency. In the present study, whole-exome sequencing (WES) was performed to screen the causal variants in a Chinese pediatric patient who exhibited an invasive Candida infection in the abdominal cavity and central nervous system. After the disease-causing gene being confirmed, the patient was treated with a combination of G-CSF and antifungal agents. DNA sequencing revealed a homozygous insertion mutation (c.819–820insG) in exon 6 of the CARD9 gene, which led to downstream amino acids conversion on codon 274 (p.D274fsX60). Th17 cell populations and cytokine levels showed decreased levels. The treatment regimen successfully resolved the patient’s symptoms, and he remained symptom-free after more than 1 year of follow-up. This study described an invasive Candida infection in a pediatric patient and WES identified an insertion variant of the CARD9 gene. A combination of G-CSF and antifungal agents was highly effective in treating the invasive fungal infection accompanied by CARD9-induced immunodeficiency.

Introduction

Invasive fungal infections (IFIs) are a major cause of morbidity and death among immunocompromised and hospitalized pediatric patients (e.g., hematological, solid organ transplant or intensive care unit patients) [[1], [2], [3]]. It has recently become apparent that some IFIs may be caused by inborn errors of immunity [4,5], such as inborn errors of IL-17 immunity [6] and caspase-associated recruitment domain-containing protein 9 (CARD9) immunity [7]. CARD9 is an adapter protein that is mainly expressed in couples C-type lectin receptors to NF-κB-mediated gene expression and plays a vital role in host defense against fungal pathogens [8,9]. To date, more than 22 different CARD9 mutations, either homozygous or compound heterozygous, have been identified [10].

CARD9 deficiency is an autosomal-recessive primary immunodeficiency characterized by susceptibility to recurrent Candida infections [11]. The first report of CARD9 deficiency was identified in an Iranian multiplex consanguineous family in which six of the seven patients had chronic mucocutaneous candidiasis (CMC) [12]. Since then, the most striking and consistent disease attributed to CARD9 deficiency is Candida diseases of the central nervous system (CNS) [[13], [14], [15], [16]]. Meanwhile, Candida infections of other organs (colon, bone, eye) have also been reported in several patients [14,17,18].

Treatment of IFIs caused by CARD9 deficiency is challenging because treatment by the available antifungals alone cannot fully control fungal disease and leads to recurrent fungal infections [19]. Thus, adjuvant or alternative treatments may be required to cure patients. Here, we report a variant of the CARD9 gene in a Chinese pediatric patient with an invasive Candida infection and the successful use of granulocyte colony stimulating factor (G-CSF) as an adjuvant therapy to this patient.