Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections

Abstract

Autosomal recessive deficiency in the caspase recruitment domain containing protein 9 (CARD9) results in susceptibility to fungal infections. In the last decade, infections associated with CARD9 deficiency are more reported due to the advent of genome sequencing. The aim of this study was to evaluate the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency. We identified 60 patients with 24 mutations and different fungal infections. The presence of the homozygous (HMZ) p.Q295X (c.883C > T) and HMZ p.Q289X (c.865C > T) mutations were associated with an elevated risk of candidiasis (OR: 1.6; 95% CI: 1.18–2.15; p = 0.004) and dermatophytosis (OR: 1.85; 95% CI: 1.47–2.37; p < 0.001), respectively. The geographical distribution differed, showing that the main mutations in African patients were different Asian patients; HMZ p.Q289X (c.865C > T) and HMZ p.Q295X (c.865C > T) accounted for 75% and 37.9% of the African and Asian cases, respectively. The spectrum of CARD9 mutations in Asian patients was higher than in African. Asia is the most populous continent in the world and may have a greater genetic burden resulting in more patients with severe fungal infections. The presence of a high diversity of mutations revealing 24 distinct variations among 60 patients emphasize that the unique genetic alteration in CARD9 gene may be associated with certain geographical areas.

In vitro activities of 15 antifungal drugs against a large collection of clinical isolates of Microsporum canis

“…The high prevalence of dermatophytosis in animals is usually associated with extra costs for prevention, diagnosis and long‐term treatment . Microsporum canis is a zoophilic species, which plays a key role in human ringworm episodes along with Trichophyton rubrum , T. interdigitale and T tonsurans . In several countries, M. canis is ranked the first in frequency, exceeding those of anthropophilic species and accounting for the majority of clinical cases .…”

“…2,3 Dermatophytosis due to zoophilic agents often responds very well to antifungal drugs; however, frequent relapses and failure to control deep infections have been reported in patients who receive immunosuppressive therapy or those with inherited caspase recruitment domain family member 9 (CARD9) deficiency. 4 The high prevalence of dermatophytosis in animals is usually associated with extra costs for prevention, diagnosis and long-term treatment. 2 Microsporum canis is a zoophilic species, which plays a key role in human ringworm episodes along with Trichophyton rubrum, T. interdigitale and T tonsurans.…”

“…2 Microsporum canis is a zoophilic species, which plays a key role in human ringworm episodes along with Trichophyton rubrum, T. interdigitale and T tonsurans. [3][4][5] In several countries, M. canis is ranked the first in frequency, exceeding those of anthropophilic species and accounting for the majority of clinical cases. 5,6 M. canis is found to be the most frequently isolated species in cats and dogs, ranging from 40% to 100% in prevalence; furthermore, wild and domestic animals such as camelids, horses, goats, sheep and rabbits are also considered its reservoirs.…”

Comparison of in vitro activities of 11 antifungal agents against Trichophyton verrucosum isolates associated with a variety hosts and geographical origin

“…Although transmissions onto a human by a zoophilic species cause acute mycoses with strongly expressed symptoms of inflammatory response, dermatophytosis spread by zoophilic agents often responds very well to antifungal drugs . Nevertheless, frequent treatment failures and side effects have been reported in patients receiving immunosuppressive therapy, affected by diabetes mellitus, or those with inherited caspase recruitment domain family member 9 (CARD9) deficiency …”

“…17,18 Nevertheless, frequent treatment failures and side effects have been reported in patients receiving immunosuppressive therapy, affected by diabetes mellitus, or those with inherited caspase recruitment domain family member 9 (CARD9) deficiency. 3,19 Dermatophytosis can be treated with topical application as well as systemic administration of antifungal drugs. 18,20,21 Combination therapy with topical and systemic antifungal drugs is also prescribed.…”