Phaeohyphomycosis caused by Phialophora americana with CARD9 mutation and 20‐year literature review in China

Abstract

| INTRODUC TI ONDematiaceous fungi, also known as phaeohyphomycetes or melanized fungi, are so named owing to the dark pigmentation in the walls of their hyphae and/or spores. 1 They are ubiquitous in soil, wood and rotting vegetation worldwide and are characterised by slow growth. 2 According to the most recent literature, they are divided into 70 genera and approximately 150 species. 3 DematiaceousSummary Background: Phaeohyphomycosis is a chronic cutaneous, subcutaneous or systemic mycotic infection caused by various dematiaceous fungi. The diverse clinical manifestations and poor prognosis of phaeohyphomycosis necessitate studies on it to better recognise the disease and improve its management. Objectives: To investigate the epidemiology, aetiology, diagnosis, treatment and prognosis of phaeohyphomycosis in China over the past 20 years, and to study the first case of phaeohyphomycosis caused by Phialophora americana and the genetic and immunological mechanisms. Patients/Methods: Clinical and laboratory findings of the case were studied, and the patient's DNA was sequenced for CARD9, followed by immunological studies using patient's PBMCs. Cases of phaeohyphomycosis in China from 1998 to 2018 in both the Chinese and English literature were collected and analysed, including 45 articles and 46 patients. Results:We confirmed the patient holding a homozygous frameshift mutation of CARD9, which led to impairment of pro-inflammatory cytokine production, and lower Th17-and Th22-associated responses upon fungus-specific stimulation. From the literature review, we revealed that the clinical presentations of phaeohyphomycosis were diverse. Diagnoses were established mainly on the basis of histopathology and fungal culture. Oral itraconazole, voriconazole, and posaconazole are the first choices for treatment, and a combination with surgical excision is also recommended. Conclusions:Our study establishes that obtaining detailed histories is vital for understanding the immune state and that patients with recurrent or chronic phaeohyphomycosis in the absence of known immunodeficiencies should be tested for CARD9 mutations. We hope our findings will aid clinicians in the diagnoses and treatment of such infections.

Comparative Analysis of Clinical and Environmental Strains of Exophiala spinifera by Long-Reads Sequencing and RNAseq Reveal Adaptive Strategies

“…An overview was made of published cases of fungal infections in patients with CARD9 deficiencies ( Table 2 ; Glocker et al, 2009 ; Drewniak et al, 2013 ; Lanternier et al, 2013 , 2015a , b ; Gavino et al, 2014 , 2016 ; Drummond et al, 2015 ; Grumach et al, 2015 ; Herbst et al, 2015 ; Jachiet et al, 2015 ; Alves de Medeiros et al, 2016 ; Celmeli et al, 2016 ; Yan et al, 2016 ; Boudghene et al, 2017 ; Zhang et al, 2017 ; Arango-Franco et al, 2018 ; Cetinkaya et al, 2018 ; De Bruyne et al, 2018 ; Zhong et al, 2018 ; Huang et al, 2019 ). Sixteen different mutations have been observed.…”

Comparative genomics of opportunistic Phialophora species involved in divergent disease types

“…Black yeast‐like infections by members of Chaetothyriales are known to be associated with 7 different mutations in CARD9 (Figure 10): p.L64fsX59/p.Q158X ( Phialophora verrucosa ), 28 p.R35Q/p.E81K ( P verrucosa ), 27 p.D274fsX60 ( P verrucosa, P expanda and P americana ), 9,10,28 p.E232 ( Exophiala spinifera ), 29 p.S23X/p.D274fsX60 ( E spinifera ), 30 p.R18W ( E dermatitidis ) 29 and S12N ( Fonsecaea pedrosoi ) 31 . Other, unrelated melanised fungi were associated with p.D274fsX60 ( Ochroconis musae ) 30 and p.L64fsX59/p.D274fsX60 30,32 and p.Ala8Alafs.10/p.Q289 ( Corynespora cassiicola ) 33 ; with these mutations also P verrucosa was noted.…”

“…BMU 09470 was clinically confirmed to be chromoblastomycosis with muriform cells in histopathology 9 and also had CARD9 immunodeficieny. BMU 09530 originated from a phaeohyphomycosis CARD9‐deficient patient 10 . All six Phialophora chinensis strains were environmental (BMU 07609, BMU 07661, BMU 07664, BMU 07637 and BMU 07630), as well as five of seven Phialophora americana strains (BMU 07696, BMU 07652, BMU 07645, BMU 00125 and BMU 06000), while two were from patients (BMU 01244 and BMU 09530).…”

Paranasal Sinus Phaeohyphomycosis: A Case Report and Literature Review

“…Phaeohyphomycosis are fungal infections caused by fungi with dark hyphae, which appear as melanized filament [3]. At present, Coniosporium, Cyphellophora, Fonsecaea, Phialophora Exophiala, Rhinocladiella and Cladophialophora species are the most clinically relevant dematiaceous fungi worldwide [3].…”