Chronic Mucocutaneous Candidiasis Due to STAT1 Gene Variant.

This case report describes a man in his 40s who presented with a 5-month history of recurrent pruritic papular erythema with mild scaling on the face, left forearm, and groin.

Progress in molecular diagnosis and treatment of chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections with Candida of the skin, nails, and mucous membrane. It is a rare and severe disease resulting from autoimmune defects or immune dysregulations. Nonetheless, the diagnosis and treatment of CMC still pose significant challenges. Erroneous or delayed diagnoses remain prevalent, while the long-term utility of traditional antifungals often elicits adverse reactions and promotes the development of acquired resistance. Furthermore, disease relapse can occur during treatment with traditional antifungals. In this review, we delineate the advancements in molecular diagnostic and therapeutic approaches to CMC. Genetic and biomolecular analyses are increasingly employed as adjuncts to clinical manifestations and fungal examinations for accurate diagnosis. Simultaneously, a range of therapeutic interventions, including Janus kinase (JAK) inhibitors, hematopoietic stem cell transplantation (HSCT), cytokines therapy, novel antifungal agents, and histone deacetylase (HDAC) inhibitors, have been integrated into clinical practice. We aim to explore insights into early confirmation of CMC as well as novel therapeutic options for these patients.

Prior selection of itraconazole in the treatment of recalcitrant Trichophyton indotineae infection: Real-world results from retrospective analysis.

BACKGROUND: The number of terbinafine-resistant Trichophyton indotineae is increasing in recent years while the treatment is still a matter to discuss. OBJECTIVES: To explore the best therapeutic approach, we present real-world treatment of T. indotineae infection by analysing publicly available data. METHODS: We have reviewed all published articles, mainly including case reports and case series, on the drug-resistant T. mentagrophytes complex by using the key search terms to search the databases. RESULTS: We enrolled 25 articles from 14 countries, including 203 times of treatment information for 113 patients. The cure rate of itraconazole 200 mg per day at the fourth, eighth and the twelfth week were 27.27%, 48.48% and 54.55%, respectively, which was significantly higher than terbinafine 250 mg per day (8.77%, 24.56% and 28.07%) and even 500 mg/d terbinafine. Griseofulvin 500-1000 mg for 2-6 months may be effective while fluconazole had no record of successful treatment. Voriconazole and ravuconazole had potential therapeutic efficacy. Topical therapy alone showed limited therapeutic efficacy, but the combination with oral antifungals can be alternative. CONCLUSION: Oral itraconazole 200 mg per day for 4-8 weeks was the most effective treatment out of these commonly used antifungal drugs, and can be prior selection.

In vitro combination with doxycycline plus antifungals against clinical Mucorales pathogens.

PURPOSE: Since systematic antifungals for mucormycosis showed variable MICs depending on strains, effective and safe antifungal therapy was still needed. This study is aimed to evaluate the in vitro activity of doxycycline combined with antifungal therapy against dominant Mucorales pathogens. METHODS: Multidrug susceptibility testing was performed with doxycycline and antifungals, including itraconazole, posaconazole, and amphotericin, in 21 isolates of 8 dominant Mucorales pathogens. RESULTS: The fractional inhibitory concentration index according to M38 showed one Rhizopus arrhizus isolate synergic (∑FICI = 0.375) and other isolates in addition (0.5 < ∑FICI < 4). CONCLUSIONS: Doxycycline was found to have in vitro advantages in combined antifungal treatment over antifungals alone.

Seborrheic dermatitis-like adult tinea capitis due to Trichophyton rubrum in an elderly man.

Adult tinea capitis is often neglected and misdiagnosed, especially in men. We herein reported an older man with seborrheic dermatitis-like tinea capitis caused by Trichophyton rubrum to raise awareness of the disease. Scale and alopecia were the critical diagnostic clues in this patient. Given the previous presence of tinea pedis and onychomycosis, relevant mycological examinations were promptly performed, and antifungal therapy, as well as patient education, were effectively administered.

Comparative genomics predict specific genes in potential mucorales identification.

Mucoralean fungi could cause mucormycosis in humans, particularly in immunodeficient individuals and those with diabetes mellitus or trauma. With plenty of species and genera, their molecular identification and pathogenicity have a large deviation. Reported cases of mucormycosis showed frequent occurrence in Rhizopus species, Mucor species, and Lichtheimia species. We analyzed the whole genome sequences of 25 species of the top 10 Mucorales genera, along with another 22 important pathogenic non-Mucorales species, to dig the target genes for monitoring Mucorales species and identify potential genomic imprints of virulence in them. Mucorales-specific genes have been found in various orthogroups extracted by Python script, while genus-specific genes were annotated covering cellular structure, biochemistry metabolism, molecular processing, and signal transduction. Proteins related to the virulence of Mucorales species varied with distinct significance in copy numbers, in which Orthofinder was conducted. Based on our fresh retrospective analysis of mucormycosis, a comparative genomic analysis of pathogenic Mucorales was conducted in more frequent pathogens. Specific orthologs between Mucorales and non-Mucoralean pathogenic fungi were discussed in detail. Referring to the previously reported virulence proteins, we included more frequent pathogenic Mucorales and compared them in Mucorales species and non-Mucorales species. Besides, more samples are needed to further verify the potential target genes.

The Domestic Isolation of Terbinafine- and Itraconazole-Resistant Trichophyton indotineae in Chinese Mainland.

BACKGROUND: Trichophyton indotineae, a new species of dermatophytes, has become a significant concern in treating dermatophytosis due to the high level of terbinafine resistance reported in India and even worldwide. OBJECTIVES: This study aimed to report the terbinafine- and itraconazole-resistant T. indotineae in Chinese mainland, by identifying the phylogenetic classification of the isolate strain, and detecting the drug resistance, gene mutation and expression. PATIENTS/METHODS: The skin scales of the patient were cultured on SDA and the isolate was authenticated by DNA sequencing and MALDI-TOF MS. Antifungal susceptibility testing was performed following the M38-A2 CLSI protocol to examine the MICs values of terbinafine, itraconazole, fluconazole, etc. The strain was screened for mutations in the squalene epoxidase (SQLE) gene by Sanger sequencing and detected the expression of CYP51A and CYP51B by qRT-PCR. RESULTS: A multi-resistant ITS genotype VIII sibling of the T. mentagrophytes complex (T. indotineae) was isolated in Chinese mainland. The strain harbored high terbinafine MIC of > 32 µg/mL and itraconazole MIC of 1.0 µg/mL, which was identified a mutation in the squalene epoxidase gene with amino acid substitution (Phe397Leu, mutation 1191C > A). In addition, overexpression of CYP51A and CYP51B was observed. With multiple relapses, the patient finally achieved clinical cure by itraconazole pulse therapy and topical clotrimazole cream for 5 weeks. CONCLUSIONS: The first domestic strain of terbinafine- and itraconazole-resistant T. indotineae from a patient in Chinese mainland was isolated. Itraconazole pulse therapy can be an effective method for the treatment of T. indotineae.

Children onychomycosis, a neglected dermatophytosis: A retrospective study of epidemiology and treatment.

BACKGROUND: Onychomycosis was an ignored disease in children, and the prevalence was still unknown worldwide. OBJECTIVES: This study was conducted to investigate the prevalence and treatment regimens of onychomycosis in children younger than 18 years old. METHODS: We systemically reviewed all publications by searching the key terms to reveal the onychomycosis in children from 1990 to 2022. RESULTS: A total of 44 articles including 2,382 children with onychomycosis were enrolled in this study. The male to female ratio was 1.29:1. The youngest child was 35 days old and the average age was 9.8 years old. The duration of disease usually ranged from 7 days to 4 years. Onychomycosis in children was more prevalent in toenails compared to fingernails (77.6% vs. 18.4%), and 4% patients had both. A total of 527 children (22.12%) had concomitant tinea pedis infection, and in 267 patients (11.21%), their family members had onychomycosis or tinea pedis. The most common clinical type of onychomycosis was DLSO (67.74%) and the predominant isolates were T. rubrum (66.13%), followed by C. albicans (9.08%) and T. mentagrophytes complex (5.34%). There were 419 children (74.03%) receiving systematic treatment only, 74 patients (13.07%) receiving topical treatment only, and 73 patients (12.90%) receiving both systematic and topical treatment. Twelve patients (2.12%) had mild drug-related side effects. During the follow-up, 71.25% children were cured, 17.50% symptoms improved and 4.17% failed. CONCLUSIONS: Onychomycosis was underestimated in children and the diagnosis of onychomycosis should be properly considered in children with nail disorders. For mild patients, topical treatment can be a good choice, and oral antifungal drugs could be added to severe individuals under monitoring.

Tinea Capitis in Children Younger than Two Years Old: A Retrospective Study and Treatment Recommendations.

BACKGROUND: Tinea capitis (TC) is a dermatophytosis of the scalp and hair, which occurs less common in children younger than two years of age, and the data of TC in this age group are still unknown. OBJECTIVES: We aimed to reveal the epidemiological, clinical and mycological characteristics of TC in children under two years old. METHODS: We retrospectively analyzed all reported cases of TC in children in their first two years of life from 1991 to 2022, by searching PubMed, Embase, Web of Science, CNKI, Wanfang and Weipu databases. RESULTS: A total of 47 articles involving 126 cases of pediatric TC were enrolled in this study. The sex ratio (M/F) was 1.28:1. The age of the children ranged from ten days old to two years old with a median age of three months. The main clinical manifestations were alopecic patches (40 cases, 31.7%) and scaling (39 cases, 31.0%) on the scalp, and 29 infants (23.0%) appeared kerion. The most common sources of contagion were animals (35 cases, 27.78%) and humans (31 cases, 24.60%). The leading pathogens were Microsporidium canis (64 cases, 50.79%), followed by Trichophyton violaceum (13 cases, 10.32%), T. mentagrophytes complex (12 cases, 9.52%) and T. tonsurans (10 cases, 7.94%). Ninety-five children (75.40%) were treated with systemic antifungal drugs and 22 patients (17.46%) were only treated with topical therapy. Except for 10 patients with unknown final prognosis, all the other cases were cured after treatment. There was one child (0.79%) relapsed after treatment with griseofulvin and one case (0.79%) presented with gastrointestinal symptoms from griseofulvin. CONCLUSION: The principal clinical symptoms of TC in children less than two years old were alopecic patches and scaling. The top four pathogens were M. canis, T. violaceum, T. mentagrophytes complex and T. tonsurans. Oral treatment for pediatric TC had achieved good therapeutic effects, and topical therapy can be an alternative choice.

Epidemiology of Onychomycosis in Chinese Mainland: A 30-year Retrospective Study.

BACKGROUND: Onychomycosis was a common nail disease caused by dermatophytes, yeasts or molds. The prevalence of onychomycosis varied in different counties and it was necessary to understand the epidemiology in China. OBJECTIVES: This study was conducted to investigate the epidemiology of onychomycosis in Chinese mainland in the past 30 years. METHODS: A 30-year systemic review was carried out by searching publications investigating the prevalence of onychomycosis in Chinese mainland from 1991 to 2020. RESULTS: A total of 90 articles involving more than 40,000 onychomycosis patients were enrolled in this study. The ratio of males to females was 1:1.32. Fingernail onychomycosis was found in 36.12% cases, toenail onychomycosis in 48.31%, and both fingernail and toenail onychomycosis in 15.57%. The most common clinical type of onychomycosis was distal lateral subungual onychomycosis (60.99%), followed by total dystrophic onychomycosis (18.91%), proximal subungual onychomycosis (10.19%) and superficial white onychomycosis (9.92%). Dermatophytes (60.59%) were the most frequently isolated pathogens, followed by yeasts (30.09%), molds (7.91%) and mixed infection (1.41%). The primary pathogens in dermatophytes, yeasts and molds were Trichophyton rubrum (49.93%), Candida albicans (10.99%) and Aspergillus (3.11%), respectively. Additionally, dermatophytes were more commonly affected males than females (63.69% vs. 51.57%), and mostly involved in toenail onychomycosis (75.63%). The infection of yeasts was higher in females than males (40.97% vs. 29.52%), often causing onychomycosis in fingernail than toenail (41.03% vs. 17.08%), and it was more common in warm and humid southern regions than northern area (34.07% vs. 24.41%). CONCLUSION: The proportion of the causative agents changed over time, dermatophytes, especially T. rubrum had always been the predominant pathogen, followed by yeasts and molds. The distribution of fungal pathogens varied among clinical types, gender, infection sites and geography gender.

Changing face of epidemiology of dermatophytoses in Chinese Mainland: A 30 years nationwide retrospective study from 1991 to 2020.

BACKGROUND: Dermatophytoses are the most common infectious skin disease. Its epidemiology varies in different countries and regions, and its prevalence in China is still unknown. OBJECTIVES: We aimed to reveal the epidemiological features of dermatophytoses in Chinese mainland in the past thirty years. METHODS: From 1991 to 2020, a 30-year retrospective epidemiological study was carried out. All published literatures containing dermatophytoses and dermatophytes were collected and analysed. RESULTS: A total of more than 180,000 cases in 124 articles from more than 100 hospitals were included and analysed. Among dermatophytoses, tinea cruris (24.92%) was the predominant clinical type, followed by tinea pedis (22.97%) and tinea corporis (18.12%). In recent 10 years, tinea pedis (25.40%) was more common than tinea cruris (22.39%) and became the most common infection. Among dermatophytes, T rubrum (69.48%) has always been the most common isolates, followed by T mentagrophytes (16.45%) and M canis (8.09%). Other species were found below 3%. In superficial mycoses, dermatophytes accounted for 75.52%, higher than that of yeasts/yeast-like (21.83%) and moulds (2.65%). The prevalence of tinea capitis was lower in economically developed eastern region than that in central and western regions. Tinea cruris was more common in warm zones than cold zones. CONCLUSIONS: The top three dermatophytoses are tinea cruris, tinea pedis and tinea corporis, while the top three dermatophytes are T rubrum, T mentagrophytes and M canis. The distribution of dermatophytoses may be influenced by socioeconomic status and geographical-meteorological conditions.

Association between tocilizumab treatment and clinical outcomes of COVID-19 patients: a systematic review and meta-analysis.

To explore and summarize the association between treatment with tocilizumab and clinical outcomes in COVID-19 patients. We performed a systematic review and meta-analysis (10 RCTs including 3378 patients in the tocilizumab group and 3142 patients in the control group). We systematically searched PubMed and MedRxiv for all RCTs as of June 1, 2021, to assess the benefits and harms of tocilizumab to treat patients with COVID-19. All analyses were carried out using RevMan version 5.4.1. There were nine RCTs published in peer-reviewed journals and one RCTs published as a preprint. The summary RR for all-cause mortality with tocilizumab was 0.89 (95% CI= 0.82-0.96, P= 0.003). There was no significant between-trial heterogeneity (I2= 28%, P= 0.19). However, all peer-reviewed RCTs showed no significant associations between treatment with tocilizumab and reductions in all-cause mortality. We notably found that tocilizumab significantly reduced the rate of intubation or death in patients with COVID-19 with 3 RCTs. Across the 8 RCTs, the summary RR for discharge with tocilizumab was 1.10 (95% CI= 1.03-1.16, P< 0.00001). There was no significant association of tocilizumab with harm on other patient-relevant clinical outcomes, including increasing secondary infection risk, patients of adverse events, or patients of serious adverse events. Tocilizumab significantly increased the rate of hospital discharges in COVID-19 patients. Still, it did not decrease all-cause mortality or increase the risk of secondary infections, patients of adverse events, or patients for serious adverse events. Evidence that tocilizumab affects clinical outcomes in patients with COVID-19 requires further proof.

A thermal adaptation landscape related to virulence in Mucor irregularis transcriptional profiles.

OBJECTIVES: Our study aimed to better understand the different thermal adaptation in Mucor irregularis (M. irregularis) strains under high temperature and the involved virulence-related genes, and to offer more appropriate explanation for the diverse pathogenicity of M. irregularis in human infections. METHODS: M. irregularis isolates were incubated at 30 and 35°C for Illumina HiSeq technology (RNA-seq), as well as the virulence difference detected through Galleria mellonella infection models. We verified their transcriptional profile with RT-PCR and analysed differentially expressed genes with GO and KEGG annotations. RESULTS: All 25 isolates formed the biggest colonies at 28°C and did not grow at 37°C, while were differently inhibited at 22 and 35°C. Six selected M. irregularis displayed virulence in sync with their growth condition at high temperature. From the outcomes of RNA-seq, a total of 1559 differentially expressed genes (FC ≥ 2, FDR < 0.05) were obtained, of which 1021 genes were upregulated, and 538 genes were downregulated. Cell wall structure genes related to Ras-like and GH16 proteins, influx-efflux pumps consist of transmembrane proteins as ABC and MFS proteins, and metabolic genes as DGKɛ and Hsfs, seem to be essential in thermal adaptation and virulence of M. irregularis. CONCLUSION: We found some common genes expressed at high temperature, while some others specifically related to M. irregularis isolates with different virulence and thermal adaptation. Further research of genes involved in the pathogenic process is needed for the development of potential targeted antifungal.

Efficacy and secondary infection risk of tocilizumab, sarilumab and anakinra in COVID-19 patients: A systematic review and meta-analysis.

As the pandemic progresses, the pathophysiology of coronavirus disease 2019 (COVID-19) is becoming clearer and the potential for immunotherapy is increasing. However, clinical efficacy and safety of immunosuppressants (including tocilizumab, sarilumab and anakinra) treatment in COVID-19 patients are not yet known. We searched PubMed, Embase Medline, Web of Science and MedRxiv using specific search terms in studies published from 1 January 2020 to 20 December 2020. In total, 33 studies, including 3073 cases and 6502 controls, were selected for meta-analysis. We found that immunosuppressant therapy significantly decreased mortality in COVID-19 patients on overall analysis (odds ratio = 0.71, 95% confidence interval = 0.57-0.89, p = 0.004). We also found that tocilizumab and anakinra significantly decreased mortality in patients without any increased risk of secondary infection. In addition, we found similar results in several subgroups. However, we found that tocilizumab therapy significantly increased the risk of fungal co-infections in COVID-19 patients. This represents the only systematic review and meta-analysis to investigate the efficacy and secondary infection risk of immunosuppressant treatment in COVID-19 patients. Overall, immunosuppressants significantly decreased mortality but had no effect on increased risk of secondary infections. Our analysis of tocilizumab therapy showed a significantly increased risk of fungal co-infections in these patients.

Characterization of mitogenomes from four Mucorales species and insights into pathogenicity.

BACKGROUND: Mucorales, as one major order of Zygomycetes fungi, can infect human beings and cause serious consequence. We have noticed the pathogenicity of Mucorales is closely related to energy metabolism, while mitochondria play the role of energy factories in almost all biological activities. METHODS: Virulence of M irregularis, M hiemalis, L corymbifera and R arrhizus were verified in Galleria mellonella larvae, as well as mitochondrial gene copies analysed with RT-qPCR. Mitogenomes of the four Mucorales species were sequenced based on illumina NovaSeq technology to study their characteristic features and functional regions. RESULTS: Variant virulence of M irregularis, M hiemalis, L corymbifera and R arrhizu were verified by clinical retrospective data and our G mellonella infection models, also copies of mitochondrial genes indicated the significant associations with pathogenicity. A total of 274.18 clean reads were generated to be assembled; the complete mitogenomes of the four Mucorales species were obtained with totally different length. After the genomes annotated and compared, M irregularis was found more similar with M hiemalis than those of L corymbifera and R arrhizus, especially the small (rrns) and large (rrnl) subunits of mitochondrial ribosomal RNA (rRNA) genes. The GC content, ncRNAs and the distribution of the SNPs and InDels were also compared, and the GC content rate of fungi seems to be related to the fungal thermal adaptability. In addition, linear mitogenomes of these four Mucorales showed diverse arrangements of orf genes and directionality of some conserved gene elements. CONCLUSION: This study uncovered the pathogenicity variances among the four Mucorales species and the relationship between their mitogenomic features and clinical pathogenicity. Further studies like spatial structure of mitochondrial genomes and the comprehensive analysis of transcription regulation are needed.

Comparative Genomics and Molecular Analysis of Epidermophyton floccosum.

Epidermophyton floccosum is one of the most common agents of human superficial fungal infections, compared with genus Trichophyton and Microsporum, it possesses uniqueness in ecology traits and rarely causing hair infections. E. floccosum is so far the only representative species of genera Epidermophyton, and it is known as anthropophilic dermatophytes. To further reveal the genome sequences and clues of virulence factors, thus in this study, we sequenced the genome of E. floccosum (CGMCC (F) E1d), and performed comparative genomic analysis with other dermatophytes. It is revealed that E. floccosum owns the largest genome size and similar GC content compared with other dermatophytes. A total of 7565 genes are predicted. By comparing with the closest species N. gypseum, our study reveals that number and structure of adhesion factors, secreted proteases and LysM domain might contribute to the pathogenic and ecological traits of E. floccosum. Mating genes is also detected in genome data. Furthermore, we performed AFLP analysis trying to discuss intraspecific differences of E. floccosum, but no significant relationship is found between genotype and geographical distribution. Upon above, our study provides a deeper understanding and strong foundation for future researches about E. floccosum.