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Similar to scabies, there has been an increase in familial clustering and connubial dermatophytosis with even infants presenting with extensive tinea corporis.3 Hesitancy and embarrassment leads to substantial under-reporting, particularly in women and the underprivileged, and what is being observed is just the tip of the iceberg with many hidden cases in the community that account for the relapse and ongoing transmission of dermatophytosis. Supplementary Material 1 DC Cole, NP Govender, A Chakrabarti, J Sacarlal, DW Denning, Improvement of fungal disease identification and management: combined health systems and public health approaches, Lancet Infect Dis, Vol. 17, 2017, e412-e419 2 S Panda, S Verma, The menace of dermatophytosis in India: the evidence that we need, Indian J Dermatol Venereol Leprol, Vol. 83, 2017, 281-284 3 S Verma, R Madhu, The great Indian epidemic of superficial dermatophytosis: an appraisal, Indian J Dermatol, Vol. 62, 2017, 227-236 4 S Dogra, S Uprety, Indian Dermatol Online J, Vol. 7, 2016, 73-76 5 T Narang, R Mahajan, S Dogra, Dermatophytosis: fighting the challenge: conference proceedings and learning points. September 2-3, 2017, PGIMER, Chandigarh, India, Indian Dermatol Online J, Vol. 8, 2017, 527-533 6 SB Verma, R Vasani, Male genital dermatophytosis-clinical features and the effects of the misuse of topical steroids and steroid combinations-an alarming problem in India, Mycoses, Vol. 59, 2016, 606-614 7 M Schaller, M Friedrich, M Papini, RM Pujol, S Veraldi, Topical antifungal-corticosteroid combination therapy for the treatment of superficial mycoses: conclusions of an expert panel meeting, Mycoses, Vol. 59, 2016, 365-373

A severe outbreak of highly virulent and multi-resistant dermatophytosis by species in the Trichophyton mentagrophytes / T . interdigitale complex is ongoing in India. The correct identity of the etiologic agent is a much-debated issue. In order to define species limits, a taxonomic study was undertaken combining molecular, morphological, and physiological characteristics as evidence of classification. Molecular characteristics show that T. mentagrophytes s. str . and T. interdigitale s. str . can be distinguished with difficulty from each other, but are unambiguously different from the Indian genotype, T . indotineae by sequences of the HMG gene. The entities were confirmed by multilocus analysis using tanglegrams. Phenotypic characters of morphology and physiology are not diagnostic, but statistically significant differences are observed between the molecular siblings. These properties may be drivers of separate evolutionary trends. Trichophyton mentagrophytes represents the ancestral, homothallic cloud of genotypes with a probable geophilic lifestyle, while T . indotineae and T . interdigitale behave as anthropophilic, clonal offshoots. The origin of T . indotineae , which currently causes a significant public health problem, is zoonotic, and its emergence is likely due to widespread misuse of antifungals.

The whole genome sequencing analysis of 20 T. indotineae strains demonstrate that this new species is distinct clonal offshoot of T. mentagrophytes/T. interdigitale spp. complex. [...]naming of this emerging antifungal-resistant species was essential as it could not be unambiguously identified as either T. mentagrophytes or T. interdigitale based on ITS sequencing, mycological and physiological characteristics. [...]in the last 5 years before labelling T. indotineae as a species de novo, studies based on rDNA ITS region sequencing identified Indian Trichophyton strains as T. mentagrophytes/interdigitale; further, Nenoff and colleagues grouped the strains as T. mentagrophytes Type VIII [3,4,6,26,32]. The BLAST searches of ITS sequences of T. indotineae on NCBI database still show ≥99% sequence similarity with T. mentagrophytes, T. interdigitale, and T. indotineae. [...]to obtain accurate identification (i.e., sequence similarity of 100% with T. indotineae), ITS sequences of well-defined reference strains described by Tang and colleagues [30], importantly, primary T. indotineae strains (NUBS19006 and NUBS19007), should be included in the analysis. Notably, TRB-resistant T. indotineae strains isolated from cases in Germany, Denmark, and Switzerland during 2016 to 2020 exhibited Phe397Leu and Leu393Phe amino acid substitutions that confer resistance to TRB [11,15,22,33]. Since 2018, several cases of clinically resistant tinea corporis with extensive lesions that do not respond to TRB have been reported from France [13,14].

Human T-cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that causes a lifelong infection. Several diseases, including an aggressive form of leukaemia, have been designated as associated with HTLV-1, whereby having HTLV-1 is a necessary condition for diagnosis. Beyond these diseases, there is uncertainty about other health effects of HTLV-1. We aimed to synthesise evidence from epidemiological studies on associations between health outcomes and HTLV-1. For this systematic review and meta-analysis, we searched Embase, MEDLINE, MEDLINE In-Process, and Global Health for publications from their inception to July, 2018. We included cohort, case-control, and controlled cross-sectional studies that compared mortality or morbidity between people with and without HTLV-1. We excluded studies of psychiatric conditions, of symptoms or clinical findings only, of people who had undergone blood transfusion or organ transplant, and of population groups defined by a behavioural characteristic putting them at increased risk of co-infection with another virus. We extracted the risk estimates (relative risks [RRs] or odds ratios [ORs]) that reflected the greatest degree of control for potential confounders. We did a random-effects meta-analysis for groups of effect estimates where case ascertainment methods, age groups, and confounders were similar, presenting pooled estimates with 95% CIs and prediction intervals. Of the 3318 identified studies, 39 met the inclusion criteria, examining 42 clinical conditions between them. The adjusted risk of death due to any cause was higher in people with HTLV-1 when compared with HTLV-1-negative counterparts (RR 1·57, 95% CI 1·37–1·80). From meta-analysis, HTLV-1 was associated with increased odds of seborrheic dermatitis (OR 3·95, 95% CI 1·99–7·81), Sjogren's syndrome (3·25, 1·85–5·70), and, inversely, with lower relative risk of gastric cancer (RR 0·45, 0·28–0·71). There were a further 14 diseases with significant associations or substantially elevated risk with HTLV-1 from single studies (eczema [children]; bronchiectasis, bronchitis and bronchiolitis [analysed together]; asthma [males]; fibromyalgia; rheumatoid arthritis; arthritis; tuberculosis; kidney and bladder infections; dermatophytosis; community acquired pneumonia; strongyloides hyperinfection syndrome; liver cancer; lymphoma other than adult T-cell leukaemia-lymphoma; and cervical cancer). There is a broad range of diseases studied in association with HTLV-1. However, the elevated risk for death among people with HTLV-1 is not explained by available studies of morbidity. Many of the diseases shown to be associated with HTLV-1 are not fatal, and those that are (eg, leukaemia) occur too rarely to account for the observed mortality effect. There are substantial research gaps in relation to HTLV-1 and cardiovascular, cerebrovascular, and metabolic disease. The burden of disease associated with the virus might be broader than generally recognised. Commonwealth Department of Health, Australia.

Due to its high degree of natural resistance to terbinafine in vitro and its tendency to spread globally from the Indian subcontinent, the emerging dermatophyte Trichophyton indotineae has become a major concern in dermatology. Herein, we present the first report of T. indotineae from mainland China. The transmission of the fungus to Guizhou Province in central China and eventual host susceptibilities were investigated. We studied 31 strains of the T. mentagrophytes complex from outpatient clinics of our hospital collected during the past 5 years. The set comprised four ITS genotypes, two of which were T. mentagrophytes genotype VIII, now known as Trichophyton indotineae ; the earliest isolation in the Guiyang area appeared to date back to 2018. The isolate was derived from an Indian patient, while local Chinese patients had no dermatophytosis caused by this genotype. Reports from around the world indicated that almost all of the globally reported T. indotineae cases originated from the Indian subcontinent and surrounding countries without transmission among native populations, suggesting deviating local conditions or racial differences in immunity against this fungus.

Trichophyton (T.) indotineae is a newly identified dermatophyte species that has been found in a near-epidemic form on the Indian subcontinent. There is evidence of its spread from the Indian subcontinent to a number of countries worldwide. The fungus is identical to genotype VIII within the T. mentagrophytes/T. interdigitale species complex, which was described in 2019 by sequencing the Internal Transcribed Spacer (ITS) region of ribosomal DNA of the dermatophyte. More than 10 ITS genotypes of T. interdigitale and T. mentagrophytes can now be identified. T. indotineae causes inflammatory and itchy, often widespread, dermatophytosis affecting the groins, gluteal region, trunk, and face. Patients of all ages and genders are affected. The new species has largely displaced other previously prevalent dermatophytes on the Indian subcontinent. T. indotineae has become a problematic dermatophyte due to its predominantly in vitro genetic resistance to terbinafine owing to point mutations of the squalene epoxidase gene. It also displays in vivo resistance to terbinafine. The most efficacious drug currently available for this terbinafine-resistant dermatophytoses, based on sound evidence, is itraconazole.

Curcumin is a bioactive compound that is extracted from Curcuma longa and that is known for its antimicrobial properties. Curcuminoids are the main constituents of curcumin that exhibit antioxidant properties. It has a broad spectrum of antibacterial actions against a wide range of bacteria, even those resistant to antibiotics. Curcumin has been shown to be effective against the microorganisms that are responsible for surgical infections and implant-related bone infections, primarily Staphylococcus aureus and Escherichia coli. The efficacy of curcumin against Helicobacter pylori and Mycobacterium tuberculosis, alone or in combination with other classic antibiotics, is one of its most promising antibacterial effects. Curcumin is known to have antifungal action against numerous fungi that are responsible for a variety of infections, including dermatophytosis. Candidemia and candidiasis caused by Candida species have also been reported to be treated using curcumin. Life-threatening diseases and infections caused by viruses can be counteracted by curcumin, recognizing its antiviral potential. In combination therapy with other phytochemicals, curcumin shows synergistic effects, and this approach appears to be suitable for the eradication of antibiotic-resistant microbes and promising for achieving co-loaded antimicrobial pro-regenerative coatings for orthopedic implant biomaterials. Poor water solubility, low bioavailability, and rapid degradation are the main disadvantages of curcumin. The use of nanotechnologies for the delivery of curcumin could increase the prospects for its clinical application, mainly in orthopedics and other surgical scenarios. Curcumin-loaded nanoparticles revealed antimicrobial properties against S. aureus in periprosthetic joint infections.

Autosomal recessive CARD9 deficiency underlies life-threatening, invasive fungal infections in otherwise healthy individuals normally resistant to other infectious agents. In less than 10 years, 58 patients from 39 kindreds have been reported in 14 countries from four continents. The patients are homozygous (n = 49; 31 kindreds) or compound heterozygous (n = 9; 8 kindreds) for 22 different CARD9 mutations. Six mutations are recurrent, probably due to founder effects. Paradoxically, none of the mutant alleles has been experimentally demonstrated to be loss-of-function. CARD9 is expressed principally in myeloid cells, downstream from C-type lectin receptors that can recognize fungal components. Patients with CARD9 deficiency present impaired cytokine and chemokine production by macrophages, dendritic cells, and peripheral blood mononuclear cells and defective killing of some fungi by neutrophils in vitro. Neutrophil recruitment to sites of infection is impaired in vivo. The proportion of Th17 cells is low in most, but not all, patients tested. Up to 52 patients suffering from invasive fungal diseases (IFD) have been reported, with ages at onset of 3.5 to 52 years. Twenty of these patients also displayed superficial fungal infections. Six patients had only mucocutaneous candidiasis or superficial dermatophytosis at their last follow-up visit, at the age of 19 to 50 years. Remarkably, for 50 of the 52 patients with IFD, a single fungus was involved; only two patients had IFDs due to two different fungi. IFD recurred in 44 of 45 patients who responded to treatment, and a different fungal infection occurred in the remaining patient. Ten patients died from IFD, between the ages of 12 and 39 years, whereas another patient died at the age of 91 years, from an unrelated cause. At the most recent scheduled follow-up visit, 81% of the patients were still alive and aged from 6.5 to 75 years. Strikingly, all the causal fungi belonged to the phylum Ascomycota: commensal Candida and saprophytic Trychophyton, Aspergillus, Phialophora, Exophiala, Corynesprora, Aureobasidium, and Ochroconis. Human CARD9 is essential for protective systemic immunity to a subset of fungi from this phylum but seems to be otherwise redundant. Previously healthy patients with unexplained invasive fungal infection, at any age, should be tested for inherited CARD9 deficiency.Key Points• Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state.• CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands.• Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein).• The functional impacts of CARD9 mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity.• The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular) Candida infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis.• The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned.• Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease.• All patients with unexplained IFD should be tested for CARD9 mutations. Familial screening and genetic counseling should be proposed.• The treatment of patients with CARD9 mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing Candida infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.

The burden of fungal infections is not widely appreciated. Although these infections are responsible for over one million deaths annually, it is estimated that one billion people are affected by severe fungal diseases. Mycoses of nails and skin, primarily caused by fungi known as dermatophytes, are the most common fungal infections. Trichophyton rubrum appears to be the most common causative agent of dermatophytosis, followed by Trichophyton interdigitale. An estimated 25% of the world’s population suffers from dermatomycosis. Although these infections are not lethal, they compromise the quality of life of infected patients. The outcome of antidermatophytic treatments is impaired by various conditions, such as resistance and tolerance of certain dermatophyte strains. The adage “know your enemy” must be the focus of fungal research. There is an urgent need to increase awareness about the significance of these infections with precise epidemiological data and to improve knowledge regarding fungal biology and pathogenesis, with an emphasis on adaptive mechanisms to tackle adverse conditions from host counteractions. This review outlines the current knowledge about dermatophyte infections, with a focus on signaling pathways required for fungal infection establishment and a broad perspective on cellular and molecular factors involved in antifungal resistance and tolerance.