Mycoses最新文献

Background: Atopic dermatitis (AD) is a common chronic skin disorder characterised by a highly inflamed local environment and elevated epidermal proteolytic activity. Changes in the skin mycobiome have been observed in this disease, specifically Candida albicans colonization positively correlating with AD severity, yet the mechanisms by which this fungus contributes to disease features remain elusive.

Objectives: This study aimed to elucidate how C. albicans can influence AD pathogenesis through its influence on keratinocyte (KC) proteolytic activity, inflammatory cytokine secretion and epidermal barrier integrity, as well as define the signaling pathways mediating these effects.

Methods: Immortalized human KC were co-cultured with C. albicans and changes in KC protease expression and activity, along with the secretion of the pro-inflammatory cytokine IL-1β were assessed. Additionally, the impact of IL-1β on KC barrier formation was determined using transepithelial electrical resistance. To identify signalling pathways mediating Candida-induced phenotypes, CRISPR/Cas9 was used to establish cell lines deficient in myeloid differentiation primary response protein 88 (MyD88) or matrix metalloprotease-9 (MMP-9).

Results: C. albicans induced proteolytic activity from KC through fungal secreted aspartyl proteases (Sap4-6) and promoted IL-1β secretion via MyD88 signalling. This response increased expression and activation of host MMP-9 and led to impaired barrier function. Genetic deletion of either MYD88 or MMP9 restored barrier function in IL-1β treated cells, suggesting MMP-9 serves as a downstream effector of IL-1β/MyD88 signalling.

Conclusion: These findings establish a mechanistic link between skin resident fungi and epidermal barrier dysfunction. We demonstrate a pathway linking fungal colonization to innate immune responses by skin cells, providing insight into how the commensal fungus C. albicans may contribute to AD pathogenesis.

Background: The global prevalence and incidence of fungal skin diseases continue to rise due to population ageing, urbanisation and environmental changes, posing a significant public health challenge. These infections are particularly severe in immunocompromised individuals, potentially leading to deep-seated infections and life-threatening complications. However, comprehensive data on the global burden of fungal skin diseases remain limited, especially in low- and middle-income countries (LMICs) with constrained resources.

Methods: Using Global Burden of Disease (GBD) data from 1990 to 2021, this study analysed trends in incidence, prevalence and disability-adjusted life years (DALYs) across 204 countries and territories. Joinpoint regression was employed to identify temporal trend changes, while the Age-Period-Cohort (APC) model was used to disentangle age, period and cohort effects. Additionally, the Bayesian Age-Period-Cohort (BAPC) model was applied to project disease burden from 2022 to 2036.

Results: In 2021, the global age-standardised incidence rate (ASIR) was 21,668.4 per 100,000 population, showing a slight increase compared to 1990 (Estimated annual percentage change [EAPC] = 0.11). The burden exhibited marked disparities by Socio-demographic Index (SDI): low-SDI countries had the highest ASIR and DALYs (e.g., Ethiopia's ASIR reached 45,535.04 per 100,000), whereas high-SDI countries demonstrated a declining trend. Joinpoint regression revealed pronounced fluctuations in low-SDI nations, contrasting with sustained declines in high-SDI regions. APC analysis indicated elevated risks among older populations and younger birth cohorts. BAPC projections suggested a continued rise in global incidence by 2030, with females likely facing a higher burden than males.

Conclusion: The burden of fungal skin diseases is closely linked to socioeconomic development, with resource-limited regions bearing the highest risks. The projected upward trend underscores the urgent need for targeted public health interventions, particularly in strengthening prevention and management systems in low-SDI countries. This study provides critical evidence to inform global strategies for mitigating the impact of fungal skin diseases.

Background: Posaconazole (POS) prophylaxis is recommended for the prevention of invasive mould infections among patients with haematologic cancer and prolonged neutropenia or following allogeneic haematopoietic cell transplantation. Albeit rare, breakthrough invasive mould infections (bIMI) are associated with high mortality rates.

Objectives: To assess the epidemiology, causes and outcomes of bIMI under POS prophylaxis.

Patients/methods: Haematologic cancer patients with a diagnosis of proven/probable bIMI while receiving POS prophylaxis for ≥ 7 days were retrospectively included in five hospitals (Switzerland and Germany). For each bIMI case, one to two non-bIMI controls receiving POS prophylaxis for the same haematologic condition were included.

Results: A total of 29 bIMI episodes and 46 controls were included. Baseline characteristics and median POS trough concentrations did not significantly differ between the two groups. Invasive aspergillosis was the most frequent bIMI (52%), followed by invasive mucormycosis (31%). POS non-susceptible pathogens were the causes of bIMI in 14% of cases. While insufficient POS exposure was observed in 39% of bIMI cases, this proportion was similar in the control group. Most bIMI were treated with liposomal amphotericin B first-line therapy and received multiple antifungal therapies. Overall mortality was significantly higher among bIMI compared to controls (52% vs. 20%, p = 0.005). Surgery was the only parameter significantly associated with survival.

Conclusions: This case-control study shows that bIMI is associated with a significant impact on mortality. Most bIMI were attributed to presumably POS-susceptible pathogens without a clear association with POS underexposure. The causes of bIMI remain unclear and may be the conjunction of multiple parameters.

Background: Antifungals are the standard treatment for onychomycosis. However, oral antifungals present contraindications and potential drug-drug interactions, while topical antifungals suffer from limited efficacy and penetration. Recently, researchers have explored physical therapies, including laser and photodynamic therapy.

Objective: To evaluate the clinical efficacy of combining diode laser therapy with photodynamic therapy and ciclopirox 8% hydroxypropyl chitosan (HPCH) nail lacquer in treating onychomycosis.

Methods: We conducted a randomised controlled clinical trial involving patients with onychomycosis. A total of 26 patients were enrolled and followed for 12 months. Participants received either eight sessions of laser treatment combined with three sessions of photodynamic therapy, or daily treatment with ciclopirox 8% HPCH.

Results: The clinical cure rate was 94.1% in the group treated with laser and photodynamic therapy, compared to 53.3% in the group treated with ciclopirox 8% HPCH (p = 0.008). All patients who achieved clinical cure with either treatment also reached mycologic and complete cure, with a rate of 100%. The average time to healing was significantly shorter for the group receiving laser and photodynamic therapy (3.6 ± 1.2 months) than for those treated with ciclopirox 8% HPCH nail lacquer (9.2 ± 1.6 months) (p < 0.001). In the laser and photodynamic therapy group, adverse events, specifically subungual hematoma and blisters, occurred in 11.4% of patients, with a recurrence rate of 33.3%. No adverse events or recurrence were observed in patients treated with ciclopirox 8% HPCH.

Conclusions: Treatment of onychomycosis using diode laser and photodynamic therapy results in higher clinical cure rates and shorter healing times compared to the reference treatment with 8% ciclopirox HPCH.

Trial registration: ClinicalTrials.gov identifier: NCT05809297.

Background: Early diagnosis of invasive aspergillosis (IA) is critical for the initiation of effective antifungal therapy. Currently, detection of galactomannan (GM), a secreted fungal glycan, is the most used culture-independent diagnostic test for IA. However, limitations in the sensitivity and specificity of this test have led to interest in identifying other target molecules. Galactosaminogalactan (GAG), a polysaccharide cell wall component secreted by Aspergillus hyphae, is a potential diagnostic marker for IA.

Objectives: To evaluate the utility of GAG as a diagnostic target, we generated a monoclonal antibody against GAG (mAb 1D1), established a GAG enzyme-linked immunosorbent assay (ELISA), evaluated its cross-reactivity with other respiratory pathogens, and compared the performance of the GAG detection ELISA with GM antigen detection in both an in vivo mouse model and human samples from patients with pulmonary aspergillosis.

Results: The GAG ELISA demonstrated strong reactivity with culture supernatants from Aspergillus fumigatus and Aspergillus flavus but limited reactivity with culture supernatants of other Aspergillus spp. and non-Aspergillus filamentous fungi. In a mouse model of IA, GAG was detected in lung tissue, serum, bronchoalveolar lavage fluid (BALF), and urine samples. Although GAG was detected by mAb 1D1 staining of Aspergillus hyphae in infected human lung tissue samples, it was not detectable in the serum, BALF, and urine of patients with pulmonary aspergillosis.

Conclusions: Further studies are required to determine whether the failure to detect GAG in the serum, BALF, and urine of patients with pulmonary aspergillosis is due to absence or low GAG levels or other reasons.

Background: Pneumocystis jirovecii pneumonia (PCP) is a severe opportunistic infection affecting immunocompromised patients. Quantitative polymerase chain reaction (qPCR) is widely used for the detection of P. jirovecii in respiratory samples. However, the diagnosis of PCP remains challenging and the high prevalence of P. jirovecii airway colonisation complicates the interpretation of positive results. The aim of this study was to assess the utility of P. jirovecii PCR Quantification Cycle (Cq) values in differentiating between PCP and colonisation in PCR-positive respiratory samples from immunocompromised patients.

Methods: Adult patients with P. jirovecii detected by qPCR in respiratory samples (bronchoalveolar lavage (BAL), sputum and oral wash) collected between 2017 and 2023 were retrospectively enrolled in the study. Patients were classified as having PCP or P. jirovecii colonisation and Cq values were compared between the groups. Receiver-operating characteristics (ROC) curve analyses were used to assess the performance of Cq values to distinguish between PCP and colonisation, and to establish Cq cut-off values for the different sample types.

Result: Of 520 included participants, 247 patients (47.5%) were classified as PCP and 273 (52.5%) as colonised. The median Cq value was significantly lower in the PCP group compared to colonised patients in BAL (33.0 vs. 36.6, p < 0.001) and sputum (33.4 vs. 36.0, p < 0.0001), yielding a ROC area under the curve of 0.75 and 0.73, respectively. Cq levels for oral wash did not differ between PCP and colonisation and lacked discriminatory power with a ROC AUC of 0.45. A Cq cut-off level at 31 for BAL and sputum could predict PCP with a positive predictive value of > 85% while Cq < 38 provided a negative predictive value of 89% for BAL and 73% for sputum.

Conclusion: Different Cq cut-off values in BAL and sputum may support discrimination between PCP and colonisation and assist physicians in their clinical management of PCP.

Objectives: To evaluate the susceptibility and resistance of Aspergillus and Mucorales isolates to antifungal agents.

Methods: Studies in susceptibility or resistance of Aspergillus and Mucorales isolates to antifungal agents published between January 2010 and June 2023 were systematically searched in PubMed, EMBASE and the Cochrane Library. The minimum inhibitory concentration (MIC), susceptibility and resistance data were analysed using CLSI or EUCAST methods.

Results: After following the systematic review processes, 96 studies were included. The total number of isolates was 16,258. Compared with existing MIC distributions and breakpoints or epidemiological cutoff values (ECVs) established by CLSI or EUCAST, for A. flavus, the posaconazole and voriconazole MIC values were at or below the ECV, indicating that the isolates were wild-type (WT) strains; however, the amphotericin B, isavuconazole and itraconazole MIC values were elevated. For A. fumigatus, the isavuconazole MIC values were within ECV limits, indicating that the isolates were WT strains; however, the amphotericin B, posaconazole and voriconazole MIC values were elevated. For A. niger, the isavuconazole and voriconazole MIC values were within ECV limits, indicating that the isolates were WT strains; however, the amphotericin B and posaconazole MIC values were elevated. A. flavus had consistently high in vitro susceptibility to voriconazole, and A. fumigatus and A. niger had consistently high in vitro susceptibility to amphotericin B. For Mucorales, the resistance to amphotericin B was consistently at the lowest level. The subgroup analysis indicated that the resistance among the strains in the environment was higher than that of the clinical isolates.

Conclusion: Trends in susceptibility and resistance of Aspergillus and Mucorales isolates should be adequately considered in antifungal therapy. The evaluation of drug resistance is beneficial in that it enables clinicians to choose suitable drugs and appropriate doses.

Background: Malassezia genus includes lipodependent commensal yeasts of humans and animals' skin and mucous membranes. It can cause dermatological pathologies, and azoles are mainly used for treatment. However, in vitro susceptibility testing has shown decreased sensitivity to these antifungals. Some publications have suggested that resistance mechanisms to azoles include biofilm formation and efflux pump expression, which are proteins encoded by the ATM1 gene, among others.

Objective: This work aimed to characterise Colombian isolates of Malassezia spp. resistant to azoles.

Methods: Twenty-six Malassezia spp. isolates were identified via PCR, ribosomal gene sequencing and phylogenetic analyses. Susceptibility tests were performed on planktonic and sessile cells by microdilution against azoles and by adding efflux pump inhibitors. The relative expression levels of the ATM1 gene in fluconazole-resistant isolates were evaluated via RT-qPCR.

Results: It was observed that 42% of the isolates in their planktonic form were resistant to voriconazole, 31% to fluconazole, 23% to itraconazole and 15% to ketoconazole. The minimum inhibitory concentration (MIC) was higher in sessile cells than planktonic cells, especially for fluconazole. The MICs of itraconazole, ketoconazole and voriconazole decreased in the presence of haloperidol, promethazine and tacrolimus, while this effect did not occur with fluconazole. The expression of the ATM1 gene was markedly greater in Malassezia spp. isolates resistant to fluconazole than in those susceptible (p < 0.05), both in those exposed and not exposed to the antifungal agent.

Conclusions: We observed resistance of Colombian Malassezia spp. isolates to azoles, mainly fluconazole, through the expression of efflux pumps and biofilm formation.

Introduction: Intra-abdominal candidiasis (IAC) still has a high mortality rate despite prompt antifungal therapy due to immunosuppression. T cell exhaustion is an important manifestation of immunosuppression. This study aimed to explore the expression pattern of exhaustion-related molecules in patients with IAC and determine the possible association between dynamic trends and prognosis.

Methods: Patients with IAC were enrolled, and non-IAC critically ill patients were included as controls. Peripheral blood mononuclear cells (PBMCs) were analysed by flow cytometry to determine the expression levels of T cell exhaustion-related markers. T cells isolated from PBMCs were stimulated by IL-2 in α-CD3/α-CD28 medium to compare intracellular cytokine production and proliferative capacity.

Results: A total of 34 patients with IAC and 35 controls were enrolled in this study. Patients with IAC had a significant decrease in lymphocytes. CD4+ and CD8+ T cells from patients with IAC had a significantly higher level of immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA4), and B and T lymphocyte attenuator (BTLA), and exhibited a consistently impaired cytokine-secreting function. Increased exhaustion-associated molecules and deteriorating dysfunction were detected in non-survivors, while survivors demonstrated the opposite tendency. Patients with impaired granzyme B (GZMB) production function who died from IAC over the course of the disease had higher levels of PD-1 expression in CD8+ T cells.

Conclusions: T cells from patients with IAC displayed an immunosuppressive phenotype of T cell exhaustion. Sustaining exhaustion status and deteriorated dysfunction were associated with poor prognosis. Persistently increased PD-1 expression and impaired GZMB secretion in CD8+ T cells were linked to worse outcomes. Immunoadjuvants reversing T cell exhaustion have promising prospects in treating IAC and improving prognosis.

Introduction: Candidaemia is a life-threatening infection with a persistently high mortality rate, despite significant advances in antifungal therapy and supportive care. The European Confederation of Medical Mycology developed the EQUAL Candida Score as a standardised tool to evaluate adherence to guideline-based management; however, its prognostic value has not been consistently demonstrated in different patient populations. This study aimed to evaluate the clinical impact of adhering to guidelines and determine the predictive value of the EQUAL Candida Score for mortality risk in candidaemia patients.

Methods: This retrospective cohort study included adult patients with candidaemia who were treated at a tertiary care hospital. Patients were classified as survivors or nonsurvivors based on 90-day candidaemia-related mortality. We identified independent predictors of mortality using multivariable Cox regression analysis and subsequently developed a prognostic nomogram based on the final model.

Results: A total of 189 patients with candidaemia were included in the study, of whom 88 (46.6%) died within 90 days. The median EQUAL Candida Score was significantly lower among nonsurvivors compared with survivors (8 vs. 13, p < 0.001). This prognostic association remained consistent in subgroup analyses, both in patients with (10 vs. 13, p < 0.001) and without (10 vs. 13, p = 0.022) central venous catheters. An optimal cut-off score of 12 was identified across all groups, yielding a sensitivity of 70%-80% and a specificity of 79%. Kaplan-Meier survival analysis further confirmed that patients with an EQUAL Score ≥ 12 had significantly higher survival rates in all subgroups. In multivariable Cox regression, immunosuppressive treatment (HR 1.728), septic shock (HR 2.035), lack of source control (HR 2.013) and an EQUAL Score < 12 (HR 3.503) were identified as independent predictors of candidaemia-related mortality. Based on these variables, a nomogram was developed to estimate individualised survival probabilities at 1, 3 and 6 months. External validation in an independent cohort (n = 64) confirmed the model's prognostic performance, with a Harrell's C-index of 0.704 (95% CI: 0.587-0.821), despite the limited sample size.

Conclusion: The EQUAL Candida Score serves as a reliable prognostic marker for candidaemia. When combined with clinical parameters, it enhances the accuracy of mortality risk estimation. Our novel nomogram provides a practical framework for early risk stratification and may optimise management strategies for high-risk patients.