Azole resistance in Aspergillus fumigatus (Af) has become a widespread threat and a major concern for optimal management of patients with invasive aspergillosis (IA). Combination of echinocandins with azoles is an attractive alternative option for the treatment of IA due to azole-resistant Af strains. The aim of this study was to evaluate the in vitro and in vivo combination of caspofungin (CAS) with either voriconazole (VRZ) or posaconazole (PSZ). In vitro interactions were assessed by two methods, and an animal model of IA in Galleria mellonella was used for in vivo evaluation. Assessment of efficacy was based on larvae mortality. Groups of 10 larvae were infected by 3 clinical strains of Af (azole susceptible, AfS; PSZ resistant, AfR1; VRZ and PSZ resistant strain, AfR2). In vitro, combination of CAS and azoles was indifferent against AfS, and AfR2, and a synergy was found for AfR1. When compared to VRZ monotherapy, the combination of VRZ at 4 µg/larva with CAS at 4 µg/larva improved survival of AfR2-infected larvae (p=0.0066). Combination of PSZ at 4µg/larva with CAS at 4 µg/larva improved survival of AfR1-infected larvae compared to CAS (p=0.0002) and PSZ (0.0024) monotherapy. Antagonism was never observed. In conclusion, the combination of caspofungin with azoles is a promising alternative for the treatment of azole resistant strains of Af.

Invasive isolated renal aspergilloma in an immunocompetent host is rare, and few cases have been reported in the literature. It is a unique entity encountered by a urologist that can lead to catastrophic complications like end-stage renal disease. Infective pathology may closely resemble renal mass, and timely, appropriate investigations are obligatory for early intervention. This case report highlights the importance of strong consideration of renal fungal infections in the differential diagnosis of a renal mass with atypical radiological findings in an immunocompetent host. Meticulous decision-making and appropriate management help to prevent disastrous sequelae.

Germination from conidia to hyphae and hyphal propagation of Aspergillus fumigatus are the key pathogenic steps in the development of invasive pulmonary aspergillosis (IPA). By applying in vitro observations in a clinical study of 13 patients diagnosed with probable IPA, here, we show that the transition from colonization to the A. fumigatus invasive stage is accompanied by the secretion of triacetylfusarinine C (TafC), triacetylfusarinine B (TafB), and ferricrocin (Fc) siderophores into urine, with strikingly better sensitivity performance than serum sampling. The best-performing index, the TafC/creatinine index, with a median value of 17.2, provided 92.3% detection sensitivity (95% confidence interval [CI], 64.0 to 99.8%) and 100% specificity (95% CI, 84.6 to 100%), i.e., substantially better than the corresponding indications provided by galactomannan (GM) and β-d-glucan (BDG) serology. For the same patient cohort, the serum GM and BDG sensitivities were 46.2 and 76.9%, respectively, and their specificities were 86.4 and 63.6%, respectively. The time-dependent specific appearance of siderophores in the host's urine represents an impactful clinical diagnostic advantage in the early discrimination of invasive aspergillosis from colonization. A favorable concentration of TafC in a clinical specimen distant from a deep infection site enables the noninvasive sampling of patients suffering from IPA. IMPORTANCE The importance of this research lies in the demonstration that siderophore analysis can distinguish between asymptomatic colonization and invasive pulmonary aspergillosis. We found clear associations between phases of fungal development, from conidial germination to the proliferative stage of invasive aspergillosis, and changes in secondary metabolite secretion. The critical extracellular fungal metabolites triacetylfusarinines C and B are produced during the polarized germination or postpolarized growth phase and reflect the morphological status of the proliferating pathogen. False positivity in Aspergillus diagnostics is minimized as mammalian cells do not synthesize Aspergillus siderophore or mycotoxin molecules.

Aspergillus fumigatus, an environmental mold, causes life-threatening infections. Studies on the phylogenetic structure of human clinical A. fumigatus isolates are limited. Here, we performed whole-genome sequencing of 24 A. fumigatus isolates collected from 18 patients in U.S. healthcare facilities in California. Single-nucleotide polymorphism (SNP) differences between patient isolates ranged from 187-70 829 SNPs. For five patients with multiple isolates, we calculated the within-host diversities. Three patients had a within-host diversity that ranged from 4-10 SNPs and two patients ranged from 2-16 977 SNPs. Findings revealed highly diverse A. fumigatus strains among patients and two patterns of diversity for isolates that come from the same patient, low and extremely high diversity.

Invasive fungal infections cause over 1.5 million deaths worldwide. Despite increases in fungal infections as well as the numbers of individuals at risk, there are no clinically approved fungal vaccines. We produced a "pan-fungal" peptide, NXT-2, based on a previously identified vaccine candidate and homologous sequences from Pneumocystis, Aspergillus,Candida, and Cryptococcus. We evaluated the immunogenicity and protective capacity of NXT-2 in murine and nonhuman primate models of invasive aspergillosis, systemic candidiasis, and pneumocystosis. NXT-2 was highly immunogenic and immunized animals had decreased mortality and morbidity compared to nonvaccinated animals following induction of immunosuppression and challenge with Aspergillus, Candida, or Pneumocystis. Data in multiple animal models support the concept that immunization with a pan-fungal vaccine prior to immunosuppression induces broad, cross-protective antifungal immunity in at-risk individuals.

Background Both pulmonary tuberculosis (PTB) and chronic pulmonary aspergillosis (CPA) significantly affect health-related quality of life (HR-QoL). We aimed to determine the impact of CPA co-infection on the HR-QoL of Ugandans with PTB. Methods We conducted a prospective study among participants with PTB with persistent pulmonary symptoms after 2 months of anti-TB treatment at Mulago Hospital, Kampala, Uganda between July 2020 and June 2021. HR-QoL was assessed using St. George Respiratory Questionnaire (SGRQ) at enrollment and at the end of PTB treatment (4 months apart). SGRQ scores range from 0 to 100, with higher score representing a poorer HR-QoL. Results Of the 162 participants enrolled, 32 (19.8%) had CPA + PTB and 130 (80.2%) had PTB only. The baseline characteristics of the two groups were comparable. Regarding overall health, a higher proportion of the PTB only group rated their HR-QoL as "very good" compared to those who had both TB and CPA (68 (54.0%) versus 8 (25.8%)). At enrollment, both groups had comparable median SGRQ scores. However, at follow up, the PTB only group had statistically significantly better SGRQ scores (interquartile range); symptoms (0 (0 - 12.4) versus 14.4 (0 - 42.9), p < 0.001), activity ((0 (0 - 17.1) versus 12.2 (0 - 35.5), p = .03), impact (0 (0 - 4.0) versus 3.1 (0 - 22.5), p = 0.004), and total scores ((0 (0 - 8.5) versus 7.6 (0 - 27.4), p = 0.005). Conclusion CPA co-infection impairs HR-QoL of people with PTB. Active screening and management of CPA in patients with PTB is recommended to improve HR-QoL of these individuals.

Chronic obstructive pulmonary disease (COPD) is a chronic airway non-specific inflammatory disease characterised by airway obstruction and alveolar destruction. In recent years, due to the extensive use of antibiotics, glucocorticoids, immunosuppressants and other drugs, pulmonary fungal infection in patients with AECOPD, especially aspergillus infection, has gradually increased. The forms of aspergillus infection present in COPD patients include sensitisation, chronic pulmonary aspergillosis (CPA) and invasive pulmonary aspergillosis (IPA). This review will summarise diagnostic and treatment of aspergillus in COPD patients.

Patients with severe fever with thrombocytopenia syndrome (SFTS) had been confirmed to have immune dysfunction and were prone to invasive pulmonary aspergillosis (IPA), which was directly related to the increased mortality. The aim of this study was to investigate the predictors for IPA in SFTS patients, and the results were expected to be helpful for early identification of IPA and initiation of anti-fungal therapy. The study was performed to review laboratory confirmed SFTS patients in two tertiary hospitals in Shandong province (Qilu Hospital of Shandong University and Shandong Public Health Clinical Center) from April 2021 to August 2022. The enrolled patients were further divided into IPA group and non-IPA group. Demographic characteristics, clinical manifestations and laboratory parameters between IPA group and non-IPA group patients were analyzed and compared to identify the independent predictors for IPA by univariate analysis and multivariable logistic regression analysis. Sensitivity and specificity of independent predictors were evaluated by receiver operating characteristic (ROC) curve analysis. In total, 67 SFTS patients were enrolled with an average age of 64.7 (± 8.4) years old. The incidence of IPA was 32.8% (22/67). Mortality of patients in IPA group was 27.3% (6/22), which was significantly higher than that in non-IPA group. Results of univariate analysis showed that uncontrolled diabetes, central nervous system symptoms, platelet < 40 × 109/L, CD4+ T cell < 300/μL and CD8+ T cell < 400/μL were risk factors for development of IPA. These factors were further analyzed by multivariable logistic regression analysis and the results indicated that uncontrolled diabetes, platelet < 40 × 109/L, CD4+ T cell < 300/μL and CD8+ T cell < 400/μL could be recognized as independent predictors for IPA in SFTS patients. In conclusion, IPA is a serious complication for SFTS patients and increases mortality. It is necessary to early identify predictors of IPA for improving survival of SFTS patients.

There are limited cases of heart-lung transplantation (HLT) in children worldwide owing to lack of donors, demanding surgical teamwork, and arduous post-operative management. Post-transplant management difficulties stem from the possible development of several post-operative complications, with infection being a common complication. Intracranial fungal infections are difficult to diagnose and prone to treatment delays because of their relatively insidious onset and atypical clinical presentation. Here, we present a case of a cerebral infection developed 3 months after HLT in a 10-year-old child, showing no positive results on conventional imaging or cerebrospinal fluid (CSF) examination and culture. On metagenomic next-generation sequencing of the cerebrospinal fluid, the causative organism was finally determined as Aspergillus. After administering 1-year anti-Aspergillus treatment, no recurrence of intracranial fungal infection was noted during the 3-year follow-up. This case illustrates the multifaceted diagnostic techniques for cerebral aspergillosis after HLT and shows the significance of dynamic monitoring of symptoms, such as headache, and of metagenomic sequencing results, trends in intracranial pressure and (1-3)-β-D-glucan levels for guiding diagnosis and treatment.

India is well known as the diabetes "capital" of the world but now it is also becoming the mucormycosis "capital" of the world. Indian Council of Medical Research has formed an "Evidence-Based Advisory in The Time of COVID-19 on Screening, Diagnosis, and Management of Mucormycosis." As per this advisory, an oral and maxillofacial surgeon forms an integral part of the team dedicated to fight this epidemic of mucormycosis. Also, there are other fungal infections such as aspergillosis which are getting reported in these patients affecting the paranasal sinuses and the jaws. Aggressive surgical debridement and a thorough knowledge of anti-fungal therapy are must in treating these fungal infections. The aim of this article is to give an overview on the available anti-fungal therapy required to manage the ever-increasing rise in fungal infections faced by maxillofacial surgeons in post-COVID-19 patients.

Invasive fungal infections increase mortality and morbidity rates worldwide. The treatment of these infections is still limited due to the low bioavailability and toxicity, requiring therapeutic monitoring, especially in the most severe cases. Voriconazole is an azole widely used to treat invasive aspergillosis, other hyaline molds, many dematiaceous molds, Candida spp., including those resistant to fluconazole, and for infections caused by endemic mycoses, in addition to those that occur in the central nervous system. However, despite its broad activity, using voriconazole has limitations related to its non-linear pharmacokinetics, leading to supratherapeutic doses and increased toxicity according to individual polymorphisms during its metabolism. In this sense, nanotechnology-based drug delivery systems have successfully improved the physicochemical and biological aspects of different classes of drugs, including antifungals. In this review, we highlighted recent work that has applied nanotechnology to deliver voriconazole. These systems allowed increased permeation and deposition of voriconazole in target tissues from a controlled and sustained release in different routes of administration such as ocular, pulmonary, oral, topical, and parenteral. Thus, nanotechnology application aiming to delivery voriconazole becomes a more effective and safer therapeutic alternative in the treatment of fungal infections.

Invasive fungal infections (IFIs) represent a severe complication of COVID-19, yet they are under-estimated. We conducted a retrospective analysis including all the COVID-19 patients admitted to the Infectious Diseases Unit of the Federico II University Hospital of Naples until the 1 July 2021. Among 409 patients, we reported seven cases of IFIs by Candida spp., seven of Pneumocystis jirovecii pneumonia, three of invasive pulmonary aspergillosis, and one of Trichosporon asahii. None of the cases presented underlying predisposing conditions, excluding one oncohematological patient treated with rituximab. Ten cases showed lymphopenia with high rates of CD4+ < 200/µL. All cases received high-dose steroid therapy (mean duration 33 days, mean cumulative dosage 1015 mg of prednisone equivalent), and seven cases had severe COVID-19 disease (OSCI ≥ 5) prior to IFI diagnosis. The cases showed a higher overall duration of hospitalization (63 vs 24 days) and higher mortality rate (23% vs. 7%) compared with the COVID-19 patients who did not developed IFIs. Cases showed a higher prevalence of high-dose steroid therapy and lymphopenia with CD4+ < 200/µL, primarily due to SARS-CoV-2 infection and not related to underlying comorbidities. IFIs strongly impact the overall length of hospitalization and mortality. Therefore, clinicians should maintain a high degree of suspicion of IFIs, especially in severe COVID-19 patients.

Allergic asthma has traditionally been treated with inhaled and systemic glucocorticosteroids. A continuum of allergic fungal airways disease associated with Aspergillus fumigatus colonization and/or atopic immune responses that encompasses fungal asthma, severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis is now recognized along a phenotypic severity spectrum of T2-high immune deviation lung disease. Oral triazoles have shown clinical, anti-inflammatory and microbiologic efficacy in this setting; in the future inhaled antifungals may improve the therapeutic index. Humanized monoclonal antibody biologic agents targeting T2-high disease also show efficacy and promise of improved control in difficult cases. Developments in these areas are highlighted in this overview.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has emerged as an important complication among patients with acute respiratory failure due to SARS-CoV-2 infection. Almost 2.5 years since the start of the COVID-19 pandemic, it continues to raise concerns as an extra factor that contributes to increased mortality, which is mostly because its diagnosis and management remain challenging. The present study utilises the cases of forty-three patients hospitalised between August 2020 and February 2022 whose information was gathered from ten ICUs and special care units based in northern Greece. The main aim was to describe the gained experience in diagnosing CAPA, according to the implementation of the main existing diagnostic consensus criteria and definitions, and present the different classification of the clinical cases due to the alternative algorithms.

Aspergillosis is a disease caused by some species of the fungus Aspergillus, occurring in both mammals (including humans) and birds, the latter being the most susceptible group. Aspergillus must be considered a public health concern as it affects the poultry industry economically and is an occupational risk to its workers. A retrospective study of fungal isolates from the lungs of chickens (Gallus gallus), analyzed between 2008 and 2021 at the Mycology Laboratory, School of Veterinary Medicine, Universidad Nacional, Heredia, Costa Rica was performed to report the prevalence of Aspergillus spp. in poultry farms in Costa Rica and their associated factors. A total of 1113 cases were received, of which 31% (n = 392; 95% CI: 28.3-33.7) were positive for fungal isolation. Aspergillus was the most frequently detected genus, and the most frequent sections were Fumigati (n = 197/392, 50.3%), Flavi (n = 90/392, 22.9%), and Nigri (n = 50/392, 12.7%). Significant effects (p < 0.05) related to the year, geographical origin, purpose, and age were identified in relation to the Aspergillus infection. The identified factors are explained by climatic variations in the tropics and the particularities of the birds. Future research including molecular characterization and antifungal susceptibility tests in animals, humans, and the environment, are needed to better understand the risks of the diseases caused by those fungi in this country.

The prevalence of fungal infections is increasing worldwide, especially that of aspergillosis, which previously only affected people with immunosuppression. Aspergillus fumigatus can cause allergic bronchopulmonary aspergillosis and endangers public health due to resistance to azole-type antimycotics such as fluconazole. Antifungal peptides are viable alternatives that combat infection by forming pores in membranes through electrostatic interactions with the phospholipids as well as cell death to peptides that inhibit protein synthesis and inhibit cell replication. Engineering antifungal peptides with nanotechnology can enhance the efficacy of these therapeutics at lower doses and reduce immune responses. This manuscript explains how antifungal peptides combat antifungal-resistant aspergillosis and also how rational peptide design with nanotechnology and artificial intelligence can engineer peptides to be a feasible antifungal alternative.

Chronic pulmonary aspergillosis (CPA) often occurs in patients that have been previously treated for pulmonary tuberculosis (PTB). A limited number of studies have looked at the development of CPA at different times following the completion of a PTB treatment course. This prospective longitudinal study aimed to determine the incidence of CPA at two timepoints, at the end of the PTB treatment (T1) and six months post-treatment (T2). Patients with confirmed PTB from a previous study who were placed on anti-TB medication were followed up and screened for CPA at T1 and T2 by assessing their symptoms, evaluating their quality of life, and screening them for Aspergillus infection by performing antibody testing and cultures. CPA was defined by the Global Action for Fungal Infections (GAFFI) diagnostic algorithm. Forty-one patients were enrolled, of whom thirty-three patients (80%) and twenty-eight patients (68%) were resurveyed at T1 and T2, respectively. The rate of new CPA was 3.3% (1/33) and 7.4% (2/27) at T1 and T2, respectively, with an overall incidence of 10.7% (3/28) among the patients at both T1 and T2. A positive Aspergillus-specific antibody test was an indicator for CPA in all three patients. Aspergillus-specific antibody screening during and after the end of an anti-TB treatment regimen may be important for early detection of CPA in high-PTB-burden settings.

Serum 1,3-β-d-glucan(BDG) is a broad fungal biomarker for invasive fungal disease (IFD). More data is still required to support the Fujifilm Wako assay as a valuable alternative to the widely used Fungitell assay. We included archived serum samples from 157 individuals (97 cases; 33-IA, 64-IC, and 60 controls) for the comparative performance evaluation of the Fungitell assay and the Fujifilm Wako assay for IFD diagnosis. The BDG value was significantly higher in patients with IFD vs. controls (70.79 pg/mL vs. 3.03 pg/mL, p: 0.0002). An area under the curve (AUC) for the IFD, IC, and IA diagnosis was 0.895, 0.910, and 0.866, respectively, for the Fujifilm Wako assay. Based on the highest Youden's index (0.667), a cutoff of 5 pg/mL was selected as the optimum for the Fujifilm Wako assay with good sensitivity (79.4%), specificity (88.3%) and agreement (84.7%, Cohen's k:0.691) with the Fungitell assay. The mean run-time of the Fujifilm Wako assay was 70.12 min, and real-time observation allowed earlier time to result in Fujifilm Wako vs. Fungitell assay (37 vs. 120 min, p: &lt; 0.0001). Thus, our findings support the diagnostic value of the Fujifilm Wako assay for the diagnosis of IFD. However, there is still a need to validate diagnostic protocols to optimize their use in multi-centre studies with different patient groups.