Search Results (183)

Purpose: This study aims to determine the incidence of kidney injury associated with liposomal amphotericin B (L-AmB) treatment, based on RIFLE criteria, in patients admitted to the intensive care unit (ICU) with invasive pulmonary aspergillosis (IPA). Materials and Methods: A retrospective, multicenter observational study including patients treated with L-AmB for IPA while admitted to the ICU between 1 January 2015, and 31 December 2022. Results: A total of 65 patients were included. The prevalence of renal failure was 35.39%. Renal failure was mostly mild and reversible. The need for major surgery (OR 6.71; p = 0.121) and concomitant use of other nephrotoxic treatments (OR 2.5; p = 0.194) emerged as potential risk factors for the development of renal failure; however, neither association reached statistical significance. Overall mortality was 66.2%, significantly higher in the group with renal failure (82.6% vs. 57.1%; p = 0.03). Factors associated with mortality included concomitant use of other nephrotoxic agents (OR 4.51; p = 0.024) and development of renal failure (OR 3.66; p = 0.068). Duration of L-AmB treatment was not associated with mortality. Regarding creatinine recovery, all patients who developed renal failure but survived showed creatinine levels below 1.5 mg/dL after completion of treatment. Conclusions: Renal impairment was common in this high-risk population of critically ill patients, with renal function impairment in one-third of exposed patients, although most cases were mild. In this population, concomitant administration of other nephrotoxic drugs was associated with both renal failure and mortality. Treatment duration with L-AmB was not linked to mortality, and creatinine levels normalized after therapy completion. Full article

Aspergillosis encompasses a heterogeneous spectrum of diseases caused by filamentous fungi of the genus Aspergillus, ranging from allergic airway disorders and chronic pulmonary infection to rapidly progressive invasive disease. Aspergillus fumigatus is the predominant pathogen worldwide, although other species, including Aspergillus flavus, Aspergillus terreus and cryptic species, contribute to morbidity and may exhibit intrinsic or acquired antifungal resistance. Early and accurate laboratory diagnosis is essential for timely treatment, appropriate antifungal selection, and stewardship. Traditional culture remains foundational, enabling confirmation of viable organisms, species-level identification, and antifungal susceptibility testing, but sensitivity is limited and turnaround times are prolonged. Non-culture approaches—including galactomannan, β-D-glucan, lateral flow assays, PCR, and next-generation sequencing—enhance diagnostic sensitivity, facilitate early detection, and allow identification of resistance-associated mutations. Optimal diagnostic performance is achieved through integrated, multimodal strategies combining laboratory tests with clinical and radiological findings. In invasive disease, concurrent use of biomarkers and molecular assays improves specificity and positive predictive value, while in allergic bronchopulmonary aspergillosis, immunological markers remain central. Future directions include standardised molecular protocols, novel antigenic and host-based biomarkers, and cost-effective, risk-adapted diagnostic algorithms to refine detection, guide therapy, and improve patient outcomes. Full article

Invasive pulmonary mold infections (IPMIs) are critical complications in immunocompromised patients, contributing significantly to morbidity and mortality. Diagnosing pathogens like Aspergillus species (spp.) and the Mucorales remains challenging due to non-specific clinical presentations and the limitations of traditional culture methods. This review provides an up-to-date synopsis of IPMI diagnostic tools, focusing on their diagnostic performance, turnaround time (TAT), and cost-effectiveness. We conducted a narrative review of the current literature regarding clinical evaluation, radiographic findings, invasive diagnostics, and non-invasive assays, including next-generation sequencing (NGS) and volatile organic compounds (VOCs). Chest computerized tomography (CT) remains a vital first step, though classic signs like the “halo” or “reverse halo” are neither sensitive nor specific. Traditional diagnostics are limited by low sensitivity and delayed results. While plasma microbial cell-free DNA (mcfDNA) NGS offers rapid TAT (24–48 h) and high specificity, its suboptimal sensitivity for Aspergillus spp. (<50%) and high cost remain significant barriers. Investigational VOC “breath tests” show promising sensitivity (77–96%) but lack standardization. Future research must prioritize the standardization of non-invasive microbiologic testing modalities, particularly those with rapid TAT such as bedside “breath tests” and high-throughput mcfDNA NGS. Development of clinical algorithms that balance cost-effectiveness with timely pathogen diagnosis based on the patient’s degree of immunosuppression is essential to improve survival in high-risk populations. Full article

COVID-19-associated pulmonary aspergillosis (CAPA) is a frequent and severe complication among critically ill patients with COVID-19. The absence of a clear diagnostic gold standard and the multiplicity of proposed definitions (EORTC/MSG, AspICU, and ISHAM) complicate its diagnosis. This study aimed to compare the performance of the EORTC/MSG, AspICU, and ISHAM classifications in diagnosing CAPA among mechanically ventilated COVID-19 patients and to assess their correlations with clinical outcomes. We conducted a retrospective, monocentric study including all adult COVID-19 patients requiring invasive mechanical ventilation admitted to the ICUs of CHU-Charleroi Chimay between March 2020 and December 2021. Patients were classified according to EORTC/MSG, AspICU, and ISHAM criteria. Demographics, comorbidities, management, and outcomes were compared across groups. In total, 405 patients were included during the four waves. The incidence of probable or possible CAPA varied widely: 6.1% with EORTC/MSG, 9.7% with AspICU, and 15.1% with ISHAM criteria. ICU mortality reached approximately 76% among patients with probable CAPA versus 43% in patients without aspergillosis. The frequency of CAPA diagnosis increased across COVID-19 waves, possibly correlating with changes in management, particularly corticosteroid use. The choice of CAPA diagnostic criteria has a major impact on incidence estimates and patient management. Prospective validation of CAPA definitions, integrating multiple mycological criteria, is urgently needed to guide clinical decision-making and antifungal therapy. Full article

Invasive pulmonary aspergillosis (IPA) poses a serious threat to immunocompromised hosts, with limited therapeutic options highlighting the need for novel strategies. Coptis chinensis Franch. (CCF), a traditional Chinese herb containing antimicrobial alkaloids like berberine, was investigated for its therapeutic efficacy and immunological effects in a murine IPA model. Immunosuppressed female KM mice infected with Aspergillus fumigatus AF293 were treated with CCF or amphotericin B (AmB). CCF significantly improved survival, reduced fungal burden, and alleviated lung pathology, without inducing hepatotoxicity or nephrotoxicity. Transcriptomic profiling revealed a time-dependent immune response. Complement-related pathways were enriched at 2 days post-infection, whereas neutrophil recruitment and NET-related pathways became more prominent by day 4. Hub gene analysis identified Syk, Rac2, Ncf1, and Cybb as key nodes associated with the NADPH oxidase complex. Western blot and inhibitor experiments further supported the involvement of this pathway in CCF-mediated protection. Additionally, 16S rDNA sequencing indicated enrichment of Clostridium species in the gut microbiota of CCF-treated mice, which was positively correlated with the expression of NADPH oxidase-related genes, suggesting a potential gut–lung association. In conclusion, these findings support the antifungal efficacy of CCF in IPA and suggest that its protective effects may involve coordinated changes in complement-related responses, NADPH oxidase-associated neutrophil activity, and gut microbiota composition. Full article

In clinical practice, healthcare providers encounter a rising incidence of aspergillosis, which significantly affects morbidity and mortality in vulnerable patients. Over the past few decades, molds have increasingly affected patients with underlying pleuropulmonary, hematological, or oncological diseases undergoing cytotoxic treatment or immunosuppression, leading to impaired cell-mediated immunity and an increased risk of postoperative complications. Although the spectrum of Aspergillus infection is variable, ranging from allergic to chronic, invasive manifestation, pleural involvement is rarely reported. Pleural aspergillosis is an extrapulmonary manifestation of invasive aspergillosis, associated with thoracic surgical procedures and with a bronchopleural fistula, not necessarily combined with pulmonary aspergillosis. An elective or emergency thoracic surgery in immunocompromised patients increases the risk of postoperative infectious complications. Herein, we report a case of isolated postoperative pleural aspergillosis in a 28-year-old immunocompromised man with metastatic synovial sarcoma in the lungs, who underwent pleurodesis for pneumothorax, lobectomy for lung metastasis, and subsequently required decortication and thoracoplasty to achieve effective control of infection. To address this, the patient responded well to aggressive surgical debridement along with both systemic and intrapleural antifungal agent instillation. The essential in vitro diagnostics, including microscopy, microbiological culture and histopathological examination, both from necrotic pleural specimens, detected Aspergillus fumigatus, a global priority species of invasive aspergillosis. Postoperative aspergillosis with pleural involvement and bronchopleural fistula, in immunocompromised patients with sarcoma, is rarely reported, requiring a combination of surgical approach and optimized antifungal treatment regimens. The current knowledge on pleural aspergillosis management remains limited, and highlights the need for case reporting to refine expertise. Full article

Background: Extracorporeal membrane oxygenation (ECMO) support is associated with potentially life-threatening complications, among which nosocomial infections play a significant role. The increasing incidence of fungi as causative agents of ECMO-associated infections is a growing concern. Methods: This case series includes all patients admitted to the Intensive Care Unit (ICU) of the “Renato Dulbecco” Teaching Hospital in Catanzaro who developed invasive fungal infections (IFIs) during ECMO support. Results: Of the 70 patients, 15.7% (N = 11) developed IFIs during ECMO. Among these, 91% (N = 10) died, while one patient survived and was discharged. Of the IFIs, 72.7% (N = 8) were cases of invasive candidiasis (IC), and 18.2% (N = 2) were cases of invasive pulmonary aspergillosis (IPA). One patient developed both IC and IPA during ECMO treatment. Additionally, 54.5% (N = 6) of the patients with IFIs also had bacterial co-infections, most of which were caused by multidrug-resistant (MDR) Gram-negative bacteria. Conclusions: This study highlights the high incidence and mortality of IFIs in ECMO patients. It underscores the urgent need for clear definitions, better diagnostic strategies, pharmacokinetic data on antifungal therapies, and the implementation of therapeutic drug monitoring (TDM) to optimize outcomes in this vulnerable population. Full article

Invasive pulmonary fungal infections remain a major cause of morbidity and mortality among immunocompromised and critically ill patients. Rapid and accurate diagnosis is crucial for improving outcomes, yet conventional methods such as culture and histopathology suffer from limited sensitivity and slow turnaround times. Recently, significant progress has been made in the development and standardization of serological and molecular biomarkers that enhance the early detection of the key pulmonary fungal diseases, particularly invasive pulmonary aspergillosis and pneumocystosis. Diagnostic tools for mucormycosis, however, remain scarce. PCR tools have strong potential to significantly improve early detection, but they are not yet widely implemented, and standardized commercial assays remain limited. Accessible antigen-based tests with robust performance are highly anticipated and expected to become available soon. This review summarizes the current evidence regarding the optimal use of galactomannan, β-D-glucan and PCR-based assays, emphasizing how their performance varies according to the pathogen, the type of specimen and the host population. Specific challenges, such as differentiating colonization from infection in non-HIV Pneumocystis pneumonia or interpreting galactomannan and PCR in patients receiving mold-active prophylaxis, are highlighted. We also discuss how combining biomarkers can enhance diagnostic accuracy and support timely therapeutic decisions. A clear understanding of the strengths, limitations and appropriate interpretation of these diagnostic tools is crucial in an era of increasing host complexity, shifting fungal epidemiology, and expanding antifungal options. Full article

KSRP (KH-type splicing regulatory protein) has emerged as a pivotal regulator of gene expression at multiple levels, acting as a transcription and splicing factor in the nucleus, and mediating AU-rich element (ARE)-dependent mRNA decay, translational silencing, and microRNA (miRNA) maturation in the cytoplasm. We and others have shown that KSRP acts as a regulator of immune responses, e.g., by dampening the expression of proinflammatory cytokines such as TNF-α, IL-6, IL-8, but also of NOS2, and facilitating the maturation of regulatory miRNAs, including let-7a, miR-129, and miR-155. This review aims to present current knowledge on the regulation of KSRP activity as conferred by miRNAs, phosphorylation, ubiquitination, SUMOylation, and interactions with long non-coding RNAs to enable dynamic responses towards inflammatory stimuli, and the effects of KSRP on innate immune reactions. Here, KSRP acts as an inhibitor by attenuating RIG-I-mediated antiviral signaling, cytokine production, and phagocytosis. In vivo, KSRP deficiency reduced arthritis severity but heightened inflammatory responses in sepsis and enhanced pathogen clearance in invasive pulmonary aspergillosis. These findings position KSRP as a dual regulator that limits tissue damage while constraining antimicrobial immunity. As a perspective, modulation of KSRP activity by applying pharmacological inhibitors may provide strategies to either suppress hyperinflammation in autoimmunity and sepsis or enhance host defense in immunocompromised states. Full article

Invasive pulmonary aspergillosis (IPA), traditionally associated with severe immunosuppression and neutropenia, is increasingly reported among non-neutropenic patients. This epidemiological shift highlights the need for a revised understanding of IPA’s pathogenesis, clinical presentation, and management strategies. The rising incidence in these populations likely reflects improved diagnostic capabilities and recognition of additional predisposing factors. Although profound immunosuppression remains a key risk, even moderate alterations in innate or adaptive immunity can promote Aspergillus spp. invasion. This review summarizes current knowledge and recent advances in the diagnosis and treatment of IPA. Specifically, treatment strategies must be tailored to comorbidities, infection severity, and drug tolerance. Early diagnosis and prompt antifungal therapy are crucial for improving outcomes. Voriconazole remains the first-line treatment, though therapeutic drug monitoring is essential to ensure efficacy and minimize toxicity. Isavuconazole represents an effective alternative, offering comparable efficacy, improved safety, predictable pharmacokinetics, and convenient once-daily dosing. Liposomal amphotericin B serves as a valuable option in severe or refractory cases due to its broad-spectrum activity and reduced nephrotoxicity. Supportive measures—such as respiratory optimization, comorbidity management, and immunomodulatory therapies—are integral to care. Prognosis depends on infection extent, immune status, and timeliness of therapy. Emerging antifungal agents, including olorofim, ibrexafungerp, and fosmanogepix, show promise against resistant Aspergillus species, expanding treatment options. Overall, IPA management in non-neutropenic patients requires a multidisciplinary, patient-centered approach integrating established antifungals, supportive care, and novel therapeutic advances. Full article

Background: Invasive fungal infections (IFIs) in patients with COVID-19 contribute to significant morbidity and mortality, with reported incidence between 5% and 26.7%. COVID-19-associated pulmonary aspergillosis (CAPA), candidiasis (CAC), mucormycosis (CAM), and Pneumocystis jirovecii pneumonia (PJP) are the most common IFIs in this population. Methodology: We conducted a case–control study in the ratio of 1:2 between March 2020 and April 2022 using institutional COVID-19 registry data. The cases were severe COVID-19 patients with IFIs, and the controls were severe COVID-19 patients without IFIs. Multivariate logistic regression was used to identify independent risk factors, with adjusted odds ratios (aOR) and 95% confidence intervals (CIs). The outcomes for the study were to assess the clinical outcomes, i.e., in-hospital mortality and length of hospitalization in a subgroup of severe COVID-19 patients who had IFIs. A p-value < 0.05 was considered significant. Results: Among 5368 COVID-19 patients admitted to hospital during the study period, 1333 had a severe infection. Of these, 158/1333 (11.8%) met the criteria for IFIs, with a median age of 65 years and 71% male predominance. Diabetes (53.8%) and hypertension (57.6%) were the most common comorbid conditions. Acute respiratory distress syndrome (ARDS) developed in 55% of patients. Overall mortality was 48%. For the case control analysis, 119 patients with IFIs were selected as cases and 240 patients without IFIs were selected as controls. On univariate analysis ARDS was significantly associated with IFIs (OR: 1.91; 95% CI: 1.23–2.99, p-value = 0.004). Patients with IFIs had higher odds of being on hemodialysis compared to those without IFIs (OR: 2.17; 95% CI: 1.18–3.99; p-value = 0.013). Mechanical ventilation was found to be independently associated with IFIs in multivariate logistic regression analysis (OR: 2.5, 95% CI: 1.58–3.96, p-value < 0.001). The odds for in-hospital death in patients with IFIs were 2.19 (95% CI: 1.35–3.56; p-value < 0.001) compared to patients without IFIs. The median hospital stay for patients with IFIs was markedly longer (14 days) compared to 8 days in patients without IFIs. Conclusions: IFIs significantly worsened outcomes in severe COVID-19 patients, leading to increased mortality and prolonged hospital stays. Mechanical ventilation was an independent risk factor for IFIs. Full article

Aspergillosis includes a variety of diseases caused by species of the genus Aspergillus, ranging from non-invasive allergic diseases to chronic, invasive pulmonary infections, which are potentially fatal in immunocompromised hosts. Therefore, there is an urgent need for new diagnostic tools and the optimization of existing tests to improve patient care. This work reviews the most commonly used molecular methods for the diagnosis of aspergillosis from clinical samples, emphasizing their advantages. These methods included HTS, NTS, ISH, microarrays, PCR-RFLP, LAMP, and PCR in various modalities (qPCR, multiplex PCR, nested PCR, RT-PCR, endpoint PCR, U-dHRM, and ddPCR). The review showed that the most commonly used methods for diagnosing aspergillosis are NGS and PCR in their different modalities; however, each method has advantages and disadvantages. qPCR is the method that has demonstrated the greatest sensitivity and specificity on clinical samples (such as blood, serum, bronchoalveolar lavage [BAL], tissue, or sputum), since it detects specific sequences, and the validation of this method shows greater progress in achieving this objective. Likewise, NGS showed that BAL is the most suitable sample, with a higher fungal load than sputum or blood. On the other hand, NGS is not a targeted technique, since it sequences all the genetic material present. Additionally, the sensitivity for detecting pathogens decreases when clinical samples are used due to the high background of nucleic acids present in the human host. Full article

Background/Objectives: Invasive pulmonary aspergillosis (IPA) represents a critical respiratory condition mainly caused by Aspergillus fumigatus and other ubiquitous species such as Aspergillus flavus, Aspergillus niger, and Aspergillus terreus. IPA clinical management has been complicated by diagnostic challenges and therapeutic difficulties due to antifungal intrinsic or secondary resistance episodes. Despite this assumption, few scientific data have been reported about possible antifungal drug combinations. Herein, we propose an experimental evaluation using isavuconazole/amphotericin B and isavuconazole/caspofungin in vitro synergy assays to investigate their combined activity on Aspergillus spp. IPA clinical isolates. Methods: We globally analyzed 55 Aspergillus spp. isolates, practicing the gradient test methods with single and combined antifungal drugs through the MIC Strip test (Liofilchem, Roseto degli Abruzzi, Italy). The collected MIC values were interpreted according to the EUCAST guidelines and classified as synergy, additivity, indifference, and antagonism cases through a FIC index calculation. A statistical analysis on species’ correlation with particular synergy testing results was finally provided. Results: Despite an interesting activity against A. fumigatus, isavuconazole/amphotericin B did not report statistical significance, obtaining a consistent antagonism percentage (43.6%). On the other hand, isavuconazole/caspofungin showed a promising in vitro synergic activity, except for A. flavus isolates. Conclusions: Synergy testing demonstrated a significant species-specific trend. Future studies should be focused on Aspergillus spp. isolates and antifungal in vitro synergy testing, aiming to discourage or recommend any specific antifungal combinations, depending on the isolated species. Full article

Aspergillus fumigatus is an opportunistic filamentous fungus that primarily affects the respiratory tract of the human body. Depending on its host’s immune response, the pathogen can cause invasive pulmonary aspergillosis (IPA). Biofilm formation by A. fumigatus increases virulence and resistance against antifungals and immune response and is one important factor in IPA development. Here, two human-like models, precision cut lung slices (PCLS) and a biofilm co-culture model, have been developed to test the anti-biofilm activity of voriconazole, amphotericin B, as well as luliconazole against A. fumigatus. In both assays, metabolically active A. fumigatus biofilms were examined at different biofilm developmental stages using an XTT assay. A decrease in the metabolic activity of the fungal biofilms was detected for each of the tested agents in both assays. Significant anti-biofilm effects exist against early-stage biofilm in the co-culture model. In the PCLS assay, amphotericin B showed the strongest inhibition after 24 h. In conclusion, the applied PCLS ex vivo model can be used to study the property and activity of certain antifungal compounds against Aspergillus biofilm. With its close resemblance to human conditions, the PCLS model has the potential for improving the current understanding of biofilm treatments in laboratory settings. Full article

The genus Aspergillus, widely distributed across natural and urban environments, may cause allergies and opportunistic infections such as chronic or invasive pulmonary aspergillosis. Its high pathogenic potential for immunocompromised patients, together with the alarming increase of azole resistance reported in clinical and environmental isolates, claims urgent actions to assess and control the Aspergillus community in hospital environments. To contribute to that, here, we combine a large environmental survey covering numerous air and surface samples from different zones of three hospitals in Spain, with an integrated approach including general and selective culture- and eDNA-based analyses. Despite the high prevalence of Aspergillus observed, present in almost all indoor zones (mostly in air but also on surfaces) of the three hospitals, its relative abundance in the whole fungal community was limited and dependent on the used methods, with median values ranging from 1.4% (eDNA data) and 6.8% (cultivation at 28 °C) to 28.3% (cultivation at 37 °C). Remarkably, the most protected zones (intensive care units) showed the highest proportion of Aspergillus eDNA sequences. A total of 32 species belonging to 10 Aspergillus sections were molecularly identified, including well-known causal agents of invasive pulmonary infections such as A. fumigatus, A. flavus, A. terreus, A. niger, A. oryzae, A. sydowii, and A. tubingensis. This highlights the importance of such environmental assessments for monitoring and controlling the fungal burden in hospitals. Full article