Search Results (13)

We present a challenging case of a patient admitted to an intensive care unit with influenza-associated pulmonary aspergillosis (IAPA). The clinical course was characterised by refractory fungal pneumonia and tracheobronchitis, suspected drug-induced liver injury due to triazole antifungals, and secondary bacterial infections with multidrug-resistant microorganisms, resulting in a fatal outcome despite the optimisation of antifungal treatment through therapeutic drug monitoring. This case underscores the complexity that clinicians face in managing critically ill patients with invasive fungal infections. Full article

Several single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) have been observed in association with susceptibility to various pathologies, including autism, major depression, age-related changes in cognitive functioning, and Parkinson’s and Alzheimer’s diseases. This study aimed to establish the association between Fok1/Apa1 polymorphic variants and anxious/depressive symptoms in nonclinical adolescents from central Italy, with the goal of identifying the risk of developing both symptoms. We found no significant difference in genotype distribution or dominant/recessive models of Fok1/Apa1 VDR polymorphic variants between subjects with anxious/depressive symptoms and controls. HN9.10e cell lines carrying the AA genotype for Fok1 and the CC genotype for Apa1 responded better to treatment with vitamin D3 than cell lines carrying the AG genotype for Fok1 and CA genotype for Apa1. Cell lines carrying the GG genotype for Fok1 and the AA genotype for Apa1 did not respond at all, suggesting avenues for future studies in both the general population and individuals with mental and/or neuropsychiatric disorders. These studies suggest that the level of response to vitamin D3 administered to prevent and/or treat mental or neurological disorders could depend on the polymorphic variants of the vitamin D receptor. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8⁺ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8⁺ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8⁺ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA. Full article

Salmonella enterica serovar Derby (S. Derby) ranks fifth among nontyphoidal Salmonella serovars causing human infections in the European Union. S. Derby isolates (36) collected between 2006 and 2018 in a Spanish region (Asturias) from human clinical samples (20) as well as from pig carcasses, pork- or pork and beef-derived products, or wild boar (16) were phenotypically characterized with regard to resistance, and 22 (12 derived from humans and 10 from food-related samples) were also subjected to whole genome sequence analysis. The sequenced isolates belonged to ST40, a common S. Derby sequence type, and were positive for SPI-23, a Salmonella pathogenicity island involved in adherence and invasion of the porcine jejune enterocytes. Isolates were either susceptible (30.6%), or resistant to one or more of the 19 antibiotics tested for (69.4%). Resistances to tetracycline [tet(A), tet(B) and tet(C)], streptomycin (aadA2), sulfonamides (sul1), nalidixic acid [gyrA (Asp87 to Asn)] and ampicillin (bla_TEM-1-like) were detected, with frequencies ranging from 8.3% to 66.7%, and were higher in clinical than in food-borne isolates. The fosA7.3 gene was present in all sequenced isolates. The most common phenotype was that conferred by the tet(A), aadA2 and sul1 genes, located within identical or closely related variants of Salmonella Genomic Island 1 (SGI1), where mercury resistance genes were also present. Diverse IncI1-I(α) plasmids belonging to distinct STs provided antibiotic [bla_TEM-1, tet(A) and/or tet(B)] and heavy metal resistance genes (copper and silver), while small pSC101-like plasmids carried tet(C). Regardless of their location, most resistance genes were associated with genetic elements involved in DNA mobility, including a class one integron, multiple insertion sequences and several intact or truncated transposons. By phylogenetic analysis, the isolates were distributed into two distinct clades, both including food-borne and clinical isolates. One of these clades included all SGI1-like positive isolates, which were found in both kinds of samples throughout the entire period of study. Although the frequency of S. Derby in Asturias was very low (0.5% and 3.1% of the total clinical and food isolates of S. enterica recovered along the period of study), it still represents a burden to human health linked to transmission across the food chain. The information generated in the present study can support further epidemiological surveillance aimed to control this zoonotic pathogen. Full article

The aim of this study was to establish practical recommendations for the diagnosis and treatment of influenza-associated invasive aspergillosis (IAPA) based on the available evidence and experience acquired in the management of patients with COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA/IAPA expert group defined 14 areas in which recommendations would be made. To search for evidence, the PICO strategy was used for both CAPA and IAPA in PubMed, using MeSH terms in combination with free text. Based on the results, each expert developed recommendations for two to three areas that they presented to the rest of the group in various meetings in order to reach consensus. As results, the practical recommendations for the management of CAPA/IAPA patients have been grouped into 12 sections. These recommendations are presented for both entities in the following situations: when to suspect fungal infection; what diagnostic methods are useful to diagnose these two entities; what treatment is recommended; what to do in case of resistance; drug interactions or determination of antifungal levels; how to monitor treatment effectiveness; what action to take in the event of treatment failure; the implications of concomitant corticosteroid administration; indications for the combined use of antifungals; when to withdraw treatment; what to do in case of positive cultures for Aspergillus spp. in a patient with severe viral pneumonia or Aspergillus colonization; and how to position antifungal prophylaxis in these patients. Available evidence to support the practical management of CAPA/IAPA patients is very scarce. Accumulated experience acquired in the management of CAPA patients can be very useful for the management of IAPA patients. The expert group presents eminently practical recommendations for the management of CAPA/IAPA patients. Full article

Fungal infections have become a common threat in Intensive Care Units (ICU). The epidemiology of invasive fungal diseases (IFD) has been extensively studied in patients severely immunosuppressed over the last 20–30 years, however, the type of patients that have been admitted to hospitals in the last decade has made the healthcare system and ICU a different setting with more vulnerable hosts. Patients admitted to an ICU tend to have older age and higher severity of disease. Moreover, the number of patients being treated in ICU are often immunosuppressed as a result of the widespread use of immunomodulatory agents, such as corticosteroids, chemotherapy, and biological agents. The development of Invasive Pulmonary aspergillosis (IPA) reflects a different clinical trajectory to affected patients. The increasing use of corticosteroids would probably explain the higher incidence of IPA especially in critically ill patients. In refractory septic shock, severe community-acquired pneumonia (SCAP), and acute respiratory distress syndrome (ARDS), the use of corticosteroids has re-emerged in order to decrease unacceptably high mortality rates associated with these clinical conditions. It is also pertinent to note that different reports have used different diagnosis criteria, and this might explain the different incidence rates. Another layer of complexity to better understand current IPA data is related to more aggressive acquisition of samples through invasive respiratory examinations. Full article

Background: Different compositions of DSF/NaOH/IA-PAE/R. spp. composite particleboard phantoms were constructed. Methods: Photon attenuation characteristics were ascertained using gamma rays from ¹³⁷Cs and ⁶⁰Co. Absorbed doses at the location of an ionization chamber and Gafchromic EBT3 radiochromic films were calculated for high-energy photons (6 and 10 MV) and electrons (6, 9, 12, and 15 MeV). Results: The calculated TPR_20,10 values indicate that the percentage discrepancy for 6 and 10 MV was in the range of 0.29–0.72% and 0.26–0.65%. It was also found that the relative difference in the $d_{max}$ to water and solid water phantoms was between 1.08–1.28% and 5.42–6.70%. The discrepancies in the determination of PDD curves with 6, 9, 12, and 15 MeV, and those of water and solid water phantoms, ranged from 2.40–4.84%. Comparable results were found using the EBT3 films with variations of 2.0–7.0% for 6 and 10 MV photons. Likewise, the discrepancies for 6, 9, 12, and 15 MeV electrons were within an acceptable range of 2.0–4.5%. Conclusions: On the basis of these findings, the DSF/NaOH/IA-PAE/R. spp. particleboard phantoms with 15 wt% IA-PAE addition level can be effectively used as alternative tissue-equivalent phantom material for radiation therapy applications. Full article

Rates of invasive aspergillosis (IA) among COVID-19 ICU patients seem to reach over 30% in certain settings. At Vienna General Hospital (VGH), all rooms in COVID-19 ICUs were put under negative pressure as a protective measure, thus increasing the risk of exposure to environmental pathogens for patients. Even though all ICU patients are surveilled for healthcare-associated infections (HAI), there were concerns that the routine protocol might not be sufficient for IA detection. We reviewed the electronic patient charts of all patients with COVID-19 admitted to ICUs between 1 March 2020 and 31 July 2021 for fungal co- or superinfections, comparing four diagnostic algorithms based on different recommendations for the diagnosis of IA (according to EORTC/MSG, BM-AspICU, IAPA and CAPA) to our routine surveillance protocol. We found that out of 252 patients who were admitted to the ICU during the study period, 25 (9.9%) fulfilled the criteria of probable or possible IA of at least one algorithm. The IAPA definitions detected 25 and the CAPA definition 23 probable and 2 possible cases, out of which only 16 were classified as hospital-acquired IA by routine surveillance. In conclusion, adjustment of the routine protocol using a classification system especially designed for respiratory viral illness seems useful for the surveillance of IA in a highly vulnerable patient cohort. Full article

In recent years, research in the areas of Aspergillus and aspergillosis has continued to advance rapidly, including advancements in genomics, immunological studies, clinical areas, and diagnostic areas. Recently, new risk groups for the development of aspergillosis have emerged—patients with influenza- or COVID-19-ssociated pulmonary aspergillosis. The rise and spread of antifungal resistances have also become a clinical concern in some geographic areas and have drawn the attention of clinicians due to difficulties in treating these infections. In this paper, a snapshot of these issues is presented, emphasizing these novel clinical and laboratorial challenges in the aspergillosis field and focusing on their actual relevance. Full article

This study delineated the characteristics of 24 (11.2%) culture-positive, influenza-associated pulmonary aspergillosis (IAPA) patients out of 215 patients with severe influenza during 2016–2019 in a medical center in southern Taiwan. Twenty (83.3%) patients did not have EORTC/MSG-defined host factors. The mean time from influenza diagnosis to Aspergillus growth was 4.4 days, and 20 (83.3%) developed IAPA within seven days after influenza diagnosis. All patients were treated in intensive care units and all but one (95.8%) received mechanical ventilation. Aspergillus tracheobronchitis was evident in 6 (31.6%) of 19 patients undergoing bronchoscopy. Positive galactomannan testing of either serum or bronchoalveolar lavage was noted in all patients. On computed tomography imaging, IAPA was characterized by peribronchial infiltrates, multiple nodules, and cavities superimposed on ground-glass opacities. Pure Aspergillus growth without bacterial co-isolation in culture was found in 17 (70.8%) patients. A. fumigatus (15, 62.5%), A. flavus (6, 25.0%), and A. terreus (4, 16.7%) were the major causative species. Three patients had mixed Aspergillus infections due to two species, and two had mixed azole-susceptible and azole-resistant A. fumigatus infection. All patients received voriconazole with an all-cause mortality of 41.6%. Of 14 survivors, the mean duration of antifungal use was 40.5 days. In conclusion, IAPA is an early and rapidly deteriorating complication following influenza that necessitates clinical vigilance and prompt diagnostic workup. Full article

Influenza-associated pulmonary aspergillosis (IAPA) is a global recognized superinfection in critically ill influenza patients. Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is a newly approved anti-influenza therapeutic. Although the benefits as a treatment for influenza are clear, its efficacy against an influenza-A. fumigatus co-infection has yet to be determined. We investigated the therapeutic effect of baloxavir marboxil in a murine model for IAPA. Immunocompetent mice received intranasal instillation of influenza A followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Administration of baloxavir marboxil or sham was started at day 0, day 2 or day 4. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). In vivo imaging was supplemented with virological, mycological and biochemical endpoint investigations. We observed an improved body weight, survival and viral clearance in baloxavir marboxil treated mice. µCT showed less pulmonary lesions and bronchial dilation after influenza and after Aspergillus co-infection in a treatment-dependent pattern. Furthermore, baloxavir marboxil was associated with effective inhibition of fungal invasion. Hence, our results provide evidence that baloxavir marboxil mitigates severe influenza thereby decreasing the susceptibility to a lethal invasive Aspergillus superinfection. Full article

Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a severe fungal infection complicating critically ill COVID-19 patients. Numerous retrospective and prospective studies have been performed to get a better grasp on this lethal co-infection. We performed a qualitative review and summarized data from 48 studies in which 7047 patients had been included, of whom 820 had CAPA. The pooled incidence of proven, probable or putative CAPA was 15.1% among 2953 ICU-admitted COVID-19 patients included in 18 prospective studies. Incidences showed great variability due to multiple factors such as discrepancies in the rate and depth of the fungal work-up. The pathophysiology and risk factors for CAPA are ill-defined, but therapy with corticosteroids and anti-interleukin-6 therapy potentially confer the biggest risk. Sampling for mycological work-up using bronchoscopy is the cornerstone for diagnosis, as imaging is often aspecific. CAPA is associated with an increased mortality, but we do not have conclusive data whether therapy contributes to an increased survival in these patients. We conclude our review with a comparison between influenza-associated pulmonary aspergillosis (IAPA) and CAPA. Full article

Invasive pulmonary aspergillosis (IPA) in intensive care unit patients is a major concern. Influenza-associated acute respiratory distress syndrome (ARDS) and severe COVID-19 patients are both at risk of developing invasive fungal diseases. We used the new international definitions of influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) to compare the demographic, clinical, biological, and radiological aspects of IAPA and CAPA in a monocentric retrospective study. A total of 120 patients were included, 71 with influenza and 49 with COVID-19-associated ARDS. Among them, 27 fulfilled the newly published criteria of IPA: 17/71 IAPA (23.9%) and 10/49 CAPA (20.4%). Kaplan–Meier curves showed significantly higher 90-day mortality for IPA patients overall (p = 0.032), whereas mortality did not differ between CAPA and IAPA patients. Radiological findings showed differences between IAPA and CAPA, with a higher proportion of features suggestive of IPA during IAPA. Lastly, a wide proportion of IPA patients had low plasma voriconazole concentrations with a higher delay to reach concentrations > 2 mg/L in CAPA vs. IAPA patients (p = 0.045). Severe COVID-19 and influenza patients appeared very similar in terms of prevalence of IPA and outcome. The dramatic consequences on the patients’ prognosis emphasize the need for a better awareness in these particular populations. Full article