European Study of Cerebral Aspergillosis treated with Isavuconazole: an EFISG study.

INTRODUCTION: Cerebral aspergillosis (CA) is associated with high mortality. According to ECIL-6 and ESCMID guidelines, the recommended first-line treatment for all forms of aspergillosis is voriconazole or isavuconazole. However, little is known about the efficacy and safety of isavuconazole in CA. METHODS: We conducted a European multi-centre retrospective study of patients treated with isavuconazole for proven or probable CA between 2014 and 2022 and compared the outcomes to those of weighted control groups from the previously published French national cohort of CA, the Cerebral Aspergillosis Lesional Study. RESULTS: Forty patients from 10 countries were included. The main underlying conditions were hematological malignancies (53%) and solid organ transplantation (20%). Isavuconazole was administered as a first-line treatment to 10 patients, primarily in combination therapy, resulting in control of CA in 70% of these cases. Thirty patients received isavuconazole after a median of 65 days on another therapy, mostly because of side effects (50%) or therapeutic failure (23%) of the previous treatment. Predominantly given as monotherapy, it achieved control of CA in 73% of the patients. Seventeen patients (43%) undergone neurosurgery. When measured, isavuconazole levels were low in cerebrospinal fluid but adequate in serum and brain tissue. Isavuconazole toxicity led to treatment interruption in 7.5% of the patients. Twelve-week mortality was 18%. Comparison with the CEREALS cohort showed a comparable survival in patients receiving isavuconazole or voriconazole as a first line treatment. CONCLUSION: Isavuconazole appears to be a well-tolerated treatment. Mortality of CA treated with isavuconazole is similar to that reported with voriconazole.

Polymerase Chain Reaction on Respiratory Tract Specimens of Immunocompromised Patients to Diagnose Pneumocystis Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations. METHODS: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies. Using a bivariate and random-effects meta-regression analysis, the diagnostic performance of PCR against the European Organisation for Research and Treatment of Cancer-Mycoses Study Group definition of proven PCP was examined. RESULTS: Quantitative PCR (qPCR) on bronchoalveolar lavage fluid provided the highest pooled sensitivity of 98.7% (95% confidence interval [CI], 96.8%-99.5%), adequate specificity of 89.3% (95% CI, 84.4%-92.7%), negative likelihood ratio (LR-) of 0.014, and positive likelihood ratio (LR+) of 9.19. qPCR on induced sputum provided similarly high sensitivity of 99.0% (95% CI, 94.4%-99.3%) but a reduced specificity of 81.5% (95% CI, 72.1%-88.3%), LR- of 0.024, and LR+ of 5.30. qPCR on upper respiratory tract samples provided lower sensitivity of 89.2% (95% CI, 71.0%-96.5%), high specificity of 90.5% (95% CI, 80.9%-95.5%), LR- of 0.120, and LR+ of 9.34. There was no significant difference in sensitivity and specificity of PCR according to HIV status of patients. CONCLUSIONS: On deeper respiratory tract specimens, PCR negativity can be used to confidently exclude PCP, but PCR positivity will likely require clinical interpretation to distinguish between colonization and active infection, partially dependent on the strength of the PCR signal (indicative of fungal burden), the specimen type, and patient population tested.

Histoplasma capsulatum as a cause for prolonged pulmonary illness in an immunocompetent returning traveller from Bangladesh.

Fungal infections can be challenging to diagnose in returning travellers due to their non-specific clinical manifestations and changing epidemiology. We present a case of progressive disseminated histoplasmosis in a returning traveller from Bangladesh. The patient had a progressive and prolonged respiratory illness necessitating mechanical ventilatory support. The clue to potential fungal aetiology was provided by serum fungal markers - 1-3-ß-D-glucan and Aspergillus galactomannan. Diagnosis was eventually made using panfungal PCR on bronchioalveolar lavage fluid.

Expression of Toll-like receptors in oral squamous cell carcinoma.

Almost 380,000 new cases of oral cancer were reported worldwide in 2020. Oral squamous cell carcinoma (OSCC) accounts for 90% of all types of oral cancers. Emerging studies have shown association of Toll-like receptors (TLRs) in carcinogenesis. The present study aimed to investigate the expression levels and tissue localization of TRL1 to TRL10 and NF-κB between OSCC and healthy oral mucosa, as well as effect of Candida colonization in TRL expression in OSCC. Full thickness biopsies and microbial samples from 30 newly diagnosed primary OSCC patients and 26 health controls were collected. The expression of TLR1 to TLR10 and NF-κB was analyzed by immunohistochemistry. Microbial samples were collected from oral mucosa to detect Candida. OSCC epithelium showed lower staining intensity of TRL1, TRL2 TRL5, and TRL8 as compared to healthy controls. Similarly, staining intensity of TRL3, TRL4, TRL7, and TRL8 were significantly decreased in basement membrane (BM) zone. Likewise, OSCC endothelium showed lower staining intensity of TLR4, TLR7 and TLR8. Expression of NF-κB was significantly stronger in normal healthy tissue compared to OSCC sample. Positive correlation was found between the expression of NF-κB, TRL9 and TRL10 in basal layer of the infiltrative zone OSCC samples (P = 0.04 and P = 0.002, respectively). Significant increase in TRL4 was seen in BM zone of sample colonized with Candida (P = 0.01). According to the limited number of samples, our data indicates downregulation of TLRs and NF-κB in OSCC, and upregulation of TLR4 expression with presence of Candida.

The Impact of the Fungal Priority Pathogens List on Medical Mycology: A Northern European Perspective.

Fungal diseases represent a considerable global health concern, affecting >1 billion people annually. In response to this growing challenge, the World Health Organization introduced the pivotal fungal priority pathogens list (FPPL) in late 2022. The FPPL highlights the challenges in estimating the global burden of fungal diseases and antifungal resistance (AFR), as well as limited surveillance capabilities and lack of routine AFR testing. Furthermore, training programs should incorporate sufficient information on fungal diseases, necessitating global advocacy to educate health care professionals and scientists. Established international guidelines and the FPPL are vital in strengthening local guidance on tackling fungal diseases. Future iterations of the FPPL have the potential to refine the list further, addressing its limitations and advancing our collective ability to combat fungal diseases effectively. Napp Pharmaceuticals Limited (Mundipharma UK) organized a workshop with key experts from Northern Europe to discuss the impact of the FPPL on regional clinical practice.

Attributable mortality of candidemia - Results from the ECMM Candida III multinational European Observational Cohort Study.

INTRODUCTION: Despite antifungal advancements, candidaemia still has a high mortality rate of up to 40%. The ECMM Candida III study in Europe investigated the changing epidemiology and outcomes of candidaemia for better understanding and management of these infections. METHODS: In this observational cohort study, participating hospitals enrolled the first ten consecutive adults with blood culture-proven candidemia. Collected data included patient demographics, risk factors, hospital stay duration (follow-up of 90 days), diagnostic procedures, causative Candida spp., management details, and outcome. Controls were included in a 1:1 fashion from the same hospitals. The matching process ensured similarity in age (10-year range), primary underlying disease, hospitalization in intensive care versus non-ICU ward, and major surgery within 2 weeks before candidemia between cases and controls. Overall and attributable mortality were described, and a survival probability for cases and controls was performed. RESULTS: One hundred seventy-one pairs consisting of patients with candidemia and matched controls from 28 institutions were included. In those with candidemia, overall mortality was 40.4%. Attributable mortality was 18.1% overall but differed between causative Candida species (7.7% for Candida albicans, 23.7% for Candida glabrata/Nakaseomyces glabratus, 7.7% for Candida parapsilosis and 63.6% for Candida tropicalis). Regarding risk factors, the presence of a central venous catheter, total parenteral nutrition and acute or chronic renal disease were significantly more common in cases versus controls. Duration of hospitalization, and especially that of ICU stay, was significantly longer in candidemia cases (20 (IQR 10-33) vs 15 days (IQR 7-28); p = 0.004). CONCLUSIONS: Although overall and attributable mortality in this subgroup analysis of matched case/control pairs remains high, the attributable mortality appears to have decreased in comparison to historical cohorts. This decrease may be driven by improved prognosis of Candida albicans and Candida parapsilosis candidemia; whereas candidemia due to other Candida spp. exhibits a much higher attributable mortality.