BACKGROUND:Candida infections are a leading cause of invasive fungal disease (IFD), especially among critically ill and immunocompromised patients. Despite available pathogen-directed antifungal therapies, outcomes remain unsatisfactory with high associated morbidity and mortality rates. Increasing recognition of immune dysregulation of the host, including immunoparalysis and impaired antifungal effector responses, has driven interest in immunotherapeutic strategies as adjuncts to conventional treatment. OBJECTIVES:To provide a comprehensive overview of emerging immunotherapeutic approaches for invasive Candida infections and evaluate their mechanistic rationale, current evidence, and potential for clinical translation. SOURCES:Relevant literature was identified through a focused search of PubMed/MEDLINE, Embase, and ClinicalTrials.gov, supplemented by the authors' personal collection of key studies and reference screening. CONTENT:Immunotherapeutic strategies targeting invasive Candida infections encompass both non-cellular and cellular approaches. Cytokine-based therapies, including interferon-gamma and granulocyte/macrophage colony-stimulating factors, aim to restore impaired innate immunity and have demonstrated preliminary clinical benefits in selected populations. Immune checkpoint inhibitors represent a novel strategy to reverse T-cell exhaustion, supported by preclinical data but with limited clinical evidence to date in IFD. Cellular therapies, such as granulocyte transfusions, adoptive T-cell transfer, and engineered CAR T and CAR NK cells, offer innovative means to augment antifungal immunity, though their use remains largely preclinical. Preventive and therapeutic strategies involving vaccines and monoclonal antibodies are advancing, with several candidates showing promising immunogenicity and antifungal activity in preclinical and early clinical studies. IMPLICATIONS:Immunotherapy has the potential to transform the management of invasive candidiasis by complementing antifungal therapy with host-directed interventions. Successful clinical translation will require real-time biomarker-driven patient stratification and rigorous safety evaluations to account for the heterogeneity of patients according to their immune status. Future research should prioritize adaptive, mechanism-based trial designs to enable precision immunotherapy and improve outcomes in high-risk populations.
OBJECTIVES:EBV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is typically monitored by plasma viral load, but this fails to capture cellular reservoirs. Lineage-specific testing, though usually performed in high-risk patients, may identify biologically distinct disease states. We aimed to evaluate the clinical and biological significance of lineage-specific EBV quantification especially ectopic EBV infection in T cells in allo-HSCT recipients with EBV reactivation. METHODS:We analyzed 144 allo-HSCT recipients with EBV reactivation who underwent lineage-specific EBV quantification, assessed whether T-cell tropic EBV burden identifies a phenotype with reduced responsiveness to rituximabtherapy, an increased risk of post-transplant lymphoproliferative disorder (PTLD), and specific features of underlying immune dysfunction. RESULTS:Among the tested high-risk patients with high EBV loads and clinical symptoms, 66.6% exhibited T-cell tropic EBV infection. Compared with non-T-cell tropic infection, T-cell tropism was associated with higher rituximab courses and lower complete response rates (67% vs. 81%, P=0.029), suggesting insufficient efficacy of CD20-directed therapy. Patients with T-cell tropic infection had a significantly higher 1-year cumulative incidence of PTLD compared to the non-T-cell tropic group(77% vs. 41.6%; P < 0.001). Single-cell RNA sequencing and mass cytometry analyses revealed an exhausted T-cell phenotype with diminished stemness in T-cell tropic EBV infected patients. CONCLUSIONS:These findings suggest that T-cell EBV quantification distinguishes a therapeutically challenging subtype of EBV reactivation characterized by immune dysfunction and reduced responsiveness to rituximab-based therapy. Incorporating assessment of cellular viral reservoirs into post-transplant EBV monitoring strategies may facilitate early risk stratification and support timely therapeutic escalation beyond rituximab alone.
BACKGROUND:Malaria is a life-threatening but preventable and treatable parasitic disease which remains a serious global health challenge. To meet the World Health Organization (WHO) Global Technical Strategy for Malaria 2016-2030, that aims to achieve 90% reduction of global malaria incidence by 2030, accelerated efforts are required. Interestingly, the advent of the first two licensed malaria vaccines RTS,S/AS01 (RTS,S) and R21/Matrix-M (R21) has marked a new era in global fight against malaria. OBJECTIVE:to provide an update on malaria vaccines deployment and challenges in the field. SOURCES:this narrative review is based on a relevant literature search spanning the last five years as well as reports and policy documents from global health organizations including WHO and GAVI (The vaccine alliance). CONTENT:the following topics are covered: (i) what is known about the first two WHO-recommended malaria vaccines (RTS,S and R21); (ii) Current delivery strategies used for malaria vaccine deployment in the field; (iii) Challenges in current malaria vaccines deployment; (iv) Current malaria vaccine implementation studies; and (v) Upcoming perspectives in the field of malaria vaccine development. IMPLICATIONS:The roll-out of the first two malaria vaccines at large scale is progressing rapidly in sub-Saharan Africa, with 25 countries having introduced the vaccines in their routine immunization programs as of February 2026. However, current implementation challenges including funding constraints, manufacturing capacity, delivery strategies and vaccine hesitancy should be quickly addressed to gain significant impact in targeted populations. Next-generation vaccines might improve the protective efficacy and durability against clinical malaria and reduce the transmission activity of the vectors to support global elimination efforts.
BACKGROUND:Bloodstream infections (BSIs) are a leading cause of morbidity and mortality, yet their clinical heterogeneity continues to challenge effective patient stratification and treatment optimisation. In other heterogeneous conditions such as sepsis, data-driven clinical subphenotyping has identified reproducible subgroups with distinct outcomes and treatment responses. Whether similar approaches can be applied to BSIs to improve clinical management and trial design is an area of growing interest. OBJECTIVES:We aimed to review the current evidence on the use of data-driven phenotyping and unsupervised machine learning techniques to identify clinical subphenotypes in BSIs. Methodological approaches used to derive subphenotypes, and their implications for clinical practice and trial design are elucidated. SOURCES:A literature search was performed using PubMed/MEDLINE and the Semantic Scholar AI-assisted search tool. Reference lists of included studies were hand-searched to identify additional publications. CONTENT:Data-driven subphenotyping has been most extensively studied in Staphylococcus aureus bacteraemia (SAB), where latent class analysis and cluster analysis point towards distinct subphenotypes with significantly different mortality rates across independent international cohorts. Emerging evidence extends to mixed-pathogen BSI cohorts in the intensive care unit and in immunocompromised populations including solid organ transplant recipients. Bedside tools including online calculators, and simplified scoring systems have been developed to facilitate rapid phenotype assignment. However different studies use varying methodological approaches and there is limited data on validation of these. IMPLICATIONS:Clinical subphenotyping offers a promising framework for personalising antimicrobial therapy, improving risk stratification, and enriching clinical trial populations. Future key priorities include extending phenotyping to underrepresented BSI aetiologies, integrating clinical phenotypes with biological endotypes, and conducting phenotype-stratified interventional trials.
OBJECTIVES:Skin involvement in Pseudomonas aeruginosa bloodstream infection (PA-BSI) is a clinically important but understudied manifestation in neutropenic patients that may indicate a more severe course or distinct risk profile. We aimed to identify factors associated with skin involvement among neutropenic patients with PA-BSI in a retrospective cohort. METHODS:Factors for skin involvement in PA-BSI were by using a single-centre, retrospective cohort study including 142 patients with PA-BSI (April 2003 and April 2023) from the Cologne Cohort of Neutropenic Patients study (CoCoNut) database, which comprises 2794 bloodstream infection episodes. RESULTS:Skin involvement occurred in 30/142 patients (21.1%). Patients with skin involvement were more likely to have acute myeloid leukemia (AML) (20/30 vs. 43/112; p = 0.006), recurrent PA-BSI (7/30 vs. 7/112; p = 0.005), longer neutropenia duration (median 27 days vs. 16 days; p = 0.022), and hospital stay (median 47.5 days vs. 36.5 days; p = 0.017). In multivariate analysis, AML (OR 3.430, 95% CI: 1.181 - 9.961; adjusted p = 0.023) and recurrent PA-BSI (OR 6.168, 95% CI: 1.709 - 22.261; adjusted p = 0.005) remained independently associated with skin involvement, while pre-existing cardiovascular disease was inversely associated (OR 0,359, 95% CI: 0.147 - 0.908; adjusted p = 0.031). CONCLUSIONS:In this cohort skin involvement was present in one-fifth of neutropenic patients with PA-BSI and was independently associated with underlying AML and PA-BSI recurrence. Prolonged neutropenia and hospitalization appear to be associated with a more complicated clinical course. Increased awareness of these factors may facilitate earlier recognition of skin lesions and prompt targeted management of PA-BSI in high-risk populations.
OBJECTIVES:Evaluate whether general-purpose large language models (LLMs) demonstrate competencies suitable for antimicrobial stewardship (AMS) support and characterize their failure modes. METHODS:Cross-sectional evaluation of seven LLMs (GPT-5, Claude Sonnet 4.5, Gemini 2.5 Pro, Grok 4, Llama-3.3-70b-instruct, Qwen 2.5-72b-instruct, DeepSeek-chat-v3.1) using 30 clinical scenarios mapped to ESCMID AMS competency frameworks. Scenarios included deliberate traps for fabrication and dangerous recommendations. Six AMS experts from the Netherlands and Spain performed blinded dual evaluation using content scores (0-5 scale) and binary safety flags for fabrication and danger. Standard and incentivizing prompt framings were compared. RESULTS:Four commercial models achieved mean content scores above 3.9/5.0: Claude Sonnet 4.5 (4.06), Gemini 2.5 Pro (3.96), Grok 4 (3.96), and GPT-5 (3.94). Open-weight models scored significantly lower (2.94-3.57). No model achieved more than 63% responses free of fabrication or danger flags. However, fabrication did not impair clinical utility in non-trap scenarios (all within-category comparisons p>0.20). Danger flags ranged from 6.7% to 16.7% across models, with no significant difference between commercial and open-weight models. Incentivizing prompts were associated with a consistent 0.48-point-content score improvement (p=0.006), though significance attenuated after accounting for scenario-level clustering. Evaluators endorsed LLMs as useful AMS support tools with moderate supervision (5/6), identifying documentation preparation and trainee education as promising applications. CONCLUSIONS:Medically untrained LLMs demonstrate competencies suitable for supervised AMS support. Fabrication remains the central safety challenge and requires verification workflows; danger, though less frequent (6.7-16.7%), concentrated in identifiable and therefore mitigable failure modes. Non-clinical stewardship tasks (education, documentation, communication) can benefit now, whereas clinical recommendations require expert oversight. Mapping these boundaries allows AMS teams, particularly those understaffed or without on-site infectious diseases expertise, to decide where LLM support adds value rather than risk.
OBJECTIVES:To evaluate the accuracy of MIC Test Strip (MTS, Liofilchem, Italy) and disk diffusion (DD, Liofilchem, Italy) against broth microdilution (BMD) for aztreonam/avibactam (ATM/AVI) susceptibility testing in carbapenem-resistant Enterobacterales (CRE), providing evidence for laboratory method selection and clinical therapy. METHODS:We tested 358 CRE clinical isolates (174 K. pneumoniae, 144 E. coli, 40 other Enterobacterales) by BMD (reference), MTS, and DD, interpreted per Clinical and Laboratory Standards Institute (CLSI) M100 36th Edition and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint tables v16.0. Categorical agreement (CA), essential agreement (EA), and error rates were calculated, stratified by carbapenemase genotype (KPC, NDM, KPC+NDM). RESULTS:BMD showed MIC50 of 0.5 mg/L and MIC90 of 2 mg/L (susceptibility rate 98.6%). MTS demonstrated excellent concordance: CA 99.7%, EA 90.2%, and minor error (mE) 0.3%, with 100% CA for KPC-, NDM-, and dual enzyme-producers. DD showed lower CA (90.5% and 91.1% using CLSI and EUCAST breakpoints, respectively) and higher mE (9.5%). Importantly, 9.8% (35/358) of isolates fell within the 22-24 mm intermediate/ATU zone (including 16 blaNDM-5 and 12 blaKPC-2). According to DD, NDM-producers exhibited significantly higher minor error rates than KPC-producers (10.7% vs 5.0%). CONCLUSIONS:MTS is a highly reliable alternative to BMD for ATM/AVI testing across diverse carbapenemase genotypes. While DD is acceptable, the high proportion of isolates in the 22-24 mm zone necessitates mandatory confirmatory testing to ensure precision therapy.
BACKGROUND:Malaria remains a leading cause of morbidity and mortality globally, particularly in sub-Saharan Africa. Despite repeated exposure and vaccine deployment, sterile immunity against malaria rarely develops. Advances in malaria immunology over the past decades have revealed complex host-parasite interactions that shape clinical outcomes and inform new therapeutic strategies. OBJECTIVES:This narrative review aims to highlight the emerging role of monoclonal antibody interventions for malaria prevention. SOURCES:Relevant articles were identified through search of PubMed up to June 2026.. Search terms included "malaria immunology," "Plasmodium falciparum," "monoclonal antibodies," and "immune correlates". Additional references were identified from the bibliographies of relevant publications. Articles were selected based on relevance to clinical translation. CONTENT:This review synthesizes evidence from primary immunology studies, translational research, clinical trials and review articles to provide an updated overview of Plasmodium falciparum immunity and monoclonal antibody-based interventions. It highlights key immunological mechanisms and biomarkers associated with protective immunity, including functional antibody responses, cell-mediated immunity, cytokine regulation, and immune memory. It further summarizes the clinical development of leading monoclonal antibodies, including CIS43LS, L9LS, MAM01, and TB31F, which have demonstrated favorable safety profiles, prolonged serum half-lives, and high levels of protection against P. falciparum infection in controlled human malaria infection and field trials. The findings support monoclonal antibodies as promising tools for malaria prevention. IMPLICATIONS:Current evidence indicates that long-acting monoclonal antibodies have the potential to complement existing malaria control strategies by providing rapid, highly effective, and durable protection, particularly for populations at greatest risk of infection, including young children, pregnant women and individuals in seasonal transmission settings. Continued optimization of antibody potency, durability, delivery platforms, together with the identification of robust immune correlates of protection, will be critical for integrating monoclonal antibodies into future malaria control programs.
