Tuberculosis (TB) is a critical global health concern, with about one-quarter of the world's population having an immune response against Mycobacterium tuberculosis (MTB). These individuals are at risk of developing TB disease when their immune function is reduced. Given the increasing use of immunosuppressive agents, including biological and non-biological immunomodulators, the risk of latent TB reactivation has significantly increased, highlighting the importance of screening and preventive treatment. The aim of this review is to summarize the current evidence on TBI reactivation mechanisms and risks associated with immunosuppressive agents, and to collate prescribing information from the Food and Drug Administration and the European Medicines Agency on TB screening. It covers nine major classes of immunosuppressants, including B- and T-cell depleting agents, interleukin antagonists, other cytokine antagonists, integrin antagonists, immune checkpoint inhibitors, kinase inhibitors, proteasome inhibitors, calcineurin inhibitors, glucocorticoids, and BCL-2 inhibitors.
OBJECTIVES:Investigate long-term consequences of bacterial meningitis. METHODS:A matched cohort study linking a clinical database on paediatric and adult patients with bacterial meningitis in Denmark from 1966 to 1977 with national registries until 2025. Patients were matched 1:5 with population controls and included along with sibling controls. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated for mortality from 1 year after admission and for neurological and otological disorders from 20 years after admission. RESULTS:We included 724 patients with a median age of 17 years. Initial disease and treatment characteristics were not associated with long-term mortality. Patients had higher mortality than 3620 population controls (HR 1.33 [95% CI 1.16-1.53]) and 695 siblings of patients had higher mortality than 3313 siblings of population controls (HR 1.42 [95% CI 1.06-1.91]). Patients had an increased risk of cerebrovascular diseases (HR 1.46 [95% CI 1.04-2.04]), migraine and other headache syndromes (HR 1.76 [95% CI 1.11-2.80]), and hearing loss (HR 1.56 [95% CI 1.13-2.17]), whereas the risk of dementia and residence in 24-hour care facilities was comparable to population controls. CONCLUSIONS:Patients with bacterial meningitis had modest long-term excess mortality, potentially attributable to familial factors. We found no association with neurodegenerative diseases occurring late after bacterial meningitis.
Background In 2009, England experienced an increase in serogroup W (MenW) invasive meningococcal disease (IMD) caused by the hypervirulent ST-11 clonal complex (MenW:cc11) South American strain sublineage. The ‘original UK strain’ that emerged in 2009 evolved into the ‘2013 strain’ in 2013 resulting in further increases in case numbers. Here, we compare demographics, co-morbidities, clinical characteristics and outcomes of patients with MenW IMD caused by the original UK, 2013, and other MenW strains during 2010-2019 in England. Methods The UK Health Security Agency (UKHSA) conducts enhanced national IMD surveillance in England and provides a national reference laboratory service for diagnosis confirmation and meningococcal characterisation. All confirmed cases are followed-up with general practitioners for additional information, including comorbidities, clinical presentation and outcomes. Results Between 2009/10 and 2018/2019 epidemiological years, there were 1,126 MenW IMD cases in England, of which 947 (84.1%) were confirmed by culture and 174 (15.9%) by PCR only. Cultured isolates were characterised as the original UK strain (n=361, 38.1%), 2013 strain (n=481, 50.8%), and other MenW strains (n=105, 11.1%). There were no significant differences in age, sex, risk factors, comorbidities, clinical presentation or intensive care requirement between MenW strain groups. For the cases between 2011-2017, clinical data analysis was performed. MenW IMD case fatality rate (CFR) was 12.7% (110/877) overall, but significantly higher for the 2013 strain (15.0%, 51/340) than for the original UK strain (9.8%, 30/305) for the 2013 strain and for other MenW strains (7.2%, 6/83) (p=0.05). In a multivariable logistic regression model, the 2013 strain, age ≥25 years compared to <5 year-olds and clinical presentation with septicaemia compared to other clinical presentations were independently associated with death. Implementation of an emergency adolescent MenACWY immunisation programme in 2015 was associated with large declines in MenW IMD cases and deaths across all age-groups. Conclusion The emergence of the original UK and 2013 MenW strains led to large increases in MenW IMD cases across all age groups and the latter was associated with higher case fatality. This has important implications for countries where the 2013 strain continues to circulate.
Objectives Acute respiratory viral infections, including influenza, RSV, and SARS-CoV-2, are well-recognized as being associated with cardiovascular events (CVEs). In contrast, the cardiovascular impact of human metapneumovirus (HMPV) remains poorly characterized. We aimed to describe the prevalence of pre-existing cardiovascular diseases (CVDs) and the incidence of acute CVEs in adults with laboratory-confirmed HMPV infection. Methods PRISMA-guided systematic literature review of MEDLINE, Embase, and Google Scholar (Jan.-2000/Sept.-2025). Observational studies and clinical trials reporting pre-existing CVDs and/or CVEs in adults (≥18 years) were included. Results Eighteen studies met the inclusion criteria, of which nine underwent critical appraisal. Most involved hospitalized older adults. Pre-existing CVD was reported in 10%-80% of HMPV-infected patients, with chronic heart failure and coronary artery disease being the most common conditions. Acute CVEs, particularly heart failure exacerbations, occurred in 5%-25% of hospitalized patients. Underlying CVD was consistently linked to increased severity of HMPV illness, including higher rates of ICU admission and mortality. Conclusions Acute HMPV infection frequently occurs in adults with pre-existing CVD and may be associated with CVEs in older hospitalized populations. However, evidence remains limited and largely observational. These findings highlight the need to increase awareness of the potential CV complications associated with HMPV infection. Trial registration PROSPERO [CRD420251164583]
Objectives In 2024, pertussis peaked at nearly 15,000 confirmed cases in England leading to the declaration of a national public health incident. Infants aged under 3 months had the highest incidence, with eleven deaths in 2024. The maternal programme effectiveness was reassessed as eligibility had been extended to 16 weeks since earlier estimates. Methods 188 laboratory-confirmed cases in under 3-month-olds from January 2020-March 2024, and matched coverage data from 453,740 pregnancies in the Clinical Practice Research Datalink, were used to estimate maternal vaccine effectiveness (VE) using the screening method. Cases were matched to coverage by birth-month, maternal age and region. VE was estimated against disease, hospitalisation and death. Results VE against laboratory-confirmed pertussis was 84.6% (95% CI 76.9%-89.7%) in infants under 3 months. VE against hospitalisation was 88.2% (95% CI 81%-92.7%) with VE against death at 91.5% (95% CI 75.4%-97.1%). VE estimates for each gestational age category were high, with no statistically significant differences. Conclusion High maternal VE was estimated for infant pertussis regardless of the gestational age at vaccination. Resultscomparable to earlier estimates, indicate that the high effectiveness of the programme has been maintained and was not a factor in the post-pandemic pertussis resurgence observed in England, and internationally.
OBJECTIVES:We examined how asymptomatic Plasmodium falciparum (Pf) infections and their treatment affect short-term cognitive trajectories among schoolchildren living in western Kenya and explored whether subclinical inflammation may contribute to this relationship. METHODS:In this prospective cohort study, 254 children aged 7-9 years underwent neurocognitive assessment and Pf detection by microscopy at baseline, 4, and 8 weeks. Microscopy-positive cases were treated. Haemoglobin, parasitaemia by quantitative PCR (PfqPCR), molecular force of Pf infection, and 21 plasma cytokines were measured longitudinally. Adjusted generalised linear mixed models were used to evaluate the associations between parasitaemia, treatment, and longitudinal changes in cognition. RESULTS:In pre-specified adjusted analyses, PfqPCR-detectable parasitaemia correlated with a decline in a composite cognitive score over time (adjusted β for interaction: -0.11, 95% CI -0.19--0.031), while treatment of microscopy-detectable infections correlated with improvement (0.082, 95% CI 0.0027-0.17). Higher levels of the inflammatory cytokine CXCL11/ITAC were associated with lower cognitive performance (adjusted β: -0.30, 95% CI -0.60--0.022), which was validated in an independent cross-sectional cohort (-0.18, 95% CI -0.34--0.019). CONCLUSIONS:Asymptomatic Pf parasitaemia may negatively influence short-term cognition in young schoolchildren living in an area of intense malaria transmission. Low-level inflammation may play a role in this effect.
OBJECTIVES:Invasive infections caused by different human adenovirus (HAdV) species represent a life-threatening complication in immunocompromised patients, but no approved antiviral treatment is currently available. METHODS:Using PCR-based screening and next-generation sequencing (NGS), we monitored immunocompromised patients with invasive HAdV infection (n=31) enrolled in the phase 2a ATHENA trial, which evaluated optimal dosing regimens of intravenous brincidofovir (BCV). RESULTS:Molecular typing of blood and stool specimens revealed the presence of nearly all HAdV species (A-F), including both common and rarely observed genotypes. Quantitative viral load monitoring indicated sustained clearance of any HAdV species from peripheral blood within five weeks of treatment in the patient cohort treated with the BCV dosing regimen identified as optimal (0.4 mg/kg twice weekly). CONCLUSIONS:These findings support a dose-dependent broad efficacy of intravenous BCV across all relevant HAdV species and set the stage for an ensuing phase 3 trial, facilitating future regulatory approval of the compound for this urgently needed indication.
BACKGROUND:Malaria transmission-blocking vaccines induce functional immunity, impeding Plasmodium parasite development in mosquitoes and thereby reducing malaria transmission. We aim to identify target antigens of naturally acquired transmission-blocking antibodies against Plasmodium vivax. METHODS:Thirty plasma samples obtained from Thai P. vivax patients were evaluated for the presence of IgM and IgG antibodies against a library of 659 P. vivax recombinant proteins expressed by the wheat germ cell-free protein expression system using AlphaScreen. Spearman's rank tests were used to compare the antibody levels and transmission-reducing activity (TRA) of the plasma samples, measured by direct membrane feeding assay. RESULTS:Most proteins were immunoreactive to IgM (85.4%) and IgG (97.9%). TRA is significantly correlated with the level of IgM and IgG to 89 and 8 antigens (p < 0.05), respectively. Notably, IgM responses against the N-terminal Pvs230 was identified. After false discovery rate adjustment, significant correlations of TRA and IgM responses to 11 antigens remained. Some of those TRA-associated antigens exhibited elevated IgM levels in individuals with significant TRA compared to those with non-significant TRA. CONCLUSION:Our findings demonstrate the association of IgM with naturally acquired transmission-blocking immunity and highlight potential targets of P. vivax transmission-reducing antibodies. Further investigations are needed to validate the targets, elucidate the underlying mechanisms and facilitate the research on transmission-blocking vaccines.
BACKGROUND:Neisseria meningitidis (Nm) colonizes the oropharynx of healthy individuals, yet the relationship between the oropharyngeal microbiome and meningococcal carriage remains poorly characterized. We studied the oropharyngeal microbiome in relation to Nm carriage and capsular phenotype in a cohort of healthy young adults. METHODS:We enrolled 202 Nm carriers (of whom 101 harbored invasive capsular strains (B, C, W, X, Y)) and 202 matched non-carriers for microbiome analysis using 16S rRNA gene amplicon sequencing of oropharyngeal swabs. We compared the microbiome between carriers and non-carriers, carriers of invasive and non-invasive strains, and smokers and non-smokers, using alpha and beta diversity and differential abundance analyses. Isolate genomes were analyzed for the prp locus. RESULTS:Carriers exhibited significantly higher Simpson diversity (p≤0.01) and distinct community composition (p=0.0002) compared to non-carriers. Differentially abundant taxa included Stomatobaculum, Lachnoanaerobaculum, Granulicatella, and Atopobium (enriched in carriers), and Epsilonbacteraeota and Patescibacteriota (enriched in non-carriers). Among carriers, invasive capsular strain carriers demonstrated significantly higher alpha diversity across all metrics and distinct beta diversity compared to non-capsular carriers. Notably, Campylobacter (Epsilonbacteraeota), Rothia, and Leptotrichia were enriched in capsular carriers, a pattern directionally opposite to that observed in the carrier vs. non-carrier comparison. Whole genome sequencing of Nm isolates revealed that the intact propionate utilization pathway (prp gene cluster) was far more prevalent in invasive capsular (62%) than in non-invasive isolates (10.5%, p<0.0001). Whether a metabolic relationship exists between the Campylobacter-enriched capsular carrier microbiome and propionate-utilizing Nm strains cannot be established from these genus-level data. Differences in composition between carriers and non-carriers remained after stratification by smoking status. CONCLUSIONS:Nm carriage was associated with a distinct oropharyngeal microbiome, characterized by community reorganization rather than diversity loss, with divergent profiles between capsular and non-capsular carriers and a notable enrichment of Campylobacter alongside an intact prp locus in invasive capsular strains. Taken together, these findings identify microbial features that may shape meningococcal colonization and warrant longitudinal, species-level investigations to define their mechanistic and translational relevance.
The COVID-19 pandemic has substantially reshaped population humoral immunity. However, whether individuals in the post-pandemic era have developed broader cross-neutralizing antibody responses against diverse coronaviruses remains unclear. To address this question, we evaluated serum neutralizing activity in 869 individuals from Wuhan, China, including 78 pre-pandemic samples collected in 2017 and 791 post-pandemic samples collected in 2025. Compared with pre-pandemic sera, post-pandemic sera exhibited enhanced neutralizing activity against multiple sarbecoviruses and the merbecovirus MjHKU4r-CoV-1, with mean viral inhibition increasing by 1.7% to 76.5% at a 1:20 serum dilution, most prominently against clade 1b sarbecoviruses. In contrast, no appreciable enhancement was observed against endemic human alphacoronaviruses or MERS-CoV. Neutralizing responses were strongly correlated across sarbecoviruses, particularly within clade 1b. Antigenic mapping showed that genetic relatedness did not reliably predict antigenic relationships, as Pangolin-GD, Pangolin-GX, and Khosta-2 were genetically more divergent yet antigenically closer to ancestral SARS-CoV-2 (D614G) than contemporary SARS-CoV-2 variants. Notably, both cohorts robustly neutralized Khosta-2, primarily through S1-directed antibodies, suggesting pre-existing cross-reactive immunity induced by endemic human coronaviruses that was further boosted by SARS-CoV-2 exposure. Collectively, these findings demonstrate that post-pandemic sera exhibit enhanced cross-neutralizing antibody responses predominantly against sarbecoviruses, potentially strengthening population immunity against related zoonotic sarbecoviruses and increasing the immunological barrier to their emergence in humans.
Background Rodent-borne pathogens pose important global health risks, yet national-scale assessments linking host-pathogen ecology with disease dynamics remain limited, particularly in China. Methods We compiled global (>29,000 records) and China-specific (2235 records; 1950–2023) rodent-pathogen datasets to characterize host-pathogen networks, identify hyperreservoirs, and quantify prevalence heterogeneity using hierarchical meta-regression. We applied a two-layer framework integrating 1-km host suitability surfaces (stacking ensemble of boosted regression trees and random forest models) with province-level disease inference using generalized linear models for hemorrhagic fever with renal syndrome (HFRS), leptospirosis, and plague. Human exposure was estimated by overlaying suitability with gridded population data. Results Globally, 116 pathogens of concern were identified across 206 host species, including 30 spillover-risk viruses and 34 hyperreservoirs. Meta-regression identified sample source as the only consistently robust moderator of prevalence heterogeneity; other moderators (e.g., rodent family, region, and habitat type) showed inconsistent or non-robust associations. Host suitability was positively associated with HFRS incidence (incidence rate ratio = 1.36, P < 0.01) but negatively or not significantly associated with leptospirosis and plague. In China, the three diseases showed contrasting suitability patterns, with approximately 404 million people (29.3%) residing in areas with high suitability for at least one disease. Conclusions Our analysis elucidates disease-specific ecological drivers and identifies spatial priorities to inform targeted One Health surveillance and integrated interventions.
OBJECTIVE:Cytokine storm (CS) is a critical immunopathological mechanism contributing to disease severity, organ failure, and mortality in infectious diseases. However, standardized clinical diagnostic criteria, particularly for early-stage CS, remain lacking. This systematic review and meta-analysis aimed to identify core diagnostic biomarkers and summarize early detection criteria for CS. METHODS:PubMed, Scopus, Embase, and the Cochrane Library were searched for eligible studies published between 2001 and 2025. Study selection, quality assessment, and data extraction were conducted according to predefined criteria. RESULTS:15 studies were included. Interleukin-6 (IL-6), Interleukin-10 (IL-10), C-reactive protein (CRP), serum ferritin and D-dimer were identified as core biomarkers of CS. Eight studies proposed quantitative diagnostic thresholds, including IL-6 (23-40 pg/mL), IL-10 (57 pg/mL), CRP (46-100 mg/L), serum ferritin (250-1000 ng/mL), and D-dimer (1.5-4.9 μg/mL), while nine studies relied on qualitative biomarker changes and/or clinical manifestations. Meta-analysis demonstrated that elevated levels of IL-6 (OR=11.43), CRP (OR=4.85), serum ferritin (OR=9.61), D-dimer (OR=4.60), and IL-10 (OR=7.97) were significantly associated with increased in-hospital mortality. Subgroup and sensitivity analyzes confirmed the robustness of these findings, with moderate heterogeneity observed for CRP (I²=70.9%). IL-6 (23-40 pg/mL) and IL-10 (57 pg/mL) may serve as potential early detection criteria for CS. CONCLUSION:IL-6, IL-10, serum ferritin, CRP, and D-dimer represent core diagnostic biomarkers of CS and are significantly associated with increased in-hospital mortality in infectious diseases.
OBJECTIVES:Human adenovirus type 7 (HAdV-7) has caused outbreaks of acute respiratory infections (ARIs) among children in multiple countries. This study aimed to investigate the clinical and genetic characteristics of HAdV-7 in hospitalized children with ARIs in China. METHODS:Respiratory samples were collected from hospitalized children with ARIs at 10 hospitals across Northern and Southern China between 2014 and 2025 for HAdV detection and genotyping. Clinical data of HAdV-7-positive patients were collected for clinical characteristics analysis. The whole genomes of isolated HAdV-7 strains were sequenced for bioinformatics analysis with those selected from GenBank. RESULTS:Among 250 HAdV-positive samples, 79 (31.60%) were HAdV-7, ranking second only to HAdV-114 (46.80%). Patients primarily presented with fever, cough, and sputum production. Some cases also complicated with gastrointestinal and neurological symptoms, skin rashes, and ocular diseases. Severe pneumonia occurred in 54.43% of patients, with one death. Whole genome sequence phylogenetic analysis revealed that HAdV-7 could be divided into two clusters. Cluster 1, including the prototype strain, had been rarely reported globally since the discovery of HAdV-7. Cluster 2 was the predominant cluster circulating worldwide, including China. Three novel amino acid substitutions were observed in the Loop 1 region of the Hexon protein, which might be associated with the severe disease phenotype and resulted in the emergence of a positive selection site. Recombination analysis identified a recombination event, which occurred as early as 1988. In vitro experiments demonstrated that HAdV-7 had comparable proliferation capacity with other genotypes of the HAdV-B species. CONCLUSIONS:HAdV-7 was an important pathogen of hospitalized children with ARIs in China, and associated with severe diseases and even death. Cluster 2 was the predominant epidemic cluster worldwide. Although the HAdV-7 genome was relatively conserved and stable, novel amino acid mutations have occurred.
BACKGROUND:Sepsis pathobiology is shaped by both pathogen load and host characteristics, yet pathogen load is rarely measurable in clinical cohorts. Severe HIV-associated tuberculosis (TB), a leading cause of critical illness in Africa, provides a unique model in which Mycobacterium tuberculosis bacilli load can be quantified. We investigated how pathogen load and age influence sepsis pathophysiology and mortality in this high-risk population. METHODS:We conducted a prospective cohort study of adults admitted with severe HIV-associated TB. Systemic bacillary load was estimated from multiple routinely collected TB diagnostics. Blood-based sepsis markers were summarised using principal components analysis, and pathophysiological processes were evaluated using directed acyclic graphs and regression modelling. FINDINGS:Among 519 patients with microbiologically confirmed TB, 75 (14.5%) died by day 28. Two major axes of host response were identified: PC1, capturing IL-6, CRP, and procalcitonin; and PC2, reflecting venous lactate, aspartate aminotransferase, and cytopenias. Both strongly correlated with bacilli load (PC1 r=0.46; PC2 r=0.43; both p<0.001) but not with age. Mortality independently associated with infection severity - whether defined by bacilli load (aOR 2.1, 95%CI 1.6-2.9) or by inflammatory axes (PC1 aOR 2.3, 95%CI 1.7-3.1; PC2 aOR 1.9, 95%CI 1.5-2.5) - and with age (aOR 1.84, 95%CI 1.4-2.4). Absolute mortality risk therefore reflected an interaction between pathogen load and age. Hyperlactataemia, metabolic acidosis, kidney dysfunction, and temperature were all correlated with bacilli load, inflammation and mortality (all p<0.001). Older patients showed less respiratory compensation for metabolic acidosis, higher blood glucose at a given lactate level, and attenuated fever response at a given bacilli load. INTERPRETATION:Pathogen load and associated inflammatory responses define infection severity in HIV-associated TB and interact with age to predict mortality. These findings highlight physiological constraints underlying organ dysfunction in sepsis and illustrate how pathogen load and age can illuminate mechanisms of critical illness.
BACKGROUND:Real-world data studies suggest that the vaccine effectiveness (VE) of a fourth mRNA vaccine dose against SARS-CoV2 infection related hospitalisation wanes after a few months, potentially warranting consideration of additional booster doses. METHODS:A multi-data source cohort study was conducted through the Data Analysis and Real World Interrogation Network (DARWIN EU®) using routinely collected electronic health records from the UK (CPRD GOLD), the Netherlands (IPCI), and Spain (SIDIAP) from January 2021 to June 2023. The study included individuals aged 12 and above, vaccinated with at least three doses. We matched fourth-dose to third-dose vaccinated individuals using a weekly sequential approach, defining the date of the last dose received by the exposed individual as the index date. Primary outcomes were SARS-CoV2 infection related death and hospitalisation. Hazard ratios (HR) were estimated using Cox proportional hazard models, with VE defined as the percentage of 1 minus HR. Waning of VE was assessed at monthly intervals. FINDINGS:A total number of 975,496 matched pairs were identified from the three data sources, with a median age of 63-78. The pooled VE of a fourth vaccine dose against SARS-CoV2 infection related death compared to three vaccine doses was 30% (95%CI 9 to 46, I2=0). VE against SARS-CoV2 infection related hospitalisation was 26% (19% to 33%) in Spain (SIDIAP, median follow-up 8 weeks), and 46% (15% to 66%), in the Netherlands (IPCI, median follow-up 21 weeks) respectively. VE of a fourth dose started waning at 4-8 weeks after vaccination. INTERPRETATION:A fourth dose of a mRNA COVID-19 vaccination was effective against SARS-CoV2 infection related death and hospitalisation. However, effectiveness waned over time. Periodic revaccination should be considered, with recommendations regarding booster timing taking into account circulating variants, patterns of viral transmission, and population uptake. FUNDING:European Medicines Agency.
Due to the continuous evolution of Influenza A viruses (IAVs), novel strains with efficient human-to-human transmission may emerge and cause future pandemics. Among these, highly pathogenic avian influenza (HPAI) H5N1 remains a major concern because of its impact on wildlife, livestock, and human health. The widespread circulation of H5N1 clade 2.3.4.4b, detected in hundreds of bird species and numerous mammals worldwide, highlights important changes in viral ecology and transmission, increasing its zoonotic and pandemic potential. This review summarizes current evidence on cross-reactive and cross-protective immunity to H5N1 in humans, focusing primarily on humoral immune responses. We examine the presence of pre-existing H5N1-reactive antibodies in individuals without known exposure and discuss how previous seasonal influenza infection or vaccination may contribute to their development. Particular attention is given to antibodies targeting conserved regions of hemagglutinin (HA), especially the stalk domain, as well as neuraminidase (NA), which may provide heterosubtypic protection. We also evaluate the ability of seasonal influenza vaccines and infections to induce cross-reactive responses against H5N1 and their potential role in partial protection or immune priming. Finally, we review current and emerging H5N1 vaccination strategies, including adjuvanted and mRNA-based platforms, and identify priorities for surveillance, population immunity assessment, and the development of broadly protective influenza vaccines.
OBJECTIVES:Multidrug-resistant Gram-negative bacteria (MDR-GNB) represent a major global health threat, with limited therapeutic options and high morbidity and mortality. Cefiderocol, a novel siderophore cephalosporin, has emerged as a potential treatment for MDR-GNB infections. This narrative review aims to critically appraise evidence from randomised controlled trials (RCTs) and real-world studies to clarify the clinical effectiveness, safety, and optimal place-in-therapy of cefiderocol in the management of MDR-GNB infections. METHODS:A narrative review of phase 2 and 3 RCTs and available real-world observational studies was performed. Evidence was synthesised focusing on mechanism of action, pharmacokinetic/pharmacodynamic properties, resistance mechanisms, and clinical outcomes across different infection sites, pathogens, and treatment strategies. RESULTS:RCTs demonstrated non-inferiority of cefiderocol compared with standard-of-care therapies in complicated urinary tract infections, nosocomial pneumonia, and bloodstream infections sustained by GNB. However, heterogeneous outcomes and mortality imbalances were observed in specific subgroups, particularly in Acinetobacter baumannii and metallo-β-lactamase (MBL)-producing pathogens. Real-world studies support cefiderocol use in critically ill patients, ventilator-associated pneumonia, and bloodstream infections, with more consistent benefits observed for Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales. Outcomes in carbapenem-resistant A. baumannii infections remain variable. Early initiation of therapy appears associated with improved outcomes, while no clear superiority of combination therapy over monotherapy has been established. CONCLUSIONS:Cefiderocol represents a valuable option for the treatment of MDR-GNB infections. Its optimal use requires careful patient and pathogen selection, early administration, and integration within antimicrobial stewardship strategies. Further pathogen- and infection-specific trials are needed to better define its role, particularly in carbapenem-resistant A. baumannii and MBL-producing infections.
BACKGROUND:Human immunodeficiency virus (HIV)-negative Multidrug-resistant Tuberculosis (MDR-TB) remains a major public health threat in China, Geographic heterogeneity and poorly understood epidemiological trends limit precision control and resource optimization. METHODS:This study systematically assessed the disease burden of HIV-negative MDR-TB in China and its provinces from 1990 to 2023, using data from the Global Burden of Disease Study (GBD) 2023 database. The analysis includes age-standardized rates (ASR) and absolute case numbers for incidence, prevalence, mortality, disability-adjusted life years (DALYs), years of life lost (YLL), and years lived with disability (YLD). The data spans 31 provinces, autonomous regions, municipalities, and the Special Administrative Regions of Hong Kong and Macao. The Joinpoint regression model was used to analyze trends in disease burden from 1990 to 2023 and calculate the average annual percentage change (AAPC) and annual percentage change (APC). In addition, a Bayesian age-period-cohort (BAPC) model was employed to project the disease burden trends from 2024 to 2050. RESULTS:In 2023, the age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) of HIV-negative MDR-TB in China were 1.630 per 100,000 population [95% uncertainty interval (UI): 0.196, 4.967] and 2.740 per 100,000 population (95% UI: 0.340, 8.794), respectively. From 1990 to 2023, ASIR declined significantly [AAPC = -2.859%, 95% confidence interval(CI): -3.487, -2.231], whereas ASPR increased significantly (AAPC = 7.800%, 95% CI: 7.022, 8.578); however, recent trends suggested stabilization, with ASIR plateauing from 2016 to 2023 (AAPC=-0.270%, 95%UI: -1.275, 0.746) and ASPR showing no significant change from 2017 to 2023 (APC = 0.503%, 95% CI: -1.635, 2.687). In 2023, age-standardized mortality rate (ASMR), age-standardized Disability-adjusted life years rate (ASDR), age-standardized Years of Life Lost rate(ASYLLR), and age-standardized Years Lived with Disability rate (ASYLDR) were 0.098 per 100,000 population (95% UI: 0.011, 0.354. AAPC = -6.714%, 95% CI: -7.265, -6.164), 3.718 per 100,000 population (95% UI: 0.466, 13.091. AAPC = -6.633%, 95% CI: -7.130, -6.135), 2.837 per 100,000 population (95% UI: 0.331, 10.333. AAPC = -6.633%, 95% CI: -7.130, -6.135), and 0.881 per 100,000 population (95% UI: 0.118, 2.943. AAPC = -1.614%, 95% CI: -2.366, -0.862), respectively, with significant long-term declines. ASIR (AAPC=0.160%, 95% CI: 0.137, 0.183) and ASPR (AAPC=0.086%, 95% CI: 0.073, 0.098) are forecasted to rise from 2024 to 2050 in China. CONCLUSION:Persistent HIV-negative MDR-TB challenges in China, including rising prevalence and spatial heterogeneity, demand a sustainable model combining policy, AI diagnostics, and community engagement.
