Infectious Diseases and Therapy最新文献

Introduction: Long COVID-related fatigue affects a large number of people across the world, with increasing numbers of people experiencing long-term disability as a consequence. We tested the feasibility of a self-help version of a manual osteopathic approach initially developed for people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to treat people with long COVID-related fatigue.

Methods: Our feasibility study assessed recruitment into a 1:1 randomized controlled trial (RCT) to receive (i) self-help intervention (self-massage, mobility, flexibility, and breathing exercises, and alternating cold and warm packs to the top of the spine) or (ii) wait-list control group. Follow-up was assessed by online surveys at 3 and 6 months (indicating retention). Verbal feedback was obtained from participants.

Results: Of the 138 eligible survey participants, 126 (90.6%) agreed to participate in two RCTs, achieving the required sample size of 100. Follow-up rates of 79.3% and 59.4% were achieved at 3 and 6 months, respectively. Improvements in Chalder Fatigue Questionnaire (CFQ) scores were observed in both groups between 0 and 3 months (- 4.6 and - 2.9, respectively), to a greater degree in the intervention group (p = 0.01). Feedback showed a cohort keen to engage with the intervention, although some found the intervention onerous at times.

Conclusions: We have reported the results of a feasibility study examining a potentially beneficial intervention for people with long COVID. There were indications of benefit in a patient group with often intractable symptoms. Based on this feasibility study, we believe that the low-cost self-help intervention in isolation could help support fatigue reduction in some people. This has implications for the treatment of both long COVID and ME/CFS.

Trial registration: International Standard Randomized Controlled Trial Number (ISRCTN): 99840264.

Introduction: SARS-CoV-2, influenza A and B, and respiratory syncytial virus (RSV) are the major seasonal viruses that can cause severe illness. Rapid and accurate diagnosis of these viruses may improve patient management and surveillance efforts. Here, we assessed the diagnostic performance of the STANDARD M10 Flu/RSV/SARS-CoV-2 Fast (M10Fast) real-time polymerase chain reaction assay for near-patient diagnosis of the four viruses.

Methods: This retrospective validation study included 600 nasopharyngeal swab specimens previously tested using the standard-of-care laboratory-based Allplex Respiratory Panels 1-4 and Allplex SARS-CoV-2/FluA/FluB/RSV reference assays. Of these samples, 300 were positive for SARS-CoV-2, influenza A, influenza B, or RSV, while the remaining 300 samples were negative for the four viruses. Positive and negative percent agreements between the M10Fast index and reference tests were the primary endpoints. Additionally, analytical sensitivity of the M10Fast in terms of 95% limit of detection was estimated via serial dilutions of a positive reference material.

Results: Of 600 samples processed in the M10Fast, 590 (98.3%) were fully concordant. Positive percent agreement coefficients were 98.7% for influenza A and 100% for SARS-CoV-2, influenza B, and RSV. Negative percent agreement was 99.2% for influenza A, 99.4% for both SARS-CoV-2 and RSV, and 99.8% for influenza B. Discordant results were characterized by low viral loads with cycle threshold values of 38 or greater. The rate of invalid M10Fast runs was low (1.2%). Limit of detection of the M10Fast varied from 189 copies/mL for RSV to 541 copies/mL for the N gene of SARS-CoV-2.

Conclusions: The M10Fast, developed for near-patient settings, reliably detects SARS-CoV-2, FluA, FluB, and RSV in 36 min and its performance is comparable to standard laboratory-based assays.

Introduction: The optimal duration of antibiotic therapy for Gram-negative bacteremia sourced from urinary tract infections (UTI) remains uncertain. We performed a systematic review and meta-analysis comparing short-course (approximately 7 days) versus prolonged-course (approximately 14 days) antibiotic therapy in this population.

Methods: We systematically searched PubMed, Embase, and ClinicalTrials.gov through 26 April 26 2025. Studies were included if they compared 7-day versus 14-day antibiotic therapy in Gram-negative bacteremia with ≥ 65% UTI source or performed a dedicated UTI subgroup analysis. Outcomes assessed included 30- and 90-day mortality and recurrence rates. Recurrence was defined as a repeat episode of Gram-negative bacteremia confirmed by a positive blood culture after completion of therapy, rather than recurrence of urinary tract infection alone. Risk ratios (RR) were pooled using a random-effects model. Noninferiority was assessed using a prespecified margin of RR 1.25, and superiority was assessed with a threshold of RR < 1.00.

Results: In total, six studies (three randomized trials, three observational cohorts) encompassing 4448 patients were included. There were no significant differences between short- and prolonged-course therapy for 30-day mortality (RR 0.97, 95% confident interval (CI) 0.64-1.47; p = 0.90), 30-day recurrence (RR 1.38, 95% CI 0.80-2.37; p = 0.24), 90-day mortality (RR 0.90, 95% CI 0.77-1.06; p = 0.20), or 90-day recurrence (RR 0.68, 95% CI 0.45-1.01; p = 0.06).

Conclusions: Our findings suggest that a 7-day course may be sufficient for most patients with UTI-sourced Gram-negative bacteremia.

Introduction: There is a gap in the understanding of the burden of respiratory syncytial virus (RSV) among adults in low, lower-middle, and upper-middle income countries, particularly with regard to up-to-date epidemiological data. Meta-analyses were conducted to determine pooled estimates of RSV prevalence among high-risk 18-59-year-old adults and ≥ 50-year-old adults with or without risk factors or comorbidities, who present with respiratory illnesses in low, lower-middle, and upper-middle income countries.

Methods: Using studies identified from a previously described systematic literature review, a random-effects model was used to determine pooled prevalence for each study population. Subgroup analyses and meta-regression were conducted using the moderator variables deemed most relevant a priori and a mixed-effects approach.

Results: Pooled RSV prevalence estimates were 5.1% (95% confidence interval [CI] 3.9-6.6%) and 3.9% (95% CI 3.3-4.7%) across 33 studies in 18-59-year-old high-risk adults with respiratory illnesses and 66 studies in ≥ 50-year-old adults with respiratory illnesses, respectively. Subgroup analyses for 18-59-year-old high-risk adults found geography, study setting, and respiratory illness to collectively explain ~ 54% of the variation in RSV prevalence estimates. The diagnostic method for RSV was found to explain ~ 8% of the variation in RSV prevalence estimates in ≥ 50-year-old adults; no other factors explored via subgroup analyses for ≥ 50-year-old adults had a notable effect on variation. For both populations, a substantial level of residual heterogeneity was observed using Higgin's I² when studies were split for subgroup analyses.

Conclusions: Overall, there is a considerable disease burden associated with RSV among 18-59-year-old high-risk and ≥ 50-year-old adults with respiratory illnesses in low, lower-middle, and upper-middle income countries, highlighting the need for improved prevention programs for RSV in these populations.

Introduction: Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients with acute-on-chronic liver failure (ACLF). Cytokines play essential roles in the pathogenesis of IPA and have been identified as promising diagnostic biomarkers. This study aimed to conduct a comprehensive proof-of-concept evaluation of the diagnostic potential of cytokines for IPA in patients with ACLF.

Methods: In this single-center prospective study, patients with HBV-ACLF were categorized into IPA (with diagnostic criteria of probable IPA, n = 16), bacterial pneumonia (BP, n = 32), and non-infection (n = 32) groups. Groups were matched for age, gender, and liver decompensation severity. Plasma cytokines, interleukin (IL)-33, IL-17A, IL-23, IL-31, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, interferon-γ, tumor necrosis factor alpha, and soluble IL-2 receptor, were quantified. Diagnostic accuracy was assessed via ROC analysis.

Results: IL-33 levels were markedly elevated in IPA vs. BP (163.07 [108.30-211.22] vs. 12.82 [4.24-50.55] pg/mL; P < 0.001) and non-infection groups (163.07 [108.30-211.22] vs. 4.24 [4.24-52.51] pg/mL; P < 0.001). ROC analysis identified IL-33 as a strong diagnostic marker for IPA (AUC = 0.871; sensitivity 93.80%, specificity 84.40%; P < 0.001) with optimal cutoff at 66.97 pg/mL. Furthermore, IL-33 levels were significantly elevated during IPA development compared to both the incubation phase (154.86 vs. 8.29 pg/mL, P = 0.005) and the recovery phase (154.86 vs. 28.01 pg/mL, P = 0.038).

Conclusions: Plasma IL-33 demonstrates high accuracy in diagnosing IPA and differentiating it from bacterial infections in patients with HBV-ACLF, offering a minimally invasive diagnostic tool. Graphical abstract available for this article.

Introduction: Argentina was the first South American country to adopt a single-dose hepatitis A vaccine for 1-year-old children, replacing the standard two-dose regimen in the immunization program in 2005. Here, we assessed the long-term persistence of anti-hepatitis A virus (HAV) antibodies following vaccination.

Methods: A cohort of healthy toddlers from Mendoza, Argentina, who received one (N = 436) or two (N = 108) doses of the inactivated HAV vaccine (Avaxim^® 80U Pediatric), were followed for up to 15 years post-vaccination to assess the persistence of anti-HAV antibodies. Three assays were used to measure anti-HAV antibody concentrations, depending on commercial availability. At year 15 follow-up, 161 and 48 participants who received one and two vaccine doses, respectively, without additional booster, remained in the study. Using all available data, we modeled long-term antibody persistence to project immunity to 40 years after vaccination. Antibody persistence was predicted using a hierarchical model that estimated both participant- and group-specific antibody decay, accounting for assay changes over time and natural boosting from virus exposure.

Results: At year 15, anti-HAV antibody geometric mean concentrations (GMCs) were 73.7 (95% CI 65.0-83.6) mIU/ml and 291.1 (95% CI 226.1-375.0) mIU/ml among those who received one and two vaccine doses, respectively, and all remained seroprotected. Of the four model specifications tested, the log-logistic model with natural boosting provided the best fit to the observed antibody GMCs and seroprotection rates. At 40 years post-vaccination, GMCs were predicted to be 51.8 (95% CI 36.8-75.1) mIU/ml and 134.7 (95% CI 84.5-221.1) mIU/ml after one and two vaccine doses, respectively, with seroprotection rates of 94% (95% CI 89-98) and 93% (95% CI 88-97).

Conclusions: The HAV vaccine, Avaxim^®, administered as one- or two-dose schedule, elicited long-lasting immunity in children, with a single dose sufficient to ensure long-term protection.

Methicillin-susceptible Staphylococcus aureus (MSSA) remains a major cause of morbidity and mortality worldwide, particularly owing to its role in complicated infections including bloodstream infections, osteomyelitis, and infective endocarditis. In 2017, an estimated 119,247 cases of S. aureus bloodstream infections were reported in the USA, resulting in approximately 19,832 deaths. While the prevalence of MSSA varies by region and demographic factors, MSSA has been reported to be approximately two times more common than methicillin-resistant S. aureus (MRSA) in both total and complicated infections. Cefazolin, a first-generation cephalosporin, is widely used for MSSA treatment owing to its favorable safety profile, cost-effectiveness, and availability. However, its efficacy may be compromised by the cefazolin inoculum effect (CzIE)-a phenomenon where cefazolin activity diminishes at high bacterial densities, such as those found in endocardial vegetations or abscesses. Importantly, CzIE is not universally present across all MSSA isolates and geographical areas, with reported prevalence ranging from 0% to 55%. Initially considered a result of producing specific allotypes of the staphylococcal β-lactamase enzyme BlaZ (i.e., allotypes A and C), recent work sheds new light on different BlaZ allotypes associated with the effect while establishing that no single genetic determinant or allotype is uniquely and definitively responsible. When present, CzIE can lead to elevated cefazolin MICs at high inocula, potentially resulting in treatment failure, prolonged hospitalization, and increased mortality. Despite these concerns, clinical data remain inconclusive, and the true impact of CzIE on patient outcomes is still under investigation. This review critically evaluates the molecular basis, clinical relevance, and diagnostic challenges of CzIE, with the goal of informing antibiotic stewardship and optimizing treatment strategies for serious MSSA infections.

Introduction: Detailed characterization of the antibody profile induced by SARS-CoV-2 mRNA vaccines has shown that repeat dosing boosts all immunoglobulin G (IgG) subclasses, with a notable emergence of antigen-specific IgG4 antibodies. While the IgG4 subclass is traditionally associated with limited Fc-effector functions, its role in SARS-CoV-2 mRNA vaccine-induced immunity remains unclear.

Methods: This study tracked IgG subclass dynamics, IgG Fc-mediated functions, and neutralization following immunization with two or three doses of Moderna SARS-CoV-2 mRNA vaccine (mRNA-1273) in healthy adults.

Results: We observed robust spike-specific IgG1 and IgG3 responses after the primary series (two doses) and booster dose, with a significant increase in IgG4 responses after repeated dosing. Despite this rise in spike-specific IgG4 antibodies, strong Fc-effector functions were maintained at the overall IgG level, including antibody-dependent cellular phagocytosis, antibody-dependent neutrophil phagocytosis, and antibody-dependent complement deposition, with no antagonism from IgG4 antibodies. Additionally, IgG4 antibodies exhibited enhanced affinity and potent neutralization, complementing IgG1-driven responses.

Conclusions: These findings suggest that elevated IgG4 responses did not antagonize overall Fc-mediated effector mechanisms, indicating that mRNA-1273 induces a multi-subclass antibody response that preserves antiviral functionality.

Trial registration: NCT04470427.

Introduction: Routine childhood immunization programs using pneumococcal conjugate vaccines (PCVs) significantly reduce the burden of pneumococcal disease (PD). PCV21, a 21-valent PCV, was recently approved and recommended by the European Commission for use in Norway. The objective of this study was to quantify the health and economic burden of invasive PD (IPD) and non-bacteremic pneumococcal pneumonia (NBPP) attributable to PCV21, PCV20, and PPSV23 serotypes among adults in Norway.

Methods: A published Markov model was adapted to estimate lifetime IPD/NBPP cases, deaths, and direct medical costs (in 2023 Norwegian kroner [NOK]) associated with PCV21, PCV20, and PPSV23 serotypes in Norway. Results were disaggregated by age and risk groups. A one-way sensitivity analysis examined changes in disease costs (± 20%).

Results: The projected number of PD cases and deaths attributable to PCV21 serotypes was substantially higher than those attributable to PCV20 and PPSV23 serotypes. PD cases and deaths attributable to PCV21 serotypes vs. PCV20 and PPSV23 were ~ 41% and ~ 26% higher, respectively, in adults aged 65+ years, ~ 39% and ~ 25% higher in those aged 50-64 years, and ~ 37% and ~ 22% higher in those aged 18-64 years with risk factors. Within each age group, cases and total lifetime costs increased progressively as risk categorization increased. Estimated lifetime direct treatment costs for PD attributable to PCV21 serotypes were higher than those associated with PCV20 or PPSV23, at 3.9 billion NOK, 3.5 billion NOK, and 4.4 billion NOK in adults aged 65+, 50-64, and 18-64 years with risk factors, respectively.

Conclusions: Compared with PCV20 and PPSV23, PCV21 serotypes are associated with a higher health and economic burden in Norway. The inclusion of PCV21 into national vaccine recommendations in Norway can further alleviate the burden associated with PD in adults.

Introduction: The clinical presentation of critically ill patients with coronavirus disease 2019 (COVID-19) has evolved significantly with the emergence of the Omicron variant. Current intensive care unit (ICU) admissions involve patients with diverse comorbidities and immune statuses, highlighting the need to redefine homogeneous phenotypic subgroups within this population. This study aimed to characterize distinct clinical phenotypes among critically ill patients with COVID-19 and acute respiratory failure.

Methods: This multicenter prospective substudy of the SEVARVIR cohort included adult patients from 39 French ICUs between December 2021 and October 2024 with acute respiratory failure and infected with the Omicron variant. Clustering analysis was conducted using Kohonen's self-organizing maps (SOMs) and validated with ClinTrajan, two unsupervised clustering methods, to identify homogeneous patient phenotypes.

Results: During the study period, 777 patients with Omicron infection were included, and 7 distinct clinical clusters were identified. Clusters 1 and 2 included patients with metabolic and cardiovascular comorbidities. Cluster 3 featured younger, mildly ill patients with isolated chronic respiratory failure, while cluster 4 comprised older male patients with isolated respiratory failure. Cluster 5 included patients with isolated hematologic malignancies, cluster 6 patients with multiorgan failure, and cluster 7 organ transplant recipients, with high severity scores and impaired renal function. ICU management varied substantially across clusters. Patients in clusters 5 and 7 had the highest requirements for organ support, with frequent use of invasive mechanical ventilation, vasopressors (cluster 6), and renal replacement therapy (cluster 7). Dexamethasone and tocilizumab were most commonly prescribed in cluster 4 (91.3% and 30.2%, respectively). Mortality at day 28 varied significantly across clusters, ranging from 13.1% in cluster 3 to 41.1% in cluster 6.

Conclusions: This clustering analysis highlights, for the first time, the clinical heterogeneity of critically ill patients infected with Omicron, identifying seven distinct clusters with varying clinical presentations, management strategies and outcomes. These findings underscore the relevance of a phenotype-driven approach to support personalized treatment strategies and guide future clinical trials.

Trial registration: Clinicaltrials.gov, NCT05162508. A Graphical Abstract is available for this article.