Daily Sepsis Research Analysis
A large multicenter randomized trial found no mortality benefit of adjunct oral zinc for young infants hospitalized with suspected sepsis, countering prior meta-analytic signals. Translational diagnostics and immunology studies highlight faster, accurate rapid AST for Gram-negative bacteremia and the amphiregulin–EGFR axis as a promising prognostic biomarker and therapeutic target in adult sepsis.
Summary
A large multicenter randomized trial found no mortality benefit of adjunct oral zinc for young infants hospitalized with suspected sepsis, countering prior meta-analytic signals. Translational diagnostics and immunology studies highlight faster, accurate rapid AST for Gram-negative bacteremia and the amphiregulin–EGFR axis as a promising prognostic biomarker and therapeutic target in adult sepsis.
Research Themes
- Adjunctive therapies in neonatal sepsis
- Rapid diagnostics and antimicrobial stewardship in bloodstream infection
- Host immuno-biomarkers and therapeutic targets (AREG–EGFR axis)
Selected Articles
1. Zinc as adjunct treatment for clinical severe infection in young infants: A randomized double-blind placebo-controlled trial in India and Nepal.
In 3,153 young infants with suspected sepsis (CSI), adjunct oral zinc for 14 days did not reduce in-hospital or 12-week mortality versus placebo, with relative risks of 0.83 (p=0.267) and 1.05 (p=0.674), respectively. Adverse events were similar except for slightly more vomiting with zinc. The trial was underpowered due to lower-than-expected event rates.
Impact: This large, multicenter, double-blind RCT provides high-level evidence that counters prior meta-analytic signals of benefit, directly informing guidelines on adjunct zinc therapy in neonatal sepsis.
Clinical Implications: Routine adjunctive zinc should not be recommended for young infants hospitalized with suspected sepsis (CSI) based on current evidence. Future trials should refine sepsis definitions or use biomarker-enriched enrollment to identify subgroups that may benefit.
Key Findings
- Among 3,153 infants (median age 25 days), in-hospital mortality was 4.1% with zinc vs 4.9% with placebo (RR 0.83; 95% CI 0.60–1.15; p=0.267).
- Twelve-week mortality was 9.0% with zinc vs 8.6% with placebo (RR 1.05; 95% CI 0.84–1.32; p=0.674).
- Adverse events were similar across arms, with a slight increase in vomiting in the zinc group; no events were attributed to the intervention.
- Lower-than-anticipated event rates and shortfall in sample size rendered the trial underpowered.
Methodological Strengths
- Randomized, double-blind, placebo-controlled design across seven hospitals with trial registration
- Large sample size and standardized dosing with predefined primary outcomes
Limitations
- Underpowered due to lower-than-expected event rates and shortfall in achieved sample size
- Broad CSI-based inclusion may have diluted treatment effect compared with more specific sepsis definitions
Future Directions: Conduct adequately powered RCTs using more specific or biomarker-based sepsis definitions, and explore subgroup effects (e.g., nutritional status, prematurity) to identify potential responders.
BACKGROUND: Annually, an estimated 2.3 million infants die within their first month of life, primarily in sub-Saharan Africa and South Asia. Infections, including sepsis are among the major contributors to these deaths. Effective interventions added to standard antimicrobial therapy can reduce sepsis mortality. A recent meta-analysis suggests that adjunct zinc treatment of young infants with sepsis could reduce case fatality risk. This study evaluated the efficacy of zinc as an adjunct to antibiotics in young infants with suspected sepsis, defined as clinical severe infection (CSI). METHODS AND FINDINGS: We conducted a randomized, double-blind, placebo-controlled trial across seven hospitals in India and Nepal from February 28, 2017, to February 22, 2022. Infants aged 3-59 days hospitalized with suspected sepsis, defined as CSI, adapted from the WHO Integrated Management of Childhood Illness (IMCI) criteria, were randomly assigned to receive 10 mg of elemental zinc daily or placebo orally for 14 days, in addition to standard of care. The primary outcomes were death during hospitalization and death within 12 weeks after enrollment. Among 3,153 enrolled infants (1,203 [38%] females), the median age at enrollment was 25 days (interquartile range 13-41 days), and the mean weight was 2.9 kg (standard deviation 0.8). During the hospital stay, 64 (4.1%) of 1,576 infants died in the zinc arm compared to 77 (4.9%) of 1,577 in the placebo arm (relative risk [RR] 0.83 (95% CI [0.60, 1.15]; p = 0.267)). Among those who completed 12 weeks of follow-up, 140 of 1,554 infants (9.0%) died in the zinc arm, and 133 of 1,550 (8.6%) in the placebo arm (RR 1.05 (95% CI [0.84, 1.32]; p = 0.674)). Adverse events were similar across trial arms, except for a slight increase in vomiting in the zinc arm; no events were attributed to the intervention. The main limitation of the study is that it was underpowered due to lower-than-anticipated event rates and a shortfall in the achieved sample size. CONCLUSIONS: In this setting, we found little evidence for an effect of adjunct zinc therapy on young infants with CSI on the risk of dying during hospitalization or for the subsequent 3 months. Our findings contrast previous studies that used more specific case definitions. This underscores the need for further RCTs to evaluate the effect of zinc in young infant sepsis before it can be recommended in treatment guidelines. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI/2017/02/007966) on February 27, 2017, and Universal Trial Number is U1111-1187-6479.
2. Improving time-to-result: head-to-head comparison of three rapid AST systems for Gram-negative bacteremia, including the newly developed VITEK REVEAL.
In a prospective head-to-head comparison of 220 Gram-negative positive blood cultures across 18 species, VITEK REVEAL delivered the best balance of turnaround time and accuracy, including for resistant organisms and BL/BLI combinations. Findings support laboratory adoption of rapid AST to accelerate appropriate therapy and stewardship.
Impact: This is the first prospective head-to-head evaluation including the newly developed VITEK REVEAL, directly informing diagnostic workflows to shorten time-to-result in Gram-negative bacteremia.
Clinical Implications: Adopting rapid AST (e.g., VITEK REVEAL) can accelerate susceptibility reporting directly from positive blood cultures, enabling earlier optimization of therapy and potentially improving outcomes and stewardship metrics.
Key Findings
- Prospective head-to-head comparison of VITEK REVEAL, VITEK 2-RAST, and EUCAST DD-RAST on 220 GN-positive blood cultures covering 18 species.
- VITEK REVEAL combined rapid turnaround with high accuracy, including for resistant organisms and BL/BLI antibiotics.
- Rapid AST systems can provide timely, reliable susceptibility results directly from positive blood cultures, supporting stewardship.
- Implementation success and impact on time-to-result depend on integration into laboratory workflow.
Methodological Strengths
- Prospective, head-to-head evaluation within the same cohort of positive blood cultures
- Broad organism spectrum including resistant phenotypes and BL/BLI combinations
Limitations
- Abstract does not report detailed accuracy metrics (e.g., categorical agreement, error rates) for each platform
- Findings are contextualized to EUCAST-based workflows; generalizability may vary with other standards
Future Directions: Quantify clinical impact on time-to-effective therapy, mortality, and stewardship metrics in pragmatic trials, and assess cost-effectiveness and workflow integration across diverse laboratory settings.
UNLABELLED: Early antimicrobial susceptibility testing (AST) in Gram-negative (GN) bloodstream infections is critical to guide appropriate therapy. This study evaluated three rapid AST (RAST) systems-VITEK REVEAL, direct-from-blood-culture VITEK 2 (VITEK 2-RAST), and EUCAST disk diffusion (DD-RAST)-using 220 prospectively collected GN-positive blood cultures (GN-PBCs). A total of 18 GN species were tested, including IMPORTANCE: This study is the first to conduct a direct comparison of three rapid antimicrobial susceptibility testing (RAST) systems-VITEK REVEAL, VITEK 2-RAST, and DD-RAST-on a large, prospectively collected cohort of Gram-negative-positive blood cultures (GN-PBCs). The data offer valuable insights for laboratories evaluating RAST implementation, especially in EUCAST-based contexts. Among the systems tested, VITEK REVEAL stood out for its combination of rapid turnaround and high accuracy, including for antibiotic-resistant organisms and β-lactam/β-lactamase inhibitor (BL/BLI) antibiotics. These findings underscore the potential of RAST systems to deliver timely and reliable susceptibility results directly from GN-PBCs, thereby supporting more effective antimicrobial stewardship and clinical decision-making. However, the real-world impact will also depend on how well these systems integrate into routine workflows, as seamless implementation can directly affect time-to-result (TTR)-an essential element in optimizing the management of GN-bloodstream infection (BSI).
3. The amphiregulin- epidermal growth factor receptor axis as a therapeutic target in sepsis.
In a prospective ICU cohort (n=42) with adult sepsis, serum amphiregulin was strongly associated with in-hospital mortality (AUROC 0.87). Spectral flow cytometry characterized EGFR-expressing myeloid and lymphoid cell frequencies versus healthy volunteers, positioning the AREG–EGFR axis as a prognostic biomarker and potential therapeutic target.
Impact: This study provides first-in-adult evidence linking serum amphiregulin to mortality in sepsis with strong discriminative performance, bridging pediatric findings and highlighting a druggable pathway.
Clinical Implications: AREG could complement existing biomarkers for early risk stratification in sepsis and guide enrichment in interventional trials targeting the EGFR pathway.
Key Findings
- Serum amphiregulin demonstrated strong association with in-hospital mortality in adult sepsis (AUROC 0.87).
- Prospective analysis included 42 septic ICU patients and 20 healthy volunteers with spectral flow cytometry of EGFR-expressing immune cells.
- Findings extend prior infant data and nominate the AREG–EGFR axis as a prognostic biomarker and therapeutic target in adult sepsis.
Methodological Strengths
- Prospective design with inclusion of healthy volunteer controls
- Deep immunophenotyping using spectral flow cytometry alongside serum biomarker quantification
Limitations
- Small single-center cohort limits generalizability and precision of estimates
- Observational design precludes causal inference; external validation is needed
Future Directions: Validate AREG prognostic utility in larger, multicenter cohorts; test EGFR-pathway modulation in preclinical sepsis models; evaluate biomarker-guided trial enrichment strategies.
The Epidermal Growth Factor Receptor (EGFR) and its ligand, amphiregulin (AREG) are critical for epithelial cell proliferation but their important role in inflammation and infection is increasingly described. We recently discovered that the EGFR ligand, amphiregulin, could identify a cohort of infants with sepsis, even when CRP was low, identifying it as a potentially adjunctive biomarker for early infection. Its role in adult sepsis however, has yet to be delineated. We conducted a prospective observational study of 42 critically ill septic adult patients on the Intensive Care Unit, comparing serum amphiregulin levels and the frequencies of EGFR-expressing myeloid and lymphoid cells (using spectral flow cytometry) in sepsis survivors and non-survivors, and 20 healthy volunteers. We demonstrate, for the first time, the strong association between serum amphiregulin and in-hospital mortality (AUROC = 0.87). Moreover, we demonstrate that a higher frequency of circulating CD4