Daily ReportSep 24, 2026
Sepsis, September 24 edition
We read 51 papers and selected 3.
Summary
Today’s strongest sepsis papers span mechanistic biology, risk stratification, and treatment synthesis. A mouse-human study identified durable post-sepsis monocyte reprogramming as a mechanism of recurrent lung injury, while a large Kenyan neonatal cohort developed and externally validated mortality-risk clusters that outperformed WHO severity classification. An updated network meta-analysis of 21 randomized trials suggested that hydrocortisone-based regimens, particularly when combined with fludrocortisone, may improve survival but require careful adverse-event monitoring.
Research Themes
- Post-sepsis immune reprogramming and secondary organ injury
- Data-driven neonatal sepsis risk stratification
- Dose-specific corticosteroid therapy in septic shock
Selected Articles
1. Long-term reprogramming of classical monocytes with altered ontogeny mediates enhanced lung injury in sepsis survivors.
Using depletion and adoptive-transfer experiments, the investigators showed that post-sepsis monocytes were necessary and sufficient for enhanced lipopolysaccharide-induced lung injury and promoted neutrophil degranulation. Prior sepsis increased JAK-STAT signaling and AP-1 accessibility, shifted bone marrow progenitors toward a neutrophil-like monocyte lineage, and produced cells with increased interleukin-1β expression and impaired phagocytosis. Human survivor data showed predictive and molecularly concordant neutrophil-like monocyte signatures.
Impact: This study links persistent post-sepsis clinical vulnerability to a defined, experimentally testable alteration in monocyte ontogeny and function. It identifies a potential therapeutic window after apparent recovery, rather than treating sepsis only as an acute episode.
Clinical Implications: Patients recovering from sepsis may require surveillance for persistent immune dysregulation and recurrent respiratory complications. Monocyte-state biomarkers or interventions targeting JAK-STAT, AP-1, progenitor skewing, or neutrophil-monocyte interactions could eventually support post-sepsis risk stratification, but clinical testing is required before implementation.
Key Findings
- Post-sepsis monocytes were necessary and sufficient for enhanced secondary-challenge lung injury in mice.
- Prior sepsis reprogrammed monocytes through enhanced JAK-STAT signaling and AP-1 accessibility and shifted them toward a neutrophil-like lineage.
- Neutrophil-like monocytes showed increased interleukin-1β expression, reduced phagocytic capacity, and promotion of neutrophil degranulation.
- Monocyte transcriptional and proteomic signatures in human sepsis or pneumonia survivors predicted 90-day mortality and resembled the experimental neutrophil-like phenotype.
Methodological Strengths
- Integrated mechanistic experiments including monocyte depletion, adoptive transfer, lineage/ontogeny analysis, and molecular profiling.
- Cross-species validation connected mouse causal findings with human survivor transcriptional and proteomic data.
Limitations
- The principal causal experiments were performed in mice, and the human analyses were observational.
- The study does not establish whether reversing the monocyte program improves patient outcomes or identify a clinically actionable intervention.
- The specific contribution of infection type, treatment exposure, and comorbidities to the human monocyte phenotype remains uncertain.
Future Directions: Prospective studies should validate monocyte-state biomarkers after hospital discharge and test whether targeted modulation of progenitor skewing, JAK-STAT/AP-1 signaling, or monocyte-neutrophil interactions prevents recurrent lung injury. Interventional trials should incorporate patient phenotyping and clinically meaningful post-sepsis outcomes.
Patients who survive sepsis are predisposed to new hospitalizations for respiratory failure, but the underlying mechanisms are unknown. Using a murine model in which prior sepsis predisposes to enhanced lung injury, we previously discovered that classical monocytes persist in the lungs after long-term recovery from sepsis and exhibit enhanced cytokine expression after secondary challenge with intra-nasal lipopolysaccharide. Here, we hypothesized that immune reprogramming of post-sepsis monocytes and altered ontogeny predispose to enhanced lung injury.
2. A cluster analysis of neonates using clinical signs of possible serious bacterial infection at hospital admission in Kenya: A retrospective multicentre cohort study.
Latent class analysis of 33,094 neonates from eight Kenyan hospitals identified five mortality-risk clusters ranging from minimal to critical risk using admission data. In 23,704 neonates from 13 other hospitals, cluster membership prediction had at least 83.16% accuracy, 81.02% positive predictive value, and 86.91% specificity. Internal-external cross-validation showed excellent discrimination for in-hospital mortality, with an AUROC of 0.867 compared with 0.721 for WHO neonatal sepsis severity classification.
Impact: This study demonstrates that routinely observable admission signs can support clinically meaningful, externally validated neonatal risk stratification in resource-limited hospitals. It offers a pragmatic alternative to uniform broad-spectrum antibiotic management while preserving the need for clinical judgment.
Clinical Implications: The clusters could help identify neonates requiring urgent escalation, intensive monitoring, or referral, while supporting more targeted antibiotic decisions. Before implementation, prospective impact studies must determine whether cluster-guided care improves mortality, antibiotic exposure, referral efficiency, and equity across hospitals.
Key Findings
- Five neonatal clusters with minimal, low, moderate, substantial, and critical mortality risk were identified from admission pSBI signs.
- The model was externally validated in 23,704 neonates from 13 hospitals, with at least 83.16% accuracy and 86.91% specificity for cluster membership prediction.
- Internal-external cross-validation produced an AUROC of 0.867 for in-hospital mortality, outperforming the WHO neonatal sepsis severity classification AUROC of 0.721.
- The approach uses variables available at admission, improving potential generalisability to public hospitals in Sub-Saharan Africa.
Methodological Strengths
- Very large multicentre development cohort with validation in geographically and institutionally distinct hospitals.
- Used latent class analysis and internal-external cross-validation with discrimination and calibration assessment.
- Directly compared performance with the current WHO neonatal sepsis severity classification.
Limitations
- The study was retrospective and evaluated predictive performance rather than clinical impact on treatment or outcomes.
- The clusters were derived from neonates with at least one pSBI sign, so performance may not generalise to asymptomatic neonates or other populations.
- The abstract does not report whether cluster-guided management changes antibiotic exposure or mortality.
Future Directions: Prospective implementation trials should evaluate whether cluster-based triage and treatment pathways improve neonatal survival while reducing unnecessary broad-spectrum antibiotics. Studies should also assess calibration drift, fairness across hospitals and regions, and integration with referral and resource-allocation systems.
BACKGROUND: Neonatal sepsis remains a major cause of mortality in Sub-Saharan Africa (SSA). Despite presenting with considerable clinical heterogeneity, suspected cases are managed uniformly with broad-spectrum antibiotics. Typical data-driven approaches developed in high-resource settings to identify clinically meaningful phenotypes and support management of neonatal sepsis have limited generalisability to many SSA public hospital settings, due to inclusion of variables that are largely unavailable at admission. This study's objective was to identify sepsis clusters using signs of possible Serious Bacterial Infection (pSBI) readily available at the time of admission, and to assess the clusters performance in predicting mortality.
3. Comparative efficacy and safety of hydrocortisone-based regimens in septic shock: A network meta-analysis.
This PRISMA-compliant network meta-analysis included 21 randomized trials involving 7,908 adults with septic shock. Hydrocortisone at least 300 mg/day and hydrocortisone 200–299 mg/day combined with fludrocortisone 50 μg/day were associated with lower 28-day mortality than placebo, while higher hydrocortisone doses increased superinfection risk and all regimens showed a possible increase in gastrointestinal hemorrhage.
Impact: The study addresses a clinically unresolved question by comparing dose-specific and combination corticosteroid regimens rather than treating corticosteroids as a single intervention. Its findings may refine bedside selection of steroid strategies while highlighting the trade-off between survival benefit and infectious or gastrointestinal complications.
Clinical Implications: The results support consideration of hydrocortisone-based therapy, particularly hydrocortisone with adjunctive fludrocortisone, in selected adults with septic shock, but they do not establish a universal regimen. Clinicians should individualize treatment and monitor for superinfection and gastrointestinal bleeding until dose-specific head-to-head trials are available.
Key Findings
- Twenty-one randomized controlled trials involving 7,908 patients were included in the network meta-analysis.
- Hydrocortisone at least 300 mg/day was associated with lower 28-day mortality than placebo, with an odds ratio of 0.53 and 95% confidence interval of 0.29–0.96.
- Hydrocortisone 200–299 mg/day plus fludrocortisone 50 μg/day was associated with lower 28-day mortality than placebo, with an odds ratio of 0.78 and 95% confidence interval of 0.64–0.96.
- Higher-dose hydrocortisone increased superinfection risk, while gastrointestinal hemorrhage appeared more frequent across regimens, although estimates were imprecise.
Methodological Strengths
- Included randomized controlled trials and followed a prespecified PROSPERO-registered, PRISMA-compliant systematic review framework.
- Network meta-analysis enabled comparison of multiple hydrocortisone and fludrocortisone regimens, including dose-specific strategies.
- Evaluated both mortality and clinically important adverse outcomes.
Limitations
- The analysis was based on indirect comparisons across trials with potentially different populations, cointerventions, and definitions of septic shock.
- Higher hydrocortisone doses were associated with benefit, but dose-response conclusions may be influenced by between-study heterogeneity and risk of bias.
- The abstract does not provide detailed inconsistency, heterogeneity, or certainty-of-evidence assessments for each comparison.
- The findings are comparative associations and do not replace adequately powered, dose-specific head-to-head randomized trials.
Future Directions: Future trials should directly compare hydrocortisone doses with and without fludrocortisone, stratify patients by shock phenotype and corticosteroid responsiveness, and prespecify infection, gastrointestinal, neuromuscular, and long-term outcomes. Biomarker-guided trials could determine which patients derive net benefit.
BACKGROUND: The optimal corticosteroid regimen for septic shock, particularly the dosing and combination of hydrocortisone and fludrocortisone, remains uncertain due to inconsistent mortality findings across trials. METHODS: We conducted a PRISMA-compliant systematic review and network meta-analysis of randomized controlled trials evaluating hydrocortisone and/or fludrocortisone in adults with septic shock (PubMed, Embase, CENTRAL; inception-May 1, 2025; PROSPERO CRD420251015672). Interventions were grouped into six regimens (including placebo), and outcomes were analyzed using a frequentist random-effects model; the primary outcome was 28-day mortality.