Daily Sepsis Research Analysis
Three impactful sepsis papers emerged: a prospective multicenter Japanese cohort details the heavy 1-year burden of post-intensive care syndrome among sepsis survivors; a Critical Care study shows procalcitonin is unreliable for distinguishing sepsis in AKI/ESKD patients undergoing CKRT; and a mechanistic study demonstrates BCG-induced trained immunity improves neonatal survival in polymicrobial sepsis by broad myelopoiesis reprogramming.
Summary
Three impactful sepsis papers emerged: a prospective multicenter Japanese cohort details the heavy 1-year burden of post-intensive care syndrome among sepsis survivors; a Critical Care study shows procalcitonin is unreliable for distinguishing sepsis in AKI/ESKD patients undergoing CKRT; and a mechanistic study demonstrates BCG-induced trained immunity improves neonatal survival in polymicrobial sepsis by broad myelopoiesis reprogramming.
Research Themes
- Post-sepsis survivorship and PICS burden
- Biomarker validity in sepsis with renal failure (CKRT)
- Trained immunity and neonatal host defense in sepsis
Selected Articles
1. One-year outcomes in sepsis: a prospective multicenter cohort study in Japan.
In 339 Japanese ICU patients with sepsis (median age 74; 77% septic shock), mortality reached 37% by 12 months and death or PICS occurred in roughly two-thirds across follow-up. Readmissions and emergency use were frequent, while rehabilitation and psychiatric service utilization were low; prior dysfunction predicted subsequent dysfunction.
Impact: This is a rigorous prospective multicenter study quantifying 1-year mortality and PICS burden in sepsis survivors, revealing critical care pathways gaps in rehabilitation and mental health support.
Clinical Implications: Implement structured post-sepsis follow-up with early rehabilitation and mental health screening, and target interventions to those with early PICS-related dysfunction to prevent persistence.
Key Findings
- 12-month mortality was 37% after sepsis ICU admission; hospital discharge mortality was 23%.
- Death or PICS occurred in 73%, 64%, and 65% at 3, 6, and 12 months, respectively.
- High healthcare utilization (40% readmissions; 31% emergency visits) with low rehabilitation (15%) and psychiatric service (7%) use.
- PICS-related dysfunction independently predicted the same dysfunction at subsequent follow-ups.
Methodological Strengths
- Prospective multicenter cohort with Sepsis-3 criteria and standardized 3-, 6-, 12-month follow-up.
- Multivariable analyses linking dysfunction trajectories across time points.
Limitations
- Single-country cohort may limit generalizability.
- Telephone/mail follow-up risks response bias and missing data; observational design precludes causal inference.
Future Directions: Test structured post-ICU rehabilitation and mental health programs in pragmatic trials and develop risk-stratified pathways based on early PICS indicators.
BACKGROUND: Sepsis is a leading cause of death in intensive care units (ICU). Sepsis survivors are often left with significant morbidity, termed post-intensive care syndrome (PICS), impacting post-sepsis life. The aim was to present detailed data on the prognostic and functional long-term outcomes of ICU patients with sepsis in Japan, which is currently lacking and therefore prevents development of targeted solutions. METHODS: A multicenter prospective study, involving 21 ICUs in 20 tertiary hospitals in Japan, included all consecutive adult ICU patients between November 2020 and April 2022, and diagnosed with sepsis at ICU admission (Sepsis 3). Follow-ups were performed at 3, 6, and 12 months after hospital discharge by telephone and mail. Primary outcome was death or incidence of PICS, defined by any of physical dysfunction (Barthel Index ≤ 90), cognitive dysfunction (Short Memory Questionnaire < 40), or mental disorder (any subscales for anxiety or depression of Hospital Anxiety and Depression Scale ≥ 8, or Impact of Event Scale-Revised ≥ 25). Secondary outcomes included Quality of Life (QOL), employment, and use of hospital, emergency, rehabilitation, and psychiatric services. A multivariable analysis investigated independent factors associated with each dysfunction at each follow-up. RESULTS: A total of 339 patients were included (median age 74 [67-82] years, 60% male, 77% septic shock, and a median SOFA of 9 [6-12]). Mortality was 23% at hospital discharge, increasing to 37% at 12 months. The rate of death for those who met PICS Criteria at hospital discharge was 89%, with a death or PICS incidence of 73%, 64%, and 65% at 3, 6, and 12 months, respectively. Limited improvements in QOL and return to work (44%), high rates of hospital readmissions (40%), frequent emergency service usage (31%), and low utilization of rehabilitation and psychiatric services (15% and 7%) were identified over the first year. The incidence of any PICS-related dysfunction was consistently an independent factor for the incidence of the same dysfunction at the following follow-ups. CONCLUSIONS: This multicenter study identified the distinct realities of post-sepsis life in Japanese ICU patients, highlighting the unique challenges in improving their functions and returning to daily life. Trial Registration University Hospital Medical Information Network UMIN000041433.
2. Innate immune training in the neonatal response to sepsis.
BCG vaccination increased survival in neonatal polymicrobial sepsis by broadly reprogramming myelopoiesis, expanding multiple myeloid subsets beyond emergency granulopoiesis. These data support trained immunity as a systems-level mechanism for neonatal host defense.
Impact: Provides mechanistic evidence that trained immunity via BCG can enhance neonatal resistance to sepsis by reconfiguring myelopoiesis, potentially informing vaccine-based preventive strategies.
Clinical Implications: While preclinical, findings motivate evaluation of timing and use of BCG or trained-immunity-based approaches to reduce neonatal sepsis mortality, especially in high-risk settings.
Key Findings
- BCG vaccination improved survival in neonatal polymicrobial sepsis models.
- Trained immunity involved broad reprogramming of myelopoiesis, expanding multiple myeloid subsets.
- Findings extend beyond emergency granulopoiesis, indicating systems-level innate immune training.
Methodological Strengths
- Mechanistic in vivo study linking a defined intervention (BCG) to survival outcomes.
- Integration of immunologic profiling to demonstrate myelopoiesis reprogramming.
Limitations
- Preclinical neonatal models limit direct clinical generalizability.
- Partial mechanistic pathways may remain undefined; human validation required.
Future Directions: Design controlled human studies to test BCG timing/dosing for neonatal sepsis prevention and dissect cell-intrinsic epigenetic programs underlying trained myelopoiesis.
Neonates, especially those born prematurely, are highly vulnerable to infection-induced mortality. Numerous observational and immunological studies in newborns have shown that live attenuated vaccines have beneficial, non-specific effects (NSEs) against secondary infections to unrelated pathogens. These beneficial effects have been attributed to trained immunity, and emergency granulopoiesis plays an essential role. However, trained immunity has been shown to affect multiple myeloid subsets and how trained immunity influences the host protective response is still undefined. Here we show that Bacillus-Calmette-Guérin (BCG) vaccination improves survival to polymicrobial sepsis by simultaneously reprogramming broad aspects of myelopoiesis. Specifically, BCG vaccination expands multiple myeloid subsets, including the lineage (Lin)
3. Procalcitonin levels in septic and nonseptic subjects with AKI and ESKD prior to and during continuous kidney replacement therapy (CKRT).
In 41 AKI/ESKD patients (111 samples), nonseptic individuals frequently had procalcitonin ≥0.5 ng/mL; no ROC cutoff distinguished sepsis status before or during CKRT. Effluent levels were ~20% of plasma, but plasma procalcitonin did not decline over 3 days, indicating limited diagnostic utility in kidney failure.
Impact: Provides actionable evidence against using procalcitonin to diagnose sepsis in AKI/ESKD patients on CKRT, reducing misclassification and unnecessary antibiotic exposure.
Clinical Implications: Avoid relying on procalcitonin for sepsis diagnosis in kidney failure and CKRT; base decisions on clinical assessment and alternative diagnostics.
Key Findings
- 92% of nonseptic measurements in AKI/ESKD were ≥0.5 ng/mL, undermining specificity.
- No ROC cutoff reliably separated septic from nonseptic status before or during CKRT.
- Effluent procalcitonin was ~20% of plasma (sieving coefficient ~0.2), yet plasma levels did not significantly decline over days 1–3 of CKRT.
Methodological Strengths
- Stringent culture-based sepsis definition with serial plasma and effluent measurements.
- Direct assessment of CKRT clearance (sieving coefficient) alongside diagnostic performance.
Limitations
- Single-center retrospective cohort with small sample size limits generalizability.
- Potential confounders (e.g., inflammation severity, antibiotic timing) cannot be fully controlled.
Future Directions: Prospective multicenter validation and evaluation of alternative biomarkers or panels for sepsis diagnosis in kidney failure and CKRT settings.
BACKGROUND: Procalcitonin is a 14.5 kDa protein used clinically as a marker of sepsis and therapeutic response to antibiotic therapy. However, its utility in critically ill patients with either acute kidney injury (AKI) or end-stage kidney disease (ESKD) who require continuous kidney replacement therapy (CKRT) is unknown. The aim of this study was to determine if plasma levels of procalcitonin could reliably distinguish septic from nonseptic status in patients with AKI or ESKD prior to or during CKRT. METHODS: Procalcitonin concentrations were measured in plasma of 41 critically ill septic or non-septic subjects with AKI or ESKD prior to CKRT (pre-CKRT) and on days 1, 2, and 3 of CKRT in this retrospective cohort study (n = 111 total plasma measurements). Continuous venovenous hemodialysis was the modality of CKRT in these patients. Sepsis status was stringently defined based on culture results. Effluent procalcitonin levels were ascertained on days 1, 2, and 3 of CKRT to assess the clearance of procalcitonin and effects on plasma levels. RESULTS: 92% (66/72) of the plasma procalcitonin measurements among nonseptic patients with either AKI or ESKD were ≥ 0.5 ng/mL (the diagnostic threshold beyond which bacterial infection is very likely). Prior to CKRT initiation, procalcitonin levels were (median (IQR), ng/mL) 5.6 (1.5-18.9) in nonseptic AKI and 58.1 (6.9-195.5) in septic AKI (P = 0.03) and were 3.3 (1.2-8.3) in nonseptic ESKD and 3.7 (1.4-209.8) in septic ESKD (P = 0.79). However, despite being significantly elevated in septic patients with AKI, substantial overlap among procalcitonin levels was present and ROC curve analysis found no cut point that could reliably separate septic from nonseptic patients. Effluent procalcitonin levels were consistently ~ 20% of plasma levels throughout the course of CKRT (i.e., sieving coefficient was 0.2) suggesting that clearance occurs during therapy. However, plasma procalcitonin levels did not significantly decline during CKRT in either AKI or ESKD. CONCLUSION: Procalcitonin levels are markedly elevated in nonseptic critically ill patients with either AKI or ESKD and do not effectively distinguish sepsis from nonseptic status prior to or during CKRT. We conclude that procalcitonin testing should be avoided in critically ill patients with kidney failure since results are nonspecific in this population.