Daily Sepsis Research Analysis
Multi-omics profiling in lung transplant recipients reveals a baseline immune state resembling severe COVID-19 and sepsis, linked to impaired SARS-CoV-2 mRNA vaccine responses. A mechanistic mouse study identifies acitretin as an NLRP3 inflammasome inhibitor that mitigates sepsis-induced acute lung injury. Longitudinal surveillance across 55 hospitals shows shifting epidemiology of catheter-related bacteremia toward peripheral devices, informing prevention strategies.
Summary
Multi-omics profiling in lung transplant recipients reveals a baseline immune state resembling severe COVID-19 and sepsis, linked to impaired SARS-CoV-2 mRNA vaccine responses. A mechanistic mouse study identifies acitretin as an NLRP3 inflammasome inhibitor that mitigates sepsis-induced acute lung injury. Longitudinal surveillance across 55 hospitals shows shifting epidemiology of catheter-related bacteremia toward peripheral devices, informing prevention strategies.
Research Themes
- Sepsis-like immunoparalysis and vaccine responsiveness in transplantation
- Inflammasome-targeted drug repurposing for sepsis-induced organ injury
- Healthcare-associated bacteremia surveillance and prevention priorities
Selected Articles
1. Altered baseline immunological state and impaired immune response to SARS-CoV-2 mRNA vaccination in lung transplant recipients.
Using systems immunology, the study shows that lung transplant recipients have a baseline immune state akin to sepsis and severe COVID-19 (high EN-RAGE/IL-6, low HLA-DR), and mount blunted antibody, B-cell, T-cell, and innate responses to mRNA vaccination. Single-cell and plasma analyses link these baseline features to impaired vaccine responsiveness.
Impact: This study unifies sepsis-like immunoparalysis and vaccine hyporesponsiveness in transplantation with multi-omics depth, providing mechanistic targets and stratification markers for precision immunization strategies.
Clinical Implications: Suggests individualized vaccine schedules, adjuncts (e.g., adjuvants), and immune monitoring (e.g., HLA-DR, EN-RAGE) in lung transplant recipients; informs risk assessment for infections including sepsis-like complications.
Key Findings
- Baseline immune profile in lung transplant recipients mirrors severe COVID-19/sepsis: high EN-RAGE (S100A12) and IL-6, reduced HLA-DR on monocytes/dendritic cells, impaired cytokine production, and elevated plasma microbial products.
- Single-cell RNA-seq reveals an expanded monocyte cluster with high S100A family expression and reduced cytokine/antigen presentation gene expression.
- Post-vaccination, antibody, B-cell, T-cell, and innate immune signatures are diminished compared to healthy controls.
- Integrative analysis links baseline immune dysregulation to impaired vaccine responses.
Methodological Strengths
- Multi-omics integration (plasma proteomics, single-cell RNA-seq, cellular phenotyping).
- Comparison with healthy controls and pre/post-vaccination profiling.
- Linking baseline immune states to functional vaccine responses.
Limitations
- Sample size and center-level details are not specified in the abstract, limiting assessment of generalizability.
- Observational design precludes causal inference; immunosuppressive regimens may confound associations.
Future Directions: Test immunomodulatory or adjuvant strategies to enhance vaccine responses; validate biomarkers (HLA-DR, EN-RAGE/S100A12) for risk stratification across transplant centers.
The effectiveness of COVID-19 mRNA vaccines is diminished in organ transplant patients. Using a multi-omics approach, we investigate the immunological state of lung transplant (LTX) recipients at baseline and after SARS-CoV-2 mRNA vaccination compared to healthy controls (HCs). LTX patients exhibit a baseline immune profile resembling severe COVID-19 and sepsis, characterized by elevated pro-inflammatory cytokines (e.g., EN-RAGE [also known as S100A12], interleukin [IL]-6), reduced human leukocyte antigen (HLA)-DR expression on monocytes and dendritic cells, impaired cytokine production, and increased plasma microbial products. Single-cell RNA sequencing identifies an enriched monocyte cluster in LTX patients marked by high S100A family expression and reduced cytokine and antigen presentation genes. Post vaccination, LTX patients show diminished antibody, B cell, and T cell responses, along with blunted innate immune signatures. Integrative analysis links these altered baseline immunological features to impaired vaccine responses. These findings provide critical insights into the immunosuppressed condition of LTX recipients and their reduced vaccine-induced adaptive and innate immune responses.
2. Modulating the NLRP3 Inflammasome: Acitretin as a potential treatment for Sepsis-induced acute lung injury.
Acitretin, a clinically used retinoid, suppresses NLRP3 inflammasome activation by blocking ASC oligomerization, thereby reducing IL-1β maturation and pyroptosis. In LPS-induced sepsis models, it mitigates acute lung injury and improves survival, with effects dependent on NLRP3/GSDMD signaling.
Impact: Demonstrates a mechanistic basis for repurposing acitretin as an inflammasome-targeted therapy in sepsis-induced lung injury, validated with genetic knockouts and transcriptomics.
Clinical Implications: While preclinical, findings support exploring acitretin in early-phase trials for sepsis-related lung injury or hyperinflammation, with careful safety and dosing evaluation.
Key Findings
- Acitretin reduced mortality and attenuated lung inflammation and edema in LPS-induced septic mice.
- Transcriptomics and in vitro assays showed suppression of the NLRP3 inflammasome pathway, with decreased IL-1β, caspase-1 p20, and GSDMD cleavage.
- Acitretin blocked ASC oligomerization and interaction with NLRP3, inhibiting inflammasome assembly.
- Protective effects were lost in Nlrp3 and Gsdmd knockout mice, confirming target dependence.
Methodological Strengths
- Convergent in vivo and in vitro evidence with dose-response testing.
- Use of Nlrp3 and Gsdmd knockout mice to establish pathway dependence.
- Transcriptome sequencing to identify and confirm pathway modulation.
Limitations
- Relies on LPS-induced models; lacks polymicrobial or CLP models of sepsis.
- No pharmacokinetic/safety data in sepsis context; clinical translatability and dosing remain unknown.
Future Directions: Validate efficacy in polymicrobial sepsis (e.g., CLP), assess lung-targeted delivery, and conduct early-phase clinical trials with biomarker-guided selection (IL-1β, inflammasome signatures).
BACKGROUND: Acitretin, a well-established dermatological drug primarily used for psoriasis treatment, has been clinically used for several decades. However, its potential role in modulating inflammation in sepsis remains unexplored. OBJECTIVE: This study seeks to explore the impact of acitretin on sepsis-induced acute lung injury (ALI) and to elucidate the underlying mechanisms involved. METHODS: In a mouse model of sepsis induced by lipopolysaccharide (LPS), we assessed the effects of acitretin on ALI. Transcriptome sequencing of lung tissue was performed to identify relevant signaling pathways. In vitro, bone marrow-derived macrophages (BMDMs) were treated with acitretin (1 μM, 5 μM and 10 μM) to evaluate its impact on NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome activation and pyroptosis. In vivo, wild-type, Nlrp3 knockout, and Gsdmd knockout mice were used to confirm the role of the NLRP3 inflammasome in mediating acitretin's effects. RESULTS: Acitretin significantly mitigated sepsis-induced ALI, reducing mortality in LPS-challenged mice. Transcriptome analysis revealed that acitretin suppressed the NLRP3 inflammasome pathway in lung tissue. In vitro, acitretin dose-dependently inhibited interleukin (IL)-1β release, caspase-1 p20 production, and GSDMD cleavage in BMDMs. Furthermore, acitretin inhibited inflammasome activation by preventing ASC oligomerization and its interaction with NLRP3. In vivo, acitretin reduced lung tissue inflammation, IL-1β levels in bronchoalveolar lavage fluid, and the ratio of wet to dry in wide-type mice, but these effects were abolished in Nlrp3 and Gsdmd knockout mice. CONCLUSION: Acitretin demonstrated significant anti-inflammatory properties through the suppression of the NLRP3 inflammasome, suggesting its potential as a therapeutic strategy for sepsis and related complications.
3. Surveillance of catheter-related bacteremia in VINCat program.
A 15-year, 55-hospital surveillance cohort (10,212 CRB episodes) shows declining ICU/central-line CRB but significant increases in peripheral venous and PICC-associated bacteremia. Findings refocus prevention on peripheral devices, especially in non-ICU wards.
Impact: High-quality, multicenter longitudinal surveillance identifies a shift toward peripheral-device bacteremia, directly informing infection prevention priorities and sepsis reduction strategies.
Clinical Implications: Implement targeted bundles for peripheral IVs and PICCs (asepsis, dwell time, securement, surveillance) in non-ICU settings; sustain central-line bundle adherence in ICUs.
Key Findings
- 55 hospitals (2008–2023) reported 10,212 nosocomial CRB episodes; overall incidence 0.21/1000 patient-days (ICU 1.13; medical 0.16; surgical 0.15).
- Gram-positive organisms caused 68.3% of CRB episodes.
- ICU-acquired and central venous catheter-associated CRB rates decreased over time, while peripheral venous catheter and PICC-associated CRB significantly increased (p<0.001).
Methodological Strengths
- Large, multicenter, longitudinal surveillance with standardized incidence metrics.
- Stratified analyses across care areas and device types with IRR comparisons.
Limitations
- Surveillance data may be affected by underreporting or changes in diagnostics and documentation over time.
- Limited patient-level covariates restrict adjustment for confounders and severity.
Future Directions: Develop and evaluate PVC/PICC-specific prevention bundles and monitor outcomes with standardized metrics; explore device- and unit-level risk factors.
BACKGROUND: Catheter-related bacteremia (CRB) is one of the most frequent infections acquired during hospitalization. We summarize the results of CRB surveillance conducted by the Catalan Program of Surveillance of Nosocomial Infections (VINCat) over the past fifteen years. METHODS: All episodes of hospital-acquired CRB diagnosed in the 55 Catalan hospitals participating in the VINCat program (2008-2023) were recorded. Annual incidence rates per 1000 patient-days were calculated. Analyses were stratified into three relevant five-year periods: 2008-2012, 2013-2017, and 2018-2022. Incidence rate ratios (IRRs) were used to compare infection rates. RESULTS: During the study period, 10,212 episodes of nosocomial CRB were diagnosed. The global incidence rate was 0.21 episodes per 1000 patient-days (intensive care units (ICUs): 1.13; medical wards: 0.16; surgical wards: 0.15). Gram-positive bacteria caused 68.3% of the episodes. The incidence rate of CRB acquired in ICUs and that of CRB associated with central venous catheters decreased during the study period, while episodes associated with peripheral venous catheters (PVCs) and peripherally-inserted central venous catheters (PICVCs) significantly increased (p<0.001). CONCLUSIONS: The current study underscores the necessity for interventional programs targeting PVCs, particularly in non-ICU wards.