Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Currently, the incidence and fatality rate of SARS-CoV-2 remain continually high worldwide. COVID-19 patients infected with SARS-CoV-2 exhibited decreased type I interferon (IFN-I) signal, along with limited activation of antiviral immune responses as well as enhanced viral infectivity. Dramatic progresses have been made in revealing the multiple strategies employed by SARS-CoV-2 in impairing canonical RNA sensing pathways. However, it remains to be determined about the SARS-CoV-2 antagonism of cGAS-mediated activation of IFN responses during infection. In the current study, we figure out that SARS-CoV-2 infection leads to the accumulation of released mitochondria DNA (mtDNA), which in turn triggers cGAS to activate IFN-I signaling. As countermeasures, SARS-CoV-2 nucleocapsid (N) protein restricts the DNA recognition capacity of cGAS to impair cGAS-induced IFN-I signaling. Mechanically, N protein disrupts the assembly of cGAS with its co-factor G3BP1 by undergoing DNA-induced liquid-liquid phase separation (LLPS), subsequently impairs the double-strand DNA (dsDNA) detection ability of cGAS. Taken together, our findings unravel a novel antagonistic strategy by which SARS-CoV-2 reduces DNA-triggered IFN-I pathway through interfering with cGAS-DNA phase separation.

Background: Immunosuppression is a risk factor for poor prognosis of critically ill patients, but current monitoring of the immune status in clinical practice is still inadequate. Absolute lymphocyte count (ALC) is not only a convenient biomarker for immune status monitoring but is also suitable for clinical application. In this study, we aimed to explore different trajectories of ALC, and evaluate their relationship with prognosis in critically ill patients.Methods: We retrospectively enrolled 10,619 critically ill patients admitted to a general intensive care unit (ICU) with 56 beds from February 2016 to May 2020. Dynamic ALC was defined as continuous ALC from before ICU admission to 5 days after ICU admission. Initial ALC was defined as the minimum ALC within 48 h after ICU admission. Group-based trajectory modeling (GBTM) was used to group critically ill patients according to dynamic ALC. Multivariate cox regression model was used to determine the independent association of trajectory endotypes with death and persistent inflammation, immunosuppression, catabolism syndrome (PICS).Results: A total of 2022 critically ill patients were unsupervisedly divided into four endotypes based on dynamic ALC, including persistent lymphopenia endotype (n = 1,211; 58.5%), slowly rising endotype (n = 443; 22.6%), rapidly decreasing endotype (n = 281; 14.5%) and normal fluctuation endotype (n = 87; 4.4%). Among the four trajectory endotypes, the persistent lymphopenia endotype had the highest incidence of PICS (24.9%), hospital mortality (14.5%) and 28-day mortality (10.8%). In multivariate cox regression model, persistent lymphopenia was associated with increased risk of 28-day mortality (HR: 1.54; 95% CI: 1.06–2.23), hospital mortality (HR: 1.66; 95% CI: 1.20–2.29) and PICS (HR: 1.79; 95% CI: 1.09–2.94), respectively. Sensitivity analysis further confirmed that the ALC trajectory model of non-infected patients and non-elderly patients can accurately distinguished 91 and 90% of critically ill patients into the same endotypes as the original model, respectively.Conclusion: The ALC trajectory model is helpful for grouping critically ill patients, and early persistent lymphopenia is associated with poor prognosis. Notably, persistent lymphopenia may be a robust signal of immunosuppression in critically ill patients.

Objective To evaluate whether the immunomodulatory drug thymosin α1 reduces mortality in adults with sepsis. Design Multicentre, double blinded, placebo controlled phase 3 trial. Setting 22 centres in China, September 2016 to December 2020. Participants 1106 adults aged 18-85 years with a diagnosis of sepsis according to sepsis-3 criteria and randomly assigned in a 1:1 ratio to receive thymosin α1 (n=552) or placebo (n=554). A stratified block method was used for randomisation, and participants were stratified by age (<60 and ≥60 years) and centre. Interventions Subcutaneous injection of thymosin α1 or placebo every 12 hours for seven days unless discontinued owing to discharge from the intensive care unit, death, or withdrawal of consent. Main outcome measure The primary outcome was 28 day all cause mortality after randomisation. All analyses were based on a modified intention-to-treat set, including participants who received at least one dose of study drug. Results Of 1106 adults with sepsis enrolled in the study, 1089 were included in the modified intention-to-treat analyses (thymosin α1 group n=542, placebo group n=547). 28 day all cause mortality occurred in 127 participants (23.4%) in the thymosin α1 group and 132 (24.1%) in the placebo group (hazard ratio 0.99, 95% confidence interval 0.77 to 1.27; P=0.93 with log-rank test). No secondary or safety outcome differed statistically significantly between the two groups. The prespecified subgroup analysis showed a potential differential effect of thymosin α1 on the primary outcome based on age (<60 years: hazard ratio 1.67, 1.04 to 2.67; ≥60 years: 0.81, 0.61 to 1.09; P for interaction=0.01) and diabetes (diabetes: 0.58, 0.35 to 0.99; no diabetes: 1.16, 0.87 to 1.53; P for interaction=0.04). Conclusions This trial found no clear evidence to suggest that thymosin α1 decreases 28 day all cause mortality in adults with sepsis. Trial registration ClinicalTrials.gov NCT02867267.

Spatiotemporal separation of cellular components is vital to ensure biochemical processes. Membrane-bound organelles such as mitochondria and nuclei play a major role in isolating intracellular components, while membraneless organelles (MLOs) are accumulatively uncovered via liquid-liquid phase separation (LLPS) to mediate cellular spatiotemporal organization. MLOs orchestrate various key cellular processes, including protein localization, supramolecular assembly, gene expression, and signal transduction. During viral infection, LLPS not only participates in viral replication but also contributes to host antiviral immune responses. Therefore, a more comprehensive understanding of the roles of LLPS in virus infection may open up new avenues for treating viral infectious diseases. In this review, we focus on the antiviral defense mechanisms of LLPS in innate immunity and discuss the involvement of LLPS during viral replication and immune evasion escape, as well as the strategy of targeting LLPS to treat viral infectious diseases.

Purpose: Targeted next-generation sequencing (tNGS) has emerged as an advanced diagnostic technique. While tNGS is increasingly recognized as a valuable tool for detecting infections, its most relevant clinical indications remain underdefined. This study aimed to evaluate the clinical utility of tNGS for lower respiratory tract infections (LRTIs). Methods: We conducted a prospective, observational study to evaluate the clinical diagnostic value of broad-spectrum targeted Next-Generation Sequencing (bstNGS) covering 1872 microorganisms in critically ill patients with LRTIs. We compared the microbial detection performance of bstNGS, mNGS, and traditional culture methods in bronchoalveolar lavage fluid (BALF). Additionally, we used the odds ratio (OR) from multiple logistic regression to assess the impact of relevant clinical variables on the detection of pathogens by bstNGS. We also examined the correlation between bstNGS pathogen detection results and clinical outcomes. Results: Between August 23, 2023, and April 24, 2024, samples from 150 patients were analyzed. bstNGS detected 96.33% and 91.15% of the microorganisms discovered by mNGS and culture respectively, and was capable of identifying microorganisms with even lower loads. According to the diagnostic criteria, bstNGS, mNGS, and culture methods detected pathogens in 87.33%, 82.00%, and 46.00% of the samples respectively. Moreover, the NGS methods demonstrated a stronger pathogen detection ability compared to culture (p < 0.05). Further comparing the diagnostic performance of the three methods, bstNGS exhibited higher diagnostic accuracy than both mNGS (90.67% vs 86.00%, p < 0.05) and culture (90.67% vs 49.33%, p < 0.0001). Multivariate analysis revealed that immunocompromise was associated with a lower efficiency of pathogen detection by bstNGS (p = 0.04), while other included clinical features had no significant correlation with bstNGS detection. Additionally, compared with patients in whom no pathogen was detected, patients in whom a pathogen was detected by bstNGS were associated with better outcomes of antibiotic treatment (89.68% vs. 62.50%; OR 7.53, 95% CI 1.41–45.30; p = 0.02). Conclusion: This study shows the effectiveness of bstNGS in detecting pathogens of LRTIs, as well as its value as a potential auxiliary diagnostic method in the ICU.