Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent. Objectives: We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock. Methods: A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes. Measurements and Main Results: Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6–39.9). Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).

The aim of this study was to compare laparoscopic versus open live donor nephrectomy using meta-analytical techniques. Laparoscopic live donor nephrectomy has gained widespread acceptance and is increasingly performed. The body of evidence assessing the safety and efficacy of laparoscopic compared with established open techniques is growing; however, very few randomized control trials exist and individual studies often have small patient numbers with varying results. We combined the available raw data to strengthen the current literature in comparing these techniques. A literature search was performed and comparative studies published between 1997 and 2006 of open versus laparoscopic donor nephrectomy were included. Outcomes evaluated were operative and warm ischemia times, blood loss, donor complications, length of hospital stay, time to return to work, and delayed graft function. Seventy-three studies matched the selection criteria and included 6594 patients, 3751 (57%) had undergone laparoscopic surgery and 2843 (43%) open nephrectomy. The open nephrectomy group had shorter operative and warm ischemia times by 52 minutes (P < 0.001) and 102 seconds (P < 0.001), respectively. This did not translate into higher delayed graft function or graft loss rates between the 2 groups. Patients in the laparoscopic group had a shorter hospital stay and a faster return to work by 1.58 days (P < 0.001) and 2.38 weeks (P < 0.001), respectively. There was a significantly higher rate of overall donor complications in the open group (P = 0.007), a finding not reproduced in any subsequent sensitivity analyses. When only randomized control trials were considered, there were shorter operative times (P = 0.002) for the open group but nonsignificantly different warm ischemia times. In contrast to the main analysis there were no differences in the overall complication rate, postoperative analgesia, hospital stay, or time taken to return to work. Laparoscopic nephrectomy in live donor transplantation is a safe alternative to the open technique. Although open nephrectomy may be associated with shorter operative and warm ischemia times, patients undergoing laparoscopic nephrectomy may benefit from a shorter hospital stay and faster return to work without compromising graft function.

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.

Heterogeneity between critically ill patients with sepsis is a major barrier to the discovery of effective therapies. The use of machine learning techniques, coupled with improved understanding of sepsis biology, has led to the identification of patient subphenotypes. This exciting development may help overcome the problem of patient heterogeneity and lead to the identification of patient subgroups with treatable traits. Re-analyses of completed clinical trials have demonstrated that patients with different subphenotypes may respond differently to treatments. This suggests that future clinical trials that take a precision medicine approach will have a higher likelihood of identifying effective therapeutics for patients based on their subphenotype. In this review, we describe the emerging subphenotypes identified in the critically ill and outline the promising immune modulation therapies which could have a beneficial treatment effect within some of these subphenotypes. Furthermore, we will also highlight how bringing subphenotype identification to the bedside could enable a new generation of precision-medicine clinical trials.

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography–mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis.