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Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. In this review, we discuss mechanisms of sepsis-induced immunosuppression and biomarkers that identify a state of impaired immunity. We also highlight immune-enhancing strategies that have been evaluated in patients with sepsis, as well as therapeutics under current investigation. Finally, we describe future challenges and the need for a new treatment paradigm, integrating predictive enrichment with patient factors that may guide the future selection of tailored immunotherapy. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The spouse of MEC is a cofounder and shareholder and serves on the Scientific Advisory Board of Proterris Inc. AMKC is a cofounder and stockholder and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. AMKC also has a use patent on (no. 7,678,390) carbon monoxide.

BACKGROUND: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it.METHODS: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a PaO 2 to FIO 2 ratio (PaO 2 :FIO 2 ) > 300 on the first study day following enrollment. RESULTS:The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. PaO 2 :FIO 2 at screening, change in PaO 2 :FIO 2 from screening to enrollment, use of vasopressor agents, FIO 2 at enrollment, and serum bilirubin levels were useful predictive variables.CONCLUSIONS: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials.

BACKGROUND: Moderate hypothermia (temperature ,36°C) at birth is common in premature infants and is associated with increased mortality and morbidity.METHODS: A multidisciplinary practice plan was implemented to determine in premature infants ,35 weeks old whether a multifaceted approach would reduce the number of inborn infants with an admitting axillary temperature ,36°C by 20% without increasing exposure to a temperature .37.5°C. The plan included use of occlusive wrap a transwarmer mattress and cap for all infants and maintaining an operating room temperature between 21°C and 23°C. Data were obtained at baseline (n = 66), during phasing in (n = 102), and at full implementation (n = 193).RESULTS: Infant axillary temperature in the delivery room (DR) increased from 36.1°C 6 0.6°C to 36.2°C 6 0.6°C to 36.6°C 6 0.6°C (P , .001), and admitting temperature increased from 36.0°C 6 0.8°C to 36.3°C 6 0.6°C to 36.7°C 6 0.5°C at baseline, phasing in, and full implementation, respectively (P , .001). The number of infants with temperature ,36°C decreased from 55% to 6.2% at baseline versus full implementation (P , .001), and intubation at 24 hours decreased from 39% to 17.6% (P = .005). There was no increase in the number of infants with a temperature .37.5°C over time. The use of occlusive wrap, mattress, and cap increased from 33% to 88% at baseline versus full implementation. Control charts showed significant improvement in DR ambient temperature at baseline versus full implementation. CONCLUSIONS:The practice plan was associated with a significant increase in DR and admitting axillary infant temperatures and a corresponding decrease in the number of infants with moderate hypothermia. There was an associated reduction in intubation at 24 hours. These positive findings reflect increased compliance with the practice plan. Dr Russo helped develop the practice plan and the algorithms, helped collect and oversee the data, and was involved in writing the manuscript; Ms McCready and Ms Venturini helped develop the practice plan and the algorithms and were involved in writing the manuscript; Ms Torres helped develop the practice plan and the algorithms, facilitated temperature regulation of the operating room and implementation of the practice plan in labor and delivery, and was involved in writing the manuscript; Ms Theuriere helped develop the practice plan and the algorithms and in review of the data and was involved in writing the manuscript; Dr Spaight helped in the data collection and was involved in writing the manuscript; Ms Hemway helped develop the practice plan and collect data and was involved in writing the manuscript; Ms Handrinos helped develop the practice plan; Ms Perlmutter and Drs Huynh and Grunebaum helped develop the practice plan and were involved in writing the manuscript; Dr Perlman was involved in developing and implementing the practice plan, conceptualized and designed the study, contributed to design of the analyses and interpretation of the results, and took the lead in drafting the init...

Linear binding of IgG to the glomerular basement membrane (GBM) is the hallmark of anti-GBM glomerulonephritis (GN).However, the precise mechanism by which diverse autoantibodies to GBM are induced in GN has not been determined.

Background Sepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis. Methods We created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies. Results A total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n = 612, 13.1%), Delayed Worsening (n = 960, 20.5%), Rapidly Improving (n = 1932, 41.3%), and Delayed Improving (n = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P-value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers. Conclusions Four novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.

AMKC is a cofounder, stockholder, and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. AMKC also has a use patent on CO. AMKC served as a consultant at Teva Pharmaceuticals in July 2018.