Sepsis

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.

Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.

To define the terms "sepsis" and "organ failure" in a precise manner.

Ryan M. Brown, Li Wang, Taylor D. Coston, Nathan I. Krishnan, Jonathan D. Casey, Jonathan P. Wanderer, Jesse M. Ehrenfeld, Daniel W. Byrne, Joanna L. Stollings, Edward D. Siew, Gordon R. Bernard, Wesley H. Self, Todd W. Rice, Matthew W. Semler

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 12, Page 1487-1495, December 15, 2019. …

Paul J. Young

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 12, Page 1456-1458, December 15, 2019. …

Binnie, Alexandra; Walsh, Christopher J.; Hu, Pingzhao; Dwivedi, Dhruva J.; Fox-Robichaud, Alison; Liaw, Patricia C.; Tsang, Jennifer L. Y.; Batt, Jane; Carrasqueiro, Gabriela; Gupta, Sahil; Marshall, John C.; Castelo-Branco, Pedro; dos Santos, Claudia C.; for the Epigenetic Profiling in Severe Sepsis (EPSIS) Study of the Canadian Critical Care Translational Biology Group (CCCTBG)

Objectives: Epigenetic alterations are an important regulator of gene expression in health and disease; however, epigenetic data in sepsis are lacking. To demonstrate proof of concept and estimate effect size, we performed the first epigenome-wide methylation analysis of whole blood DNA samples from a cohort of septic and nonseptic critically ill patients. Design: A nested case-control study using genomic DNA isolated from whole blood from septic (n = 66) and nonseptic (n = 68) critically ill patients on “Day 1” of ICU admission. Methylation patterns were identified using Illumina 450K arrays with percent methylation expressed as β values. After quality control, 134 participants and 414,818 autosomal cytosine-phosphate-guanine sites were used for epigenome-wide methylation analyses. Setting: Tertiary care hospitals. Subjects: Critically ill septic and nonseptic patients. Interventions: Observational study. Measurements and Main Results: A total of 668 differentially methylated regions corresponding to 443 genes were identified. Known sepsis-associated genes included complement component 3; angiopoietin 2; myeloperoxidase; lactoperoxidase; major histocompatibility complex, class I, A; major histocompatibility complex, class II, isotype DR β I; major histocompatibility complex, class I, C; and major histocompatibility complex, class II, isotype DQ β I. When compared with whole blood gene expression data from seven external datasets containing septic and nonseptic patients, 81% of the differentially methylated region–associated genes were differentially expressed in one or more datasets and 31% in three or more datasets. Functional analysis showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion, and cell junctions. Analysis by weighted gene coexpression network analysis revealed DNA comethylation modules that were associated with clinical traits including severity of illness, need for vasopressors, and length of stay. Conclusions: DNA methylation marks may provide important causal and potentially biomarker information in critically ill patients with sepsis. Drs. Binnie, Walsh, Castelo-Branco, and dos Santos contributed equally to this work. Drs. Binnie, Dwivedi, Liaw, Tsang, Marshall, Castelo-Branco, and dos Santos designed the study. Drs. Dwivedi, Fox-Robichaud, and Liaw and Mr. Gupta collected the clinical specimens. Drs. Binnie, Walsh, Hu, and Batt, Ms. Carrasqueiro, and Drs. Castelo-Branco and dos Santos performed the analysis and interpretation of the data. All authors contributed to drafting the article and revising it critically for intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the McLaughlin Foundation Accelerator Grant in Genomic Medicine and Health Informatics (2015–2016) and Canadian Institutes of Health Research (grant number: MOP-130331 to Dr. dos Santos). Dr. Walsh disclosed that he is the recipient of the Canadian Thoracic Society Research Committee of The Lung Association Studentship award. Dr. Fox-Robichaud’s institution received funding from the Canadian Institute of Health Research (CIHR), CIHR/Natural Sciences and Engineering Research Council of Canada, Hamilton Academic Health Sciences Organization, and ICU Medical. Dr. Liaw’s institution received funding from CIHR; she received support for article research from the CIHR; and she disclosed government funding. The remaining authors have disclosed that they do not have any potential conflicts of interest. The dataset used in the current study is available from the corresponding author on reasonable request. Informed consent was obtained from all participants and the study received ethical approval from the two participating institutions: Hamilton General Hospital and St Joseph’s Healthcare Hamilton. The participants/patients have given their consent for their data to be published in the report. For information regarding this article, E-mail: dossantosc@smh.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Zhang H, Li H, Shaikh A, et al.

The authors retract the article titled “Inhibition of microRNA-23b attenuates immunosuppression during late sepsis through NIK, TRAV1, and XIAP” published in the July 15, 2018 issue of the Journal of Infectious Diseases (218;300–11). An editorial expression of concern regarding this article was published in the January 15, 2019 issue of the Journal (219:339). All authors have agreed to the retraction of this article. The retraction notice follows.

Seman, B. G., Vance, J. K., Rawson, T. W., Witt, M. R., Huckaby, A. B., Povroznik, J. M., Bradford, S. D., Barbier, M., Robinson, C. M.

Neonates are at increased risk for bacterial sepsis. We established that the immune suppressive cytokine interleukin (IL)-27 is elevated in neonatal mice. Similarly, human cord blood-derived macrophages express IL-27 genes and secrete more cytokine than macrophages from adults. In the present work, we hypothesized that increased levels of IL-27 predispose neonatal mice to more severe infection during Gram-negative sepsis. Serum IL-27 levels continued to rise during infection. Peripheral tissue analysis revealed systemic IL-27 expression, while myeloid cell profiling identified Gr-1 and F4/80-expressing cells as the most abundant producers of IL-27 during infection. Increased IL-27 levels were consistent with increased mortality that was improved in IL-27-receptor α (Rα)-/- mice that lack a functional IL-27 receptor. Infected IL-27Rα-/- pups also exhibited improved weight gain and reduced morbidity. This was consistent with reduced bacterial burdens and more efficient bacterial killing by Ly6B.2+ myeloid cells and macrophages compared to WT neonates. Live animal imaging further supported a more severe and disseminated infection in WT neonates. This is the first report to describe the impact of elevated early life IL-27 on the host response in a neonatal infection model while also defining the cell and tissue sources of cytokine. IL-27 is frequently associated with suppressed inflammation. In contrast, our findings demonstrate that IL-27 indirectly promotes an inflammatory cytokine response during neonatal sepsis by directly compromising control of bacteria that drive the inflammatory response. Collectively, our results suggest that IL-27 represents a therapeutic target to limit susceptibility and improve infectious outcomes in neonatal sepsis.…

Xie, Jianfeng; Wang, Hongliang; Kang, Yan; Zhou, Lixin; Liu, Zhongmin; Qin, Bingyu; Ma, Xiaochun; Cao, Xiangyuan; Chen, Dechang; Lu, Weihua; Yao, Chen; Yu, Kaijiang; Yao, Xiaoqing; Shang, Hongcai; Qiu, Haibo; Yang, Yi; for the CHinese Epidemiological Study of Sepsis (CHESS) Study Investigators

Objectives: We performed a national cross-sectional survey to determine the epidemiologic characteristics of patients with sepsis in ICU in China. Design: A cross-section survey study. Setting: Forty-four hospitals in mainland China from December 1, 2015, to January 31, 2016. Patients: All septic patients diagnosed according sepsis-1 criteria admitted to participating ICU. Interventions: None. Measurements and Main Results: We recorded demographic, physiologic, and microbiological data with follow-up for 90 days or death, if sooner. The frequency of sepsis and 90-day mortality rate were computed, and the relationship with gross domestic product determined. Multivariate logistic regression analysis was used to determine risk factors for 90-day mortality in patients with sepsis. Two-thousand three-hundred twenty-two patients with sepsis were included in the analysis, of whom 786 patients (33.9%) had hospital-acquired sepsis. The most common infection site was the lung (68.2%), followed by abdomen (26.6%) and bloodstream (7.8%). The frequency of sepsis in the ICU was 20.6 cases per 100 ICU admissions (95% CI, 15.8–25.4) with a 90-day mortality of 35.5%. The proportion of sepsis, severe sepsis, and septic shock were 3.10%, 43.6%, and 53.3% with a 90-day mortality of 2.78%, 17.69%, and 51.94%, respectively. Older age, low body weight, higher Sequential Organ Failure Assessment score, the number of systemic inflammatory response syndrome criteria, comorbid with heart failure, hematologic cancer, immunosuppression, higher level of lactate, infection site (pneumonia and bloodstream) were associated with 90-day mortality. Conclusions: Sepsis affects a fifth of patients admitted to ICUs in mainland China with a 90-day mortality rate of 35.5%. Our findings indicate that a large burden of sepsis, and we need to focus on sepsis as a quality improvement target in China given the high mortality. In addition, further studies are needed to delineate the epidemiology of sepsis outside the ICU. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grant from the Development Center for Medical Science and Technology National Health and Family Planning Commission of the People’s Republic of China (WH2015-01-01), a grant from Jiangsu Provincial Key Medical Discipline (ZDXKA2016025) and a grant from Jiangsu Provincial Medical Talent (ZDRCA2016082) and a grant from the Key Research and Development Plan of Jiangsu Province (BE2018743). The authors have disclosed that they do not have any potential conflicts of interest. Trial Registration: ClinicalTrials.gov NCT02448472. For information regarding this article, E-mail: yiyiyang2004@163.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Prasad, Priya A.; Fang, Margaret C.; Abe-Jones, Yumiko; Calfee, Carolyn S.; Matthay, Michael A.; Kangelaris, Kirsten N.

Objectives: Early identification of sepsis is critical to improving patient outcomes. Impact of the new sepsis definition (Sepsis-3) on timing of recognition in the emergency department has not been evaluated. Our study objective was to compare time to meeting systemic inflammatory response syndrome (Sepsis-2) criteria, Sequential Organ Failure Assessment (Sepsis-3) criteria, and quick Sequential Organ Failure Assessment criteria using electronic health record data. Design: Retrospective, observational study. Setting: The emergency department at the University of California, San Francisco. Patients: Emergency department encounters between June 2012 and December 2016 for patients greater than or equal to 18 years old with blood cultures ordered, IV antibiotic receipt, and identification with sepsis via systemic inflammatory response syndrome or Sequential Organ Failure Assessment within 72 hours of emergency department presentation. Interventions: None. Measurements and Main Results: We analyzed timestamped electronic health record data from 16,612 encounters identified as sepsis by greater than or equal to 2 systemic inflammatory response syndrome criteria or a Sequential Organ Failure Assessment score greater than or equal to 2. The primary outcome was time from emergency department presentation to meeting greater than or equal to 2 systemic inflammatory response syndrome criteria, Sequential Organ Failure Assessment greater than or equal to 2, and/or greater than or equal to 2 quick Sequential Organ Failure Assessment criteria. There were 9,087 patients (54.7%) that met systemic inflammatory response syndrome-first a median of 26 minutes post-emergency department presentation (interquartile range, 0–109 min), with 83.1% meeting Sequential Organ Failure Assessment criteria a median of 118 minutes later (interquartile range, 44–401 min). There were 7,037 patients (42.3%) that met Sequential Organ Failure Assessment-first, a median of 113 minutes post-emergency department presentation (interquartile range, 60–251 min). Quick Sequential Organ Failure Assessment was met in 46.4% of patients a median of 351 minutes post-emergency department presentation (interquartile range, 67–1,165 min). Adjusted odds of in-hospital mortality were 39% greater in patients who met systemic inflammatory response syndrome-first compared with those who met Sequential Organ Failure Assessment-first (odds ratio, 1.39; 95% CI, 1.20–1.61). Conclusions: Systemic inflammatory response syndrome and Sequential Organ Failure Assessment initially identified distinct populations. Using systemic inflammatory response syndrome resulted in earlier electronic health record sepsis identification in greater than 50% of patients. Using Sequential Organ Failure Assessment alone may delay identification. Using systemic inflammatory response syndrome alone may lead to missed sepsis presenting as acute organ dysfunction. Thus, a combination of inflammatory (systemic inflammatory response syndrome) and organ dysfunction (Sequential Organ Failure Assessment) criteria may enhance timely electronic health record-based sepsis identification. The contents are solely the responsibility of the authors and do not necessarily represent the official views of University of California San Francisco or the National Institutes of Health. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Prasad’s institution received funding from National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through University of California San Francisco (UCSF)-Clinical & Translational Science Institute (CTSI) grant number #A127552, and she received funding as an epidemiologist for EpiExcellence, LLC (consultant). Drs. Prasad, Fang, Abe-Jones, Matthay, and Kangelaris received support for article research from the NIH. Dr. Fang’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) K24HL141354 and Patient-Centered Outcomes Research Institute. Dr. Abe-Jones disclosed that data acquisition for this publication was supported by UCSF Academic Research Systems and by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI Grant Number UL1 TR001872. Dr. Calfee’s institution received funding from the NHLBI HL140026, GlaxoSmithKline, and Bayer, and she received funding from Bayer, CSL Behring, Prometic, Roche/Genentech, and Quark Pharmaceuticals. Dr. Matthay’s institution received funding from the NIH/NHLBI, GlaxoSmithKline, Bayer, and a Department of Defense grant. Dr. Kangelaris’s institution received funding from NHLBI 1K23HL116800. For information regarding this article, E-mail: Priya.Prasad@ucsf.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background Vitamin D deficiency, determined by blood levels of 25-hydroxyvitamin D [25(OH) D, i.e. the major vitamin D form in blood], has been shown to associate with all-cause mortalities. We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)2D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)2D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)2D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)2D deficiency, disorders leading to the 1,25(OH)2D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)2D deficiency. Methods We studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1α-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)2D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function. Results We demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)2D deficiency could not be overcome by increased production of PTH which stimulates 1α-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)2D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver. Conclusions Because FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1α-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)2D deficiency and for the improvement of survival among sepsis patients.…

Souto F, Castanheira F, Trevelin S, et al.

AbstractLiver X receptors (LXRs) are nuclear receptors activated by oxidized lipids and were previously implicated in the several metabolic development and inflammatory disorders. Although neutrophils express both LXR-α and LXR-β, the consequences of their activation, particularly during sepsis, remain unknown. Here, we verified that LXR activation reduces neutrophil chemotactic and killing abilities in vitro. Mice treated with LXR agonists showed higher sepsis-induced mortality, which could be associated with reduced neutrophil infiltration at the infectious foci, increased bacteremia, systemic inflammatory response and multi-organ failure. In contrast, septic mice treated with LXR antagonist showed increased number of neutrophils in the peritoneal cavity, reduced bacterial load and multi-organ dysfunction. Importantly, neutrophils from septic patients showed increased ABCA1 mRNA levels (a marker of LXR activation) and impaired chemotactic response toward CXCL8 compared to cells from healthy individuals. Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.

Prout, Andrew J.; Talisa, Victor B.; Carcillo, Joseph A.; Decker, Brooke K.; Yende, Sachin

Objectives: Timely empiric antimicrobial therapy is associated with improved outcomes in pediatric sepsis, but minimal data exist to guide empiric therapy. We sought to describe the prevalence of four pathogens that are not part of routine empiric coverage (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, and fungal infections) in pediatric sepsis patients in a contemporary nationally representative sample. Design: This was a retrospective cohort study using administrative data. Setting: We used the Nationwide Readmissions Database from 2014, which is a nationally representative dataset that contains data from nearly half of all discharges from nonfederal hospitals in the United States. Patients: Discharges of patients who were less than 19 years old at discharge and were not neonatal with a discharge diagnosis of sepsis. Interventions: None. Measurements and Main Results: Of the 19,113 pediatric admissions with sepsis (6,300 [33%] previously healthy and 12,813 [67%] with a chronic disease), 31% received mechanical ventilation, 19% had shock, and 588 (3.1%) died during their hospitalization. Among all admissions, 8,204 (42.9%) had a bacterial or fungal pathogen identified. S. aureus was the most common pathogen identified in previously healthy patients (n = 593, 9.4%) and those with any chronic disease (n = 1,430, 11.1%). Methicillin-resistant S. aureus, P. aeruginosa, C. difficile, and fungal infections all had high prevalence in specific chronic diseases associated with frequent contact with the healthcare system, early surgery, indwelling devices, or immunosuppression. Conclusions: In this nationally representative administrative database, the most common identified pathogen was S. aureus in previously healthy and chronically ill children. In addition, a high proportion of children with sepsis and select chronic diseases had infections with methicillin-resistant S. aureus, fungal infections, Pseudomonas infections, and C. difficile. Clinicians caring for pediatric patients should consider coverage of these organisms when administering empiric antimicrobials for sepsis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Prout’s (T32HL007820) and Yende’s institutions received funding from National Heart, Lung and Blood Institute of the National Institutes of Health (NIH). Drs. Prout, Carcillo, and Yende received support for article research from the NIH. Dr. Carcillo’s institution received funding from the National Institute of Child Health and Human Development and National Institute of General Medical Sciences. Dr. Decker disclosed government work. Dr. Talisa disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: yendes@upmc.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lewis J, Abouyannis M, Katha G, et al.

AbstractBackgroundSepsis is an important cause of mortality globally, though population incidence estimates from low income settings, including sub-Saharan Africa (sSA), are absent. We aimed to estimate sepsis incidence burden using routinely available data from a large urban hospital in Malawi.MethodWe linked routine-care databases at Queen Elizabeth Central Hospital, Blantyre, Malawi, to provide admission and discharge data for 217,149 adults from 2013-2016. Using a definition of sepsis based on systemic inflammatory response syndrome (SIRS) criteria, and Blantyre census population data, we calculated population incidence estimates of sepsis and severe sepsis and used negative binomial regression to assess for trends over time. Missing data were multiply imputed with chained equations.ResultsWe estimate that the incidence rate of emergency department-attending sepsis and severe sepsis in adults was 1772 per 100,000 person-years (95% CI 1754-1789) and 303 per 100,000 person-years (95% CI 295-310) respectively, between 2013 and 2016, with a year-on-year decrease in incidence. In-hospital mortality for patients admitted to the hospital with sepsis and severe sepsis was 23.7% (95% CI 22.7-24.7%) and 28.1% (95% CI 26.1 – 30.0%) respectively, with no clear change over time.ConclusionsSepsis incidence is higher in Blantyre, Malawi, than in high-income settings, from where the majority of sepsis incidence data derive. Worldwide sepsis burden is likely to be underestimated, and data from low income countries are needed to inform the public health response.

Abstract Background This study investigated the clinical value of interleukin-6 (IL-6), pentraxin 3 (PTX3), and procalcitonin (PCT) in patients with sepsis and septic shock diagnosed according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Methods Serum levels of IL-6, PTX3, and PCT were measured in 142 enrolled subjects (51 with sepsis, 46 with septic shock, and 45 as controls). Follow-up IL-6 and PTX3 levels were measured in patients with initial septic shock within 24 h of hospital discharge. Optimal cut-off values were determined for sepsis and septic shock, and prognostic values were evaluated. Results Serum IL-6 levels could discriminate sepsis (area under the curve [AUC], 0.83–0.94, P 

Shubin, Nicholas J.; Navalkar, Krupa; Sampson, Dayle; Yager, Thomas D.; Cermelli, Silvia; Seldon, Therese; Sullivan, Erin; Zimmerman, Jerry J.; Permut, Lester C.; Piliponsky, Adrian M.

Objectives: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death and disability among children worldwide. Identifying sepsis in pediatric patients is difficult and can lead to treatment delay. Our objective was to assess the host proteomic response to infection utilizing an aptamer-based multiplexed proteomics approach to identify novel serum protein changes that might help distinguish between pediatric sepsis and infection-negative systemic inflammation and hence can potentially improve sensitivity and specificity of the diagnosis of sepsis over current clinical criteria approaches. Design: Retrospective, observational cohort study. Setting: PICU and cardiac ICU, Seattle Children’s Hospital, Seattle, WA. Patients: A cohort of 40 children with clinically overt sepsis and 30 children immediately postcardiopulmonary bypass surgery (infection-negative systemic inflammation control subjects) was recruited. Children with sepsis had a confirmed or suspected infection, two or more systemic inflammatory response syndrome criteria, and at least cardiovascular and/or pulmonary organ dysfunction. Interventions: None. Measurements and Main Results: Serum samples from 35 of the sepsis and 28 of the bypass surgery subjects were available for screening with an aptamer-based proteomic platform that measures 1,305 proteins to search for large-scale serum protein expression pattern changes in sepsis. A total of 111 proteins were significantly differentially expressed between the sepsis and control groups, using the linear models for microarray data (linear modeling) and Boruta (decision trees) R packages, with 55 being previously identified in sepsis patients. Weighted gene correlation network analysis helped identify 76 proteins that correlated highly with clinical sepsis traits, 27 of which had not been previously reported in sepsis. Conclusions: The serum protein changes identified with the aptamer-based multiplexed proteomics approach used in this study can be useful to distinguish between sepsis and noninfectious systemic inflammation. Drs. Shubin and Navalkar contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Navalkar, Sampson, Yager, Cermelli, and Seldon disclosed that they are present or past employees and/or shareholders in Immunexpress. Dr. Navalkar received funding from Immunexpress and the University of Washington, and she received support for article research from the Seattle Children’s Hospital. Drs. Navalkar, Yager, and Cermelli disclosed that Seattle Children’s Hospital paid Somalogic directly to conduct screening. Dr. Yager received funding from ORC International and Foundation for Innovative New Diagnostics (Geneva) for consulting. Dr. Seldon received funding from Immunexpress. Dr. Zimmerman disclosed that he received funding from the Society of Critical Care Medicine (travel reimbursement to attend board meetings) and Elsevier Publishing (royalties for the textbook, Pediatric Critical Care), and that his institution (Seattle Children’s Hospital) received research grant funding from the National Institutes of Health (NIH)/National Institute of Child Health and Human Development. Dr. Zimmerman and Ms. Sullivan disclosed that their institution (Seattle Children’s Hospital) received funding from the Seattle Children’s Research Institute and from Immunexpress for the present study. Dr. Piliponsky’s institution received funding from NIH/National Heart, Lung, and Blood Institute and NIH/National Institute of Child Health and Human Development. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: adrian.piliponsky@seattlechildrens.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ignacio Rubio, Marcin F Osuchowski, Manu Shankar-Hari, Tomasz Skirecki, Martin Sebastian Winkler, Gunnar Lachmann, Paul La Rosée, Guillaume Monneret, Fabienne Venet, Michael Bauer, Frank M Brunkhorst, Matthijs Kox, Jean-Marc Cavaillon, Florian Uhle, Markus A Weigand, Stefanie B Flohé, W Joost Wiersinga, Marta Martin-Fernandez, Raquel Almansa, Ignacio Martin-Loeches, Antoni Torres, Evangelos J Giamarellos-Bourboulis, Massimo Girardis, Andrea Cossarizza, Mihai G Netea, Tom van der Poll, André Scherag, Christi

Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy.

Abstract Background In the pre-vaccine era, invasive disease with Haemophilus influenzae, type b (Hib) commonly presented with osteoarticular involvement. Haemophilus influenzae, type a (Hia) sepsis is a rare but emerging problem in recent years. Here, we report a case of sepsis with concomitant osteoarthritis due to Hia that was the presenting infectious disease manifestation of isolated asplenia in a young child. This unique observation adds to our understanding of sepsis and asplenia in children. Case presentation A five-year-old girl developed acute Hia bacteremia and sepsis. The patient developed arthritis shortly after onset of septic shock. Arthrocentesis was culture-negative, but given the difficulty differentiating between septic and reactive arthritis, prolonged antibiotic administration was provided for presumed osteoarticular infection, and the patient had an uneventful recovery. The finding of Howell-Jolly bodies on blood smear at the time of presentation prompted an evaluation that revealed isolated congenital asplenia. Evaluation for known genetic causes of asplenia was unrevealing. Investigation by the Minnesota Department of Health revealed an emergence of Hia infections over the past 5 years, particularly in children with an American Indian background. Conclusions Hia is an important pathogen in the differential diagnosis of invasive bacterial infections in children and shares overlap in clinical presentation and pathogenesis with Hib. Invasive Hia disease can be a presenting manifestation of asplenia in children. Hia is an emerging pathogen in American Indian children.…

Abstract Background The sepsis-induced immunodepression contributes to impaired clinical outcomes of various stress conditions. This syndrome is well documented and characterized by attenuated function of innate and adaptive immune cells. Several pharmacological interventions aimed to restore the immune response are emerging of which interferon-gamma (IFNγ) is one. It is of paramount relevance to obtain clinical information on optimal timing of the IFNγ-treatment, −tolerance, −effectiveness and outcome before performing a RCT. We describe the effects of IFNγ in a cohort of 18 adult and 2 pediatric sepsis patients. Methods In this open-label prospective multi-center case-series, IFNγ treatment was initiated in patients selected on clinical and immunological criteria early ( 7 days) following the onset of sepsis. The data collected in 18 adults and 2 liver transplanted pediatric patients were: clinical scores, monocyte expression of HLA-DR (flow cytometry), lymphocyte immune-phenotyping (flow cytometry), IL-6 and IL-10 plasma levels (ELISA), bacterial cultures, disease severity, and mortality. Results In 15 out of 18 patients IFNγ treatment was associated with an increase of median HLA-DR expression from 2666 [IQ 1547; 4991] to 12,451 [IQ 4166; 19,707], while the absolute number of lymphocyte subpopulations were not affected, except for the decrease number of NK cells 94.5 [23; 136] to 32.5 [13; 90.8] (0.0625)]. Plasma levels of IL-6 464 [201–770] to 108 (89–140) ng/mL (p = 0.04) and IL-10 from IL-10 from 29 [12–59] to 9 [1–15] pg/mL decreased significantly. Three patients who received IFNγ early after ICU admission (

Nadeem Rashid, Jawed Shafaq

Fei Peng, Wei Chang, Qin Sun, Yi Yang

Nathan El Bèze, Antoine Kimmoun, Pierre Asfar

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 9, Page 1191-1192, November 1, 2019. …

Matthew Tung, Jerome Cerullo Crowley

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 9, Page 1192-1192, November 1, 2019. …