Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.

Home Oxygen After Hospitalization for COVID-19: Results From the Multi-Center OXFORD Study.

BACKGROUND: In the first months of the pandemic, prior to the introduction of proven-effective treatments, 15-37% of patients hospitalized with COVID-19 were discharged on home oxygen. After proven-effective treatments for acute COVID-19 were established by evidence-based guidelines, little remains known about home oxygen requirements following hospitalization for COVID-19. METHODS: This was a retrospective, multi-center cohort study of subjects hospitalized for COVID-19 between October 2020-September 2021 at 3 academic health centers. Information was abstracted from electronic health records at the index hospitalization and for 60 d after discharge. The World Health Organization COVID-19 Clinical Progression Scale score was used to identify patients with severe COVID-19. RESULTS: Of 517 subjects (mean age 58 y, 47% female, 42% Black, 36% Hispanic, 22% with severe COVID-19), 81% were treated with systemic corticosteroids, 61% with remdesivir, and 2.5% with tocilizumab. About one quarter of subjects were discharged on home oxygen (26% [95% CI 22-29]). Older age (adjusted odds ratio [aOR] 1.02 per 5 y [95% CI 1.02-1.02]), higher body mass index (aOR 1.02 per kg/m2 [1.00-1.04]), diabetes (yes vs no, aOR 1.73 [1.46-2.02]), severe COVID-19 (vs moderate, aOR 3.19 [2.19-4.64]), and treatment with systemic corticosteroids (yes vs no, aOR 30.63 [4.51-208.17]) were associated with an increased odds of discharge on home oxygen. Comorbid hypertension (yes vs no, aOR 0.71 [0.66-0.77) was associated with a decreased odds of home oxygen. Within 60 d of hospital discharge, 50% had documentation of pulse oximetry; in this group, home oxygen was discontinued in 46%. CONCLUSIONS: About one in 41 subjects were prescribed home oxygen after hospitalization for COVID-19, even after guidelines established proven-effective treatments for acute illness. Evidence-based strategies to reduce the requirement for home oxygen in patients hospitalized for COVID-19 are needed.

Written Communication, Visitation Policies, and Awareness of Medical Issues Among Intensive Care Unit Families.

BACKGROUND: Open intensive care unit (ICU) visitation policies facilitate communication between clinicians and patients' families. Restrictive visitation policies (eg, during a pandemic) may reduce families' comprehension of information. OBJECTIVES: To determine whether written communication increased awareness of medical issues among ICU families and whether the effect size depended on the visitation policies in place when participants were enrolled. METHODS: Families of ICU patients were randomly assigned to receive usual care with or without daily written patient care updates from June 2019 to January 2021. Participants were asked whether patients had experienced 6 ICU problems at up to 2 time points during the ICU stay. Responses were compared with the study investigators' consensus. RESULTS: Of 219 participants, 131 (60%) were restricted from visiting. Participants in the written communication group were more likely than participants in the control group to correctly identify shock, renal failure, and weakness and were just as likely as participants in the control group to correctly identify respiratory failure, encephalopathy, and liver failure. Participants in the written communication group were more likely than participants in the control group to correctly identify the patient's ICU problems when all 6 were grouped as a composite outcome, with the adjusted odds ratio of correct identification tending to be higher among participants enrolled during restricted versus open visitation periods: 2.9 (95% CI, 1.9-4.2; P < .001) vs 1.8 (95% CI, 1.1-3.1; P = .02), P = .17 for difference. CONCLUSIONS: Written communication helps families correctly identify ICU issues. The benefit may be enhanced when families cannot visit the hospital. ClinicalTrials.gov Identifier: NCT03969810.

Symptoms of Anxiety, Depression, and Stress among Families of Critically Ill Patients with COVID-19: A Longitudinal Clinical Trial.

Rationale: Families of critically ill patients with coronavirus disease (COVID-19) may be at particularly high risk for anxiety, depression, and post-traumatic stress disorder after hospital discharge. Objectives: To assess symptoms of anxiety, depression, and stress among families of patients with COVID-19 during and after intensive care unit (ICU) admissions and to use qualitative methods to determine the sources of emotional distress. Methods: Families of patients with COVID-19 who participated in an ICU study were approached for participation in this post-hospital discharge study. Participants completed the Hospital Anxiety and Depression Scale (HADS) and the Impact of Events Scale-Revised (IES-R) at up to three points during the ICU stay and once after the ICU stay. Mixed-effects models were used to compare trajectories of HADS and IES-R scores over the ICU and post-ICU periods. Telephone interviews with participants were evaluated using thematic content analysis. Results: Among the 90 families that participated from September 2020 to April 2021, 47 respective patients were alive and 43 were deceased. Average HADS anxiety, HADS depression, and IES-R scores after hospital discharge were significantly higher (greater symptom burden) among families of deceased versus surviving patients: 9.2 (95% confidence interval [CI], 7.8-10.6) versus 6.3 (95% CI, 4.9-7.6) (P < 0.01), 7.1 (95% CI, 5.7-8.6) versus 3.2 (95% CI, 2.3-4.1) (P < 0.001), and 36.1 (95% CI, 31.0-41.2) versus 20.4 (95% CI, 16.1-24.8) (P < 0.001), respectively. HADS anxiety and HADS depression scores began to diverge during the ICU stay, whereas IES-R scores diverged after the stay for families of surviving versus deceased patients. Qualitative analysis confirmed a higher burden of psychological symptoms among families of deceased patients. Memories from the ICU stay became a focal point for participants who lost their loved ones, whereas families of surviving patients were able to look positively toward the future. In addition, families of deceased patients often viewed friends and family as sources of stress, whereas families of surviving patients typically viewed their community as a source of support. Conclusions: Patient death was associated with symptoms of anxiety, depression, and post-traumatic stress disorder among families of ICU patients with COVID-19. Psychological support interventions may be most beneficial for families of patients who died of COVID-19. Clinical trial registered with www.clinicaltrials.gov (NCT04501445).

Clinician-initiated written communication for families of patients at a long-term acute care hospital.

Objective: To assess the experience of families and clinicians at a long term acute care hospital (LTACH) after implementing a written communication intervention. Methods: Written communication templates were developed for six clinical disciplines. LTACH clinicians used templates to describe the condition of 30 mechanically ventilated patients at up to three time points. Completed templates were the basis for written summaries that were sent to families. Impressions of the intervention among families (n = 21) and clinicians (n = 17) were assessed using a descriptive correlational design. Interviews were analyzed using thematic content analysis. Results: We identified four themes during interviews with families: Written summaries 1) facilitated communication with LTACH staff, 2) reduced stress related to COVID-19 visitor restrictions, 3) facilitated understanding of the patient condition, prognosis, and goals and 4) facilitated communication among family members. Although clinicians understood why families would appreciate written material, they did not feel that the intervention addressed their main challenge - overly optimistic expectations for patient recovery among families. Conclusion: Written communication positively affected the experience of families of LTACH patients, but was less useful for clinicians. Innovation: Use of written patient care updates helps LTACH clinicians initiate communication with families.

Piloting Group-Based Behavioral Activation Therapy for Families of Deceased COVID-19 Patients.

Surrogate decision-making is a stressful process for many family members of critically ill patients. The COVID-19 pandemic may have amplified the risk for anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms in ICU surrogates. OBJECTIVES: This study piloted an online group-based behavioral intervention with family members of deceased COVID-19 patients. Participant engagement, perceptions, and responses related to the intervention were assessed. DESIGN: A single-arm pilot study was conducted with bereaved families. Quantitative analysis of measures of anxiety, depression, and PTSD symptoms was conducted with mixed models. Qualitative data were analyzed to identify themes in surrogates' experiences with the intervention. SETTING: Participants were recruited from ICUs at a tertiary academic medical center. Participants completed the intervention, measures, and interviews online. SUBJECTS: Participants were family members of patients who died from COVID-19. INTERVENTIONS: The intervention involved six online group-based behavioral activation sessions. Sessions covered topics pertinent to grieving and engagement in personally meaningful activities. MEASUREMENTS AND MAIN RESULTS: Semi-structured interviews explored participants' experiences with the intervention. Surrogates also completed measures of anxiety, depression, and PTSD symptoms before and after the intervention. Nineteen of 26 participants (73.1%) completed the study. Thematic analysis suggested that surrogates found the group helpful for overcoming perceived isolation, receiving validation, and developing coping skills. Significant pre-to-post reductions were observed in symptoms of Hospital and Anxiety Disorder Scale (HADS) anxiety (pre-mean = 9.27, sd = 5.30 vs post-mean = 6.80, sd = 4.16; p = 0.0271), HADS depression (pre-mean =6 .65, sd = 4.58 vs post- mean = 4.89, sd = 3.40; p = 0.0436), and Impact of Events Scale-Revised PTSD (pre-mean = 36.86, sd = 16.97 vs post-mean = 24.14, sd = 13.49; p = 0.0008). LIMITATIONS: This was a preliminary study based on qualitative and self-report measures. Future studies should include a control group. CONCLUSIONS: Online group-based behavioral activation therapy appears to be a potentially useful intervention for family members of ICU patients who died from COVID-19.

Daily Written Care Summaries for Families of Critically Ill Patients: A Randomized Controlled Trial.

OBJECTIVES: To determine the effect of daily written updates on the satisfaction and psychologic symptoms of families of ICU patients. DESIGN: Randomized controlled trial. SETTING: Single, urban academic medical center. SUBJECTS: Surrogates of nondecisional, critically ill adults with high risk of mortality ( n = 252) enrolled from June 2019 to January 2021. INTERVENTIONS: Usual communication with the medical team with or without written communication detailing the suspected cause and management approach of each ICU problem, updated each day. MEASUREMENTS AND MAIN RESULTS: Participants completed surveys at three time points during the ICU stay: enrollment ( n = 252), 1 week ( n = 229), and 2 weeks ( n = 109) after enrollment. Satisfaction with care was measured using the Critical Care Family Needs Inventory (CCFNI). The presence of anxiety, depression, and acute stress were assessed using the Hospital Anxiety and Depression Scale (HADS) and Impact of Events Scale Revised (IES-R). CCFNI, HADS, and IES-R scores were similar among participants assigned to the intervention group and control group upon enrollment and during the first week after enrollment ( p > 0.05). From enrollment to the second week after enrollment, there was an improvement in CCFNI and HADS scores among participants assigned to the intervention group versus the control group. At week 2, CCFNI scores were significantly lower among participants in the intervention group versus the control group, indicating greater satisfaction with care: 15.1 (95% CI, 14.2-16.0) versus 16.4, (95% CI, 15.5-17.3); p = 0.04. In addition, 2 weeks after enrollment, the odds of symptoms of anxiety, depression, and acute stress among participants assigned to the intervention versus control group were 0.16 (95% CI, 0.03-0.82; p = 0.03); 0.15 (95% CI, 0.01-1.87; p = 0.14); and 0.27 (95% CI, 0.06-1.27; p = 0.10), respectively. CONCLUSIONS: Written communication improved satisfaction and the emotional well-being of families of critically ill patients, supporting its use as a supplement to traditional communication approaches.

Surrogate and Physician Decision Making for Mechanically Ventilated Patients According to Expected Patient Outcome.

Background: Surrogates and physicians may differ in their priorities and perspectives when making decisions for incapacitated, critically ill patients. Objectives: To determine the extent to which surrogate and physician decisions to sustain life support are associated with their expectations for patient outcomes. Setting/Subjects: Surrogates and physicians of 100 mechanically ventilated patients at an academic, tertiary care medical center in the United States were surveyed. Measurements: Linear regression was used to determine if participant expectations for patient survival, good quality of life, and confidence in these expectations were associated with their agreement that mechanical ventilation should be continued if required for patient survival. Results: Surrogates were more likely than physicians to expect that patients would be alive in three months (91% interquartile range [IQR 70-95%] vs. 65% [IQR 43-77%], p < 0.001) and have good quality of life in three months (71% [IQR 50-90%] vs. 40% [IQR 19-50%], p < 0.001). Surrogates who were most confident in their prognostic abilities were also the most optimistic for good patient outcomes. As such, expectations for patient survival and good quality of life were not associated with level agreement that mechanical ventilation should be continued among confident surrogates, (R2 = 0.03, p = 0.13) and (R2 = 0.01, p = 0.53), respectively. In contrast, among physicians, confidence was not synonymous with optimism. Instead, the significant associations between expectations for patient survival and good quality of life with the agreement that mechanical ventilation should be continued were strengthened when physicians were confident, (R2 = 0.34, p < 0.01) and (R2 = 0.47, p < 0.001), respectively. Conclusion: Surrogates and physicians have different approaches to incorporating their expectations for patient prognosis and their confidence in these expectations when they are making decisions for incapacitated critically ill patients.

Challenges faced by families of critically ill patients during the first wave of the COVID-19 pandemic.

OBJECTIVE: To understand how surrogates of critically ill patients adjusted to challenges that resulted from the COVID-19 pandemic. METHODS: Participants (N = 62) were surrogates of critically ill adults with COVID-19 in the ICU at an urban, academic medical center from March to June 2020. Participants were recruited using convenience sampling and took part in one-time qualitative individual interviews via telephone. Qualitative data were analyzed using thematic content analysis. RESULTS: Qualitative analyses yielded four types of challenges: Communication with the medical team, communication among family members, understanding and tracking medical information, and distress related to visitor restrictions. To adjust to challenges related to communication, participants developed routines for receiving updates from the medical team and providing updates to other family members. To adjust to the challenge related to comprehension, participants sought information from external sources such as family members in healthcare fields. To adjust to the challenge related to visitation, participants found some comfort in video calls with the patient. CONCLUSIONS: Surrogates of critically ill patients with COVID-19 faced multiple types of challenges yet adjusted to those challenges. PRACTICAL IMPLICATIONS: Future research should focus on ways to support the wellbeing of surrogates during times of restricted hospital visitation. Clinical trial registered at ClinicalTrials.gov (NCT03969810).

Written Care Summaries Facilitate Communication Between Families and Providers of ICU Patients: A Pilot Study.

ICU providers may invite families to participate in daily rounds to inform them of the patient's condition and to support their emotional well-being. Daily written summaries of care may provide complementary benefits. DESIGN: Qualitative interviews with surrogates of ICU patients who received daily written summaries of care. SETTING: Single, urban academic medical center. PATIENTS/SUBJECTS: A convenience sample of 30 surrogates of nondecisional, medical ICU patients. INTERVENTIONS: Daily written summaries detailed each of the patient's main ICU problems, the presumed causes of each of the problems, and the medical team's plan to address each of the problems for each ICU day. MEASUREMENTS AND MAIN RESULTS: There were four ways that written summaries affected the participant's experience: 1) providing clarity to participants regarding the patient's condition, 2) facilitating participant understanding of the patient's clinical course, 3) facilitating communication between participants and medical providers, and 4) facilitating communication between participants and other family members. Overarching themes were that summaries were understandable, had appropriate level of detail, and added value to the ICU experience. CONCLUSIONS: In this pilot study, family members had positive impressions of receiving daily written summaries of care. Further study is needed to determine the extent to which written communication may affect family and patient outcomes.

Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis.

OBJECTIVES: We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN: Prospective observational study. SETTING: Large academic medical center between 2013 and 2019. SUBJECTS: Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS: Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS: The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS: Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

Surrogates and Physician Preferences regarding the Continuation of Mechanical Ventilation among Critically Ill Adults.

Rationale: For an incapacitated patient who is difficult to liberate from mechanical ventilation, surrogates and physicians will decide to continue life support if they believe doing so is consistent with the patient's prognosis and values. Little is known about the factors that surrogates and physicians prioritize during this decision-making process, in part because there is not a validated method to assess their preferences.Objectives: To evaluate trends in surrogate and physician preferences for continuing mechanical ventilation.Methods: One hundred surrogates and respective physicians of patients requiring mechanical ventilation for at least 7 days were prospectively enrolled at an academic, tertiary care medical center. During the second and third week of mechanical ventilation, participant preferences for continuing mechanical ventilation were assessed in two ways, the first emphasizing patient survival and the second emphasizing patient comfort as the primary goal.Results: During the patient's second week of mechanical ventilation, surrogates agreed more strongly than did physicians that mechanical ventilation should be continued to maximize the chance for patient survival (73% vs. 63%, respectively, P = 0.02 for difference). In contrast, at this same point in time, surrogates and physicians agreed similarly that mechanical ventilation should be discontinued to maximize patient comfort (37% vs. 38%, respectively, P = 0.34 for difference). Both surrogates and physicians agreed less strongly during week 3 than they did during week 2 that mechanical ventilation should be continued with a goal of maximizing patient survival, with preferences to limit the use of mechanical ventilation for patients with the poorest prognoses according to physiological variables. In contrast, only physicians agreed more strongly during week 3 than they did during week 2 that mechanical ventilation should be discontinued to maximize patient comfort.Conclusions: Level of surrogate and physician agreement that mechanical ventilation should be continued to maximize the chance for patient survival reflected their preferences more accurately than level of surrogate and physician agreement that mechanical ventilation should be discontinued to maximize patient comfort. Over time, surrogates and physicians were less likely to agree that mechanical ventilation should be continued, particularly when patients had poor prognoses.

A Multidisciplinary Team-Based Approach to Improve Communication With Surrogates of Patients With Chronic Critical Illness.

BACKGROUND: Clinicians need to deliver prognostic information to surrogates of nondecisional, critically ill patients so that surrogates can make informed medical decisions that reflect the patient's values. Our objective was to implement a new approach for communicating with surrogates of patients with chronic critical illness. METHODS: Surrogate decision makers of patients who were difficult to liberate from mechanical ventilation were prospectively enrolled. Surrogates met with different members of the intensive care unit treatment team for sequential 15-minute appointments to receive patient-specific assessments and education on chronic critical illness. The feasibility and acceptability of this approach were determined. A 24-question comprehension instrument was developed to assess a participant's understanding that a family member was displaying features of chronic critical illness. Each question was scored from 1 to 5, with larger scores indicating greater comprehension. RESULTS: Over a 15-week period, educational sessions for 9 mechanically ventilated patients were conducted. On average, 2 surrogates per patient (range: 1-4) and 6 members of the interdisciplinary team (range: 4-6) were at each meeting. Surrogates and clinicians had very positive impressions of the communication intervention. The average preintervention comprehension score was 85 of 120 (standard deviation [SD]: 8, range: 71-101). The postintervention comprehension score was greater by 5 points on average (SD: 9, range: -11 to +20 points, P = .04). CONCLUSIONS: Surrogates of critically ill patients approved of this novel communication approach and had a greater understanding of the patient's medical condition after the intervention.

Physician agreement on the diagnosis of sepsis in the intensive care unit: estimation of concordance and analysis of underlying factors in a multicenter cohort.

BACKGROUND: Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting. METHODS: We conducted a post hoc analysis of previously collected data from a prospective, observational trial (N = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa (κ free) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups. RESULTS: Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator (κ free 0.68), (2) the consensus discharge diagnosis of the site investigators (κ free 0.62), and (3) the consensus diagnosis of the external expert panel (κ free 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel (κ free 0.79). When stratified by infection site, κ free for agreement between initial and later diagnoses had a mean value + 0.24 (range - 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics. CONCLUSIONS: Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis.

Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils.

The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.