Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

Changes in temperature management and outcome after out-of-hospital cardiac arrest in United Kingdom intensive care units following publication of the targeted temperature management trial.

AIM: To investigate how the publication of the targeted temperature management (TTM) trial in December 2013 affected the trends in temperature management and outcome following admission to UK intensive care units (ICUs) after out-of-hospital cardiac arrest (OHCA). METHODS: We used a national ICU database of 1,181,405 consecutive admissions to 235 adult ICUs. OHCA admissions mechanically ventilated in the first 24 h in the ICU were divided into a pre-TTM trial cohort of patients admitted before publication of the TTM trial (January 2010-December 2013) and post-TTM cohort of patients admitted after TTM trial publication (January 2014-December 2017). The primary outcome variables were lowest temperature in the first 24 h in ICU and survival to hospital discharge. RESULTS: The lowest temperature recorded in the first-24 h of admission was significantly higher in the post-TTM cohort (n = 18,106) than in the pre-TTM cohort (n = 12,162) (mean 34.7 (±1.6) versus 33.6 °C (±1.8); absolute difference 1.12 °C (95% CI 1.08-1.16). The post-TTM cohort had a greater prevalence of fever (>38.0 °C) (24.8% vs 14.7%; (odds ratio (OR) 1.91 (95% CI 1.80-2.03); p < 0.001)) and higher unadjusted in-hospital mortality (63.7% vs 61.6%). In a multilevel model, accounting for time trend and including site as a random effect, neither the step change in acute hospital mortality following publication of the TTM trial result (OR 1.04, 95% CI 0.95-1.15; p = 0.37), nor the change in slope (from OR 1.00 per year, 95% CI 0.97-1.04, to 1.04 per year, 95% CI 1.02-1.07; p = 0.059), was statistically significant. Adjusted analyses were limited by the models' dependence on temperature and temperature-related variables. CONCLUSIONS: The lowest temperature recorded in the first-24 h of admission in OHCA patients was higher in the post-TTM cohort compared with the pre-TTM cohort. There has been an increase in the proportion of patients with fever (>38 °C) in the first 24 h. Although crude mortality was slightly higher in the post-TTM cohort, an analysis accounting for time trend and variation between critical care units, found no significant change associated with the TTM publication.

Update on Climate Change: Its Impact on Respiratory Health at Work, Home, and at Play.

Climate change is a crisis of vast proportions that has serious implications for pulmonary health. Increasing global temperatures influence respiratory health through extreme weather events, wildfires, prolonged allergy seasons, and worsening air pollution. Children, elderly patients, and patients with underlying lung disease are at elevated risk of complications from these effects of climate change. This paper summarizes the myriad ways in which climate change affects the respiratory health of patients at home and in outdoor environments and outlines measures for patients to protect themselves.

Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction.

The novel concepts within Sepsis­3 criteria include a focus on dysregulated host responses, removal of the systemic inflammation response syndrome (SIRS) criteria from sepsis diagnosis, the use of Sepsis-related (Sequential) Organ Failure Assessment (SOFA) scores to define organ dysfunction, and the explicit recognition of the septic shock as a subset of sepsis. Protection against infection requires a surveillance system, an effector response against "perceived" pathogens, a method for regaining immune homeostasis following an immune response, and generation of immunological memory. In comparison to normally regulated responses to infection, the innate immune system shows profoundly abnormal neutrophil and macrophage function. Similarly, the adaptive immune system is typically depleted numerically of lymphocytes and functionally with T and B cell exhaustion. Although there are numerous proposed mechanisms by which these dysregulated immune responses may be associated with organ failure, it is unclear what the unifying organ failure mechanisms in sepsis are. Furthermore, in sepsis survivors, the epigenetic changes on immune cells and widespread changes to lymphocyte populations may increase the risk of adverse events such as rehospitalisation and mortality. Finally, our current gaps in understanding of the immune response trajectory and the associated modifiable mechanisms in sepsis leave us a long way from successful immunomodulation for these patients. This article is freely available.

Molecular analysis of bacterial contamination on stethoscopes in an intensive care unit.

BACKGROUND: Culture-based studies, which focus on individual organisms, have implicated stethoscopes as potential vectors of nosocomial bacterial transmission. However, the full bacterial communities that contaminate in-use stethoscopes have not been investigated. METHODS: We used bacterial 16S rRNA gene deep-sequencing, analysis, and quantification to profile entire bacterial populations on stethoscopes in use in an intensive care unit (ICU), including practitioner stethoscopes, individual-use patient-room stethoscopes, and clean unused individual-use stethoscopes. Two additional sets of practitioner stethoscopes were sampled before and after cleaning using standardized or practitioner-preferred methods. RESULTS: Bacterial contamination levels were highest on practitioner stethoscopes, followed by patient-room stethoscopes, whereas clean stethoscopes were indistinguishable from background controls. Bacterial communities on stethoscopes were complex, and community analysis by weighted UniFrac showed that physician and patient-room stethoscopes were indistinguishable and significantly different from clean stethoscopes and background controls. Genera relevant to healthcare-associated infections (HAIs) were common on practitioner stethoscopes, among which Staphylococcus was ubiquitous and had the highest relative abundance (6.8%-14% of contaminating bacterial sequences). Other HAI-related genera were also widespread although lower in abundance. Cleaning of practitioner stethoscopes resulted in a significant reduction in bacterial contamination levels, but these levels reached those of clean stethoscopes in only a few cases with either standardized or practitioner-preferred methods, and bacterial community composition did not significantly change. CONCLUSIONS: Stethoscopes used in an ICU carry bacterial DNA reflecting complex microbial communities that include nosocomially important taxa. Commonly used cleaning practices reduce contamination but are only partially successful at modifying or eliminating these communities.

Acceptance and transfer to a regional severe respiratory failure and veno-venous extracorporeal membrane oxygenation (ECMO) service: predictors and outcomes.

The use of extracorporeal membrane oxygenation for respiratory failure is high risk and resource intensive. In England, five centres provide this service and patients who are referred have four possible outcomes: declined transfer due to perceived futility; accepted in principle but remain at the referring centre with ongoing surveillance; retrieved using conventional ventilation; or retrieved on extracorporeal support. The decision-making process leading to these outcomes has not previously been examined. We evaluated referrals to one centre and identified factors associated with each decision outcome. Five hundred and sixty-four patients were analysed from January 2012 to October 2015. One hundred and fifty-seven patients were declined; multivariate analysis demonstrated associated factors to be: age (odds ratio (95% confidence interval) 1.05 (1.04-1.07)); immunocompromise (4.95 (2.58-9.67)); lactate (1.11 (1.01-1.22)); duration of ventilation (1.08 (1.04-1.14)); and cardiac failure (3.22 (1.04-10.51)). Factors associated with the decision to retrieve an accepted patient were: plateau pressure (1.05 (1.01-1.10)); ratio of arterial oxygen partial pressure to fractional inspired oxygen (0.89 (0.85-0.93)); partial pressure of carbon dioxide in arterial blood (1.13 (1.03-1.25)); and the absence of non-pulmonary infection (0.31 (0.15-0.61)). Only pH was independently associated with the decision to transfer on extracorporeal support (0.020 (0.002-0.017)). Six-month survival in the declined, non-retrieved, conventionally retrieved and extracorporeal-retrieved groups was 16.6%, 71.1%, 76.7% and 72.1%, respectively, substantially supporting the decision-making model. Survival in the accepted group exceeds that reported previously. However, a proportion of those declined do survive and some remotely managed patients die. This suggests the approach does not account for some important survival-determining factors.

Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database.

BACKGROUND: New sepsis and septic shock definitions could change the epidemiology of sepsis because of differences in criteria. We therefore compared the sepsis populations identified by the old and new definitions. METHODS: We used a high-quality, national, intensive care unit (ICU) database of 654 918 consecutive admissions to 189 adult ICUs in England, from January 2011 to December 2015. Primary outcome was acute hospital mortality. We compared old (Sepsis-2) and new (Sepsis-3) incidence, outcomes, trends in outcomes, and predictive validity of sepsis and septic shock populations. RESULTS: From among 197 724 Sepsis-2 severe sepsis and 197 142 Sepsis-3 sepsis cases, we identified 153 257 Sepsis-2 septic shock and 39 262 Sepsis-3 septic shock cases. The extrapolated population incidence of Sepsis-3 sepsis and Sepsis-3 septic shock was 101.8 and 19.3 per 100 000 person-years, respectively, in 2015. Sepsis-2 severe sepsis and Sepsis-3 sepsis had similar incidence, similar mortality and showed significant risk-adjusted improvements in mortality over time. Sepsis-3 septic shock had a much higher Acute Physiology And Chronic Health Evaluation II (APACHE II) score, greater mortality and no risk-adjusted trends in mortality improvement compared with Sepsis-2 septic shock. ICU admissions identified either as Sepsis-3 sepsis or septic shock and as Sepsis-2 severe sepsis or septic shock had significantly greater risk-adjusted odds of death compared with non-sepsis admissions (P<0.001). The predictive validity was greatest for Sepsis-3 septic shock. CONCLUSIONS: In an ICU database, compared with Sepsis-2, Sepsis-3 identifies a similar sepsis population with 92% overlap and much smaller septic shock population with improved predictive validity.

How could we enhance translation of sepsis immunology to inform immunomodulation trials in sepsis?

Sepsis results in complex alterations to the immune system. Our understanding of how these alterations in immune responses could help characterize extreme immune phenotypes, identify biomarkers with the ability to stratify patients for therapeutic interventions, surrogates in the causal pathway of clinical end-points, and treatable traits are still rudimentary. A methodologically rigorous, consensus-based approach should enrich sepsis immune subpopulations to increase the probability of successful trials.

International survey on the management of mechanical ventilation during ECMO in adults with severe respiratory failure.

BACKGROUND: No consensus exists on the optimal settings of mechanical ventilation during veno-venous extracorporeal membrane oxygenation (ECMO). Our aim was to describe how mechanical ventilation and related interventions are managed by adult ECMO centres. METHODS: A cross-sectional, multi-centre, international survey of 173 adult respiratory ECMO centres. The survey was generated through an iterative process and assessed for clarity, content and face validity. RESULTS: One hundred thirty-three centres responded (76.8%). Pressure control was the most commonly used mechanical ventilation mode (64.4%). Although the median PEEP was 10 cmH2O, 22.6% set PEEP <10 cmH2O and 15.5% used 15-20 cmH2O. In 63% of centres PEEP was fixed and not titrated. Recruitment maneuvres, were never used in 34.1% of centres, or used daily in 13.2%. Centres reported using either a "lung rest" (45.7%), or an "open lung" strategy (44.2%). Only 24.8% used chest CT to guide mechanical ventilation. Adjunctive treatments were never or occasionally used. Only 10% of centres extubated patients on ECMO, mainly in more experienced centres. 71.3% of centres performed tracheostomy on ECMO, with large variability in timing (most frequent on days 6-10). Only 27.1% of ECMO centres had a protocol for mechanical ventilation on ECMO. CONCLUSION: We found large variability in ventilatory practices during ECMO. The clinicians' training background and the centres' experience had no influence on the approach to ventilation. This survey shows that well conducted studies are necessary to determine the best practice of mechanical ventilation during ECMO and its impact on patient outcome.

An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis.

BACKGROUND: Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. OBJECTIVES: To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. DATA SOURCES: Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. REVIEW METHODS: Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. RESULTS: Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control - as an indicator of proper blinding to treatment as a proxy for study quality - associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. LIMITATIONS: As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. CONCLUSIONS: Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. FUNDING: The National Institute for Health Research Health Technology Assessment programme.