An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

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

Clinical and survival differences during separate COVID-19 surges: Investigating the impact of the Sars-CoV-2 alpha variant in critical care patients.

A number of studies have highlighted physiological data from the first surge in critically unwell Covid-19 patients but there is a paucity of data describing emerging variants of SARS-CoV-2, such as B.1.1.7. We compared ventilatory parameters, biochemical and physiological data and mortality between the first and second COVID-19 surges in the United Kingdom, where distinct variants of SARS-CoV-2 were the dominant stain. We performed a retrospective cohort study investigating critically unwell patients admitted with COVID-19 across three tertiary regional ICUs in London, UK. Of 1782 adult ICU patients screened, 330 intubated and ventilated patients diagnosed with COVID-19 were included. In the second wave where B.1.1.7 variant was the dominant strain, patients were had increased severity of ARDS whilst compliance was greater (p<0.05) and d-dimer lower. The 28-day mortality was not statistically significant (1st wave: 42.2% vs 2nd wave: 39.8%). However, when adjusted for key covariates, the hazard ratio for 28-day mortality in those patients with B.1.1.7 was 3.79 (CI 1.04-13.8; p = 0.043) compared to the original strain. During the second surge in the UK, where the COVID-19 variant B.1.1.7 was most prevalent, significantly more patients presented to critical care with severe ARDS. Furthermore, mortality risk was significantly greater in our ICU population during the second wave of the pandemic in those patients with B.1.1.7. As ICUs are experiencing further waves (particularly by the delta (B.1.617.2) variant), we highlight the urgent need for prospective studies describing immunological and pathophysiological differences across novel emerging variants.

An observational study to determine the effect of delayed admission to the intensive care unit on patient outcome.

INTRODUCTION: Delayed patient admission to the intensive care unit (ICU) due to lack of bed availability is a common problem, but the effect on patient outcome is not fully known. METHODS: A retrospective study was performed using departmental computerised records to determine the effect of delayed ICU admission and temporary management within the operating theatre suite on patient outcome. Emergency surgical and medical patients admitted to the ICU (2003 to 2007) were divided into delay (more than three hours from referral to admission) and no-delay (three or fewer hours from referral to admission) groups. Our primary outcome measure was length of ICU stay. Secondary outcome measures were mortality rates and duration of organ support. RESULTS: A total of 1,609 eligible patients were included and 149 (9.3%) had a delayed admission. The delay and no-delay groups had similar baseline characteristics. Median ICU stay was 5.1 days (delay) and 4.5 days (no-delay) (P = 0.55) and ICU mortality was 26.8% (delay) and 24.2% (no-delay) (P = 0.47). Following adjustment for demographic and baseline characteristics there was no difference in either length of ICU stay or mortality rates between groups. ICU admission delay was associated with both an increased requirement for advanced respiratory support (92.3% delay vs. 76.4% no-delay, P <0.01) and a longer time spent ventilated (median four days delay vs. three days no-delay, P = 0.04). CONCLUSIONS: No significant difference in length of ICU stay or mortality rate was demonstrated between the delay and no-delay cohorts. Patients within the delay group had a significantly greater requirement for advanced respiratory support and spent a longer time ventilated.

Long-term renal function and survival of renal transplant recipients admitted to the intensive care unit.

INTRODUCTION: We determined the long-term mortality and renal allograft function of renal transplant recipients admitted to the intensive care unit (ICU). METHODS: A single institution retrospective observational cohort study of all renal transplant patients admitted to the ICU was performed. Serum creatinine was recorded up to one yr after hospital discharge and survival data were collected for three yr. RESULTS: Chest sepsis was the commonest reason for ICU admission. ICU and hospital mortality were 32% and 19% respectively. Predictors of hospital mortality included the presence of sepsis and duration of mechanical ventilation (MV). Of the patients who were discharged from ICU, three-yr mortality was 50%. Renal function at one yr was worse than that at hospital discharge and at baseline, though not statistically significant. Death-censored allograft loss was 11% over the three-yr follow up period. CONCLUSIONS: Sepsis and requirement for MV are independent predictors of mortality in renal transplant recipients admitted to ICU. Renal transplant recipients with chest sepsis may warrant earlier ICU admission. Any loss of renal allograft function during an episode of critical illness appears to have a lasting effect, and longterm patient and allograft survival is poor.

Long-term survival of chronic dialysis patients following survival from an episode of multiple-organ failure.

INTRODUCTION: This study aimed to examine the long-term outcome for patients with end-stage renal failure (ESRF) who survived multiple-organ failure. METHODS: We performed a review of databases from the renal medicine service and intensive care units (ICU) of the participating hospitals within Imperial College Healthcare NHS Trust, London, UK. Patients with ESRF admitted to ICU who required support of two or more organ systems or were ventilated for more than 36 hours were included. To provide a comparison we examined the survival of a comparator group of ESRF patients in the general population with similar demographic and disease characteristics to our study group. We also examined the outcome for ESRF patients admitted to ICU who died prior to discharge. RESULTS: Survival data for two years following discharge from ICU were examined for the impact of age, prior dialysis history, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and medical or surgical status. Of the 199 patients who met the inclusion criteria, 111 (56%) survived their ICU stay. Sixty-two (56%) of the survivors remained alive two years following discharge. There was no group difference in survival with regards to age, dialysis history or APACHE II scores. Those admitted with a medical rather than surgical diagnosis were less likely to survive two years (P < 0.01). Patients who died in ICU had higher APACHE II scores (P < 0.0001) and were more likely to have a medical diagnosis. By log rank analysis two-year mortality was significantly higher (P = 0.003) in the ICU survivors than the comparator group with ESRF. This difference was lost when patients who died within a month of discharge were excluded. CONCLUSIONS: ESRF patients with multiple-organ failure have a high mortality, with the increased risk of death continuing into the early post-ICU period. Those with non-surgical diagnoses have the highest risk. Survival within the group who live beyond the early post-ICU period appears similar to the background population of ESRF patients.

Chest physiotherapy prolongs duration of ventilation in the critically ill ventilated for more than 48 hours.

OBJECTIVE: This study aimed to determine the impact of providing chest physiotherapy after routine clinical assessment on the duration of mechanical ventilation, outcome and intensive care length of stay. DESIGN AND SETTING: Single-centre, single-blind, prospective, randomised, controlled trial in a university hospital general intensive care unit. PATIENTS AND PARTICIPANTS: 180 patients requiring mechanical ventilation for more than 48 h. INTERVENTIONS: Patients randomly allocated, one group receiving physiotherapy as deemed appropriate by physiotherapists after routine daily assessments and another group acting as controls were limited to receiving decubitus care and tracheal suctioning. MEASUREMENTS AND RESULTS: Primary endpoints were initial time to become ventilator-free, secondary endpoints included intensive care unit (ICU) and hospital mortality and ICU length of stay. Kaplan-Meier analysis censored for death revealed a significant prolongation of median time to become ventilator-free among patients receiving physiotherapy (p=0.047). The time taken for 50% of patients (median time) to become ventilator-free was 15 and 11 days, respectively, for physiotherapy and control groups. There were no differences between groups in ICU or hospital mortality rates, or length of ICU stay. The number of patients needing re-ventilation for respiratory reasons was similar in both groups.