Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.

BACKGROUND: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. METHODS AND FINDINGS: We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. CONCLUSIONS: IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

ERS/ESTS statement on the management of pleural infection in adults.

Pleural infection is a common condition encountered by respiratory physicians and thoracic surgeons alike. The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) established a multidisciplinary collaboration of clinicians with expertise in managing pleural infection with the aim of producing a comprehensive review of the scientific literature.Six areas of interest were identified including the epidemiology of pleural infection, the optimal antibiotic strategy, diagnostic parameters for chest tube drainage, the status of intrapleural therapies, the role of surgery and the current place of outcome prediction in management.The literature revealed that recently updated epidemiological data continue to show an overall upwards trend in incidence, but there is an urgent need for a more comprehensive characterisation of burden of pleural infection in specific populations such as immunocompromised hosts. There is a sparsity of regular analyses and documentation of microbiological patterns at a local level to inform geographical variation and ongoing research efforts are needed to improve antibiotic stewardship. The evidence remains in favour of a small-bore chest tube optimally placed under image guidance as an appropriate initial intervention for most cases of pleural infection. With a growing body of data suggesting delays to treatment are key contributors to poor outcomes, this suggests that earlier consideration of combination intrapleural enzyme therapy (IET) with concurrent surgical consultation should remain a priority. Since publication of the MIST-2 study, there has been considerable data supporting safety and efficacy of IET, but further studies are needed to optimise dosing using individualised biomarkers of treatment failure. Pending further prospective evaluation, the MIST-2 regimen remains the most evidence based. Several studies have externally validated the RAPID score, but it requires incorporating into prospective intervention studies prior to adopting into clinical practice.

Effectiveness of BNT162b2 COVID-19 vaccination in prevention of hospitalisations and severe disease in adults with SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant between June 2021 and July 2022: A prospective test negative case–control study

Summary Background Whilst other studies have reported the effectiveness of mRNA vaccination against hospitalisation, including emergency department or intensive care admission, few have assessed effectiveness against other more clinically robust indices of COVID-19 severity. Methods A prospective single-centre test-negative design case–control study of adults hospitalised with COVID-19 disease or other acute respiratory disease between 1 June 2021 and 20 July 2022. We assessed VE (vaccine effectiveness) against hospitalisation, length of stay [LOS] >3 days, WHO COVID Score >5 and supplementary oxygen FiO2 (fraction inspired oxygen) >28%, conducting regression analyses controlling for age, gender, index of multiple deprivation, Charlson comorbidity index, time, and community infection prevalence. Findings 935 controls and 546 cases were hospitalised during the Delta period, with 721 controls and 372 cases hospitalised during the Omicron study period. Two-dose BNT162b2 was associated with VE 82.5% [95% confidence interval 76.2%–87.2%] against hospitalisation following Delta infection, 63.3% [26.9–81.8%], 58.5% [24.8–77.3%], and 51.5% [16.7–72.1%] against LOS >3 days, WHO COVID Score >5, and requirement for FiO2 >28% respectively. Three-dose BNT162b2 protection against hospitalisation with Omicron infection was 30.9% [5.9–49.3%], with sensitivity analyses ranging from 28.8–72.6%. Protection against LOS >3 days, WHO COVID Score >5 and requirement for FiO2 >28% was 56.1% [20.6–76.5%], 58.8% [31.2–75.8%], and 41.5% [−0.4–66.3%], respectively. In the UK, BNT162b2 was prioritised for high-risk individuals and those aged >75 years. In the latter group we found a higher estimate of VE against hospitalisation of 47.2% [16.8–66.6%]. Interpretation BNT162b2 vaccination results in risk reductions for hospitalisation and multiple patient outcomes following Delta and Omicron COVID-19 infection, particularly in older adults. BNT162b2 remains effective against severe SARS-CoV-2 disease. Funding AvonCAP is an investigator-led project funded under a collaborative agreement by 10.13039/100004319Pfizer.

Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 infection among hospitalised adults: A prospective cohort study in Bristol, United Kingdom.

Background: There is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity. Methods: A prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection. Findings: Independent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 [Relative Risk (RR) = 0.42 (95%CI: 0.34-0.52), P < 0.001], WHO outcome score >5 [RR = 0.33 (95%CI: 0.21-0.50), P < 0.001], and to have had a LOS > 3 days [RR = 0.84 (95%CI: 0.76-0.92), P < 0.001]. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Interpretation: We provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

Effectiveness of BNT162b2 COVID-19 vaccination in prevention of hospitalisations and severe disease in adults with SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant between June 2021 and July 2022: A prospective test negative case-control study.

Background: Whilst other studies have reported the effectiveness of mRNA vaccination against hospitalisation, including emergency department or intensive care admission, few have assessed effectiveness against other more clinically robust indices of COVID-19 severity. Methods: A prospective single-centre test-negative design case-control study of adults hospitalised with COVID-19 disease or other acute respiratory disease between 1 June 2021 and 20 July 2022. We assessed VE (vaccine effectiveness) against hospitalisation, length of stay [LOS] >3 days, WHO COVID Score >5 and supplementary oxygen FiO2 (fraction inspired oxygen) >28%, conducting regression analyses controlling for age, gender, index of multiple deprivation, Charlson comorbidity index, time, and community infection prevalence. Findings: 935 controls and 546 cases were hospitalised during the Delta period, with 721 controls and 372 cases hospitalised during the Omicron study period. Two-dose BNT162b2 was associated with VE 82.5% [95% confidence interval 76.2%-87.2%] against hospitalisation following Delta infection, 63.3% [26.9-81.8%], 58.5% [24.8-77.3%], and 51.5% [16.7-72.1%] against LOS >3 days, WHO COVID Score >5, and requirement for FiO2 >28% respectively. Three-dose BNT162b2 protection against hospitalisation with Omicron infection was 30.9% [5.9-49.3%], with sensitivity analyses ranging from 28.8-72.6%. Protection against LOS >3 days, WHO COVID Score >5 and requirement for FiO2 >28% was 56.1% [20.6-76.5%], 58.8% [31.2-75.8%], and 41.5% [-0.4-66.3%], respectively. In the UK, BNT162b2 was prioritised for high-risk individuals and those aged >75 years. In the latter group we found a higher estimate of VE against hospitalisation of 47.2% [16.8-66.6%]. Interpretation: BNT162b2 vaccination results in risk reductions for hospitalisation and multiple patient outcomes following Delta and Omicron COVID-19 infection, particularly in older adults. BNT162b2 remains effective against severe SARS-CoV-2 disease. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

A feasibility randomised trial comparing therapeutic thoracentesis to chest tube insertion for the management of pleural infection: results from the ACTion trial.

BACKGROUND: Pleural infection is a complex condition with a considerable healthcare burden. The average hospital stay for pleural infection is 14 days. Current standard of care defaults to chest tube insertion and intravenous antibiotics. There have been no randomised trials on the use of therapeutic thoracentesis (TT) for pleural fluid drainage in pleural infection. AIMS AND OBJECTIVES: To assess the feasibility of a full-scale trial of chest tube vs TT for pleural infection in a single UK centre. The primary outcome was defined as the acceptability of randomisation to patients. METHODS: Adult patients admitted with a pleural effusion felt to be related to infection and meeting criteria for drainage (based on international guidelines) were eligible for randomisation. Participants were randomised (1:1) to chest tube insertion or TT with daily review assessing need for further drainages or other therapies. Neither participant nor clinician were blinded to treatment allocation. Patients were followed up at 90 days post-randomisation. RESULTS: From September 2019 to June 2021, 51 patients were diagnosed with pleural infection (complex parapneumonic effusion/empyema). Eleven patients met the inclusion criteria for trial and 10 patients were randomised (91%). The COVID-19 pandemic had a substantial impact on recruitment. Data completeness was high in both groups with no protocol deviations. Patients randomised to TT had a significantly shorter overall mean hospital stay (5.4 days, SD 5.1) compared to the chest tube control group (13 days, SD 6.0), p = 0.04. Total number of pleural procedures required per patient were similar, 1.2 in chest tube group and 1.4 in TT group. No patient required a surgical referral. Adverse events were similar between the groups with no readmissions related to pleural infection. CONCLUSIONS: The ACTion trial met its pre-specified feasibility criteria for patient acceptability but other issues around feasibility of a full-scale trial remain. From the results available the hypothesis that TT can reduce length of stay in pleural infection should be explored further. TRIAL REGISTRATION: ISRCTN: 84674413.

Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: A prospective cohort study.

Background: The emergence of COVID-19 and public health measures implemented to reduce SARS-CoV-2 infections have both affected acute lower respiratory tract disease (aLRTD) epidemiology and incidence trends. The severity of COVID-19 and non-SARS-CoV-2 aLRTD during this period have not been compared in detail. Methods: We conducted a prospective cohort study of adults age ≥18 years admitted to either of two acute care hospitals in Bristol, UK, from August 2020 to November 2021. Patients were included if they presented with signs or symptoms of aLRTD (e.g., cough, pleurisy), or a clinical or radiological aLRTD diagnosis. Findings: 12,557 adult aLRTD hospitalisations occurred: 10,087 were associated with infection (pneumonia or non-pneumonic lower respiratory tract infection [NP-LRTI]), 2161 with no infective cause, with 306 providing a minimal surveillance dataset. Confirmed SARS-CoV-2 infection accounted for 32% (3178/10,087) of respiratory infections. Annual incidences of overall, COVID-19, and non- SARS-CoV-2 pneumonia were 714.1, 264.2, and 449.9, and NP-LRTI were 346.2, 43.8, and 302.4 per 100,000 adults, respectively. Weekly incidence trends in COVID-19 aLRTD showed large surges (median 6.5 [IQR 0.7-10.2] admissions per 100,000 adults per week), while other infective aLRTD events were more stable (median 14.3 [IQR 12.8-16.4] admissions per 100,000 adults per week) as were non-infective aLRTD events (median 4.4 [IQR 3.5-5.5] admissions per 100,000 adults per week). Interpretation: While COVID-19 disease was a large component of total aLRTD during this pandemic period, non- SARS-CoV-2 infection still caused the majority of respiratory infection hospitalisations. COVID-19 disease showed significant temporal fluctuations in frequency, which were less apparent in non-SARS-CoV-2 infection. Despite public health interventions to reduce respiratory infection, disease incidence remains high. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

A clinical observational analysis of aerosol emissions from dental procedures.

Aerosol generating procedures (AGPs) are defined as any procedure releasing airborne particles <5 µm in size from the respiratory tract. There remains uncertainty about which dental procedures constitute AGPs. We quantified the aerosol number concentration generated during a range of periodontal, oral surgery and orthodontic procedures using an aerodynamic particle sizer, which measures aerosol number concentrations and size distribution across the 0.5-20 µm diameter size range. Measurements were conducted in an environment with a sufficiently low background to detect a patient's cough, enabling confident identification of aerosol. Phantom head control experiments for each procedure were performed under the same conditions as a comparison. Where aerosol was detected during a patient procedure, we assessed whether the size distribution could be explained by the non-salivary contaminated instrument source in the respective phantom head control procedure using a two-sided unpaired t-test (comparing the mode widths (log(σ)) and peak positions (DP,C)). The aerosol size distribution provided a robust fingerprint of aerosol emission from a source. 41 patients underwent fifteen different dental procedures. For nine procedures, no aerosol was detected above background. Where aerosol was detected, the percentage of procedure time that aerosol was observed above background ranged from 12.7% for ultrasonic scaling, to 42.9% for 3-in-1 air + water syringe. For ultrasonic scaling, 3-in-1 syringe use and surgical drilling, the aerosol size distribution matched the non-salivary contaminated instrument source, with no unexplained aerosol. High and slow speed drilling produced aerosol from patient procedures with different size distributions to those measured from the phantom head controls (mode widths log(σ)) and peaks (DP,C, p< 0.002) and, therefore, may pose a greater risk of salivary contamination. This study provides evidence for sources of aerosol generation during common dental procedures, enabling more informed evaluation of risk and appropriate mitigation strategies.

Predicting outcomes of COVID-19 from admission biomarkers: a prospective UK cohort study.

INTRODUCTION: COVID-19 has an unpredictable clinical course, so prognostic biomarkers would be invaluable when triaging patients on admission to hospital. Many biomarkers have been suggested using large observational datasets but sample timing is crucial to ensure prognostic relevance. The DISCOVER study prospectively recruited patients with COVID-19 admitted to a UK hospital and analysed a panel of putative prognostic biomarkers on the admission blood sample to identify markers of poor outcome. METHODS: Consecutive patients admitted to hospital with proven or clinicoradiological suspected COVID-19 were consented. Admission bloods were extracted from the clinical laboratory. A panel of biomarkers (interleukin-6 (IL-6), soluble urokinase plasminogen activator receptor (suPAR), Krebs von den Lungen 6, troponin, ferritin, lactate dehydrogenase, B-type natriuretic peptide, procalcitonin) were performed in addition to routinely performed markers (C reactive protein (CRP), neutrophils, lymphocytes, neutrophil:lymphocyte ratio). Age, National Early Warning Score (NEWS2), CURB-65 and radiographic severity score on initial chest radiograph were included as comparators. All biomarkers were tested in logistic regression against a composite outcome of non-invasive ventilation, intensive care admission or death, with area under the curve (AUC) (figures calculated). RESULTS: 187 patients had 28-day outcomes at the time of analysis. CRP (AUC: 0.69, 95% CI: 0.59 to 0.78), lymphocyte count (AUC: 0.62, 95% CI: 0.53 to 0.72) and other routine markers did not predict the primary outcome. IL-6 (AUC: 0.77, 0.65 to 0.88) and suPAR (AUC: 0.81, 0.72 to 0.88) showed some promise, but simple clinical features alone such as NEWS2 score (AUC: 0.70, 0.60 to 0.79) or age (AUC: 0.70, 0.62 to 0.77) performed nearly as well. DISCUSSION: Admission blood biomarkers have only moderate predictive value for predicting COVID-19 outcomes, while simple clinical features such as age and NEWS2 score outperform many biomarkers. IL-6 and suPAR had the best performance, and further studies should focus on the additive value of these biomarkers to routine care.

Obesity, Diabetes and COVID-19: An Infectious Disease Spreading From the East Collides With the Consequences of an Unhealthy Western Lifestyle.

The pandemic of COVID-19, caused by the coronavirus, SARS-CoV-2, has had a global impact not seen for an infectious disease for over a century. This acute pandemic has spread from the East and has been overlaid onto a slow pandemic of metabolic diseases of obesity and diabetes consequent from the increasing adoption of a Western-lifestyle characterized by excess calorie consumption with limited physical activity. It has become clear that these conditions predispose individuals to a more severe COVID-19 with increased morbidity and mortality. There are many features of diabetes and obesity that may accentuate the clinical response to SARS-CoV-2 infection: including an impaired immune response, an atherothrombotic state, accumulation of advanced glycation end products and a chronic inflammatory state. These could prime an exaggerated cytokine response to viral infection, predisposing to the cytokine storm that triggers progression to septic shock, acute respiratory distress syndrome, and multi-organ failure. Infection leads to an inflammatory response and tissue damage resulting in increased metabolic activity and an associated increase in the mechanisms by which cells ingest and degrade tissue debris and foreign materials. It is becoming clear that viruses have acquired an ability to exploit these mechanisms to invade cells and facilitate their own life-cycle. In obesity and diabetes these mechanisms are chronically activated due to the deteriorating metabolic state and this may provide an increased opportunity for a more profound and sustained viral infection.