Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study (preprint)

Introduction 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 downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. 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 in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, 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 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 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. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Impact of dexamethasone on persistent symptoms of COVID-19: an observational study (preprint)

Introduction Dexamethasone has been shown to reduce mortality for patients hospitalised with acute COVID-19 pneumonia. However, a significant proportion of patients suffer persistent symptoms following COVID-19 and little is known about the longer-term impact of this intervention on symptom burden. Methods Patients initially hospitalised with COVID-19 were prospectively recruited to an observational study (April-August 2020) with follow-up at 8 months (Dec 2020-April 2021) post-admission. A review of ongoing symptoms using a standardised systems-based proforma was performed alongside health-related quality of life assessment. In the UK, patients with COVID-19 (requiring oxygen) only received dexamethasone following the pre-print of the RECOVERY trial (June 2020), or as part of randomisation to that trial, allowing for a comparison between patients treated and not treated with dexamethasone. Results Between April to August 2020, 198 patients were recruited to this observational study. 87 required oxygen and were followed up at 8-months, so were eligible for this analysis. Of these 39 received an inpatient course of dexamethasone (cases) and 48 did not (controls). The groups were well matched at baseline in terms of age, comorbidity and frailty score. Over two-thirds of patients reported at least 1 ongoing symptom at 8-month follow-up. Patients in the dexamethasone group reported fewer symptoms (n=73, 1.9 per patient) than the non-dexamethasone group (n=152, 3.2 per patient) (p = 0.01). Conclusions In conclusion, in this case-control observational study, patients who received oral dexamethasone for hospitalised COVID-19 were less likely to experience persistent symptoms at 8-month follow-up. These are reassuring results for physicians administering dexamethasone to this patient group.

Is convalescent plasma futile in COVID-19? A Bayesian re-analysis of the RECOVERY randomised controlled trial (preprint)

Introduction: Randomised trials are generally performed from a frequentist perspective reporting point estimates and 95% confidence intervals. This approach can confuse 'evidence of no effect' with 'no evidence of an effect' and does not allow for contextual knowledge. The RECOVERY trial evaluated convalescent plasma for patients hospitalised with COVID-19, the interaction test for the primary outcome was not statistically significant, and the trial concluded no evidence of an effect. From the clinical immunology perspective, there is strong justification to expect differential responses to convalescent plasma in patients who already have their own antibodies to SARS-CoV2 (seropositive) versus those who do not (seronegative). Methods: Outcome data was extracted from the RECOVERY trial both overall and for seronegative participants. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, skeptical and pessimistic) was performed calculating the posterior probability for both any benefit or a modest benefit (number needed to treat of 100). Results: Across all patients, when analysed with a vague prior the likelihood of any benefit or a modest benefit was estimated to be 64% and 18% respectively. In contrast, in the seronegative subgroup, the likelihood of any benefit or a modest benefit was estimated to be 90% and 74%. Results were broadly consistent across all prior distributions. Conclusion: Performing clinical trials during a pandemic is challenging, and RECOVERY has provided high quality evidence for numerous therapies. However, the use of frequentist hypothesis testing in this trial has led to the trialists and governing bodies to conclude a strong evidence of no effect. Based on this trial, and other prior knowledge there remains a strong probability that convalescent plasma provides at least a modest benefit in seronegative patients.

Are vaccines safe in patients with Long COVID? A prospective observational study. (preprint)

IntroductionAlthough the efficacy of SARS-CoV-2 vaccination to prevent symptomatic COVID-19 is well established, there are no published studies on the impact on symptoms in patients with Long Covid. Anecdotal reports have suggested both a potential benefit and worsening of symptoms post vaccination with the uncertainty leading to some vaccine hesitancy amongst affected individuals. MethodsPatients initially hospitalised with COVID-19 were prospectively recruited to an observational study with clinical follow-up at 3 months (June-July 2020) and 8 months (Dec 2020-Jan 2021) post-admission. Participants who received the Pfizer-BioNTech (BNT162b2) or Oxford-AstraZeneca (ChAdOx1 nCoV-19) vaccine between January to February 2021 were identified and matched 2:1 (in terms of 8-month symptoms) with participants from the same cohort who were unvaccinated. All were re-assessed at 1 month post vaccination (or matched timepoint for unvaccinated cohort). Validated quality of life (SF-36), mental wellbeing (WEMWBS) and ongoing symptoms were assessed at all timepoints. Formal statistical analysis compared the effect of vaccination on recent quality of life using baseline symptoms, age, and gender in linear regression. ResultsForty-four vaccinated participants were assessed at a median of 32 days (IQR 20-41) post vaccination with 22 matched unvaccinated participants. Most were highly symptomatic of Long Covid at 8 months (82% in both groups had at least 1 persistent symptom), with fatigue (61%), breathlessness (50%) and insomnia (38%) predominating. There was no significant worsening in quality-of-life or mental wellbeing metrics pre versus post vaccination. Nearly two-thirds (n=27) reported transient (<72hr duration) systemic effects (including fever, myalgia and headache). When compared to matched unvaccinated participants from the same cohort, those who had receive a vaccine had a small overall improvement in Long Covid symptoms, with a decrease in worsening symptoms (5.6% vaccinated vs 14.2% unvaccinated) and increase in symptom resolution (23.2% vaccinated vs 15.4% unvaccinated) (p=0.035). No difference in response was identified between Pfizer-BioNTech or Oxford-AstraZeneca vaccines. ConclusionsReceipt of vaccination with either an mRNA or adenoviral vector vaccine was not associated with a worsening of Long Covid symptoms, quality of life, or mental wellbeing. Individuals with prolonged COVID-19 symptoms should receive vaccinations as suggested by national guidance.

Aerosol emission from the respiratory tract: an analysis of relative risks from oxygen delivery systems (preprint)

Background: Risk of aerosolisation of SARS-CoV-2 directly informs organisation of acute healthcare and PPE guidance. Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are widely used modes of oxygen delivery and respiratory support for patients with severe COVID-19, with both considered as high risk aerosol generating procedures. However, there are limited high quality experimental data characterising aerosolisation during oxygen delivery and respiratory support. Methods: Healthy volunteers were recruited to breathe, speak, and cough in ultra-clean, laminar flow theatres followed by using oxygen and respiratory support systems. Aerosol emission was measured using two discrete methodologies, simultaneously. Hospitalised patients with COVID-19 were also recruited and had aerosol emissions measured during breathing, speaking, and coughing. Findings: In healthy volunteers (n = 25 subjects; 531 measures), CPAP (with exhalation port filter) produced less aerosols than breathing, speaking and coughing (even with large >50L/m facemask leaks). HFNO did emit aerosols, but the majority of these particles were generated from the HFNO machine, not the patient. HFNO-generated particles were small (<1 micron), passing from the machine through the patient and to the detector without coalescence with respiratory aerosol, thereby unlikely to carry viral particles. Coughing was associated with the highest aerosol emissions with a peak concentration at least 10 times greater the mean concentration generated from speaking or breathing. Hospitalised patients with COVID-19 (n = 8 subjects; 56 measures) had similar size distributions to healthy volunteers. Interpretation: In healthy volunteers, CPAP is associated with less aerosol emission than breathing, speaking or coughing. Aerosol emission from the respiratory tract does not appear to be increased by HFNO. Although direct comparisons are complex, cough appears to generate significant aerosols in a size range compatible with airborne transmission of SARS-CoV-2. As a consequence, the risk of SARS-CoV-2 aerosolisation is likely to be high in all areas where patients with Covid-19 are coughing. Guidance on personal protective equipment policy should reflect these updated risks. Funding: NIHR-UKRI Rapid COVID call (COV003), Wellcome Trust GW4-CAT Doctoral Training Scheme (FH), MRC CARP Fellowship(JD, MR/T005114/1). Natural Environment Research Council grant (BB, NE/P018459/1)

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort. (preprint)

Background: COVID19 causes a wide spectrum of disease. However, the incidence and severity of sequelae after the acute infection is uncertain. Data measuring the longer-term impact of COVID19 on symptoms, radiology and pulmonary function are urgently needed to inform patients and plan follow up services. Methods: Consecutive patients hospitalised with COVID19 were prospectively recruited to an observational cohort with outcomes recorded at 28 days. All were invited to a systematic follow up at 12 weeks, including chest radiograph, spirometry, exercise test, blood tests, and health-related quality of life (HRQoL) questionnaires. Findings: Between 30th March and 3rd June 2020, 163 patients with COVID19 were recruited. Median hospital length of stay was 5 days (IQR 2 to 8) and 30 patients required ITU or NIV, 19 patients died. At 12 weeks post admission, 134 were available for follow up and 110 attended. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) with reduced HRQoL. Only patients with disease sufficiently severe to warrant oxygen therapy in hospital had abnormal radiology, clinical examination or spirometry at follow up. Thirteen (12%) patients had an abnormal chest X-ray with improvement in all but 2 from admission. Eleven (10%) had restrictive spirometry. Blood test abnormalities had returned to baseline in the majority (104/110). Interpretation: Patients with COVID19 remain highly symptomatic at 12 weeks, however, clinical abnormalities requiring action are infrequent, especially in those without a supplementary oxygen requirement during their acute illness. This has significant implications for physicians assessing patients with persistent symptoms, suggesting that a more holistic approach focussing on rehabilitation and general wellbeing is paramount. Funding: Southmead Hospital Charity

Kinetics and performance of the Abbott Architect SARS-CoV-2 IgG antibody assay (preprint)

Objectives: To assess the performance (sensitivity and specificity) of the Abbott Architect SARS-CoV-2 IgG antibody assay across three clinical settings. Methods: Antibody testing was performed on three clinical cohorts of COVID-19 disease: hospitalised patients with PCR confirmation, hospitalized patients with a clinical diagnosis but negative PCR, and symptomatic healthcare workers (HCWs). Pre-pandemic respiratory infection sera were tested as negative controls. The sensitivity of the assay was calculated at different time points (<5 days, 5-9 days, 10-14 days, 15-19 days, >20 days, >42 days), and compared between cohorts. Results: Performance of the Abbot Architect SARS-CoV-2 assay varied significantly between cohorts. For PCR confirmed hospitalised patients (n = 114), early sensitivity was low: <5 days: 44.4% (95%CI: 18.9%-73.3%), 5-9 days: 32.6% (95%CI, 20.5%-47.5%), 10-14 days: 65.2% (95% CI 44.9%-81.2%), 15-20 days: 66.7% (95% CI: 39.1%-86.2%) but by day 20, sensitivity was 100% (95%CI, 86.2-100%). In contrast, 17 out of 114 symptomatic healthcare workers tested at >20 days had negative results, generating a sensitivity of 85.1% (95%CI, 77.4% - 90.5%). All pre-pandemic sera were negative, a specificity of 100%. Seroconversion rates were similar for PCR positive and PCR negative hospitalised cases. Conclusions: The sensitivity of the Abbot Architect SARS-CoV-2 IgG assay increases over time, with sensitivity not peaking until 20 days post symptoms. Performance varied markedly by setting, with sensitivity significantly worse in symptomatic healthcare workers than in the hospitalised cohort. Clinicians, policymakers, and patients should be aware of the reduced sensitivity in this setting.

Blood parameters measured on admission as predictors of outcome for COVID-19; a prospective UK cohort study (preprint)

Abstract: 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 recruited. Admission bloods were extracted from the clinical laboratory. A panel of biomarkers (IL-6, suPAR, KL-6, Troponin, Ferritin, LDH, BNP, Procalcitonin) were performed in addition to routinely performed markers (CRP, neutrophils, lymphocytes, neutrophil:lymphocyte ratio). Age, NEWS score and CURB-65 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: 155 patients had 28-day outcomes at the time of analysis. CRP (AUC 0.51 ,CI:0.40-0.62), lymphocyte count (AUC 0.62 ,CI:0.51-0.72), and other routine markers did not predict the primary outcome. IL-6 (AUC: 0.78,0.65-0.89) and suPAR (AUC 0.77 ,CI: 0.66-0.85) showed some promise, but simple clinical features alone such as NEWS score (AUC: 0.74 ,0.64-0.83) or age (AUC: 0.70 ,0.61-0.78) 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 NEWS score outperform many biomarkers. IL-6 and suPAR had the best performance, and further studies should validate these biomarkers in a prospective fashion.