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.

Persistent SARS-CoV-2 infection in immunocompromised patients facilitates rapid viral evolution: Retrospective cohort study and literature review.

Background: Most patients with SARS-CoV-2 are non-infectious within 2 weeks, though viral RNA may remain detectable for weeks. However there are reports of persistent SARS-CoV-2 infection, with viable virus and ongoing infectivity months after initial detection. Beyond individuals, viral evolution during persistent infections may be accelerated, driving emergence of mutations associated with viral variants of concern. These patients often do not meet inclusion criteria for clinical trials, meaning clinical and virologic characteristics, and optimal management strategies are poorly evidence-based. Methods: We analysed cases of SARS-CoV-2 infection from a regional testing laboratory in South-West England between March 2020 and December 2021, with at least two SARS-CoV-2 positive samples separated by ≥ 56 days were identified. Excluding those with confirmed or likely re-infection, we identified patients with persistent infection, characterised by an ongoing clinical syndrome consistent with COVID-19 alongside monophyletic viral lineage of SARS-CoV-2. We examined clinical and virologic characteristics, treatment, and outcome. We further performed a literature review investigating cases of persistent SARS-CoV-2 infection, reviewing patient characteristics and treatment. Results: We identified six patients with persistent SARS-CoV-2 infection. All were hypogammaglobulinaemic and had underlying haematological malignancy, with four having received B-cell depleting therapy. Evidence of viral evolution, including accrual of mutations associated with variants of concern, was demonstrated in five cases. Four patients ultimately cleared SARS-CoV-2. In two patients, clearance followed treatment with casirivimab/imdevimab. Both survived beyond thirty days following viral clearance, having experienced infections of 305- and 269-days duration respectively, after failed attempts at clearance with alternative therapies. We found 60 cases of confirmed persistent infection in the literature, with a further 31 probable cases. Of those, 80% of patients treated with monoclonal antibodies cleared SARS-CoV-2, and none died. Conclusion: Haematological malignancy and patients receiving B-cell depleting therapies represent key groups at risk of persistent SARS-CoV-2 infection. Throughout persistent infection, SARS-CoV-2 can evolve rapidly, giving rise to significant mutations, including those implicated in variants of concern. Monoclonal antibodies appear to be a promising therapeutic option, potentially in combination with antivirals, crucial for individuals, and for public health.

Treatment of chronic or relapsing COVID-19 in immunodeficiency.

BACKGROUND: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. OBJECTIVE: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting ≥21 days) or relapsing (≥2 episodes) of COVID-19. RESULTS: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of ≤20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise.

Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial.

BACKGROUND: Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine. METHODS: In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248. FINDINGS: Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos -1·29%, 95% CI -14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, -6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (-12·9%, -34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, -13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, -5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, -11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected. INTERPRETATION: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need. FUNDING: National Institute for Health Research Policy Research Programme.

Aerosol emission from the respiratory tract: an analysis of aerosol generation from oxygen delivery systems.

INTRODUCTION: continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) provide enhanced oxygen delivery and respiratory support for patients with severe COVID-19. CPAP and HFNO are currently designated as aerosol-generating procedures despite limited high-quality experimental data. We aimed to characterise aerosol emission from HFNO and CPAP and compare with breathing, speaking and coughing. MATERIALS AND METHODS: Healthy volunteers were recruited to breathe, speak and cough in ultra-clean, laminar flow theatres followed by using CPAP and HFNO. Aerosol emission was measured using two discrete methodologies, simultaneously. Hospitalised patients with COVID-19 had cough recorded using the same methodology on the infectious diseases ward. RESULTS: In healthy volunteers (n=25 subjects; 531 measures), CPAP (with exhalation port filter) produced less aerosol than breathing, speaking and coughing (even with large >50 L/min face mask leaks). Coughing was associated with the highest aerosol emissions of any recorded activity. HFNO was associated with aerosol emission, however, this was from the machine. Generated particles were small (<1 µm), passing from the machine through the patient and to the detector without coalescence with respiratory aerosol, thereby unlikely to carry viral particles. More aerosol was generated in cough from patients with COVID-19 (n=8) than volunteers. CONCLUSIONS: In healthy volunteers, standard non-humidified 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 be the main aerosol-generating risk out of all measured activities.

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

The longer-term consequences of SARS-CoV-2 infection are uncertain. Consecutive patients hospitalised with COVID-19 were prospectively recruited to this observational study (n=163). At 8-12 weeks postadmission, survivors were invited to a systematic clinical follow-up. Of 131 participants, 110 attended the follow-up clinic. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) and limitations in reported physical ability. However, clinically significant abnormalities in chest radiograph, exercise tests, blood tests and spirometry were less frequent (35%), especially in patients not requiring supplementary oxygen during their acute infection (7%). Results suggest that a holistic approach focusing on rehabilitation and general well-being is paramount.