Syndromic case definitions for Lower Respiratory Tract Infection (LRTI) are less sensitive in older age: an analysis of symptoms among hospitalised adults (preprint)

Background Lower Respiratory Tract Infections (LRTI) pose a serious threat to older adults but may be underdiagnosed due to atypical presentations. Here we assess LRTI symptom profiles and syndromic (symptom-based) case ascertainment in older (≥65y) as compared to younger adults (<65y). Methods We included adults (≥18y) with confirmed LRTI admitted to two acute care Trusts in Bristol, UK from 1st August 2020- 31st July 2022.  Logistic regression was used to assess whether age ≥65y reduced the probability of meeting syndromic LRTI case definitions, using patients’ symptoms at admission. We also calculated relative symptom frequencies (log-odds ratios) and evaluated how symptoms were clustered across different age groups. Results Of 17,620 clinically confirmed LRTI cases, 8,487 (48.1%) had symptoms meeting the case definition. Compared to those not meeting the definition these cases were younger, had less severe illness and were less likely to have received a SARS-CoV-2 vaccination or to have active SARS-CoV-2 infection. Prevalence of dementia/cognitive impairment and levels of comorbidity were lower in this group. After controlling for sex, dementia and comorbidities, age ≥65y significantly reduced the probability of meeting the case definition (aOR=0.67, 95% CI:0.63-0.71). Cases aged ≥65y were less likely to present with fever and LRTI-specific symptoms (e.g., pleurisy, sputum) than younger cases, and those aged ≥85y were characterised by lack of cough but frequent confusion and falls. Conclusions LRTI symptom profiles changed considerably with age in this hospitalised cohort. Standard screening protocols may fail to detect older and frailer cases of LRTI based on their symptoms.

Relative vaccine effectiveness (rVE) of mRNA COVID-19 boosters in the UK vaccination programme, during the Spring-Summer (monovalent vaccine) and Autumn-Winter 2022 (bivalent vaccine) booster campaigns: a prospective test negative case-control study (preprint)

Background Understanding the relative vaccine effectiveness (rVE) of new COVID-19 vaccine formulations against SARS-CoV-2 infection is an urgent public health priority. A precise comparison of the rVE of monovalent and bivalent boosters given during the 2022 Spring-Summer and Autumn-Winter campaigns, respectively, in a defined population has not been reported. We therefore assessed rVE against hospitalisation for the Spring-Summer (fourth vs third monovalent mRNA vaccine doses) and Autumn-Winter (fifth BA.1/ancestral bivalent vs fourth monovalent mRNA vaccine dose) boosters. Methods A prospective single-centre test-negative design case-control study of [≥]75 year-olds hospitalised with COVID-19 or other acute respiratory disease. We conducted regression analyses controlling for age, gender, socioeconomic status, patient comorbidities, community SARS-CoV-2 prevalence, vaccine brand and time between baseline dose and hospitalisation. Results 682 controls and 182 cases were included in the Spring-Summer booster analysis; 572 controls and 152 cases for the Autumn-Winter booster analysis. A monovalent mRNA COVID-19 vaccine as fourth dose showed rVE 46*9% (95% confidence interval [CI] 14*4-67*3) versus those not boosted. A bivalent mRNA COVID-19 vaccine as fifth dose had rVE 46*4% (95%CI 17*5-65), compared to a fourth monovalent mRNA COVID-19 vaccine dose. Interpretation Both fourth monovalent and fifth BA.1/ancestral mRNA bivalent COVID-19 vaccine doses demonstrated benefit as a booster in older adults. Bivalent mRNA boosters offer equivalent protection against hospitalisation with Omicron infection to monovalent mRNA boosters given earlier in the year. These findings support the current UK immunisation programme that advises the use of bivalent booster doses.

Severity of Omicron (B.1.1.529) and Delta (B.1.1.617.2) SARS-CoV-2 infection among hospitalised adults: a prospective cohort study (preprint)

Limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 variant infections, and to what extent patient-factors, including vaccination and pre-existing disease, affect variant-dependent disease severity. This prospective cohort study of all adults ([≥]18 years of age) hospitalised at acute care hospitals in Bristol, UK assessed disease severity using 3 different measures: FiO2 >28%, World Health Organization (WHO) outcome score >5, and hospital length of stay (LOS) >3 days following admission for Omicron or Delta variant infection. Independent of other variables, including vaccination, Omicron variant infection was associated with a statistically lower severity compared to Delta; risk reductions were 58%, 67%, and 16% for FiO2, WHO score, and LOS, respectively. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden following admission.

Severity of Omicron (B.1.1.529) and Delta (B.1.1.617.2) SARS-CoV-2 infection among hospitalised adults: a prospective cohort study (preprint)

Limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 variant infections, and to what extent patient-factors, including vaccination and pre-existing disease, affect variant-dependent disease severity. This prospective cohort study of all adults (≥18 years of age) hospitalised at acute care hospitals in Bristol, UK assessed disease severity using 3 different measures: FiO2 >28%, World Health Organization (WHO) outcome score >5, and hospital length of stay (LOS) >3 days following admission for Omicron or Delta variant infection. Independent of other variables, including vaccination, Omicron variant infection was associated with a statistically lower severity compared to Delta; risk reductions were 58%, 67%, and 16% for FiO2, WHO score, and LOS, respectively. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden following admission.

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

BackgroundPleural 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 ObjectivesTo 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.MethodsAdult 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.ResultsFrom 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.ConclusionsThe 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 registrationISRCTN: 84674413 (registered 29/04/2019)

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.

A clinical observational analysis of aerosol emissions from dental procedures. (preprint)

There remains uncertainty as to which dental procedures constitute aerosol generating procedures. We aimed to quantify aerosol concentration produced during different dental procedures. Where aerosol was detected, we assessed whether the aerosol size distribution from patient procedures was explained by the non-salivary contaminated instrument source, using phantom head controls. This study obtained ethical approval within the AERATOR grant. Patients were recruited consecutively, and written consent was obtained. Both an optical and an aerodynamic particle sizer were used to measure aerosol, attached to a 3D-printed polylactide funnel 22cm from the patients face. A range of periodontal, oral surgery and orthodontic procedures were captured using time-stamped protocols. High-fidelity phantom head control experiments for each procedure were performed, under the same conditions. Aerosol was measured for each procedure. Where aerosol was detected, phantom head control and patient procedure aerosol size distributions were compared, with the assumption that if the distributions were the same, aerosol detected from the patient could be explained by the instrument source. 41 patients underwent fifteen different dental procedures. For nine procedures, no aerosol was detected. 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. High and slow speed drilling produced aerosol from patient procedures which appear to have different size distributions from a phantom head control and so may pose a greater risk of (potentially infected) salivary contamination. Ultrasonic scaling does not appear to generate additional aerosol above that of the instrument itself and therefore does not increase the risk to dental teams, relative to the risk from being in close proximity to the patient.

Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual. (preprint)

There is widespread interest in the capacity for SARS-CoV-2 evolution in the face of selective pressures from host immunity, either naturally acquired post-exposure or from vaccine acquired immunity. Allied to this is the potential for long perm persistent infections within immune compromised individuals to allow a broader range of viral evolution in the face of sub-optimal immune driven selective pressure. Here we report on an immunocompromised individual who is hypogammaglobulinaemic and was persistently infected with SARS-CoV-2 for over 290 days, the longest persistent infection recorded in the literature to date. During this time, nine samples of viral nucleic acid were obtained and analysed by next-generation sequencing. Initially only a single mutation (L179I) was detected in the spike protein relative to the prototypic SARS-CoV-2 Wuhan-Hu-1 isolate, with no further changes identified at day 58. However, by day 155 the spike protein had acquired a further four amino acid changes, namely S255F, S477N, H655Y and D1620A and a two amino acid deletion ({Delta}H69/{Delta}V70). Infectious virus was cultured from a nasopharyngeal sample taken on day 155 and next-generation sequencing confirmed that the mutations in the virus mirrored those identified by sequencing of the corresponding swab sample. The isolated virus was susceptible to remdesivir in vitro, however a 17-day course of remdesivir started on day 213 had no effect on the viral RT-PCR cycle threshold (Ct) value. On day 265 the patient was treated with the combination of casirivimab and imdevimab. The patient experienced progressive resolution of all symptoms over the next 8 weeks and by day 311 the virus was no longer detectable by RT-PCR. The {Delta}H69/{Delta}V70 deletion in the N-terminus of the spike protein which arose in our patient is also present in the B.1.1.7 variant of concern and has been associated with viral escape mutagenesis after treatment of another immunocompromised patient with convalescent plasma. Our data confirms the significance of this deletion in immunocompromised patients but illustrates it can arise independently of passive antibody transfer, suggesting the deletion may be an enabling mutation that compensates for distant changes in the spike protein that arise under selective pressure.

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)

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.

Hydroxychloroquine serum concentrations in non-critical care patients infected with SARS CoV 2 (preprint)

Hydroxychloroquine(HCQ) has been widely used to treat SARS-CoV-2 infection however HCQ pharmacokinetics in this condition have not been studied in non-critical care patient groups. Here we report the serum concentrations of HCQ in a small cohort of patients treated with HCQ as part of the RECOVERY trial.