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.

Bayesian Prediction of Severe Outcomes in the LabMarCS: Laboratory Markers of COVID-19 Severity - Bristol Cohort (preprint)

Objectives: To develop cross-validated prediction models for severe outcomes in COVID-19 using blood biomarker and demographic data; Demonstrate best practices for clinical data curation and statistical modelling decisions, with an emphasis on Bayesian methods. Design: Retrospective observational cohort study. Setting: Multicentre across National Health Service (NHS) trusts in Southwest region, England, UK. Participants: Hospitalised adult patients with a positive SARS-CoV 2 by PCR during the first wave (March - October 2020). 843 COVID-19 patients (mean age 71, 45% female, 32% died or needed ICU stay) split into training (n=590) and validation groups (n=253) along with observations on demographics, coinfections, and 30 laboratory blood biomarkers. Primary outcome measures: ICU admission or death within 28-days of admission to hospital for COVID-19 or a positive PCR result if already admitted. Results: Predictive regression models were fit to predict primary outcomes using demographic data and initial results from biomarker tests collected within 3 days of admission or testing positive if already admitted. Using all variables, a standard logistic regression yielded an internal validation median AUC of 0.7 (95% Interval [0.64,0.81]), and an external validation AUC of 0.67 [0.61, 0.71], a Bayesian logistic regression using a horseshoe prior yielded an internal validation median AUC of 0.78 [0.71, 0.85], and an external validation median AUC of 0.70 [0.68, 0.71]. Variable selection performed using Bayesian predictive projection determined a four variable model using Age, Urea, Prothrombin time and Neutrophil-Lymphocyte ratio, with a median AUC of 0.74 [0.67, 0.82], and external validation AUC of 0.70 [0.69, 0.71]. Conclusions: Our study reiterates the predictive value of previously identified biomarkers for COVID-19 severity assessment. Given the small data set, the full and reduced models have decent performance, but would require improved external validation for clinical application. The study highlights a variety of challenges present in complex medical data sets while maintaining best statistical practices with an emphasis on showcasing recent Bayesian methods.

Use of illness severity scores to predict mortality in interstitial lung disease patients hospitalised with acute respiratory deterioration (preprint)

IntroductionHospitalisations relating to acute respiratory deteriorations (ARD) in Interstitial Lung Disease (ILD) have poor outcomes. Factors predicting adverse outcomes are not fully understood and data addressing the use of illness severity scores in prognostication are limited. ObjectiveTo validate the use of CURB-65 and NEWS-2 severity scores to predict mortality following ARD-ILD hospitalisation. MethodsA dual-centre prospective observational cohort study of all adults ([≥]18y) hospitalised with ARD-ILD in Bristol, UK (n=179). Gender-Age-Physiology (GAP), CURB-65 and NEWS-2 scores were calculated for each eligible admission. Receiver operating characteristics (ROC) curve analysis was used to quantify the strength of discrimination for NEWS-2 and CURB-65 scores. Univariable and multivariable logistic regression analyses were performed to explore the relationship between baseline severity scores and mortality. ResultsGAP showed some merit at predicting 30-day mortality (AUC=0.64, P=0.015); whereas CURB-65 showed modest predictive value for in-hospital (AUC=0.72, P<0.001) and 90-day mortality (AUC=0.67, P<0.001). NEWS-2 showed higher predictive value for in-hospital (AUC=0.80, P<0.001) and 90-day mortality (AUC=0.75, P<0.001), with an optimal derived cut-off [≥]6.5 found to be sensitive and specific for predicting in-hospital (83% and 63%) and 90-day (73% and 72%) mortality. In exploratory analyses, GAP score addition improved the predictive ability of NEWS-2 against 30-day mortality and CURB-65 across all time-periods. ConclusionNEWS-2 has good discriminatory value for predicting in-hospital mortality and moderate discriminatory value for predicting 90-day mortality. The optimal NEWS-2 cut-off value determined was the same as in a previous retrospective cohort, confirming the NEWS-2 score shows promise in predicting mortality following ARD-ILD hospitalisation. KEY MESSAGESO_ST_ABSWhat is the key question?C_ST_ABS- Can NEWS-2 and CURB-65 be used to predict inpatient mortality in a cohort of patients with acute respiratory deterioration on a background of known interstitial lung disease? What is the bottom line?- The NEWS-2 score shows high sensitivity and specificity in predicting both 90-day and in-hospital mortality in patients hospitalised with ARD-ILD - Whilst the CURB-65 score showed high sensitivity for predicting mortality, there was a low specificity, and did not add value to the predictive ability of the NEWS-2 score. Why read on?- This analysis included 179 patients from two study sites and provides, for the first time, prospective evidence for utilising NEWS-2 and CURB-65 as tools to predict in-hospital and post hospitalisation morbidity.

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.

Neutrophils in severe COVID-19 are characterized by a hyperactive immature state and maintained CXCR2 expression (preprint)

Neutrophils are vital in defence against pathogens but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome (ARDS). COVID-19 is associated with systemic expansion of immature neutrophils but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in COVID-19. First, we demonstrate hyperactivation of immature CD10- subpopulations in severe disease, with elevated degranulation of secondary granule markers. Partially activated immature neutrophils are detectable three months post symptom onset, indication long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients downregulate the chemokine receptor CXCR2, while neutrophils from severely ill individuals failed to do so, suggesting altered ability for organ trafficking. CD10- and CXCR2hi neutrophil subpopulations were enriched in severe disease and may represent biomarkers for early identification of individuals at high risk of progressing to severe COVID-19.

Radiological follow-up of adults hospitalised with pneumonia and SARS-CoV-2 infection, in Bristol UK, during the COVID19 pandemic (preprint)

For patients with pneumonia and COVID19 repeating chest radiography is recommend in current British Thoracic Society (BTS) guidelines. Over two distinct time periods during the COVID19 pandemic (Aug-Dec 2020, Jun-Aug 2021) we undertook an audit of 829 patients hospitalised with infective radiological change (pneumonia=481, COVID19=348). 654/829 patients (79%) required radiological follow-up under BTS guideline criteria. 414/654 (63%) were planned, 322/654 (49%) occurred and, of patients receiving radiological follow-up, most occurred within BTS timelines (86%). Further audits should be conducted to ensure BTS guidelines adherence, to avoid delay in diagnosing underlying malignancy or chronic lung disease.

Assessing the Effectiveness of BNT162b2 and ChAdOx1nCoV-19 COVID-19 Vaccination in Prevention of Hospitalisations in Elderly and Frail Adults: A Single Centre Test Negative Case-Control Study (preprint)

Background: On 8th December 2020, deployment of the first vaccine against SARS-CoV-2 authorised for UK use, the mRNA-based vaccine BNT162b2, began, followed by the adenoviral vector vaccine ChAdOx1nCoV-19 on 4th January 2021. Initially care home-residents and staff, frontline healthcare workers and adults from age 80 were targeted. In phase 3 trials, BNT162b2 and ChAdOx1nCoV-19 demonstrated 95% and 70% efficacy, respectively, after two doses against symptomatic SARS-CoV-2 infection. However, few data exist regarding the effectiveness of these vaccines in elderly frail people. Evaluation following implementation to determine the effectiveness of one dose in reducing hospitalisations due to SARS-CoV-2 infection in elderly adults is urgent.Methods: A prospective single-centre test-negative design case-control study of adults aged ≥80 years hospitalised with COVID-19 disease or other acute respiratory disease. We conducted logistic regression controlling for time (week), gender, index of multiple deprivations (IMD), and care residency status (CRS), and sensitivity analyses matched for time and gender using a conditional logistic model adjusting for IMD and CRS.Findings: First dose vaccine effectiveness of BNT162b2 was 71.4% (95% confidence interval [CI] 46.5-90.6). ChAdOx1nCoV-19 first dose vaccine effectiveness was 80.4% (95% CI 36.4-94.5). When effectiveness analysis for BNT162b2 was restricted to the period covered by ChAdOx1nCoV-19, the estimate was 79.3% (95% CI 47.0-92.5).Interpretation: A single dose of either BNT162b2 or ChAdOx1nCoV-19 vaccine resulted in substantial reductions in the risk of COVID-19-related hospitalisation in elderly, frail patients with extensive co-morbid disease.Funding: The AvonCAP study is an investigator-led project funded under a collaborative agreement by Pfizer.Conflict of Interest: CH is Principal Investigator of the Avon CAP study which is an investigator-led University of Bristol study funded by Pfizer and has previously received support from the NIHR in an Academic Clinical Fellowship. JO is a Co-Investigator on the Avon CAP Study. AF is a member of the Joint Committee on Vaccination and Immunization (JCVI) and chair of the World Health Organization European Technical Advisory Group of Experts on Immunization (ETAGE) committee. In addition to receiving funding from Pfizer as Chief Investigator of this study, he leads another project investigating transmission of respiratory bacteria in families jointly funded by Pfizer and the Gates Foundation. The other authors have no relevant conflicts of interest to declare.Ethical Approval: The study was approved by the Health Research Authority Research Ethics Committee (East of England, Essex), REC 20/EE/0157, including data collection under Section 251 of the 2006 NHS Act authorised by the Confidentiality Advisory Group.

Blood group A Secretors are associated with a higher risk of COVID-19 cardiovascular disease complications (preprint)

The SARS-CoV-2 virus causes COVID-19, an infection capable of causing severe disease and death but which may also be asymptomatic or oligosymptomatic in many individuals. While several risk factors, including age, have been described, the mechanisms of this variation are poorly understood. Several studies have described associations between blood group and COVID-19 severity, while others do not. Expression of ABO glycans on secreted proteins and non-erythroid cells is controlled by a fucosyltransferase (FUT2). Inactivating mutations result in a non-secretor phenotype which is known to protect against some viral infections. We investigated whether ABO or secretor status was associated with COVID-19 severity. Data combined from healthcare records and laboratory tests (n=275) of SARS-CoV-2 PCR positive patients hospitalised with COVID-19, confirmed higher than expected numbers of blood group A individuals compared to O (RR=1.24, CI 95% [1.05,1.47], P=0.0111). There was also a significant association between group A and COVID-19-related cardiovascular complications (RR=2.56, CI 95% [1.43,4.55], P=0.0011) which is independent of gender. Molecular analysis of phenotype revealed that group A patients who are non-secretors are significantly less likely to be hospitalised than secretors. In a larger cohort of 1000 convalescent plasma donors, among whom the majority displayed COVID-19 symptoms and only a small minority required hospitalisation, group A non-secretors were slightly over-represented. Our findings indicate that group A non-secretors are not resistant to infection by SARS-CoV-2, but they are likely to experience a less severe form of its associated disease. Key PointsO_LIBlood group type A is associated with an increased risk of cardiovascular complications in COVID-19 patients. C_LIO_LIFUT2 "non-secretor" status reduces the risk of severe COVID-19 outcomes in patients with blood group A. C_LI

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

Estimating the COVID-19 epidemic trajectory and hospital capacity requirements in South West England: a mathematical modelling framework (preprint)

ObjectivesTo develop a regional model of COVID-19 dynamics, for use in estimating the number of infections, deaths and required acute and intensive care (IC) beds using the South West of England (SW) as an example case. DesignOpen-source age-structured variant of a susceptible-exposed-infectious-recovered (SEIR) deterministic compartmental mathematical model. Latin hypercube sampling and maximum likelihood estimation were used to calibrate to cumulative cases and cumulative deaths. SettingSW at a time considered early in the pandemic, where National Health Service (NHS) authorities required evidence to guide localised planning and support decision-making. ParticipantsPublicly-available data on COVID-19 patients. Primary and secondary outcome measuresThe expected numbers of infected cases, deaths due to COVID-19 infection, patient occupancy of acute and IC beds and the reproduction ("R") number over time. ResultsSW model projections indicate that, as of the 11th May 2020 (when lockdown measures were eased), 5,793 (95% credible interval, CrI, 2,003 - 12,051) individuals were still infectious (0.10% of the total SW England population, 95%CrI 0.04 - 0.22%), and a total of 189,048 (95%CrI 141,580 - 277,955) had been infected with the virus (either asymptomatically or symptomatically), but recovered, which is 3.4% (95%CrI 2.5 - 5.0%) of the SW population. The total number of patients in acute and IC beds in the SW on the 11th May 2020 was predicted to be 701 (95%CrI 169 - 1,543) and 110 (95%CrI 8 - 464) respectively. The R value in SW England was predicted to be 2.6 (95%CrI 2.0 - 3.2) prior to any interventions, with social distancing reducing this to 2.3 (95%CrI 1.8 - 2.9) and lockdown/ school closures further reducing the R value to 0.6 (95CrI% 0.5 - 0.7). ConclusionsThe developed model has proved a valuable asset for local and regional healthcare services. The model will be used further in the SW as the pandemic evolves, and - as open source software - is portable to healthcare systems in other geographies. Future work/ applicationsO_LIOpen-source modelling tool available for wider use and re-use. C_LIO_LICustomisable to a number of granularities such as at the local, regional and national level. C_LIO_LISupports a more holistic understanding of intervention efficacy through estimating unobservable quantities, e.g. asymptomatic population. C_LIO_LIWhile not presented here, future use of the model could evaluate the effect of various interventions on transmission of COVID-19. C_LIO_LIFurther developments could consider the impact of bedded capacity in terms of resulting excess deaths. C_LI