Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study.

INTRODUCTION: The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. METHODS: The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. RESULTS: Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. CONCLUSION: We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. TRIAL REGISTRATION: BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

Short-term risk prediction after major lower limb amputation: PERCEIVE study.

BACKGROUND: The accuracy with which healthcare professionals (HCPs) and risk prediction tools predict outcomes after major lower limb amputation (MLLA) is uncertain. The aim of this study was to evaluate the accuracy of predicting short-term (30 days after MLLA) mortality, morbidity, and revisional surgery. METHODS: The PERCEIVE (PrEdiction of Risk and Communication of outcomE following major lower limb amputation: a collaboratIVE) study was launched on 1 October 2020. It was an international multicentre study, including adults undergoing MLLA for complications of peripheral arterial disease and/or diabetes. Preoperative predictions of 30-day mortality, morbidity, and MLLA revision by surgeons and anaesthetists were recorded. Probabilities from relevant risk prediction tools were calculated. Evaluation of accuracy included measures of discrimination, calibration, and overall performance. RESULTS: Some 537 patients were included. HCPs had acceptable discrimination in predicting mortality (931 predictions; C-statistic 0.758) and MLLA revision (565 predictions; C-statistic 0.756), but were poor at predicting morbidity (980 predictions; C-statistic 0.616). They overpredicted the risk of all outcomes. All except three risk prediction tools had worse discrimination than HCPs for predicting mortality (C-statistics 0.789, 0.774, and 0.773); two of these significantly overestimated the risk compared with HCPs. SORT version 2 (the only tool incorporating HCP predictions) demonstrated better calibration and overall performance (Brier score 0.082) than HCPs. Tools predicting morbidity and MLLA revision had poor discrimination (C-statistics 0.520 and 0.679). CONCLUSION: Clinicians predicted mortality and MLLA revision well, but predicted morbidity poorly. They overestimated the risk of mortality, morbidity, and MLLA revision. Most short-term risk prediction tools had poorer discrimination or calibration than HCPs. The best method of predicting mortality was a statistical tool that incorporated HCP estimation.

Procalcitonin Evaluation of Antibiotic Use in COVID-19 Hospitalised Patients (PEACH): Protocol for a Retrospective Observational Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is a viral illness, many patients admitted to hospital are prescribed antibiotics, based on concerns that COVID-19 patients may experience secondary bacterial infections, and the assumption that they may respond well to antibiotic therapy. This has led to an increase in antibiotic use for some hospitalised patients at a time when accumulating antibiotic resistance is a major global threat to health. Procalcitonin (PCT) is an inflammatory marker measured in blood samples and widely recommended to help diagnose bacterial infections and guide antibiotic treatment. The PEACH study will compare patient outcomes from English and Welsh hospitals that used PCT testing during the first wave of the COVID-19 pandemic with those from hospitals not using PCT. It will help to determine whether, and how, PCT testing should be used in the NHS in future waves of COVID-19 to protect patients from antibiotic overuse. PEACH is a retrospective observational cohort study using patient-level clinical data from acute hospital Trusts and Health Boards in England and Wales. The primary objective is to measure the difference in antibiotic use between COVID-19 patients who did or did not have PCT testing at the time of diagnosis. Secondary objectives include measuring differences in length of stay, mortality, intensive care unit admission, and resistant bacterial infections between these groups.

Antibiotic prescribing in hospitalized patients with COVID-19 as a function of inflammatory markers in Wave 1 versus Wave 2: a systematic review

Background Less than 10% of hospitalized cases in the United Kingdom during the first wave of the pandemic had bacterial coinfection, but approximately 75% were prescribed antibiotics contrary to NICE guidelines. We have evaluated the relationship between antibiotic prescribing and biomarker use, in hospitalized adult patients with COVID-19 in the UK, as synthesis defined by the pandemic timeline, particularly during ‘Wave 2’ is lacking. Clinical outcomes were compared in the context of antimicrobial stewardship. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT) and white cell count (WCC) were selected based on clinical relevance. Methods Studies (n = 300) dated 2019–22 were identified via EMBASE and Web of Science databases, using relevant search terms. Wave 1 and Wave 2 parameters were defined by the Office for National Statistics. Literature selection was organized by the preferred reporting items for systematic reviews and meta-analyses (PRISMA). PROSPERO registration was commenced mitigating unplanned duplication. Diagnostics, prescribing, clinical outcomes and demographics were tabulated. Ten percent of studies were cross-checked. Results Final selection criteria yielded 29 papers, of which only 4 were from Wave 2. Cohort and retrospective studies accounted for 69% and 80%, respectively. Heterogeneity of studies prevented a meta-analysis. Determining disease severity or coinfection was the focus of ( n= 6) studies. The papers referencing WCC (n = 12) established that leucocytosis, like elevated CRP, was an efficient marker for bacterial infections. Additionally, CRP >100 mg/L was associated with increased prescribing. Another common theme was cut-off values to escalate (n = 9) or de-escalate (n = 12) prescribing. In PCT papers (n = 14), common de-escalation cut-offs were 0.25 ng/mL and 0.50 ng/mL. Lower admission PCT was associated with decreased mortality, admission duration and ICU admission rate. ESR use was unevaluable as it was only mentioned in one case study. During Wave 2, the use of immunomodulatory therapy may have contributed towards lower inflammatory markers. Hospital stays decreased while ICU duration increased. In ICU patient studies (n = 4) biomarker testing was more frequent. The higher 0.50 ng/mL PCT cut-off was employed but with higher mortality and ventilation rate. Conclusions More studies of Wave 2 cohorts are required. A weakness of the evidence base is that cohort study outcomes were reported in varying detail, a potential consequence of the need for rapidly published evidence. Nonetheless, PCT and CRP were demonstrated to be useful as prognosis indicators on hospital admission, and in timely antibiotic prescribing. Updated national guidelines should include standardized biomarker thresholds to improve antimicrobial stewardship.

Perceived threat of COVID-19, attitudes towards vaccination, and vaccine hesitancy: A prospective longitudinal study in the UK.

OBJECTIVES: Using the Health Belief Model as a conceptual framework, we investigated the association between attitudes towards COVID-19, COVID-19 vaccinations, and vaccine hesitancy and change in these variables over a 9-month period in a UK cohort. METHODS: The COPE study cohort (n = 11,113) was recruited via an online survey at enrolment in March/April 2020. The study was advertised via the HealthWise Wales research registry and social media. Follow-up data were available for 6942 people at 3 months (June/July 2020) and 5037 at 12 months (March/April 2021) post-enrolment. Measures included demographics, perceived threat of COVID-19, perceived control, intention to accept or decline a COVID-19 vaccination, and attitudes towards vaccination. Logistic regression models were fitted cross-sectionally at 3 and 12 months to assess the association between motivational factors and vaccine hesitancy. Longitudinal changes in motivational variables for vaccine-hesitant and non-hesitant groups were examined using mixed-effect analysis of variance models. RESULTS: Fear of COVID-19, perceived susceptibility to COVID-19, and perceived personal control over COVID-19 infection transmission decreased between the 3- and 12-month surveys. Vaccine hesitancy at 12 months was independently associated with low fear of the disease and more negative attitudes towards COVID-19 vaccination. Specific barriers to COVID-19 vaccine uptake included concerns about safety and efficacy in light of its rapid development, mistrust of government and pharmaceutical companies, dislike of coercive policies, and perceived lack of relaxation in COVID-19-related restrictions as the vaccination programme progressed. CONCLUSIONS: Decreasing fear of COVID-19, perceived susceptibility to the disease, and perceptions of personal control over reducing infection-transmission may impact future COVID-19 vaccination uptake.

Treatment of Hidradenitis Suppurativa Evaluation Study (THESEUS): protocol for a prospective cohort study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, painful, inflammatory skin disease with estimates of prevalence in the European population of 1%-2%. Despite being a relatively common condition, the evidence base for management of HS is limited. European and North American management guidelines rely on consensus for many aspects of treatment and within the UK variations in management of HS have been identified. The HS James Lind Alliance Priority Setting Partnership (PSP) published a top 10 list of future HS research priorities including both medical and surgical interventions. The aims of the THESEUS study are to inform the design of future HS randomised controlled trials (RCTs) and to understand how HS treatments are currently used. THESEUS incorporates several HS PSP research priorities, including investigation of oral and surgical treatments. Core outcome domains have been established by the HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC) and THESEUS is designed to validate instruments to measure the domains. METHODS AND ANALYSIS: The THESEUS study is a prospective observational cohort study. Participants, adults with active HS of any severity, will be asked to select one of five HS treatment options that is appropriate for their HS care. Participants will be allocated to their chosen treatment intervention and followed for a period of up to 12 months. Outcomes will be assessed at 3-monthly intervals using HISTORIC core outcome instruments. Video recordings of the surgical and laser operations will provide informational and training videos for future trials. Nested mixed-methods studies will characterise the interventions in clinical practice, understand facilitators and barriers to recruitment into future HS RCTs and examine patients' and clinicians' perspectives on HS treatment choices. TRIAL REGISTRATION NUMBER: ISRCTN69985145.

Procalcitonin evaluation of antibiotic use in COVID-19 hospitalized patients during the first wave of COVID-19: the PEACH study

Background A minority of patients presenting to hospital with COVID-19 have bacterial coinfection. Procalcitonin testing may help identify patients for whom antibiotics should be prescribed or withheld. The PEACH study describes the use of procalcitonin in English and Welsh hospitals during the first wave of the COVID-19 pandemic to help diagnose bacterial infections and guide antibiotic treatment. There is a lack of clear evidence to support its use in lung infections, which means in some hospitals, clinicians have used the procalcitonin test to guide antibiotic decisions in COVID-19, whilst in other hospitals, they have not. Our study is analysing data from hospitals that did and did not use procalcitonin testing during the first wave of the COVID-19 pandemic. It will determine whether and how procalcitonin testing should be used in the NHS in future waves of COVID-19 to protect patients from antibiotic overuse. Methods To assess whether the use of PCT testing, to guide antibiotic prescribing, safely reduced antibiotic use among patients who were hospitalized with COVID-19 during the first wave of the pandemic, we are answering this question through three different, and complimentary, work streams (WS), each with discrete work packages (WP): (i) Work Stream 1: utilization of PCT testing to guide antibiotic prescribing during the first wave of COVID-19 pandemic;(ii) Work Stream 2: patient-level impact of PCT testing on antibiotic exposure and clinical outcome (main work stream currently in analysis);and (iii) Work Stream 3: health economics analysis of PCT testing to guide antibiotics in COVID-19. Results Our first publication from Work Stream 1 (Antibiotics 2021, 10: 516) used a web-based survey to gather data from antimicrobial leads about the use of procalcitonin testing. Responses were received from 148/151 (98%) eligible hospitals. During the first wave of the COVID-19 pandemic, there was widespread introduction and expansion of PCT use in NHS hospitals. The number of hospitals using PCT in emergency/acute admissions rose from 17 (11%) to 74/146 (50.7%) and use in ICU increased from 70 (47.6%) to 124/147 (84.4%). This increase happened predominantly in March and April 2020, preceding NICE guidance. Approximately half of hospitals used PCT as a single test to guide decisions to discontinue antibiotics and half used repeated measurements. There was marked variation in the thresholds used for empirical antibiotic cessation and guidance about interpretation of values. Conclusions Procalcitonin testing has been widely adopted in the NHS during the COVID-19 pandemic in an unevidenced, heterogeneous way and in conflict with relevant NICE guidance. Further research is needed urgently that assesses the impact of this change on antibiotic prescribing and patient safety. Work Stream 2 is ongoing, and results will be published once available.

Cohort profile: The UK COVID-19 Public Experiences (COPE) prospective longitudinal mixed-methods study of health and well-being during the SARSCoV2 coronavirus pandemic.

Public perceptions of pandemic viral threats and government policies can influence adherence to containment, delay, and mitigation policies such as physical distancing, hygienic practices, use of physical barriers, uptake of testing, contact tracing, and vaccination programs. The UK COVID-19 Public Experiences (COPE) study aims to identify determinants of health behaviour using the Capability, Opportunity, Motivation (COM-B) model using a longitudinal mixed-methods approach. Here, we provide a detailed description of the demographic and self-reported health characteristics of the COPE cohort at baseline assessment, an overview of data collected, and plans for follow-up of the cohort. The COPE baseline survey was completed by 11,113 UK adult residents (18+ years of age). Baseline data collection started on the 13th of March 2020 (10-days before the introduction of the first national COVID-19 lockdown in the UK) and finished on the 13th of April 2020. Participants were recruited via the HealthWise Wales (HWW) research registry and through social media snowballing and advertising (Facebook®, Twitter®, Instagram®). Participants were predominantly female (69%), over 50 years of age (68%), identified as white (98%), and were living with their partner (68%). A large proportion (67%) had a college/university level education, and half reported a pre-existing health condition (50%). Initial follow-up plans for the cohort included in-depth surveys at 3-months and 12-months after the first UK national lockdown to assess short and medium-term effects of the pandemic on health behaviour and subjective health and well-being. Additional consent will be sought from participants at follow-up for data linkage and surveys at 18 and 24-months after the initial UK national lockdown. A large non-random sample was recruited to the COPE cohort during the early stages of the COVID-19 pandemic, which will enable longitudinal analysis of the determinants of health behaviour and changes in subjective health and well-being over the course of the pandemic.

Impact of introducing procalcitonin testing on antibiotic usage in acute NHS hospitals during the first wave of COVID-19 in the UK: a controlled interrupted time series analysis of organization-level data.

BACKGROUND: Blood biomarkers have the potential to help identify COVID-19 patients with bacterial coinfection in whom antibiotics are indicated. During the COVID-19 pandemic, procalcitonin testing was widely introduced at hospitals in the UK to guide antibiotic prescribing. We have determined the impact of this on hospital-level antibiotic consumption. METHODS: We conducted a retrospective, controlled interrupted time series analysis of organization-level data describing antibiotic dispensing, hospital activity and procalcitonin testing for acute hospitals/hospital trusts in England and Wales during the first wave of COVID-19 (24 February to 5 July 2020). RESULTS: In the main analysis of 105 hospitals in England, introduction of procalcitonin testing in emergency departments/acute medical admission units was associated with a statistically significant decrease in total antibiotic use of -1.08 (95% CI: -1.81 to -0.36) DDDs of antibiotic per admission per week per trust. This effect was then lost at a rate of 0.05 (95% CI: 0.02-0.08) DDDs per admission per week. Similar results were found specifically for first-line antibiotics for community-acquired pneumonia and for COVID-19 admissions rather than all admissions. Introduction of procalcitonin in the ICU setting was not associated with any significant change in antibiotic use. CONCLUSIONS: At hospitals where procalcitonin testing was introduced in emergency departments/acute medical units this was associated with an initial, but unsustained, reduction in antibiotic use. Further research should establish the patient-level impact of procalcitonin testing in this population and understand its potential for clinical effectiveness.

PROCALCITONIN KINETICS MAY INDICATE PRESENCE OF SECONDARY BACTERIAL INFECTIONS IN COVID-19 ARDS

PCT rise was observed in 35 (53.8%) of patients, CRP rise in 42 (67.4%) and WCC rise in 52 (80%) of the patients. VAP was the most common ICU-acquired infection, occurring in 28/65 (43.1%) patients, of whom 8/65 (12.3%) suffered both VAP and BSI during their ICU stay. B Introduction: b Secondary bacterial infection in Covid-19 is associated with increased mortality and disproportionately affects critically ill patients. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Procalcitonin Increase Is Associated with the Development of Critical Care-Acquired Infections in COVID-19 ARDS.

Secondary bacterial infection in COVID-19 patients is associated with increased mortality and disproportionately affects critically ill patients. This single-centre retrospective observational study investigates the comparative efficacy of change in procalcitonin (PCT) and other commonly available biomarkers in revealing or predicting microbiologically proven secondary infection in critical COVID-19 patients. Adult patients admitted to an intensive care unit (ICU) with confirmed SARS-CoV-2 infection between 9 March 2020 and 5 June 2020 were recruited to the study. For daily biomarker and secondary infection, laboratory-confirmed bloodstream infection (LCBI) and ventilator-associated pneumonia/tracheobronchitis (VAP/VAT) data were collected. We observed a PCT rise in 53 (81.5%) of the patients, a C-reactive protein (CRP) rise in 55 (84.6%) and a white blood cell count (WBC) rise in 61 (93.8%). Secondary infection was confirmed in 33 (50.8%) of the patients. A PCT rise was present in 97.0% of patients with at least one confirmed VAP/VAT and/or LCBI event. CRP and WBC rises occurred in 93.9% and 97.0% of patients with confirmed VAP/VAT and/or LCBI, respectively. Logistic regression analysis found that, when including all biomarkers in the same model, there was a significant association between PCT rise and the occurrence of LCBI and/or VAP/VAT (OR = 14.86 95%CI: 2.20, 342.53; p = 0.021). Conversely, no statistically significant relationship was found between either a CRP rise (p = 0.167) or a WBC rise (p = 0.855) and the occurrence of VAP/VAT and/or LCBI. These findings provide a promising insight into the usefulness of PCT measurement in predicting the emergence of secondary bacterial infection in ICU.

Use of Procalcitonin during the First Wave of COVID-19 in the Acute NHS Hospitals: A Retrospective Observational Study.

A minority of patients presenting to hospital with COVID-19 have bacterial co-infection. Procalcitonin testing may help identify patients for whom antibiotics should be prescribed or withheld. This study describes the use of procalcitonin in English and Welsh hospitals during the first wave of the COVID-19 pandemic. A web-based survey of antimicrobial leads gathered data about the use of procalcitonin testing. Responses were received from 148/151 (98%) eligible hospitals. During the first wave of the COVID-19 pandemic, there was widespread introduction and expansion of PCT use in NHS hospitals. The number of hospitals using PCT in emergency/acute admissions rose from 17 (11%) to 74/146 (50.7%) and use in Intensive Care Units (ICU) increased from 70 (47.6%) to 124/147 (84.4%). This increase happened predominantly in March and April 2020, preceding NICE guidance. Approximately half of hospitals used PCT as a single test to guide decisions to discontinue antibiotics and half used repeated measurements. There was marked variation in the thresholds used for empiric antibiotic cessation and guidance about interpretation of values. Procalcitonin testing has been widely adopted in the NHS during the COVID-19 pandemic in an unevidenced, heterogeneous way and in conflict with relevant NICE guidance. Further research is needed urgently that assesses the impact of this change on antibiotic prescribing and patient safety.