Antivirals for influenza-Like Illness? A randomised Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4 E): the ALIC4 E protocol

INTRODUCTION: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. METHODS AND ANALYSIS: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. ETHICS AND DISSEMINATION: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations

Diagnosis and Management of Sore Throat in Young Adults

Background: Sore throat is one of the most common presentations in primary care, especially in young adults. This thesis aimed to further research in the area of improving the diagnosis and management of sore throat in young adults, with a particular focus on infectious mononucleosis (IM) and Group A Beta Haemolytic Streptococcus (GABHS). There were four broad objectives; 1) to systematically review the effectiveness of antiviral therapy for infectious mononucleosis (IM), 2) to derive and externally validate a clinical prediction rule (CPR) to aid in the positive diagnosis of IM caused by Epstein Barr Virus (EBV), 3) to validate the Centor score CPR (a widely used CPR for the diagnosis of GABHS sore throat) in an Irish setting, and 4) to explore potential associations between IM caused by EBV and fatigue and time missed from college / work in younger adults. Methods: A systematic review of the effectiveness of antivirals for IM was carried out, according to Cochrane methodology. A prospective cohort study with six-month follow-up was conducted in seven student health centres in Ireland. A CPR for the diagnosis of EBV was developed and internally validated in the thesis cohort and externally validated in a geographically separate cohort. The Centor score CPR was validated in this research cohort. The cohort study data was also used to explore outcomes (fatigue scores and time missed from college or work) of participants diagnosed with EBV IM versus those with sore throat from other aetiology.  Results: The systematic review included seven randomised controlled trials (RCTs) with a total of 333 participants. There were small statistically significant improvements in the treatment group for two of the twelve outcomes; 'time to clinical recovery as assessed by physician' and 'duration of lymphadenopathy, however these may not be clinically meaningful. A total of 348 young adults (42 (12.8%) EBV positive) were recruited to the cohort study. Response rates at three month follow up were 68.7% and at six month follow up were 56.3%, with similar rates in EBV positive and EBV negative participants. Four CPR models were developed for the diagnosis of EBV. The models performed reasonably well in internal validation and similarly when validated externally. When the Centor score was validated in this study population, it was found to have only fair performance. The cohort study was underpowered,  but a large percentage of those in both EBV and non-EBV sore throat groups (56% and 42% respectively) reported fatigue six months following acute illness. The odds ratio for missing 10 or more days (compared to 0-9 days) for EBV positive versus EBV negative patients was 3.58 (95% CI 1.47 to 8.71). Conclusions: The presentation of sore throat is a very common one in primary care. This thesis adds to the literature in the area by examining its diagnosis and management in young adults, especially focussing on two conditions; IM caused by EBV and GABHS sore throat. This thesis describes tools that can aid in the diagnostic process, suggests strategies for management, depending on which underlying pathology is suspected and highlights evidence gaps in the management of IM.</p

Management of sore throat (with focus on GAS) in young adults

Background: Sore throat is a common presentation in primary care. Approximately 15 % of sore throat in adults are caused by Group A Streptococcus (GAS). Clinical guidelines for sore throat recommend prescribing antibiotics only when there is a high probability that the condition has been caused by GAS. Most guidelines incorporate clinical prediction rules (CPRs) such as the Centor Score. Objectives: To present the prevalence and management of sore throat in young adults, with a particular focus on sore throat caused by GAS, including antibiotic prescribing and the retrospective application of the Centor Score. Methods: This prospective observational cohort study included 348 young adults with sore throat presenting in student health centres between 2017 and 2019. A descriptive overview of symptoms in participants with and without GAS is presented, and potential associations between participant characteristics and symptoms and antibiotic prescription were explored using regression analysis. The Centor Score was retrospectively calculated and explored. Results: 23 % (80) of participants had a positive throat swab for GAS. 65 % (225/345) of all participants were prescribed immediate and 12 % (43/345) delayed antibiotics. The symptoms and clinical signs most associated with antibiotic prescribing were exudate on tonsils, absence of cough and enlarged or tender anterior cervical lymph nodes. A retrospective analysis of the Centor score was possible for 337 participants of whom 49 % had a low (score ≤ 2) and 48 % a high Centor score (>2). For 50 % of participants, prescribing was in line with National Institute for Clinical Excellence (NICE) clinical guidelines, i.e. a Centor score of 3 or 4. Conclusions: Overall, the prevalence of GAS (23 %) was higher than the predicted 15 % for this population. Antibiotic prescribing was high. As the recommended maximum level of antibiotic prescribing is 20 % for sore throat, this presents an opportunity for improvement. A potential strategy could combine high Centor scores with point of care testing

Derivation and validation of clinical prediction rules for diagnosis of infectious mononucleosis: a prospective cohort study

Objectives: Infectious mononucleosis (IM) is a clinical syndrome that is characterised by lymphadenopathy, fever and sore throat. Although generally not considered a serious illness, IM can lead to significant loss of time from school or work due to profound fatigue, or the development of chronic illness. This study aimed to derive and externally validate clinical prediction rules (CPRs) for IM caused by Epstein-Barr virus (EBV). Design: Prospective cohort study. Setting and participants: 328 participants were recruited prospectively for the derivation cohort, from seven university-affiliated student health centres in Ireland. Participants were young adults (17-39 years old, mean age 20.6 years) with sore throat and one other additional symptom suggestive of IM. The validation cohort was a retrospective cohort of 1498 participants from a student health centre at the University of Georgia, USA. Main outcome measures: Regression analyses were used to develop four CPR models, internally validated in the derivation cohort. External validation was carried out in the geographically separate validation cohort. Results: In the derivation cohort, there were 328 participants, of whom 42 (12.8%) had a positive EBV serology test result. Of 1498 participants in the validation cohort, 243 (16.2%) had positive heterophile antibody tests for IM. Four alternative CPR models were developed and compared. There was moderate discrimination and good calibration for all models. The sparsest CPR included presence of enlarged/tender posterior cervical lymph nodes and presence of exudate on the pharynx. This model had moderate discrimination (area under the receiver operating characteristic curve (AUC): 0.70; 95% CI: 0.62-0.79) and good calibration. On external validation, this model demonstrated reasonable discrimination (AUC: 0.69; 95% CI: 0.67-0.72) and good calibration. Conclusions: The alternative CPRs proposed can provide quantitative probability estimates of IM. Used in conjunction with serological testing for atypical lymphocytosis and immunoglobulin testing for viral capsid antigen, CPRs can enhance diagnostic decision-making for IM in community settings.</p

A Best Evidence in Medical Education systematic review to determine the most effective teaching methods that develop reflection in medical students: BEME guide No. 51

Introduction: Reflection is thought to be an essential skill for physicians. Although much has been written about it, there is little concurrence about how to best teach reflection in medical education. The aim of this review was to determine: (i) which educational interventions are being used to develop reflection, (ii) how is reflection being assessed, and (iii) what are the most effective interventions. Methods: Inclusion criteria comprised: (i) undergraduate medical students, (ii) a teaching intervention to develop reflection, and (iii) assessment of the intervention. A review protocol was developed and nine databases were searched. Screening, data extraction, and analysis procedures were performed in duplicate. Due to the heterogeneity of studies, a narrative synthesis approach was performed for the study analysis. Results: Twenty-eight studies met the inclusion criteria. The interventions in these studies had at least of two of the following components related to reflection: (i) introduction, (ii) trigger, (iii) writing, (iv) guidelines, (v) small group discussion, (vi) tutor and (vii) feedback. Three validated rubrics were used to assess reflective writing in these studies. Conclusions: The strongest evidence from studies in this review indicates that guidelines for, and feedback on, reflective writing improve student reflection.</p

Oseltamivir for coronavirus illness: post-hoc exploratory analysis of an open-label, pragmatic, randomised controlled trial in European primary care from 2016 to 2018

BACKGROUND: Patients infected with the novel coronavirus (SARS-CoV-2) are being treated empirically with oseltamivir, but there is little evidence from randomised controlled trials to support the treatment of coronavirus infections with oseltamivir. AIM: To determine whether adding oseltamivir to usual care reduces time to recovery in symptomatic patients who have tested positive for coronavirus (not including SARS-CoV-2). DESIGN AND SETTING: Exploratory analysis of data from an open-label, pragmatic, randomised controlled trial during three influenza seasons, from 2016 to 2018, in primary care research networks, in 15 European countries. METHOD: Patients aged ≥1 year presenting to primary care with influenza-like illness (ILI), and who tested positive for coronavirus (not including SARS-CoV-2), were randomised to usual care or usual care plus oseltamivir. The primary outcome was time to recovery defined as a return to usual activities, with minor or absent fever, headache, and muscle ache. RESULTS: Coronaviruses (CoV-229E, CoV-OC43, CoV-KU1 and CoV-NL63) were identified in 308 (9%) out of 3266 randomised participants in the trial; 153 of these were allocated to usual care and 155 to usual care plus oseltamivir; the primary outcome was ascertained in 136 and 147 participants, respectively. The median time to recovery was shorter in patients randomised to oseltamivir: 4 days (interquartile range [IQR] 3-6) versus 5 days (IQR 3-8; hazard ratio 1.31; 95% confidence interval = 1.03 to 1.66; P = 0.026). CONCLUSION: Primary care patients with ILI testing positive for coronavirus (not including SARS-CoV-2) recovered sooner when oseltamivir was added to usual care compared with usual care alone. This may be of relevance to the primary care management of COVID-19

Oseltamivir for coronavirus illness: post-hoc exploratory analysis of an open-label, pragmatic, randomised controlled trial in European primary care from 2016 to 2018

Background: Patients infected with the novel coronavirus (SARS-CoV-2) are being treated empirically with oseltamivir, but there is little evidence from randomised controlled trials to support the treatment of coronavirus infections with oseltamivir.Aim: To determine whether adding oseltamivir to usual care reduces time to recovery in symptomatic patients who have tested positive for coronavirus (not including SARS-CoV-2).Design and setting: Exploratory analysis of data from an open-label, pragmatic, randomised controlled trial during three influenza seasons, from 2016 to 2018, in primary care research networks, in 15 European countries.Method: Patients aged ≥1 year presenting to primary care with influenza-like illness (ILI), and who tested positive for coronavirus (not including SARS-CoV-2), were randomised to usual care or usual care plus oseltamivir. The primary outcome was time to recovery defined as a return to usual activities, with minor or absent fever, headache, and muscle ache.Results: Coronaviruses (CoV-229E, CoV-OC43, CoV-KU1 and CoV-NL63) were identified in 308 (9%) out of 3266 randomised participants in the trial; 153 of these were allocated to usual care and 155 to usual care plus oseltamivir; the primary outcome was ascertained in 136 and 147 participants, respectively. The median time to recovery was shorter in patients randomised to oseltamivir: 4 days (interquartile range [IQR] 3-6) versus 5 days (IQR 3-8; hazard ratio 1.31; 95% confidence interval = 1.03 to 1.66; P = 0.026).Conclusion: Primary care patients with ILI testing positive for coronavirus (not including SARS-CoV-2) recovered sooner when oseltamivir was added to usual care compared with usual care alone. This may be of relevance to the primary care management of COVID-19.</div