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Background: Despite considerable research into COVID-19 sequelae, little is known about differences in illness duration and complications in patients presenting in primary care with symptoms of acute respiratory tract infections (RTI) that are and are not attributed to SARS-CoV-2 infection., Objective: To explore whether aetiology impacted course of illness and prediction of complications in patients presenting in primary care with symptoms of RTI early in the COVID-19 pandemic., Methods: Between April 2020-March 2021 general practitioners from nine European countries recruited consecutively contacting patients with RTI symptoms. At baseline, an oropharyngeal-nasal swab was obtained for aetiology determination using PCR after follow-up of 28 days. Time to self-reported recovery was analysed with Kaplan-Meier curves. Predictors (baseline variables of demographics, patient and disease characteristics) of a complicated course (composite of hospital admission and persisting signs/symptoms at 28 days follow-up) were explored with logistic regression modelling., Results: Of 855 patients with RTI symptoms, 237 (27.7%) tested SARS-CoV-2 positive. The proportion not feeling fully recovered (15.6% vs 18.1%, p  = 0.39), reporting being extremely tired (9.7% vs 12.8%, p  = 0.21), and not having returned to usual daily activities (18.1% vs 14.4%, p  = 0.18) at day 28 were comparable between SARS-CoV-2 positive ( n  = 237) and negative ( n  = 618) groups. However, among those feeling fully recovered (SARS-CoV-2 positive: 200 patients, SARS-CoV-2 negative: 506 patients), time to full recovery was significantly longer in SARS-CoV-2 patients (10.6 vs 7.7 days, p  < 0.001). We found no evidence that predictors of a complicated course differed between groups ( p  = 0.07)., Conclusion: Early in the pandemic, the proportion of patients not feeling fully recovered by 28 days was similar between SARS-CoV-2 positive and negative patients presenting in primary care with RTI symptoms, but it took somewhat longer for SARS-CoV-2 patients to feel fully recovered. More research is needed on predictors of a complicated course in RTI.

Background: Quality indicators (QIs) can be used to obtain valuable insights into prescribing quality. Five quantitative and nine diagnosis-linked QIs, aiming to provide general practitioners (GP) with feedback on their antibiotic prescribing quantity and quality, were previously developed and evaluated in a controlled study., Objective: To confirm, in a larger non-controlled study, the feasibility of using routinely collected and extracted electronic patient records to calculate the diagnosis-linked QI outcomes for antibiotic prescribing, and their reliability and validity., Methods: Retrospective study involving 299 Dutch general practices using routine care data (2018-2020). QIs describe total antibiotic and subgroup prescribing, prescribing percentages and first-choice prescribing for several clinical diagnoses. Practice variation in QI outcomes, inter-QI outcome correlations and sensitivity of QI outcomes to pandemic-induced change were determined., Results: QI outcomes were successfully obtained for 278/299 practices. With respect to reliability, outcomes for 2018 and 2019 were comparable, between-practice variation in outcomes was similar to the controlled pilot, and inter-QI outcome correlations were as expected, for example: high prescribing of second choice antibiotics with low first-choice prescribing for clinical diagnoses. Validity was confirmed by their sensitivity to pandemic-induced change: total antibiotic prescribing decreased from 282 prescriptions/1000 registered patients in 2018 to 216 in 2020, with a decrease in prescribing percentages for upper and lower respiratory infections, from 26% to 18.5%, and from 28% to 16%., Conclusions: This study confirmed the fit-for-purpose (feasibility, reliability and validity) of the antibiotic prescribing QIs (including clinical diagnosis-linked ones) using routinely registered primary health care data as a source. This feedback can therefore be used in antibiotic stewardship programmes to improve GPs' prescribing routines., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Early in the COVID-19 pandemic, GPs had to distinguish SARS-CoV-2 from other aetiologies in patients presenting with respiratory tract infection (RTI) symptoms on clinical grounds and adapt management accordingly., Objectives: To test the diagnostic accuracy of GPs' clinical diagnosis of a SARS-CoV-2 infection in a period when COVID-19 was a new disease. To describe GPs' management of patients presenting with RTI for whom no confirmed diagnosis was available. To investigate associations between patient and clinical features with a SARS-CoV-2 infection., Methods: In April 2020-March 2021, 876 patients (9 countries) were recruited when they contacted their GP with symptoms of an RTI of unknown aetiology. A swab was taken at baseline for later analysis. Aetiology (PCR), diagnostic accuracy of GPs' clinical SARS-CoV-2 diagnosis, and patient management were explored. Factors related to SARS-CoV-2 infection were determined by logistic regression modelling., Results: GPs suspected SARS-CoV-2 in 53% of patients whereas 27% of patients tested positive for SARS-CoV-2. True-positive patients (23%) were more intensively managed for follow-up, antiviral prescribing and advice than true-negatives (42%). False negatives (5%) were under-advised, particularly for social distancing and isolation. Older age (OR: 1.02 (1.01-1.03)), male sex (OR: 1.68 (1.16-2.41)), loss of taste/smell (OR: 5.8 (3.7-9)), fever (OR: 1.9 (1.3-2.8)), muscle aches (OR: 2.1 (1.5-3)), and a known risk factor for COVID-19 (travel, health care worker, contact with proven case; OR: 2.7 (1.8-4)) were predictive of SARS-CoV-2 infection. Absence of loss of taste/smell, fever, muscle aches and a known risk factor for COVID-19 correctly excluded SARS-CoV-2 in 92.3% of patients, whereas presence of 3, or 4 of these variables correctly classified SARS-CoV-2 in 57.7% and 87.1%., Conclusion: Correct clinical diagnosis of SARS-CoV-2 infection, without POC-testing available, appeared to be complicated.

Background: Most studies on long-term follow-up of patients with COVID-19 focused on hospitalised patients. No prospective study with structured follow-up has been performed in non-hospitalised patients with COVID-19., Objectives: To assess long-COVID and post-COVID (WHO definition: symptomatic at least 12 weeks), describe lingering symptoms, their impact on daily activities, and general practice visits and explore risk factors for symptom duration in outpatients., Methods: A prospective study of adult outpatients with confirmed SARS-CoV-2 infection and symptoms consistent with COVID-19 in 11 European countries, recruited during 2020 and 2021 from primary care and the community. Structured follow-up by phone interviews (symptom rating, symptom impact on daily activities and general practice visits) was performed at weeks 2, 4, 8, and 12 by study personnel. Data was analysed descriptively by using correlation matrixes and Cox regression., Results: Of 270 enrolled patients, 52% developed long-COVID and 32% post-COVID-syndrome. When only considering the presence of moderate or (very) severe symptoms at weeks 8 and 12, these percentages were 28% and 18%, respectively. Fatigue was the most often reported symptom during follow-up. The impact of lingering symptoms was most evident in sports and household activities. About half (53%) had at least one general practice contact during follow-up. Obese patients took twice as long to return to usual health (HR: 0.5, 95%CI: 0.3-0.8); no other risk profile could predict lingering symptoms., Conclusion: Long-COVID and post-COVID are also common in outpatients. In 32%, it takes more than 12 weeks to return to usual health.

Background: Resistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence., Aim: To undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs., Methods: A systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs., Trial Registration: PROSPERO Registration number: CRD42023376769., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Boateng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries., Methods: Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed., Results: The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient)., Conclusion: Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > €22,459) and cost-saving in adults/adolescents from a societal perspective., (© 2022. The Author(s).)

Background: Respiratory tract infections (RTIs) are the most common reason for prescribing antibiotics in general practice. The COVID-19 pandemic has impacted on antibiotic prescribing and delivery of primary care in Ireland., Objectives: To assess the quality of antibiotic prescribing, the impact of the COVID-19 pandemic and identify opportunities for antimicrobial stewardship (AMS) in Ireland., Methods: Point prevalence audit surveys for RTI consultations were conducted as part of a European study at three time periods: January-February 2020, March-May 2020 and March-May 2021. Antibiotic prescribing was assessed and comparisons made between the three time periods., Results: In total, 765 consultations were recorded, which were mainly face to face before the pandemic, but changed to predominantly remote consultations during the pandemic surveys in 2020 and 2021 (82% and 75%). Antibiotics were prescribed in 54% of RTI consultations before the pandemic. During pandemic surveys, this dropped to 23% in 2020 and 21% in 2021. There was a decrease in prescribing of Red (reserve) agents in 2021. Assessment against indication-specific quality indicators showed a high proportion of consultations for bronchitis and tonsillitis resulting in an antibiotic prescription (67% and 85%). Point-of-care testing (POCT) to aid diagnosis of RTIs were utilized in less than 1% of consultations., Conclusions: During the COVID-19 pandemic, there was a reduction in antibiotic prescribing. Opportunities identified to support AMS in primary care in Ireland are targeted initiatives to reduce antibiotic prescribing for bronchitis and tonsillitis and introducing POCT to support appropriate antibiotic prescribing., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Up to 80% of antibiotics are prescribed in the community. An assessment of prescribing by indication will help to identify areas where improvement can be made. A point prevalence audit study (PPAS) of consecutive respiratory tract infection (RTI) consultations in general practices in 13 European countries was conducted in January-February 2020 (PPAS-1) and again in 2022 (PPAS-4). The European Surveillance of Antibiotic Consumption quality indicators (ESAC-QI) were calculated to identify where improvements can be made. A total of 3618 consultations were recorded for PPAS-1 and 2655 in PPAS-4. Bacterial aetiology was suspected in 26% (PPAS-1) and 12% (PPAS-4), and an antibiotic was prescribed in 30% (PPAS-1) and 16% (PPAS-4) of consultations. The percentage of adult patients with bronchitis who receive an antibiotic should, according to the ESAC-QI, not exceed 30%, which was not met by participating practices in any country except Denmark and Spain. For patients (≥1) with acute upper RTI, less than 20% should be prescribed an antibiotic, which was achieved by general practices in most countries, except Ireland (both PPAS), Croatia (PPAS-1), and Greece (PPAS-4) where prescribing for acute or chronic sinusitis (0-20%) was also exceeded. For pneumonia in adults, prescribing is acceptable for 90-100%, and this is lower in most countries. Prescribing for tonsillitis (≥1) exceeded the ESAC-QI (0-20%) in all countries and was 69% (PPAS-1) and 75% (PPAS-4). In conclusion, ESAC-QI applied to PPAS outcomes allows us to evaluate appropriate antibiotic prescribing by indication and benchmark general practices and countries.

Immigrants constitute large proportions of the population in many high-income countries. Knowledge about their perceptions of antibiotics, in comparison to native populations, is limited. We explored these perceptions by organizing nine homogeneous focus group discussions (FGDs) with first-generation immigrant and native Dutch participants (N = 64) from Rotterdam and Utrecht, who were recruited with the assistance of immigrant (community support) organizations. The FGDs were audio-recorded and transcribed verbatim. Inductive thematic analyses were performed with the qualitative analysis software Atlas.ti, using open and axial coding. We did not find noteworthy differences between immigrants and native Dutch participants; all participants had an overall reluctant attitude towards antibiotics. Within-group differences were larger than between-group differences. In each FGD there were, for instance, participants who adopted an assertive stance in order to receive antibiotics, who had low antibiotic-related knowledge, or who used antibiotics incorrectly. Native Dutch participants expressed similar difficulties as immigrant participants in the communication with their GP, which mainly related to time constraints. Immigrants who encountered language barriers experienced even greater communicational difficulties and reported that they often feel embarrassed and refrain from asking questions. To stimulate more prudent use of antibiotics, more attention is needed for supportive multilingual patient materials. In addition, GPs need to adjust their information, guidance, and communication for the individual's needs, regardless of the patient's migration background.

Background: Between-country differences have been described in antibiotic prescribing for respiratory tract infection (RTI) in primary care, but not yet for diagnostic testing procedures and prescribing confidence., Aim: To describe between-country differences in RTI management, particularly diagnostic testing and antibiotic prescribing, and investigate which factors relate to antibiotic prescribing and GPs' prescribing confidence., Design & Setting: Prospective audit in 18 European countries., Method: An audit of GP-registered patient, clinical, and management characteristics for patients presenting with sore throat and/or lower RTI ( n = 4982), and GPs' confidence in their antibiotic prescribing decision. Factors related to antibiotic prescribing and confidence were analysed using multi-level logistic regression., Results: Antibiotic prescribing proportions varied considerably: <20% in four countries, and >40% in six countries. There was also considerable variation in point-of-care (POC) testing (0% in Croatia, Moldova, and Romania, and >65% in Denmark and Norway, mainly for C-reactive protein [CRP] and group A streptococcal [strep A] infection), and in laboratory or hospital-based testing (<3% in Hungary, the Netherlands, and Spain, and >30% in Croatia, Georgia, Greece, and Moldova, mainly chest X-ray and white blood cell counting). Antibiotic prescribing was related to illness severity, comorbidity, age, fever, and country, but not to having performed a POC test. In nearly 90% of consultations, GPs were confident in their antibiotic prescribing decision., Conclusion: Despite high confidence in decisions about antibiotic prescribing, there is considerable variation in the primary care of RTI in European countries, with GPs prescribing antibiotics overall more often than is considered appropriate. POC testing may enhance the quality of antibiotic prescribing decisions if it can safely reverse decisions confidently made on clinical grounds alone to prescribe antibiotics., (Copyright © 2022, The Authors.)

Objectives: Antimicrobial resistance (AMR) is a public health threat associated with antibiotic consumption. Community-acquired acute respiratory tract infections (CA-ARTIs) are a major driver of antibiotic consumption in primary care. We aimed to quantify the investments required for a large-scale rollout of point-of care (POC) diagnostic testing in Dutch primary care, and the impact on AMR due to reduced use of antibiotics., Methods: We developed an individual-based model that simulates consultations for CA-ARTI at GP practices in the Netherlands and compared a scenario where GPs test all CA-ARTI patients with a hypothetical diagnostic strategy to continuing the current standard-of-care for the years 2020-2030. We estimated differences in costs and future AMR rates caused by testing all patients consulting for CA-ARTI with a hypothetical diagnostic strategy, compared to the current standard-of-care in GP practices., Results: Compared to the current standard-of-care, the diagnostic algorithm increases the total costs of GP consultations for CA-ARTI by 9% and 19%, when priced at €5 and €10, respectively. The forecast increase in Streptococcus pneumoniae resistance against penicillins can be partly restrained by the hypothetical diagnostic strategy from 3.8 to 3.5% in 2030, albeit with considerable uncertainty., Conclusions: Our results show that implementing a hypothetical diagnostic strategy for all CA-ARTI patients in primary care raises the costs of consultations, while lowering antibiotic consumption and AMR. Novel health-economic methods to assess and communicate the potential benefits related to AMR may be required for interventions with limited gains for individual patients, but considerable potential related to antibiotic consumption and AMR., (© 2022. The Author(s).)

Background: Clinical findings do not accurately predict laboratory diagnosis of influenza. Early identification of influenza is considered useful for proper management decisions in primary care., Objective: We evaluated the diagnostic value of the presence and the severity of symptoms for the diagnosis of laboratory-confirmed influenza infection among adults presenting with influenza-like illness (ILI) in primary care., Methods: Secondary analysis of patients with ILI who participated in a clinical trial from 2015 to 2018 in 15 European countries. Patients rated signs and symptoms as absent, minor, moderate, or major problem. A nasopharyngeal swab was taken for microbiological identification of influenza and other microorganisms. Models were generated considering (i) the presence of individual symptoms and (ii) the severity rating of symptoms., Results: A total of 2,639 patients aged 18 or older were included in the analysis. The mean age was 41.8 ± 14.7 years, and 1,099 were men (42.1%). Influenza was microbiologically confirmed in 1,337 patients (51.1%). The area under the curve (AUC) of the model for the presence of any of seven symptoms for detecting influenza was 0.66 (95% confidence interval [CI]: 0.65-0.68), whereas the AUC of the symptom severity model, which included eight variables-cough, fever, muscle aches, sweating and/or chills, moderate to severe overall disease, age, abdominal pain, and sore throat-was 0.70 (95% CI: 0.69-0.72)., Conclusion: Clinical prediction of microbiologically confirmed influenza in adults with ILI is slightly more accurate when based on patient reported symptom severity than when based on the presence or absence of symptoms., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is little evidence about the relationship between aetiology, illness severity, and clinical course of respiratory tract infections (RTIs) in primary care. Understanding these associations would aid in the development of effective management strategies for these infections., Aim: To investigate whether clinical presentation and illness course differ between RTIs where a viral pathogen was detected and those where a potential bacterial pathogen was found., Design and Setting: Post hoc analysis of data from a pragmatic randomised trial on the effects of oseltamivir in patients with flu-like illness in primary care ( n = 3266) in 15 European countries., Method: Patient characteristics and their signs and symptoms of disease were registered at baseline. Nasopharyngeal (adults) or nasal and pharyngeal (children) swabs were taken for polymerase chain reaction analysis. Patients were followed up until 28 days after inclusion. Regression models and Kaplan-Meier curves were used to analyse the relationship between aetiology, clinical presentation at baseline, and course of disease including complications., Results: Except for a less prominent congested nose (odds ratio [OR] 0.55, 95% confidence interval [CI] = 0.35 to 0.86) and acute cough (OR 0.42, 95% CI = 0.27 to 0.65) in patients with flu-like illness in whom a possible bacterial pathogen was isolated, there were no clear clinical differences in presentations between those with a possible bacterial aetiology compared with those with a viral aetiology. Also, course of disease and complications were not related to aetiology., Conclusion: Given current available microbiological tests and antimicrobial treatments, and outside pandemics such as COVID-19, microbiological testing in primary care patients with flu-like illness seems to have limited value. A wait-and-see policy in most of these patients with flu-like illness seems the best option., (© The Authors.)

Objectives: The ALIC 4 E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC 4 E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI)., Methods: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (<13 years old) and adults (≥13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period., Results: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged ≥65 years, patients without relevant comorbidities, or patients experiencing symptoms for ≤48 hours. Using VAS and accounting for 28-day follow-up resulted in higher QALY gain., Conclusions: QALY gain owing to oseltamivir is limited compared with other diseases, and its clinical meaningfulness remains to be determined. Further analysis is needed to evaluate whether QALY gain and its impact on ILI treatment cost render oseltamivir cost-effective., (Copyright © 2021 ISPOR–The International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Presentation and antibiotic prescribing for common infectious disease episodes decreased substantially during the first COVID-19 pandemic wave in Dutch general practice. We set out to determine the course of these variables during the first pandemic year. We conducted a retrospective observational cohort study using routine health care data from the Julius General Practitioners' Network. All patients registered in the pre-pandemic year ( n = 425,129) and/or during the first pandemic year ( n = 432,122) were included. Relative risks for the number of infectious disease episodes (respiratory tract/ear, urinary tract, gastrointestinal, and skin), in total and those treated with antibiotics, and proportions of episodes treated with antibiotics (prescription rates) were calculated. Compared to the pre-pandemic year, primary care presentation for common infections remained lower during the full first pandemic year (RR, 0.77; CI, 0.76-0.78), mainly attributed to a sustained decline in respiratory tract/ear and gastrointestinal infection episodes. Presentation for urinary tract and skin infection episodes declined during the first wave, but returned to pre-pandemic levels during the second and start of the third wave. Antibiotic prescription rates were lower during the full first pandemic year (24%) as compared to the pre-pandemic year (28%), mainly attributed to a 10% lower prescription rate for respiratory tract/ear infections; the latter was not accompanied by an increase in complications. The decline in primary care presentation for common infections during the full first COVID-19 pandemic year, together with lower prescription rates for respiratory tract/ear infections, resulted in a substantial reduction in antibiotic prescribing in Dutch primary care.

Objective: Recovery time and treatment effect of oseltamivir in influenza-like illness (ILI) differs between patient groups. A point-of-care test to better predict ILI duration and identify patients who are most likely to benefit from oseltamivir treatment would aid prescribing decisions in primary care. This study aimed to investigate whether a C-reactive protein (CRP) concentration of ≥30 mg/L can predict (1) ILI disease duration, and (2) which patients are most likely to benefit from oseltamivir treatment., Design: Secondary analysis of randomized controlled trial data., Setting: Primary care in Lithuania, Sweden and Norway during three consecutive influenza seasons 2016-2018., Subjects: A total of 277 ILI patients aged one year or older and symptom duration of ≤72 h., Main Outcome Measures: Capillary blood CRP concentration at baseline, and ILI recovery time defined as having 'returned to usual daily activity' with residual symptoms minimally interfering., Results: At baseline, 20% (55/277) had CRP concentrations ≥30mg/L (range 0-210). CRP concentration ≥30 mg/L was not associated with recovery time (adjusted hazards ratio (HR) 0.80: 95% CI 0.50-1.3; p  = 0.33). Interaction analysis of CRP concentration ≥30 mg/L and oseltamivir treatment did not identify which patients benefit more from oseltamivir treatment (adjusted HR 0.69: 95% CI 0.37-1.3; p  = 0.23)., Conclusion: There was no association between CRP concentration of ≥30 mg/L and recovery time from ILI. Furthermore, CRP could not predict which ILI patients benefit more from oseltamivir treatment. Hence, we do not recommend CRP testing for predicting ILI recovery time or identifying patients who will receive particular benefit from oseltamivir treatment.Key PointsPredicting disease course of influenza-like illness (ILI), and identifying which patients benefit from oseltamivir treatment is a challenge for physicians.• There was no association between CRP concentration at baseline and recovery time in patients consulting with ILI in primary care.• There was no association between CRP concentration at baseline and benefit from oseltamivir treatment.• We, therefore, do not recommend CRP testing for predicting recovery time or in decision-making concerning oseltamivir prescribing in ILI patients.

Introduction: Recent reports have highlighted the impact of the COVID-19 pandemic on the incidence of infectious disease illnesses and antibiotic use. This study investigates the effect of the pandemic on childhood incidence of otitis media (OM) and associated antibiotic prescribing in a large primary care-based cohort in the Netherlands., Material and Methods: Retrospective observational cohort study using routine health care data from the Julius General Practitioners' Network (JGPN). All children aged 0-12 registered in 62 practices before the COVID-19 pandemic (1 March 2019 - 29 February 2020) and/or during the pandemic (1 March 2020 - 28 February 2021) were included. Data on acute otitis media (AOM), otitis media with effusion (OME), ear discharge episodes and associated antibiotic prescriptions were extracted. Incidence rates per 1,000 child years (IR), incidence rate ratios (IRR) and incidence rate differences (IRD) were compared between the two study periods., Results: OM episodes declined considerably during the COVID-19 pandemic: IR pre-COVID-19 vs COVID-19 for AOM 73.7 vs 27.1 [IRR 0.37]; for OME 9.6 vs 4.1 [IRR 0.43]; and for ear discharge 12.6 vs 5.8 [IRR 0.46]. The absolute number of AOM episodes in which oral antibiotics were prescribed declined accordingly (IRD pre-COVID-19 vs COVID-19: -22.4 per 1,000 child years), but the proportion of AOM episodes with antibiotic prescription was similar in both periods (47% vs 46%, respectively)., Discussion: GP consultation for AOM, OME and ear discharge declined by 63%, 57% and 54% respectively in the Netherlands during the COVID-19 pandemic. Similar antibiotic prescription rates before and during the pandemic indicate that the case-mix presenting to primary care did not considerably change. Our data therefore suggest a true decline as a consequence of infection control measures introduced during the pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hullegie, Schilder, Marchisio, de Sévaux, van der Velden, van de Pol, Boeijen, Platteel, Torretta, Damoiseaux and Venekamp.)

Background: Influenza virus (IFV) is often encountered in primary care. Implementation of a rapid diagnostic test for its detection at the point-of-care would enable discrimination from other viral causes of influenza-like-illness (ILI) and might be helpful in individual patient management. In this study, the diagnostic performance of such a point-of-care platform was evaluated., Methods: Respiratory samples (n = 1490) from ILI-patients in primary care in 15 European countries were collected as part of a prospective clinical trial. Both children (n = 252) and adults (n = 1238) were sampled during 3 consecutive periods of high IFV endemicity. Samples were analysed in a central laboratory, after storage at -70 °C, with the Idylla™ Respiratory Panel, detecting both IFV and RSV, on the Idylla™ platform. The Fast Track Diagnostics (FTD) Respiratory Pathogens 21 plus assay was used as reference. A subset of samples (n = 192) was analysed both fresh and after being frozen., Results: The reference method detected IFV-A in 42% and IFV-B in 13% of the samples. Sensitivity of the Idylla for detection of IFV-A and IFV-B was 98.2% and 92.3% and specificity 97.7% and 98.4% respectively. False negative samples contained significantly lower viral loads than true positive samples (FTD mean Ct-value 30.7 versus 26.1 for IFV-A and 30.4 versus 25.1 for IFV-B, p < 0.001). Comparable results were obtained for Idylla analysis using fresh and frozen samples., Conclusions: The Idylla Respiratory Panel is a promising point-of-care test for detection of IFV in ILI patients due to its excellent diagnostic performance, minimal training requirements and limited hands-on time., (Copyright © 2021. Published by Elsevier B.V.)

Objective: We evaluated the prevalence of microbiologically-confirmed influenza infection among patients with influenza-like symptoms and compared the clinical and epidemiological characteristics of patients with and without influenza infection., Methods: Retrospective study of a cohort of patients with influenza-like symptoms from 2016 to 2018 who participated in a clinical trial in thirteen urban primary centres in Catalonia. Different epidemiological data were collected. Patients rated the different symptoms and signs on a Likert scale (absent, little problem, moderate problem and severe problem) and self-reported the measure of health status with the EuroQol visual analogue scale. A nasopharyngeal swab was taken for microbiological isolation of influenza and other microorganisms., Results: A total of 427 patients were included. Microbiologically confirmed influenza was found in 240 patients (56.2%). The percentage of patients with moderate-to-severe cough, muscle aches, tiredness and dizziness was greater among patients with microbiologically confirmed influenza. The self-reported health status was significantly lower among patients with true flu infection (mean of 36.3 ± 18.2 vs 41.7 ± 17.8 in patients without influenza; p<0.001)., Conclusions: Clinical findings are not particularly useful for confirming or excluding the diagnosis of influenza when intensity is not considered. However, the presence of moderate-to-severe cough, myalgias, tiredness and dizziness along with a poor health status is more common in patients with confirmed flu infection., (©The Author 2021. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Background and Objective: Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone., Methods: Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed., Results: Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: €17 [0-95% Crl: 16-19] vs. €24 [5-100% Crl: 18-29]; healthcare provider: €37 [28-67] vs. €44 [25-55]; healthcare payers: €54 [45-85] vs. €68 [45-81]; and society: €423 [399-478] vs. €451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences., Conclusion: The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant., (© 2021. The Author(s).)

Objective: To describe primary health care (consultation characteristics and management) for patients contacting their general practitioner (GP) with a respiratory tract infection (RTI) early on in the COVID-19 pandemic in contrasting European countries, with comparison to prepandemic findings., Setting: Primary care in 16 countries (79 practices), when no routine SARS-CoV-2 testing was generally available., Design and Participants: Before (n=4376) and early in the pandemic (n=3301), patients with RTI symptoms were registered in this prospective audit study., Outcome Measures: Consultation characteristics (type of contact and use of PPE) and management characteristics (clinical assessments, diagnostic testing, prescribing, advice and referral) were registered. Differences in these characteristics between countries and between pandemic and prepandemic care are described., Results: Care for patients with RTIs rapidly switched to telephone/video consultations (10% in Armenia, 91% in Denmark), and when consultations were face-to-face, GPs used PPE during 97% (95% CI 96% to 98%) of contacts. Laboratory testing for SARS-CoV-2 in primary care patients with RTIs was rapidly implemented in Denmark (59%) and Germany (31%), while overall testing for C reactive protein decreased. The proportion of patients prescribed antibiotics varied considerably between countries (3% in Belgium, 48% in UK) and was lower during the pandemic compared with the months before, except for Greece, Poland and UK. GPs provided frequent and varied COVID-related advice and more frequently scheduled a follow-up contact (50%, 95% CI 48% to 52%). GPs reported a slightly higher degree of confidence in the likely effectiveness of their management in face-to-face (73% (very) confident, 95% CI 71% to 76%) than in virtual consultations (69%, 95% CI 67% to 71%)., Conclusions: Despite between-country variation in consultation characteristics, access to SARS-CoV-2 laboratory testing and medication prescribing, GPs reported a high degree of confidence in managing their patients with RTIs in the emerging pandemic. Insight in the highly variable pandemic responses, as measured in this multicountry audit, can aid in fine-tuning national action and in coordinating a pan-European response during future pandemic threats., Competing Interests: Competing interests: AWvdV, CCB, TV, ST-K, SA, EB and HGo received unrestricted funding for studies from the European Commission (IMI2 and H2020). SE is an employee of Abbott Rapid Diagnostics Germany., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In 2020, the COVID-19 pandemic brought dramatic changes in the delivery of primary health care across the world, presumably changing the number of consultations for infectious diseases and antibiotic use. We aimed to assess the impact of the pandemic on infections and antibiotic prescribing in Dutch primary care. All patients included in the routine health care database of the Julius General Practitioners' Network were followed from March through May 2019 ( n = 389,708) and March through May 2020 ( n = 405,688). We extracted data on consultations for respiratory/ear, urinary tract, gastrointestinal and skin infections using the International Classification of Primary Care (ICPC) codes. These consultations were combined in disease episodes and linked to antibiotic prescriptions. The numbers of infectious disease episodes (total and those treated with antibiotics), complications, and antibiotic prescription rates (i.e., proportion of episodes treated with antibiotics) were calculated and compared between the study periods in 2019 and 2020. Fewer episodes were observed during the pandemic months than in the same months in 2019 for both the four infectious disease entities and complications such as pneumonia, mastoiditis and pyelonephritis. The largest decline was seen for gastrointestinal infections (relative risk (RR), 0.54; confidence interval (CI), 0.51 to 0.58) and skin infections (RR, 0.71; CI, 0.67 to 0.75). The number of episodes treated with antibiotics declined as well, with the largest decrease seen for respiratory/ear infections (RR, 0.54; CI, 0.52 to 0.58). The antibiotic prescription rate for respiratory/ear infections declined from 21% to 13% (difference -8.0% (CI, -8.8 to -7.2)), yet the prescription rates for other infectious disease entities remained similar or increased slightly. The decreases in primary care infectious disease episodes and antibiotic use were most pronounced in weeks 15-19, mid-COVID-19 wave, after an initial peak in respiratory/ear infection presentation in week 11, the first week of lock-down. In conclusion, our findings indicate that the COVID-19 pandemic has had profound effects on the presentation of infectious disease episodes and antibiotic use in primary care in the Netherlands. Consequently, the number of infectious disease episodes treated with antibiotics decreased. We found no evidence of an increase in complications.

Objective: Identifying influenza A or B as cause of influenza-like illness (ILI) is a challenge due to non-specific symptoms. An accurate, cheap and easy to use biomarker might enhance targeting influenza-specific management in primary care. The aim of this study was to investigate if C-reactive protein (CRP) is associated with influenza A or B, confirmed with PCR testing, in patients presenting with ILI., Design: Cross-sectional study., Setting: Primary care in Lithuania, Norway and Sweden., Subjects: A total of 277 patients at least 1 year of age consulting primary care with ILI during seasonal influenza epidemics., Main Outcome Measures: Capillary blood CRP analysed as a point-of-care test and detection of influenza A or B on nasopharyngeal swabs in adults, and nasal and pharyngeal swabs in children using PCR., Results: The prevalence of positive tests for influenza A among patients was 44% (121/277) and the prevalence of influenza B was 21% (58/277). Patients with influenza A infection could not be identified based on CRP concentration. However, increasing CRP concentration in steps of 10 mg/L was associated with a significantly lower risk for influenza B with an adjusted odds ratio of 0.42 (0.25-0.70; p <.001). Signs of more severe symptoms like shortness of breath, sweats or chills and dizziness were associated with higher CRP., Conclusions: There was no association between CRP and influenza A. Increased concentration of CRP was associated with a lower risk for having influenza B, a finding that lacks clinical usefulness. Hence, CRP testing should be avoided in ILI, unless bacterial pneumonia is suspected. Key points Identifying influenza A or B as cause of influenza-like illness (ILI) is a challenge due to non-specific symptoms. There was no association between concentration of CRP and influenza A. Increased concentration of CRP was associated with a lower risk for having influenza B, a finding that lacks clinical usefulness. A consequence is that CRP testing should be avoided in ILI, unless bacterial pneumonia or similar is suspected.

Insight into antibiotic prescribing quality is key to general practitioners (GPs) to improve their prescribing behavior and to national antibiotic surveillance and stewardship programs. Additionally to numbers of prescribed antibiotics, quality indicators (QIs) linked to the clinical indication for prescribing are urgently needed. The aim of this proof of concept study was to define indication-linked QIs which can be easily implemented in Dutch primary care by collaborating with data-extraction/processing companies that routinely process patient data for GP practices. An expert group of academic and practicing GPs defined indication-linked QIs for which outcomes can be derived from routine care data. QI outcomes were calculated and fed back to GPs from 44 practices, associations between QI outcomes were determined, and GPs' opinions and suggestions with respect to the new set were captured using an online questionnaire. The new set comprises: (1) total number of prescribed antibiotics per 1000 registered patients and percentages of generally non-1st choice antibiotics; (2) prescribing percentages for episodes of upper and lower respiratory tract infection; (3) 1st choice prescribing for episodes of tonsillitis, pneumonia and cystitis in women. Large inter-practice variation in QI outcomes was found. The validity of the QI outcomes was confirmed by associations that were expected. The new set was highly appreciated by GPs and additional QIs were suggested. We conclude that it proved feasible to provide GPs with informative, indication-linked feedback of their antibiotic prescribing quality by collaborating with established data extraction/processing companies. Based on GPs' suggestions the set will be refined and extended and used in the near future as yearly feedback with benchmarking for GPs and for national surveillance and stewardship purposes.

Background: Acute sore throat is one of the most common problems for which patients consult their general practitioner and is a key area for inappropriate antibiotic prescribing. The objective of this study was to investigate patients' attitudes related to healthcare-seeking behavior and self-management of sore throat., Methods: We conducted an observational, questionnaire-based study across 13 countries (Australia, Brazil, China, France, Germany, Italy, the Philippines, Russia, Saudi Arabia, South Africa, Thailand, the UK and the USA) on respondents who reported having had a sore throat in the previous 12 months. Data were collected on their experiences, contact with healthcare professionals, treatment practices and opinions about antibiotics., Results: A total of 5196 respondents (approximately 400 per country) completed the survey. Over 80% of respondents sought advice for a sore throat, with 30% consulting a general practitioner. The desire to limit the worsening of symptoms was the main reason for seeking treatment. Other reasons concerned resolving persistent symptoms and reducing the impact on daily life/sleep. Self-management for sore throat was mainly medicated sore throat remedies. "Wanting an antibiotic" was rated much lower (55%) than most other reasons for visiting a doctor, but this differed greatly between countries. The percentage of respondents using antibiotics varied widely, for example, 10% in the UK and 45% in Saudi Arabia. There was considerable variation in the proportion of respondents who thought that antibiotics would be effective against sore throat (from 24% in France to 94% in Saudi Arabia)., Conclusions: Our findings suggest that knowledge of effective treatments for sore throat varied widely. The results of this study should enable healthcare professionals to better anticipate patients' needs. This will support healthcare professionals in their role as antibiotic stewards, helping to reduce the misuse of antibiotics, and further guiding patients towards symptomatic self-management of sore throat., Competing Interests: AV, AuS, AA and AP are members of the Global Respiratory Infection Partnership (supported by an unrestricted educational grant from Reckitt Benckiser Healthcare Ltd, UK). AV reports grants from Reckitt Benckiser, during the conduct of the study; AS is a full-time employee of Reckitt Benckiser Healthcare Ltd, UK and reports an unrestricted educational grant from Reckitt Benckiser, during the conduct of the study. The authors report no other potential conflicts of interest for this work., (© 2020 van der Velden et al.)

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., (©The Authors.)

Background: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups., Methods: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921., Findings: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group., Interpretation: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner., Funding: European Commission's Seventh Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Respiratory tract infections (RTIs) are a common reason for children to consult in general practice. Antibiotics are often prescribed, in part due to miscommunication between parents and GPs. The duration of specific respiratory symptoms has been widely studied. Less is known about illness-related symptoms and the impact of these symptoms on family life, including parental production loss. Better understanding of the natural course of illness-related symptoms in RTI in children and impact on family life may improve GP-parent communication during RTI consultations., Objective: To describe the general impact of RTI on children and parents regarding illness-related symptoms, absenteeism from childcare, school and work, use of health care facilities, and the use of over-the-counter (OTC) medication., Methods: Prospectively collected diary data from two randomized clinical trials in children with RTI in primary care (n = 149). Duration of symptoms was analysed using survival analysis., Results: Disturbed sleep, decreased intake of food and/or fluid, feeling ill and/or disturbance at play or other daily activities are very common during RTI episodes, with disturbed sleep lasting longest. Fifty-two percent of the children were absent for one or more days from childcare or school, and 28% of mothers and 20% of fathers reported absence from work the first week after GP consultation. Re-consultation occurred in 48% of the children. OTC medication was given frequently, particularly paracetamol and nasal sprays., Conclusion: Appreciation of, and communication about the general burden of disease on children and their parents, may improve understanding between GPs and parents consulting with their child., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is a lack of recently published data on impetigo presentation incidence and treatment practices in the routine Western European primary care setting., Objectives: To investigate impetigo incidence, treatments and recurrence in primary care in the Netherlands., Methods: A retrospective, observational study. Electronic records of patients treated for impetigo in 2015 at 29 general practices in Utrecht and surrounds were reviewed. An episode of impetigo was defined as one or more patient-doctor contacts within 8 weeks of the index consultation. Within an episode, patient demographics and prescribing patterns were analysed including number of treatments, and the category and sequence of individual medicines., Results: A total of 1761 impetigo episodes were managed, with an incidence rate of 13.6 per 1000 person years. Impetigo peaked in summer. Most patients, the majority children, experienced a single episode (93%), and 25% had eczema as comorbidity. Topical antibiotics (primarily fusidic acid) were the most prescribed initial treatments (85%), followed by oral antibiotics (14%). Topical antibiotics were progressively used less over subsequent treatments, while there was an inverse increase in oral antibiotic use. Topical fusidic acid as the most common first line treatment seemed satisfactory as only 12% of initial treatments with this drug received further therapy. Repeat treatments generally occurred within 7 days., Conclusion: This study of impetigo prescribing patterns in primary care highlighted that Dutch general practitioners were generally adherent to national treatment guidelines. Topical treatment, and if needed systemic small-spectrum antibiotic treatment, appeared satisfactory; these findings aid in antimicrobial stewardship., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progressed and killed all of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminated Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector, AKT, increased the expression of MHC Class I and CD80 on tumor cells. These changes contributed to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. Our results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.

Objectives: We evaluated costs and effects of the RAAK (RAtional Antibiotic use Kids) intervention (GP online training and information booklets for parents), aiming to reduce antibiotic prescribing for children with respiratory tract infection (RTI)., Methods: We conducted a trial-based cost-effectiveness analysis from a societal perspective. We included children consulting the GP with RTI for whom parents kept a 2 week (cost) diary. The antibiotic prescribing rate was the percentage of children receiving an antibiotic prescription at the index consultation and during the 2 weeks of follow-up. The cost difference between the intervention and usual care groups per percentage decrease in antibiotic prescribing was calculated. Bootstrapping was used to assess uncertainty surrounding the outcomes., Results: Costs and effects of 153 children in the intervention group and 107 children in the usual care group were available for analysis. Antibiotic prescribing was 12% lower in the intervention group and costs were €10.27 higher in the intervention group compared with the usual care group. This resulted in an incremental cost-effectiveness ratio of €0.85 per percentage decrease in antibiotic prescribing. The probability that the intervention was more effective, but more expensive, was 53%, whereas the probability that the intervention was more effective and less expensive compared with usual care was 41%., Conclusions: The online training for GPs and the information booklet for parents resulted in a decrease in antibiotic prescribing in children with RTI, at very low cost, and should therefore be considered for implementation in primary care., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Taking consecutive antibiotic use into account is of importance to obtain insight in treatment within disease episodes, use of 2nd- and 3rd-choice antibiotics, therapy failure and/or side effects. Nevertheless, studies dealing with consecutive antibiotic use are scarce. We aimed at evaluating switch patterns in antibiotic use in the outpatient setting in the Netherlands., Methods: Outpatient antibiotic dispensing data was processed to antibiotic treatment episodes consisting of single prescriptions or consecutive prescriptions (2006 to 2014). Consecutive prescriptions were categorised into prolongations and switches. Switches were further analysed to obtain antibiotic switch percentages and trends over time. Outcomes were compared with recommendations of Dutch guidelines., Results: A total of 43,179,867 antibiotic prescriptions were included in the analysis, consisting of single prescriptions (95%), prolongations (2%) and switches (3%). The highest switch percentages were found for trimethoprim (7.6%) and nitrofurantoin (5.4%). For fosfomycin, ciprofloxacin, flucloxacillin and trimethoprim we found the highest yearly increase in switching. Amoxicillin/clavulanic acid was most often used as second antibiotic in a switch. A surprisingly high number of 2nd- and 3rd-choice antibiotics are prescribed as first antibiotic in a treatment., Conclusions: Although the actual reason for a switch is unknown, switch patterns can reveal problems concerning treatment failure and guideline adherence. In general, switch percentages of antibiotics in the Netherlands are low. The data contributes to the knowledge regarding antibiotic switch patterns in the outpatient setting.

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 (<12, 12-64 and >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., Trial Registration Number: ISRCTN27908921; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Since the start of out-of-hours (OOH) primary care clinics, the number of patient consultations has been increasing. Triage plays an important role in patient selection for a consultation, and in providing reassurance and self-management advice., Objective: We aimed to investigate whether the smartphone application "Should I see a doctor?" (in Dutch:"moet ik naar de dokter?") could guide patients in appropriate consultation at OOH clinics by focusing on four topics: 1) app usage, 2) user satisfaction, 3) whether the app provides the correct advice, and 4) whether users intend to follow the advice., Design and Setting: A prospective, cross-sectional study amongst app users in a routine primary care setting., Methods: The app is a self-triage tool for acute primary care. A built-in questionnaire asked users about the app's clarity, their satisfaction and whether they intended to follow the app's advice (n = 4456). A convenience sample of users was phoned by a triage nurse (reference standard) to evaluate whether the app's advice corresponded with the outcome of the triage call (n = 126). Suggestions of phoned participants were listed., Results: The app was used by patients of all ages, also by parents for their children, and mostly for abdominal pain, skin disorders and cough. 58% of users received the advice to contact the clinic, 34% a self-care advice and 8% to wait-and-see. 65% of users intended to follow the app's advice. The app was rated as 'neutral' to 'very clear' by 87%, and 89% were 'neutral' to 'very satisfied'. In 81% of participants the app's advice corresponded to the triage call outcome, with sensitivity, specificity, positive- and negative predictive values of 84%, 74%, 88% and 67%, respectively., Conclusion: The app "Should I see a doctor?" could be a valuable tool to guide patients in contacting the OOH primary care clinic for acute care. To further improve the app's safety and efficiency, triaging multiple symptoms should be facilitated, and more information should be provided to patients receiving a wait-and-see advice., Competing Interests: The study was funded by Achmea, a Dutch health insurance company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

Background: Respiratory tract infection (RTI) is the most common reason to consult a GP during childhood, and often results in unnecessary prescribing of antibiotics. Using an information booklet during the consultation has been shown to be a promising tool to reduce antibiotic prescribing. The influence of such information on parents' views, knowledge, and expectations has not been investigated yet., Aim: To explore the reported attitude and knowledge of parents towards antibiotics and management of childhood RTI, as well as the added influence of an information booklet, as perceived by parents., Design & Setting: Qualitative interviews were conducted with Dutch parents who consulted the GP with their child for RTI symptoms and received an information booklet., Method: Semi-structured interviews were audio-recorded, transcribed, coded, and analysed using framework analysis by open-axial coding and describing themes., Results: Eighteen parents were interviewed. Four themes were identified: prior reticence towards antibiotics; expectations of the consultation and trust in the GPs' treatment decision; confirmation and reassurance by the booklet; self-management and future consultation intentions. Dutch parents felt reassured and more confident about their pre-existing reticent attitude towards antibiotic treatment; therefore, they thought their opinion and attitude had not really been changed by the booklet., Conclusion: In a low-prescribing country like the Netherlands, information should focus on enhancing self-efficacy and providing concrete safety-netting advice. For other countries with less reticence towards antibiotics, it is recommended that the knowledge, attitude, and perceptions of the population is studied, in order to be able to tailor interventions., Competing Interests: The authors declare that no competing interests exist.

Objectives: Antibiotics are too often prescribed in childhood respiratory tract infection (RTI), despite limited effectiveness, potential side effects and bacterial resistance. We aimed to reduce antibiotic prescribing for children with RTI by online training for general practitioners (GPs) and information for parents., Methods: A pragmatic cluster randomized controlled trial in primary care. The intervention consisted of online training for GPs and an information booklet for parents. The primary outcome was the antibiotic prescription rate for children presenting with RTI symptoms, as registered by GPs. Secondary outcomes were number of reconsultations within the same disease episode, consultations for new episodes, hospital referrals and pharmacy-dispensed antibiotic courses for children. This trial was registered at the Dutch Trial Register (NTR), registration number: NTR4240., Results: After randomization, GPs from a total of 32 general practices registered 1009 consultations. An antibiotic was prescribed in 21% of consultations in the intervention group, compared with 33% in the usual care group, controlled for baseline prescribing (rate ratio 0.65, 95% CI 0.46-0.91). The probability of reconsulting during the same RTI episode did not differ significantly between the intervention and control groups, and nor did the numbers of consultations for new episodes and hospital referrals. In the intervention group antibiotic dispensing was 32 courses per 1000 children/year lower than the control group, adjusted for baseline prescribing (rate ratio 0.78, 95% CI 0.66-0.92). The numbers and proportion of second-choice antibiotics did not differ significantly., Conclusions: Concise, feasible, online GP training, with an information booklet for parents, showed a relevant reduction in antibiotic prescribing for children with RTI.

Is non-compliance to guidelines regarding antimicrobial treatment in primary care a problem? On the one hand, individual variation in clinical problems warrants deviation from guidelines in some patients. But on the other hand, restrictive use of antibiotics is certainly necessary in primary care. Undertreatment of infectious diseases is not a major risk in primary care, but overtreatment is. Currently, steps are undertaken in the Netherlands to enhance antibiotic stewardship.

Background: Childhood infections are common in general practice. Although clinical guidelines recommend restrictive antibiotic use for children, antibiotics are too often prescribed., Objective: The aim of this study was to obtain insight in antibiotic prescribing for children related to clinical diagnoses. This is pivotal to define improvement strategies in the antibiotic management., Methods: In this observational study, we used consultation data collected from 45 general practices in the Netherlands in 2012. Infectious disease episode incidences, the number of antibiotic prescriptions per 1000 person-years, the proportion of episodes with an antibiotic prescription and the choice of antibiotic subclass were analysed for the most relevant diagnoses over different ages., Results: A total of 262 antibiotic courses were prescribed per 1000 person-years on average, with the highest number among children of 1 year (714/1000 person-years). Antibiotics were prescribed in 24% of infectious disease episodes. Acute upper respiratory tract infection (RTI) was the most common reason to visit the GP (173/1000 person-years), and the second most frequent indication to prescribe antibiotics. Antibiotics were most often prescribed for acute otitis media (58/1000 person-years). Amoxicillin dominated prescribing (55%), followed by macrolides (14%) and amoxicillin/clavulanate (10%), prescribing of narrow-spectrum antibiotics was low (10%)., Conclusion: This detailed insight in antibiotic management of childhood infections shows targets for Dutch improvement strategies: (i) prevent antibiotic prescribing for acute upper RTI and bronchitis; (ii) stimulate the use of narrow-spectrum antibiotics; and (iii) reduce the use of macrolides and amoxicillin/clavulanate. Furthermore, this information is helpful to compare antibiotic policy between countries., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Unnecessary and non-first-choice antibiotic prescribing is a significant problem in primary care. It is often argued that irrational prescribing is higher during out-of-hours (OOH) consultations., Aim: To obtain insight into the quantity and quality of OOH antibiotic prescribing for commonly presented infectious diseases., Design and Setting: Two two-way comparisons of 1) nationally dispensed antibiotics during office hours and OOH care, using data from the Dutch Foundation of Pharmaceutical Statistics, and 2) regional prescribing quality data from 45 primary care practices from Utrecht and its vicinity, and two large OOH services in Utrecht and Woerden., Method: From the national data, yearly dispensed antibiotics were analysed per prescriber type, with respect to time (office hours or OOH) of prescription, types of antibiotics, and patients' age group. Regional prescribing rates, choice of antibiotic, and appropriateness of prescribing were compared for otitis media, sinusitis, tonsillitis, bronchitis, cystitis, and impetigo. Appropriateness was assessed by comparing all relevant information from medical files with the guideline recommendations., Results: Only 6% of GP-prescribed antibiotics were prescribed OOH. OOH, cystitis and acute otitis media presented most often. First-choice prescribing was comparable for the two settings, whereas prescribing rates were higher OOH, with comparatively more amoxicillin(/clavulanate). The appropriateness evaluation, however, revealed that overprescribing was comparable, or even lower than, for daily practice., Conclusion: The suggestion that OOH antibiotic prescribing quality is worse than in daily practice does not seem founded. The higher OOH prescribing rates can be explained by a different population of presenting patients. The appropriateness of prescribing rather than prescribing rates, therefore, should be used to determine quality., (© British Journal of General Practice 2017.)

Objective: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts., Methods: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only., Results: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle., Conclusion: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles., (The Author(s). Published by S. Karger AG, Basel.)

Quality Problem: Inappropriate antibiotic use drives development of antimicrobial resistance. Worldwide, guideline adherence for antibiotic treatment of infectious disease is far from optimal. Insight in prescribing quality is pivotal for healthcare professionals and policy makers to intervene appropriately., Initial Assessments: European countries uniformly monitor antibiotic use, which is reported yearly by the European Centre for Disease Prevention and Control. Unfortunately, this has not had enough impact to decrease prescribing and resistance levels., Choice of Solution: Quality indicators (QIs) could provide better insight in prescribing quality and enable benchmarking to other countries; this could trigger action to improve antimicrobial prescribing. European Surveillance of Antimicrobial Consumption (ESAC) proposed 12 antibiotic QIs., Implementation: Trends in use of antibiotic subgroups and the 12 ESAC QI values were determined for Dutch primary care (2004-2013); outcomes were compared to other European countries. Dutch antibiotic use is low within the European context. Nitrofurantoin use is higher than the European average, use of small-spectrum antibiotics lowers. Use of macrolides, quinolones and amoxicillin/clavulanate declined, which was not supported by the broad/narrow QI results., Evaluation: QIs expressing antibiotic subgroup use in Defined Daily Doses/1000 inhabitants/day, particularly small-spectrum and non-first choices, provide proper insight in prescribing quality and are useful for benchmarking purposes. QIs measuring percentages were not considered useful. The broad/narrow ratio could be more informative when adjusted to national guidelines, or when more antibiotic subgroups are included based on better European consensus., Lessons Learnt: Benchmarking the above mentioned Dutch QI values to other countries provides direction for three specific strategies to further improve Dutch antibiotic prescribing practice., (© The Author 2016. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)