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This is one of the first studies to (1) describe the out-of-hospital burden of influenza-like-illness (ILI) and clinically diagnosed flu, also for patients not seeking professional medical care, (2) assess influential background characteristics, and (3) formally compare the burden of ILI in patients with and without a clinical diagnosis of flu. A general population sample with recent ILI experience was recruited during the 2011-2012 influenza season in Belgium. Half of the 2250 respondents sought professional medical care, reported more symptoms (especially more often fever), a longer duration of illness, more use of medication (especially antibiotics) and a higher direct medical cost than patients not seeking medical care. The disease and economic burden were similar for ambulatory ILI patients, irrespective of whether they received a clinical diagnosis of flu. On average, they experienced 5-6 symptoms over a 6-day period; required 1.6 physician visits and 86-91% took medication. An average episode amounted to €51-€53 in direct medical costs, 4 days of absence from work or school and the loss of 0.005 quality-adjusted life-years. Underlying illness led to greater costs and lower quality-of-life. The costs of ILI patients with clinically diagnosed flu tended to increase, while those of ILI patients without clinically diagnosed flu tended to decrease with age. Recently vaccinated persons experienced lower costs and a higher quality-of-life, but this was only the case for patients not seeking professional medical care. This information can be used directly to evaluate the implementation of cost-effective prevention and control measures for influenza. In particular to inform the evaluation of more widespread seasonal influenza vaccination, including in children, which is currently considered by many countries.

► The content of 11 Cochrane reviews regarding the value of inactivated influenza vaccines (TIV) summarized and updated. ► Significant efficacy of TIV in healthy adults and children (>6 years, Grade A evidence). ► No efficacy of TIV in young children (<2 years) or institutionalised elderly. ► Inconsistent results in children (<6 years), individuals with COPD, institutionalised elderly, elderly with co-morbidities and healthcare workers in elderly homes. ► Striking lack of sound evidence for the effect of TIV on influenza complications (GRADE B, C or not existing). To systematically review the evidence regarding the efficacy, effectiveness and risks of the use of inactivated influenza vaccines in children, healthy adults, elderly individuals and individuals with co-morbidities such as diabetes, chronic lung disease, cardiovascular disease, kidney or liver disease and immune suppression. The Cochrane database of systematic reviews was searched for relevant reviews and supplemented with searches of the Cochrane Central Register of Controlled Trials database and Medline. Two reviewers independently assessed review and trial quality and extracted data. The inactivated influenza vaccine has been proven effective in preventing laboratory-confirmed influenza among healthy adults (16–65 years) and children (≥6 years) (GRADE A evidence). However, there is strikingly limited good-quality evidence (all GRADE B, C or not existing) of the effectiveness of influenza vaccination on complications such as pneumonia, hospitalisation and influenza-specific and overall mortality. Inconsistent results are found in studies among children younger than 6 years, individuals with COPD, institutionalised elderly (65 years or older), elderly with co-morbidities and healthcare workers in elderly homes, which can only be explained by bias of unknown origin. The vaccination of pregnant women might be beneficial for their newborns, and vaccination of children might be protective in non-recipients of the vaccine of all ages living in the same community (one RCT, Grade B evidence).

Controversy has arisen regarding the effectiveness of neuraminidase inhibitors (NIs), especially against influenza-related complications. A literature search was performed to critically assess the evidence collected by the available systematic reviews (SRs) regarding the benefits and disadvantages of NIs (oseltamivir, zanamivir) compared to placebos in healthy and at-risk individuals of all ages for prophylaxis and treatment of seasonal influenza. A SR was done using the Cochrane Database of Systematic Reviews, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects, and Medline (January 2006-July 2012). Two reviewers selected SRs based on randomized clinical trials, which were restricted to intention-to-treat results, and they assessed review (AMSTAR) and study quality indicators (GRADE). The SRs included (N = 9) were of high quality. The efficacy of NIs in prophylaxis ranged from 64% (16-85) to 92% (37-99); the absolute risk reduction ranged from 1.2% to 12.1% (GRADE moderate to low). Clinically relevant treatment benefits of NIs were small in healthy adults and children suffering from influenza-like illness (GRADE high to moderate). Oseltamivir reduced antibiotic usage in healthy adults according to one SR, but this was not confirmed by other reviews (GRADE low). Zanamivir showed a preventive effect on antibiotic usage in children (95% (77-99);GRADE moderate) and on the occurrence of bronchitis in at-risk individuals (59% (30-76);GRADE moderate). No evidence was available on the treatment benefits of NIs in elderly and at-risk groups and their effects on hospitalization and mortality. In oseltamivir trials, nausea, vomiting and diarrhea were significant side-effects. For zanamivir trials, no adverse effects have been reported. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of oseltamivir or zanamivir for the prophylaxis and treatment of healthy individuals. No relevant benefits of these NIs on complications in at-risk individuals have been established.

Antimicrobial resistance is a global health threat. Many children with acute illness in ambulatory care are unnecessarily prescribed antibiotics. We assessed the clinical effectiveness of a clinical decision tool for these children, including a validated decision tree, guided point-of-care C-reactive protein testing (POCT of CRP), and safety-netting advice. ARON was a multicentre, unblinded, pragmatic, cluster-randomised, controlled trial conducted at eligibile Belgian general practitioner and community paediatrician practices able to recruit children with acute illness consecutively, and not already doing POCT of CRP. Practices were allocated (1:1) with equal size (n=4) block randomisation to the clinical decision tool or usual care, stratified by recruiting academic centre. Children with acute illness aged 6 months to 12 years were recruited and followed up for 30 days. The coprimary outcomes were antibiotic prescribing at the index consultation (tested for superiority), as well as recovery time, additional testing, follow-up visits, and antibiotic prescribing after index consultation (all tested for non-inferiority with margins of 1 day, 3%, 4%, and 2%, respectively). Coprimary outcomes were analysed with logistic regression, accounting for practice clustering, study arm, and age in the intention-to-treat population, except recovery time, which was analysed with Cox regression adjusting for the same covariates. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT04470518) and is completed. Of 171 eligible practices, we randomly allocated 82 to the intervention group and 89 to the usual care group. Between Feb 24, 2021, and Dec 29, 2023, 7049 participants were screened, of whom 6760 were deemed eligible. Five patients in each study arm were excluded, so we analysed data from 6750 participants (2988 in the intervention group and 3762 in the control group; 3447 [51%] boys, 3302 [49%] girls, one [<1%] did not specify). The intervention significantly reduced antibiotic prescribing at the index consultation (466 [16%] vs 817 [22%], adjusted odds ratio 0·72 [95% CI 0·55–0·94]; p=0·017). Recovery time (adjusted mean difference –0·1 day [95% CI –0·5 to 0·3]), additional testing (adjusted absolute risk reduction [aARR] 2·0% [–1·7 to 5·0]), follow-up visits (aARR 2·8% [–0·9 to 6·1]), and antibiotic prescribing after index consultation (aARR 2·4% [0·2 to 4·2]) were all non-inferior in the intervention group versus the control group. 90 (88%) of 102 adverse events were serious (30 [1%] in the intervention group and 60 [2%] in the control group); none were deemed related to the study procedures. No child died throughout the trial. The clinical decision tool reduced antibiotic prescribing in children without causing harm. Our results support its broader dissemination and implementation to improve the management of acutely ill children in ambulatory care. Belgian Health Care Knowledge Centre.

Resistance to antibiotics is a major public-health problem, and studies that link antibiotic use and resistance have shown an association but not a causal effect. We used the macrolides azithromycin and clarithromycin to investigate the direct effect of antibiotic exposure on resistance in the oral streptococcal flora of healthy volunteers. Volunteers were treated with azithromycin (n=74), clarithromycin (74), or placebo (76) in a randomised, double-blind trial. Pharyngeal swabs were obtained before and after administration of study treatment through 180 days. The proportion of streptococci that were macrolide resistant was assessed and the molecular basis of any change in resistance investigated. Analyses were done on an intent-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00354952. The number of dropouts (n=20) was much the same in all groups until day 42; dropouts increased substantially at day 180 (105). Both macrolides significantly increased the proportion of macrolide-resistant streptococci compared with the placebo at all points studied, peaking at day 8 in the clarithromycin group (mean increase 50·0%, 95% CI 41·7–58·2; p<0·0001) and at day 4 in the azithromycin group (53·4%, 43·4–63·5; p<0·0001). The proportion of macrolide-resistant streptococci was higher after azithromycin treatment than after clarithromycin use, with the largest difference between the two groups at day 28 (17·4% difference, 9·2–25·6; p<0·0001). Use of clarithromycin, but not of azithromycin, selected for the erm(B) gene, which confers high-level macrolide resistance. This study shows that, notwithstanding the different outcomes of resistance selection, macrolide use is the single most important driver of the emergence of macrolide resistance in vivo. Physicians prescribing antibiotics should take into account the striking ecological side-effects of such antibiotics.

Background COVID-19 vaccine effectiveness declines months after vaccination. Therefore, it is likely that during the next few years, people may be repeatedly offered a booster vaccine to enhance humoral immunity levels. A growing number of people are questioning whether the benefits of a booster vaccine outweigh the side-effects. Objective This study aims (1) to identify the most frequently reported side-effects after different doses of COVID-19 mRNA vaccines, (2) and the longest lasting symptoms; and (3) to predict the likelihood of having moderate-to-severe side-effects after a booster COVID-19 mRNA vaccine given individual- and vaccine-specific characteristics. Design, setting, and participants Secondary analysis of a prospective cohort study in primary health care providers (PHCPs) in Belgium conducted between December 2020 and December 2021, and in February-March 2023. Methods In nine subsequent surveys over a period of 2 years vaccine dose-number and side-effects after COVID-19 vaccines were collected. A Generalized Estimation Equations approach on the data of the first and second booster dose was used to investigate the probability of having moderate-to-severe side-effects after mRNA booster vaccination. Predictive performance of a binary classifier was assessed by looking at discrimination (i.e., quantified in terms of the area under the receiver operating characteristic curve). The final prediction model was validated using data with regard to the third booster by assessing misclassification rate, sensitivity and specificity. Results In total, 11% of the PHCPs had moderate-to-severe side-effects after their booster COVID-19 mRNA vaccine. The most common side-effects of COVID-19 mRNA doses included fatigue, local pain at the injection site, general pains, and headache. These side-effects typically lasted for a median of 1 to 2 days. The final model included five predictors: sex, alcohol consumption, history of moderate-to-severe side-effects after any previous dose, recent COVID-19 infection, and the booster dose-number (first, second). Having experienced moderate-to-severe side-effects after any previous dose was the strongest predictor of moderate-to-severe side-effects following an mRNA vaccine booster, with an odds ratio (OR) of 3.64 (95% CI: 2.80–4.75). The OR for female sex was 1.49 (95% CI: 1.21–1.84) implying that females have a higher odds of moderate-to-severe side-effects following booster vaccination. The differences in effect for booster dose-number, alcohol consumption and recent COVID-19 infection was not significant. Conclusion and relevance COVID-19 mRNA booster vaccination implies a low prevalence of moderate-to-severe side-effects among PHCPs, with a short median duration of symptoms if any. The strongest predictors are a history of moderate-to-severe side-effects after any previous dose and being female. These reassuring findings can help addressing concerns about booster vaccination and encourage their uptake. Trial Registration NCT04779424 (registration date: 2021-02-22).

Preterm birth is one of the most common obstetric complications in low- and middle-income countries, where access to advanced diagnostic tests and imaging is limited. Therefore, we developed and validated a simplified risk prediction tool to predict preterm birth based on easily applicable and routinely collected characteristics of pregnant women in the primary care setting. We used a logistic regression model to develop a model based on the data collected from 481 pregnant women. Model accuracy was evaluated through discrimination (measured by the area under the Receiver Operating Characteristic curve; AUC) and calibration (via calibration graphs and the Hosmer–Lemeshow goodness of fit test). Internal validation was performed using a bootstrapping technique. A simplified risk score was developed, and the cut-off point was determined using the “Youden index” to classify pregnant women into high or low risk for preterm birth. The incidence of preterm birth was 19.5% (95% CI:16.2, 23.3) of pregnancies. The final prediction model incorporated mid-upper arm circumference, gravidity, history of abortion, antenatal care, comorbidity, intimate partner violence, and anemia as predictors of preeclampsia. The AUC of the model was 0.687 (95% CI: 0.62, 0.75). The calibration plot demonstrated a good calibration with a p -value of 0.713 for the Hosmer–Lemeshow goodness of fit test. The model can identify pregnant women at high risk of preterm birth. It is applicable in daily clinical practice and could contribute to the improvement of the health of women and newborns in primary care settings with limited resources. Healthcare providers in rural areas could use this prediction model to improve clinical decision-making and reduce obstetrics complications.

Colistin serves as the last line of defense against multidrug resistant Gram-negative bacterial infections in both human and veterinary medicine. This study aimed to investigate the occurrence and spread of colistin-resistant Enterobacterales (ColR-E) using a One Health approach in Belgium and in the Netherlands. In a transnational research project, a total of 998 hospitalized patients, 1430 long-term care facility (LTCF) residents, 947 children attending day care centres, 1597 pigs and 1691 broilers were sampled for the presence of ColR-E in 2017 and 2018, followed by a second round twelve months later for hospitalized patients and animals. Colistin treatment incidence in livestock farms was used to determine the association between colistin use and resistance. Selective cultures and colistin minimum inhibitory concentrations (MIC) were employed to identify ColR-E. A combination of short-read and long-read sequencing was utilized to investigate the molecular characteristics of 562 colistin-resistant isolates. Core genome multi-locus sequence typing (cgMLST) was applied to examine potential transmission events. The presence of ColR-E was observed in all One Health sectors. In Dutch hospitalized patients, ColR-E proportions (11.3 and 11.8% in both measurements) were higher than in Belgian patients (4.4 and 7.9% in both measurements), while the occurrence of ColR-E in Belgian LTCF residents (10.2%) and children in day care centres (17.6%) was higher than in their Dutch counterparts (5.6% and 12.8%, respectively). Colistin use in pig farms was associated with the occurrence of colistin resistance. The percentage of pigs carrying ColR-E was 21.8 and 23.3% in Belgium and 14.6% and 8.9% in the Netherlands during both measurements. The proportion of broilers carrying ColR-E in the Netherlands (5.3 and 1.5%) was higher compared to Belgium (1.5 and 0.7%) in both measurements. mcr-harboring E. coli were detected in 17.4% (31/178) of the screened pigs from 7 Belgian pig farms. Concurrently, four human-related Enterobacter spp. isolates harbored mcr-9.1 and mcr-10 genes. The majority of colistin-resistant isolates (419/473, 88.6% E. coli; 126/166, 75.9% Klebsiella spp.; 50/75, 66.7% Enterobacter spp.) were susceptible to the critically important antibiotics (extended-spectrum cephalosporins, fluoroquinolones, carbapenems and aminoglycosides). Chromosomal colistin resistance mutations have been identified in globally prevalent high-risk clonal lineages, including E. coli ST131 (n = 17) and ST1193 (n = 4). Clonally related isolates were detected in different patients, healthy individuals and livestock animals of the same site suggesting local transmission. Clonal clustering of E. coli ST10 and K. pneumoniae ST45 was identified in different sites from both countries suggesting that these clones have the potential to spread colistin resistance through the human population or were acquired by exposure to a common (food) source. In pig farms, the continuous circulation of related isolates was observed over time. Inter-host transmission between humans and livestock animals was not detected. The findings of this study contribute to a broader understanding of ColR-E prevalence and the possible pathways of transmission, offering insights valuable to both academic research and public health policy development.

Objective: To assess the quality of antibiotic prescribing in primary care in Belgium, the Netherlands and Sweden using European disease-specific antibiotic prescribing quality indicators (APQI) and taking into account the threshold to consult and national guidelines. Design: A retrospective observational database study. Setting: Routine primary health care registration networks in Belgium, the Netherlands and Sweden. Subjects: All consultations for one of seven acute infections [upper respiratory tract infection (URTI), sinusitis, tonsillitis, otitis media, bronchitis, pneumonia and cystitis] and the antibiotic prescriptions in 2012 corresponding to these diagnoses. Main outcome measures: Consultation incidences for these diagnoses and APQI values (a) the percentages of patients receiving an antibiotic per diagnosis, (b) the percentages prescribed first-choice antibiotics and (c) the percentages prescribed quinolones. Results: The consultation incidence for respiratory tract infection was much higher in Belgium than in the Netherlands and Sweden. Most of the prescribing percentage indicators (a) were outside the recommended ranges, with Belgium deviating the most for URTI and bronchitis, Sweden for tonsillitis and the Netherlands for cystitis. The Netherlands and Sweden prescribed the recommended antibiotics (b) to a higher degree and the prescribing of quinolones exceeded the proposed range for most diagnoses (c) in Belgium. The interpretation of APQI was found to be dependent on the consultation incidences. High consultation incidences were associated with high antibiotic prescription rates. Taking into account the recommended treatments from national guidelines improved the results of the APQI values for sinusitis in the Netherlands and cystitis in Sweden. Conclusion: Quality assessment using European disease-specific APQI was feasible and their inter-country comparison can identify opportunities for quality improvement. Their interpretation, however, should take consultation incidences and national guidelines into account. Differences in registration quality might limit the comparison of diagnosis-linked data between countries, especially for conditions such as cystitis where patients do not always see a clinician before treatment. Key points The large variation in antibiotic use between European countries points towards quality differences in prescribing in primary care.  * The European disease-specific antibiotic prescribing quality indicators (APQI) provide insight into antibiotic prescribing, but need further development, taking into account consultation incidences and country-specific guidelines.  * The incidence of consultations for respiratory tract infections was almost twice as high in Belgium compared to the Netherlands and Sweden.  * Comparison between countries of diagnosis-linked data were complicated by differences in data collection, especially for urinary tract infections.