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Background The use of antibiotics is a key driver of antimicrobial resistance and is considered a major threat to global health. In Denmark, approximately 75% of antibiotic prescriptions are issued in general practice, with acute lower respiratory tract infections (LRTIs) being one of the most common indications. Adults who present to general practice with symptoms of acute LRTI often suffer from self-limiting viral infections. However, some patients have bacterial community-acquired pneumonia (CAP), a potential life-threatening infection, that requires immediate antibiotic treatment. Importantly, no single symptom or specific point-of-care test can be used to discriminate the various diagnoses, and diagnostic uncertainty often leads to (over)use of antibiotics. At present, general practitioners (GPs) lack tools to better identify those patients who will benefit from antibiotic treatment. The primary aim of the PLUS-FLUS trial is to determine whether adults who present with symptoms of an acute LRTI in general practice and who have FLUS performed in addition to usual care are treated less frequently with antibiotics than those who only receive usual care. Methods Adults (≥ 18 years) presenting to general practice with acute cough (< 21 days) and at least one other symptom of acute LRTI, where the GP suspects a bacterial CAP, will be invited to participate in this pragmatic randomized controlled trial. All participants will receive usual care. Subsequently, participants will be randomized to either the control group (usual care) or to an additional focused lung ultrasonography performed by the GP (+ FLUS). The primary outcome is the proportion of participants with antibiotics prescribed at the index consultation (day 0). Secondary outcomes include comparisons of the clinical course for participants in groups. Discussion We will examine whether adults who present with symptoms of acute LRTI in general practice, who have FLUS performed in addition to usual care, have antibiotics prescribed less frequently than those given usual care alone. It is highly important that a possible reduction in antibiotic prescriptions does not compromise patients’ recovery or clinical course, which we will assess closely. Trial registration ClinicalTrials.gov NCT06210282. Registered on January 17, 2024.

Background Lower respiratory tract infections (LRTIs) are among the most frequent infections and a significant contributor to inappropriate antibiotic prescription. Currently, no single diagnostic tool can reliably identify bacterial pneumonia. We thus evaluate a multimodal approach based on a clinical score, lung ultrasound (LUS), and the inflammatory biomarker, procalcitonin (PCT) to guide prescription of antibiotics. LUS outperforms chest X-ray in the identification of pneumonia, while PCT is known to be elevated in bacterial and/or severe infections. We propose a trial to test their synergistic potential in reducing antibiotic prescription while preserving patient safety in emergency departments (ED). Methods The PLUS-IS-LESS study is a pragmatic, stepped-wedge cluster-randomized, clinical trial conducted in 10 Swiss EDs. It assesses the PLUS algorithm, which combines a clinical prediction score, LUS, PCT, and a clinical severity score to guide antibiotics among adults with LRTIs, compared with usual care. The co-primary endpoints are the proportion of patients prescribed antibiotics and the proportion of patients with clinical failure by day 28. Secondary endpoints include measurement of change in quality of life, length of hospital stay, antibiotic-related side effects, barriers and facilitators to the implementation of the algorithm, cost-effectiveness of the intervention, and identification of patterns of pneumonia in LUS using machine learning. Discussion The PLUS algorithm aims to optimize prescription of antibiotics through improved diagnostic performance and maximization of physician adherence, while ensuring safety. It is based on previously validated tests and does therefore not expose participants to unforeseeable risks. Cluster randomization prevents cross-contamination between study groups, as physicians are not exposed to the intervention during or before the control period. The stepped-wedge implementation of the intervention allows effect calculation from both between- and within-cluster comparisons, which enhances statistical power and allows smaller sample size than a parallel cluster design. Moreover, it enables the training of all centers for the intervention, simplifying implementation if the results prove successful. The PLUS algorithm has the potential to improve the identification of LRTIs that would benefit from antibiotics. When scaled, the expected reduction in the proportion of antibiotics prescribed has the potential to not only decrease side effects and costs but also mitigate antibiotic resistance. Trial registration This study was registered on July 19, 2022, on the ClinicalTrials.gov registry using reference number: NCT05463406. Trial status Recruitment started on December 5, 2022, and will be completed on November 3, 2024. Current protocol version is version 3.0, dated April 3, 2023.

ObjectivesWe aimed to explore the acceptance and opinions of general practitioners (GPs) on the use of procalcitonin point-of-care and lung ultrasonography for managing patients with lower respiratory tract infections in primary care. We suppose that there are several factors that can influence the physician’s antibiotic prescribing decision, and the implementation of a new tool will only be possible when it can be inserted into the physician’s daily practice, helping him/her in the decision-making process.DesignSemistructured interviews; data analysis using the grounded theory method.SettingLausanne, Switzerland.Participants12 GPs who participated in the randomised clinical trial UltraPro, which evaluated the impact of the use of procalcitonin only or an algorithm combining procalcitonin and lung ultrasonography on antibiotic prescription.ResultsGPs had mostly positive attitudes towards the use of point-of-care procalcitonin in lower respiratory tract infections and uncertainties regarding the usefulness of ultrasonography. Physicians’ prescribing decisions result from interactions between three kinds of TrustS (core category): ‘self-confidence’, ‘trust in the results’ and ‘trust in the doctor–patient relationship’. Procalcitonin reinforced the three levels of trust, while ultrasonography only strengthened the physician–patient relationship. To facilitate implementation of procalcitonin, physicians pointed out the need of coverage by insurance and of clear guidelines describing the targeted patient population.ConclusionsOur data show that there is a preference for the implementation of procalcitonin rather than lung ultrasonography for the management of patients with lower respiratory tract infections in primary care. Coverage by insurance plans and updated guidelines are prerequisite to the successful implementation of procalcitonin testing in primary care.Trial Registration numberNCT03191071

There is high usage of antibiotics in the emergency department (ED) for children with acute respiratory illnesses. Studies have reported decreased antibiotic use among inpatients with rapid respiratory pathogen (RRP) testing. To determine whether RRP testing leads to decreased antibiotic use and health care use among children with influenzalike illness (ILI) in an ED. A randomized clinical trial among children aged 1 month to 18 years presenting to an ED with ILI from December 1, 2018, to November 30, 2019, was conducted. Data were analyzed March 23, 2020, to April 2, 2021. All children received a nasopharyngeal swab for RRP testing and were randomized 1:1 to the intervention group or control group (results not given, routine clinical care). Results were available in 45 minutes. Intention-to-treat analyses and modified intention-to-treat (clinician knows results) analyses were conducted using multivariable Poisson regression. Rapid respiratory pathogen test results given to clinicians. Antibiotic prescribing was the primary outcome; influenza antiviral prescribing, ED length of stay, hospital admission, and recurrent health care visits were the secondary outcomes. Among 931 ED visits (intervention group, 452 children group and control group, 456 children after exclusion of those not meeting criteria or protocol violations), a total of 795 RRP test results (85%) were positive. The median age of the children was 2.1 years (interquartile range, 0.9-5.6 years); 509 (56%) were boys. Most children (478 [53%]) were Hispanic, 688 children (76%) received government insurance, and 314 (35%) had a high-risk medical condition. In the intention-to-treat intervention group, children were more likely to receive antibiotics (relative risk [RR], 1.3; 95% CI, 1.0-1.7), with no significant differences in antiviral prescribing, medical visits, and hospitalization. In inverse propensity-weighted modified intention-to-treat analyses, children with test results known were more likely to receive antivirals (RR, 2.6; 95% CI, 1.6-4.5) and be hospitalized (RR, 1.8; 95% CI, 1.4-2.5); there was no significant difference in antibiotic prescribing (RR, 1.1; 95% CI, 0.9-1.4). The use of RRP testing in the ED for ILI did not decrease antibiotic prescribing in this randomized clinical trial. There is a limited role for RRP pathogen testing in children in this setting. ClinicalTrials.gov Identifier: NCT03756753.

ObjectiveCharacterise lung ultrasound (LUS) findings, diagnostic accuracy and agreement between novice and expert interpretations in young children with respiratory tract infections and wheeze.MethodsProspective cross-sectional study in a paediatric ED. Patients ≤2 years with a respiratory tract infection and wheeze at triage were recruited unless in severe respiratory distress. Prior to clinical management, a novice sonologist performed the LUS using a six-zone scanning protocol. The treating physician remained blinded to ultrasound findings; final diagnoses were extracted from the medical record. An expert sonologist, blinded to all clinical information, assessed the ultrasound video clips at study completion. Positive LUS was defined as the presence of ≥1 of the following findings: ≥3 B-lines per intercostal space, consolidation and/or pleural abnormalities.ResultsNinety-four patients were enrolled (median age 11.1 months). LUS was positive in 42% (39/94) of patients (multiple B-lines in 80%, consolidation in 64%, pleural abnormalities in 23%). The proportion of positive LUS, along with their diagnostic accuracy (sensitivity (95% CI), specificity (95% CI)), were as follows for children with bronchiolitis, asthma, pneumonia and asthma/pneumonia: 46% (45.8% (34.0% to 58.0%), 72.7% (49.8% to 89.3%)), 0% (0% (0.0% to 23.3%), 51.3% (39.8% to 62.6%)), 100% (100% (39.8% to 100.0%), 61.1% (50.3% to 71.2%)), 50% (50% (6.8% to 93.2%), 58.9% (48.0% to 69.2%)), respectively. There was good agreement between the novice and expert sonographers for a positive LUS (kappa 0.68 (95% CI 0.54 to 0.82)).ConclusionsAmong children with respiratory tract infections and wheeze, a positive LUS seems to distinguish between clinical syndromes by ruling in pneumonia and ruling out asthma. If confirmed in future studies, LUS may emerge as a point-of-care tool to guide diagnosis and disposition in young children with wheeze.

Background A minority of patients presenting with lower respiratory tract infection (LRTI) to their general practitioner (GP) have community-acquired pneumonia (CAP) and require antibiotic therapy. Identifying them is challenging, because of overlapping symptomatology and low diagnostic performance of chest X-ray. Procalcitonin (PCT) can be safely used to decide on antibiotic prescription in patients with LRTI. Lung ultrasound (LUS) is effective in detecting lung consolidation in pneumonia and might compensate for the lack of specificity of PCT. We hypothesize that combining PCT and LUS, available as point-of care tests (POCT), might reduce antibiotic prescription in LRTIs without impacting patient safety in the primary care setting. Methods This is a three-arm pragmatic cluster randomized controlled clinical trial. GPs are randomized either to PCT and LUS-guided antibiotic therapy or to PCT only-guided therapy or to usual care. Consecutive adult patients with an acute cough due to a respiratory infection will be screened and included if they present a clinical pneumonia as defined by European guidelines. Exclusion criteria are previous antibiotics for the current episode, working diagnosis of sinusitis, severe underlying lung disease, severe immunosuppression, hospital admission, pregnancy, inability to provide informed consent and unavailability of the GP. Patients will fill in a 28 day-symptom diary and will be contacted by phone on days 7 and 28. The primary outcome is the proportion of patients prescribed any antibiotic up to day 28. Secondary outcomes include clinical failure by day 7 (death, admission to hospital, absence of amelioration or worsening of relevant symptoms) and by day 28, duration of restricted daily activities, episode duration as defined by symptom score, number of medical visits, number of days with side effects due to antibiotics and a composite outcome combining death, admission to hospital and complications due to LRTI by day 28. An evaluation of the cost-effectiveness and of processes in the clinic using a mixed qualitative and quantitative approach will also be conducted. Discussion Our intervention targets only patients with clinically suspected CAP who have a higher pretest probability of definite pneumonia. The intervention will not substitute clinical assessment but completes it by introducing new easy-to-perform tests. Trial registration The study was registered on the 19th of June 2017 on the clinicaltrials.gov registry using reference number; NCT03191071 .

Background Infants with cystic fibrosis (CF) develop early progressive lung disease which may be asymptomatic. Infant pulmonary function tests (IPFT) and controlled ventilation-high resolution computed tomography (CV-HRCT) of chest can detect early asymptomatic lung disease. It is not well established that these objective measures can detect changes in lung disease after clinical interventions. Objective The purpose of this study was to evaluate usefulness of IPFT and CV-HRCT to detect changes in lung disease after intravenous (IV) antibiotic therapy in infants with early CF-related lung disease. Study Design IPFTs and CV-HRCT done before and after 2 weeks of IV antibiotics in infants at our institution over the last 12 years were compared. CV-HRCTs were compared using the modified Brody scoring system. Results The sample included 21 infants, mean age 85.2 ± 47.6 weeks. Mean change in weight was 0.4 ± 0.38 kg ( p  = 0.001). Significant changes in IPFT included mean % predicted FEV 0.5 (+13.5 %, p  = 0.043), mean %FEF 25–75 (+30.2 %, p  = 0.008), mean %RV/TLC (−11.2 %, p  = 0.008), and mean %FRC/TLC (−4.5 %, p  = 0.001). Total Brody scores improved from a median of 10 to 5 ( p  < 0.001) as did mean scores for airway wall thickening ( p  = 0.050), air trapping ( p  < 0.001), and parenchymal opacities ( p  = 0.003). Conclusion IPFT and CV-HRCT can be used as objective measures of improvement in lung disease for infants with CF treated with antibiotics.

Background The depth of lung consolidation (≥ 1 and ≥ 3 cm) on thoracic ultrasonography (TUS) is increasingly used as a criterion for antimicrobial treatment. However, its association with bacterial infections remains unclear. Objectives To investigate the associations of clinical and ultrasonographic findings, particularly consolidation depth, with opportunistic bacterial infections (OBI), viral infections, or Mycoplasma bovis (also known as Mycoplasmopsis bovis) infections. Different definitions of OBI were explored, based on various combinations of bacterial species, with or without a neutrophilic profile on cytology. Animals Eighty‐six group‐housed calves with at least one clinical sign of respiratory disease from 19 herds experiencing a respiratory epidemic. Methods Cross‐sectional study. A physical examination, TUS, and non‐bronchoscopic bronchoalveolar lavage were performed. The definitions of OBI were based on semi‐quantitative culture results and cytology. Results Calves with consolidations of ≥ 0.5 cm had higher odds of having an OBI considering most definitions, on M. bovis isolation (odds ratio [OR] = 57.3; 95% confidence interval [CI] = 1.5–2300; p = 0.03) and isolation of a bacterial agent in general (OR = 15.5; 95% CI = 2.3–100; p = 0.01). Animals with consolidation ≥ 1 cm had higher odds of OBI considering all definitions, virus isolation (OR = 15.6; 95% CI = 1.0–240; p = 0.05) and isolation of a bacterial agent in general (OR = 6.9; 95% CI = 1.7–28; p = 0.01). Consolidation ≥ 3 cm, cough, and the California score were not significantly associated with OBI, M. bovis, or both. Conclusion In herds experiencing a respiratory epidemic, consolidation depths ≥ 0.5 and ≥ 1 cm might indicate respiratory disease with a bacterial component.

BACH2 is required for lymphocyte differentiation. Afzali et al . describe mutations that cause BACH2 disruption, immunodeficiency and autoinflammatory disease via haploinsufficiency, a mechanism shared by other super-enhancer-regulated genes. The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2 -heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.

Background Thoracic ultrasonography (TUS) could improve antibiotic treatment selection in cattle with respiratory diseases. Hypothesis/Objectives Evaluate the association between respiratory pathogens and consolidations on TUS in feedlot cattle, at both individual and group levels. Animals A total of 221 bulls, aged 8.8 months and weighing 322.5 ± 160 kg, from nine farms. Methods Cross‐sectional study including all data from clinical examinations and TUS collected weekly during the first month on feed. Pathogens were assessed by seroconversion (all animals) and qPCR on nasal swabs (sick animals). At the individual level, the association between pathogen detection and TUS consolidation was investigated using univariate logistic regression, and the ability of consolidation size to differentiate bacterial from non‐bacterial pneumonia was assessed using receiver operating characteristic curves. Principal component analysis identified clusters at the group level based on pathogen detection and TUS results. Results At the individual level, bulls infected with multiple pathogens (odds ratio [OR], 8.1; 95% confidence interval [CI], 2.21–29.8) or a single virus (OR, 5.49; 95% CI, 1.42–21.3) were more likely to have consolidations than those not infected. A total consolidation size > 14 cm2 in the scanned thoracic region differentiated bacterial from non‐bacterial pneumonia with a sensitivity of 47.8% (95% CI, 36.4–83.3) and specificity of 94.1% (95% CI, 60.0–100.0). These results were consistent at the group level; clustering based on bacterial versus non‐bacterial etiology correlated with the number and size of consolidations. Conclusions and Clinical Importance Consolidation size could help differentiate bacterial from non‐bacterial pneumonia, guiding treatment at both individual and group levels.