Variation in antibiotic consumption in very preterm infants-a 10 year population-based study.

OBJECTIVES: Wide variations in antibiotic use in very preterm infants have been reported across centres despite similar rates of infection. We describe 10 year trends in use of antibiotics and regional variations among very preterm infants in Norway. PATIENTS AND METHODS: All live-born very preterm infants (<32 weeks gestation) admitted to any neonatal unit in Norway during 2009-18 were included. Main outcomes were antibiotic consumption expressed as days of antibiotic therapy (DOT) per 1000 patient days (PD), regional variations in use across four health regions, rates of sepsis and sepsis-attributable mortality and trends of antibiotic use during the study period. RESULTS: We included 5296 infants: 3646 (69%) were born at 28-31 weeks and 1650 (31%) were born before 28 weeks gestation with similar background characteristics across the four health regions. Overall, 80% of the very preterm infants received antibiotic therapy. The most commonly prescribed antibiotics were the combination of narrow-spectrum ß-lactams and aminoglycosides, but between 2009 and 2018 we observed a marked reduction in their use from 100 to 40 DOT per 1000 PD (P < 0.001). In contrast, consumption of broad-spectrum ß-lactams remained unchanged (P = 0.308). There were large variations in consumption of vancomycin, broad-spectrum ß-lactams and first-generation cephalosporins, but no differences in sepsis-attributable mortality across regions. CONCLUSIONS: The overall antibiotic consumption was reduced during the study period. Marked regional variations remained in consumption of broad-spectrum ß-lactams and vancomycin, without association to sepsis-attributable mortality. Our results highlight the need for antibiotic stewardship strategies to reduce consumption of antibiotics that may enhance antibiotic resistance development.

Blood eosinophils during bronchiolitis: Associations with atopy, asthma and lung function in young adults.

AIM: To study if blood eosinophils during bronchiolitis were associated with atopy, asthma and lung function in young adults and if these associations differed between respiratory syncytial virus (RSV) bronchiolitis and non-RSV bronchiolitis. METHODS: This historical cohort enrolled 225 subjects. Blood eosinophils were measured during bronchiolitis in infancy, and the subjects were invited to a follow-up at 17-20 years of age including questionnaires for asthma and examinations of lung function and atopy. RESULTS: The level of eosinophils was positively associated with subsequent atopy in the unadjusted analysis, but not in the adjusted analysis, and not with asthma. There was a negative association between the level of eosinophils and forced vital capacity (FVC) (-0.11; -0.19, -0.02) and forced expiratory volume in first second (FEV1 ) (-0.12; -0.21, -0.03) (regression coefficient; 95% confidence interval). The non-RSV group had higher levels of eosinophils during bronchiolitis, but there was no interaction between the level of eosinophils and RSV status for any outcome. CONCLUSIONS: The level of eosinophils during bronchiolitis was negatively associated with lung function in young adult age, but we found no associations with atopy or asthma. These associations were not different after RSV bronchiolitis compared to non-RSV bronchiolitis.

[Regional differences in the use of proton pump inhibitors in children]. / Regionale forskjeller i bruk av protonpumpehemmere hos barn.

BACKGROUND: Physiological gastroesophageal reflux in infancy is difficult to distinguish from reflux disease. International guidelines recommend restrictive use of acid suppression therapy for infants due to the lack of documented effect, but its use in infants and older children has increased in recent years. This study aims to describe change over time and geographic variation in the investigation and treatment of suspected gastroesophageal reflux disease. MATERIAL AND METHOD: In aggregated data from the Norwegian Prescribed Drug Registry for the period 1.1.2007-31.12.2020, we examined regional differences in the number of proton pump inhibitors dispensed for children and adolescents. Data from the Norwegian Patient Registry were analysed to identify the use of 24-hour pH measurement and gastroscopy, which can support the suspicion of gastroesophageal reflux disease. RESULTS: The number of proton pump inhibitors dispensed in the first year of life increased and was highest in South-Eastern Norway Regional Health Authority, with 10.1 per 1000 children in 2007 and 54.7 per 1000 children in 2020 (relative risk 5.4, 95 % confidence interval 4.6 to 6.4). The number dispensed in 2020 was 64 % higher in South-Eastern Norway Regional Health Authority compared to Northern Norway Regional Health Authority and Central Norway Regional Health Authority. There was little change in the number of gastroscopies, but use of 24-hour pH measurement fell by 52 % from 2016 to 2020. INTERPRETATION: Use of proton pump inhibitors in infants has increased considerably despite the guidelines. Together with geographic variation, this may point towards overtreatment of physiological reflux in infants. Few investigations indicate that an increasing proportion are treated without supporting diagnostics.

Tracking of lung function from 10 to 35 years after being born extremely preterm or with extremely low birth weight.

BACKGROUND: Lifelong pulmonary consequences of being born extremely preterm or with extremely low birth weight remain unknown. We aimed to describe lung function trajectories from 10 to 35 years of age for individuals born extremely preterm, and address potential cohort effects over a period that encompassed major changes in perinatal care. METHODS: We performed repeated spirometry in three population-based cohorts born at gestational age ≤28 weeks or with birth weight ≤1000 g during 1982-85, 1991-92 and 1999-2000, referred to as extremely preterm-born, and in term-born controls matched for age and gender. Examinations were performed at 10, 18, 25 and 35 years. Longitudinal data were analysed using mixed models regression, with the extremely preterm-born stratified by bronchopulmonary dysplasia (BPD). RESULTS: We recruited 148/174 (85%) eligible extremely preterm-born and 138 term-born. Compared with term-born, the extremely preterm-born had lower z-scores for forced expiratory volume in 1 s (FEV1) at most assessments, the main exceptions were in the groups without BPD in the two youngest cohorts. FEV1 trajectories were largely parallel for the extremely preterm- and term-born, also during the period 25-35 years that includes the onset of the age-related decline in lung function. Extremely preterm-born had lower peak lung function than term-born, but z-FEV1 values improved for each consecutive decade of birth (p=0.009). More extremely preterm-than term-born fulfilled the spirometry criteria for chronic obstructive pulmonary disease, 44/148 (30%) vs 7/138 (5%), p<0.001. CONCLUSIONS: Lung function after extremely preterm birth tracked in parallel, but significantly below the trajectories of term-born from 10 to 35 years, including the incipient age-related decline from 25 to 35 years. The deficits versus term-born decreased with each decade of birth from 1980 to 2000.

Cerebrospinal fluid cytokines and chemokines in children with Lyme neuroborreliosis; pattern and diagnostic utility.

BACKGROUND: Lyme neuroborreliosis (LNB) is characterized by cerebrospinal fluid (CSF) inflammation with several cytokines/chemokines and B-lymphocytes. Clinically, LNB in children may be difficult to discriminate from non-Lyme aseptic meningitis (NLAM). We aimed to identify CSF cytokine/chemokine patterns in children with LNB, NLAM and controls and elucidate the diagnostic value of these cytokines/chemokines alone or in combination to discriminate between LNB and NLAM. METHODS: Children with symptoms suggestive of LNB were included prospectively and categorized as LNB, NLAM or controls (no pleocytosis). Cytokines/chemokines in CSF were measured by multiplex bead assays and levels were compared between the three groups by nonparametric statistical tests. Previous results from the same children on the established biomarker, CXCL13, were included in the statistical analyses. The diagnostic properties of cytokines/chemokines to discriminate between LNB and NLAM were determined by receiver operating characteristic curve analyses with estimates of area under curve (AUC). To explore diagnostic properties of combinations of cytokines/chemokines, prediction models based on logistic regression were used. RESULTS: We included 195 children with LNB (n = 77), NLAM (n = 12) and controls (n = 106). Children with LNB had higher CSF levels of CCL19, CCL22 and CXCL13 compared to NLAM and controls, whereas INFγ was higher in NLAM than in LNB and controls. CXCL13 was the superior single cytokine/chemokine to discriminate LNB from NLAM (AUC 0.978). The combination CXCL13/CCL19 (AUC 0.992) may possibly improve the specificity for LNB, especially for children with moderate CXCL13 levels. CONCLUSIONS: The intrathecal immune reaction in LNB is characterized by B cell associated chemokines. Whether the combination CXCL13/CCL19 further improves discrimination between LNB and NLAM beyond the diagnostic improvements by CXCL13 alone needs to be tested in new studies.

Lung function and bronchial hyper-reactivity from 11 to 18 years in children with bronchiolitis in infancy.

BACKGROUND: Various trajectories for lung function and bronchial hyper-reactivity (BHR) from early childhood to adulthood are described, including puberty as a period with excessive lung growth. Bronchiolitis in infancy may be associated with increased risk of developing chronic obstructive pulmonary disease, but the development of respiratory patterns during puberty is poorly characterized for these children. We aimed to study the development and trajectories of lung function and BHR from 11 to 18 years of age in children hospitalized for bronchiolitis in infancy. METHODS: Infants hospitalized for bronchiolitis at the University Hospitals in Stavanger and Bergen, Norway, during 1997-1998, and an age-matched control group, were included in a longitudinal follow-up study and examined at 11 and 18 years of age with spirometry and methacholine provocation test (MPT). The MPT data were managed as dose-response slope (DRS) in the statistical analyses. Changes in lung function and DRS from 11 to 18 years of age were analyzed by generalized estimating equations, including interaction terms. RESULTS: z-scores for forced vital capacity (FVC), forced expiratory volume in first second (FEV1 ), FEV1 /FVC ratio, and DRS were not different from 11 to 18 years of age in both the post-bronchiolitis and the control group. The trajectories from 11 to 18 years did not differ between the two groups. BHR at age 11 was independently associated with asthma at age 18. CONCLUSION: Children hospitalized for bronchiolitis had stable predicted lung function and BHR from 11 to 18 years of age. The lung function trajectories were not different from controls.

Half of children with recurrent or chronic wet cough before three years of age were symptom-free by age seven.

AIM: We aimed to study the natural course of recurrent episodic and chronic wet cough in preschool children, the proportion and age of resolution, and risk factors for persistent symptoms. METHODS: Parents of children with recurrent or chronic wet cough who had attended the outpatient clinic before the age of three years during 2010-2013 at Stavanger University Hospital, Norway, answered a questionnaire regarding clinical symptoms and current medication at a follow-up in 2017-2018. RESULTS: We invited 840 children to participate, and parents consented for 348 (41.4%) of the children. At the first outpatient visit, 171 children (58.8%) had recurrent episodic and 120 (41.2%) had chronic wet cough. At follow-up at a median age of 82 months, 57.0% in both groups were symptom-free, and 9.4% with episodic cough and 13.3% with chronic cough had more than mild symptoms. During the last 12 months prior to the survey, 27.2% with episodic cough and 18.6% with chronic cough had used inhaled corticosteroids. CONCLUSION: Half of the preschool children with recurrent episodic or chronic wet cough outgrew their symptoms by the median age of seven years, but one in four still used inhaled corticosteroids.

Health professionals' involvement of parents in decision-making in interprofessional practice at the hospital.

Health professionals have the responsibility of involving parents in decision-making regarding children's healthcare. This is to ensure that healthcare is customised to meet children's and families' needs and preferences. There is inadequate knowledge about health professionals' role in involving parents in these decisions in interprofessional practice in hospital settings. The aim of this study was to explore health professionals' construction of the phenomenon of parental involvement in decision-making about children's healthcare at the hospital and to identify how parental involvement can be improved. This explorative, descriptive qualitative study within a constructivist research paradigm selected a purposive sample of 12 health professionals who participated in individual semi-structured interviews. This qualitative data was used to construct a description of this phenomenon. The health professionals described ethical dilemmas and challenges related to parental involvement in decision-making while also providing technically safe, justifiable healthcare. Individual health professionals' involvement of parents in decision-making and the intra- and interprofessional collaboration between health professionals seemed to be of great importance to increase parents' active involvement in the co-production of children's healthcare. Further research is required to confirm the findings for generalisation.

Vortex Whistle and Smart Phone Application for Peak Flow Recordings in Asthmatic Children: A Feasibility Study.

Introduction: Variable airflow obstruction that can be confirmed by diurnal variability of peak expiratory flow (PEF) >13% is an important characteristic of asthma. Home monitoring of PEF may be helpful to diagnose and monitor asthma. In this feasibility study, we aimed to study if asthmatic children can measure PEF at home twice daily during a 4-week period using a device designed as a "whistle" and a smart phone software application.Materials and Methods: Twice daily during 4 weeks, children aged 5-12 years with current asthma rated their asthma condition electronically on the smart phone application Blowfish before inhaling deeply then exhaling into the device to produce a high-pitched sound recorded by the application. Through mathematical algorithms, the sound was transferred to PEF, which was uploaded to a server. At inclusion, the Pediatric Asthma Quality of Life Questionnaire and the Childhood Asthma Control Test were answered. At the end, the parents graded the device and application.Results: One child did not manage to upload PEF. For the remaining 21 children, the median (quartiles) days with at least one measurement during the period were 27 (21-29.5), and on median 18 (9-24) days PEF was recorded twice daily. The median parental score (potential score 0-20) of the application was 18 (15-20).Discussion/Conclusion: The study shows promising results for home monitoring of PEF by an electronic device with automatic teletransmission. The high rate of successful recordings and parental satisfaction suggests that the clinical utility of the solution should be further studied.

Direct Molecular Detection and Genotyping of Borrelia burgdorferi Sensu Lato in Cerebrospinal Fluid of Children with Lyme Neuroborreliosis.

The current diagnostic marker of Lyme neuroborreliosis (LNB), the Borrelia burgdorferisensu lato antibody index (AI) in the cerebrospinal fluid (CSF), has insufficient sensitivity in the early phase of LNB. We aimed to elucidate the diagnostic value of PCR for B. burgdorferisensu lato in CSF from children with symptoms suggestive of LNB and to explore B. burgdorferisensu lato genotypes associated with LNB in children. Children were prospectively included in predefined groups with a high or low likelihood of LNB based on diagnostic guidelines (LNB symptoms, CSF pleocytosis, and B. burgdorferisensu lato antibodies) or the detection of other causative agents. CSF samples were analyzed by two B. burgdorferisensu lato-specific real-time PCR assays and, if B. burgdorferisensu lato DNA was detected, were further analyzed by five singleplex real-time PCR assays for genotype determination. For children diagnosed as LNB patients (58 confirmed and 18 probable) (n = 76) or non-LNB controls (n = 28), the sensitivity and specificity of PCR for B. burgdorferisensu lato in CSF were 46% and 100%, respectively. B. burgdorferisensu lato DNA was detected in 26/58 (45%) children with AI-positive LNB and in 7/12 (58%) children with AI-negative LNB and symptoms of short duration. Among 36 children with detectable B. burgdorferisensu lato DNA, genotyping indicated Borrelia garinii (n = 27) and non-B. garinii (n = 1) genotypes, while 8 samples remained untyped. Children with LNB caused by B. garinii did not have a distinct clinical picture. The rate of detection of B. burgdorferisensu lato DNA in the CSF of children with LNB was higher than that reported previously. PCR for B. burgdorferisensu lato could be a useful supplemental diagnostic tool in unconfirmed LNB cases with symptoms of short duration. B. garinii was the predominant genotype in children with LNB.

The associations between weight-related anthropometrics during childhood and lung function in late childhood: a retrospective cohort study.

BACKGROUND: An association between body weight in childhood and subsequent lung function and asthma has been suggested, but few longitudinal studies exist. Our aim was to explore whether weight-related anthropometric measurements through childhood were associated with lung function in late childhood. METHODS: From an original nested case-control study, a cohort study was conducted, where lung function was measured in 463 children aged 12.8 years, and anthropometry was measured at several ages from birth through 12.8 years of age. Associations between anthropometrics and lung function were analysed using multiple linear and fractional polynomial regression analysis. RESULTS: Birthweight and body mass index (BMI; kg/m2) at different ages through childhood were positively associated with forced vital capacity in percent of predicted (FVC %) and forced expiratory volume in the first second in percent of predicted (FEV1%) at 12.8 years of age. BMI, waist circumference, waist-to-height ratio and skinfolds at 12.8 years of age and the change in BMI from early to late childhood were positively associated with FVC % and FEV1% and negatively associated with FEV1/FVC and forced expiratory flow at 25-75% of FVC/FVC. Interaction analyses showed that positive associations between anthropometrics other than BMI and lung function were mainly found in girls. Inverse U-shaped associations were found between BMI at the ages of 10.8/11.8 (girls/boys) and 12.8 years (both genders) and FVC % and FEV1% at 12.8 years of age. CONCLUSIONS: Weight-related anthropometrics through childhood may influence lung function in late childhood. These findings may be physiological or associated with air flow limitation. Inverse U-shaped associations suggest a differential impact on lung function in normal-weight and overweight children. TRIAL REGISTRATION: This study was observational without any health care intervention for the participants. Therefore, no trial registration number is available.

Respiratory morbidity through the first decade of life in a national cohort of children born extremely preterm.

BACKGROUND: Advances in perinatal care have markedly increased the prospects of survival for infants born extremely preterm (EP). The aim of this study was to investigate hospitalisation rates and respiratory morbidity from five to 11 years of age in a prospective national cohort of EP children born in the surfactant era. METHODS: This was a national prospective cohort study of all children born in Norway during 1999 and 2000 with gestational age (GA) < 28 weeks or birth weight < 1000 grams, and of individually matched term-born controls recruited for a regional subsample. Data on hospital admissions, respiratory symptoms, and use of asthma medication was obtained by parental questionnaires at 11 years of age. RESULTS: Questionnaires were returned for 232/372 (62%) EP-born and 57/61 (93%) regional term-born controls. Throughout the study period, 67 (29%) EP-born and seven (13%) term-born controls were admitted to hospital (odds ratio (OR) 2.90, 95% confidence interval (CI): 1.25, 6.72). Admissions were mainly due to surgical procedures, with only 12% due to respiratory causes, and were not influenced by neonatal bronchopulmonary dysplasia (BPD) or low GA(≤ 25 weeks). Respiratory symptoms, asthma and use of asthma medication tended to be more common for EP-born, significantly so for medication use and wheeze on exercise. Neonatal BPD was a risk factor for medication use, but not for current wheeze. In multivariate regression models, home oxygen after discharge (OR 4.84, 95% CI: 1.38, 17.06) and parental asthma (OR 4.38, 95% CI: 1.69, 11.38) predicted current asthma, but neither BPD nor low GA were associated with respiratory symptoms at 11 years of age. CONCLUSIONS: Hospitalisation rates five to 11 years after EP birth were low, but twice those of term-born controls, and unrelated to neonatal BPD and low GA. Respiratory causes were rare. Respiratory complaints were more common in children born EP, but the burden of symptoms had declined since early childhood.

The role of tonsillectomy in the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome; a literature review.

BACKGROUND: Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge of the effect of TE or ATE in the PFAPA syndrome. METHODS: A search of PubMed, Medline, EMBASE and Cochrane was conducted for papers written in English dated from 1 January 1987 to 31 December 2016. The search included all studies reporting outcomes after TE or ATE from children aged 0 to 18 years with PFAPA. RESULTS: Two randomized controlled trials reported significantly faster resolution of febrile episodes after TE or ATE in children with PFAPA compared to controls (non-surgery groups). We identified 28 case series including 555 children with PFAPA. The diagnosis was set prospectively before surgery in 440 children and retrospectively after surgery in 115 of the children. TE or ATE had a curative effect in 509 of the 555 children with PFAPA (92%), but few studies were of high quality. CONCLUSION: TE or ATE may have a curative effect on children with PFAPA, but the evidence is of moderate quality. Further high-quality randomized controlled studies are still needed.

Prescribing of asthma drugs for children 2004-2015. / Forskrivning av legemidler mot astma til barn i perioden 2004­15.

BAKGRUNN: Astma kan være vanskelig å diagnostisere hos barn. For barn under skolealder finnes det få tilgjengelige objektive diagnostiske undersøkelser, og retningslinjene for diagnose og behandling er basert på sykehistorie og klinisk undersøkelse. Dette kan gi rom for varierende behandlingspraksis. MATERIALE OG METODE: Data fra Reseptregisteret ble brukt til å studere forskrivning av legemidler mot astma til barn i aldersgruppene 0-4 år og 5-9 år fordelt på fylker fra 2004-15. RESULTATER: Det var stor variasjon mellom fylkene i andelen per 1 000 barn som fikk forskrevet legemidler mot astma i perioden 2012-14 (aldersgruppen 0-4 år: median: 104/1 000; ekstremverdier: 64-147, aldersgruppen 5-9 år: 68/1000; 46-86). Inhalasjonssteroider var hyppigst forskrevet, og det var her variasjonen mellom fylkene var størst i begge aldersgruppene (aldersgruppen 0-4 år: 85/1 000; 42-116, aldersgruppen 5-9 år: 51/1 000; 31-70). De fleste fikk kun en eller få forskrivninger med inhalasjonssteroider over en treårsperiode. Endring i forskrivningen av inhalasjonssteroider fra 2004 til 2015 varierte betydelig mellom fylkene, mest for aldersgruppen 0-4 år. FORTOLKNING: Stor forskjell i forskrivning av legemidler mot astma fylkene imellom, høy andel sporadisk bruk og endring over tid, særlig i den yngste aldersgruppen, kan tyde på en unaturlig variasjon i behandlingen som ikke kan forklares av forskjeller i astmaforekomst. Uklare retningslinjer som ikke er tilstrekkelig innarbeidet i klinisk praksis kan være én årsak.

Increased Bronchial Hyperresponsiveness and Higher Asymmetric Dimethylarginine Levels after Fetal Growth Restriction.

Bronchial hyperresponsiveness (BHR), a feature of asthma, is observed in preterm-born children and has been linked to intrauterine growth restriction. BHR is mediated via airway smooth muscle tone and is modulated by the autonomic nervous system, nitric oxide, and airway inflammation. Interactions among these factors are insufficiently understood. Methacholine-induced BHR (Met-BHR), fractional exhaled NO, and systemic soluble markers of nitric oxide metabolism and inflammation were determined in a population-based sample of 57 eleven-year-old children born extremely preterm (gestational age [GA] < 28 wk) or with extremely low birth weight (<1,000 g), and in a matched normal-birth weight term-born control group (n = 54). Bronchopulmonary dysplasia (BPD) was defined as the need for oxygen treatment at a GA of 36 weeks. In preterm-born children, birth weight below the 10th percentile for GA was associated with increased Met-BHR and higher plasma levels of asymmetric dimethylarginine (ADMA), with an increased odds ratio for being in the upper tertile of Met-BHR (11.8; 95% confidence interval, 3.3-42.4) and of ADMA (5.2; 95% confidence interval, 1.3-20.3). Met-BHR was correlated to ADMA level (r = 0.27, P = 0.007). There were no significant differences in Met-BHR, fractional exhaled NO, or z-FEV1 according to BPD status. No associations with systemic soluble markers of inflammation were observed for Met-BHR, birth, or BPD status. Intrauterine growth restriction in preterm-born children was associated with substantially increased Met-BHR and higher ADMA levels, suggesting altered nitric oxide regulation. These findings contribute to the understanding of the consequences from an adverse fetal environment; they should also be tested in term-born children.

Protracted bacterial bronchitis in children. / Protrahert bakteriell bronkitt hos barn.

Protracted bacterial bronchitis is a common cause of persistent, wet cough in pre-school children. The condition has been described relatively recently, and knowledge of the diagnosis may be an aid to making the correct assessment of children with chronic cough, helping to ensure that the symptoms are not misinterpreted and treated as asthma.