Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark.

BACKGROUND: Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. METHODS: From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. FINDINGS: 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. INTERPRETATION: In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. FUNDING: Innovation Fund Denmark and Rigshospitalets Forskningsfond.

The effect of stress on the antibody response after vaccination in children aged 0-18 years: A systematic review.

Stress has been associated with less effective vaccine responses in adults. This review aims to investigate the evidence for a similar association in children. A systematic review search was conducted in January 2021 in three databases: Medline, Embase and PsycInfo. An updated search of the Medline database was systematically conducted until the most recent update on September 25th, 2023, to ensure the inclusion of the most current research available. Keywords related to stress, vaccines and children were used, and a total of 7263 (+1528) studies were screened by two independent investigators. Six studies met the inclusion criteria for data extraction and analysis. For quality assessment of the studies, the risk of bias in non-randomized studies-of interventions (ROBINS-I) tool was applied. Most of the studies suggest a negative role of stress on vaccine responses. However, the scarcity of studies, lack of confirmatory studies, risk of bias and heterogeneity according to age, type of vaccine, measures of stress and vaccine responses prevent a clear conclusion. Future studies should emphasize the use of as strict study designs as possible, including well-defined stress metrics and thorough examination of both pre- and post-vaccination responses. Systematic review registration: Prospero CRD42021230490.

Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial.

BACKGROUND: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. METHODS: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during the recruitment period. Participating children were randomized to receive BCG within 7 d of birth or to a no intervention control group. Parent-reported infections (events) were collected using telephone interviews at 3 and 13 mo. Data collectors were blinded to allocation. RESULTS: The analyses included 4,224/4,262 (99%) and 4,192/4,262 (98%) children at 3 and 13 mo. From 0 to 3 mo, there were 291 events in the BCG group vs. 336 events in the control group, incidence rate ratio (IRR) = 0.87 (95% confidence interval (CI): 0.72 to 1.05). In this age group, the IRR was 0.62 (95% CI: 0.39 to 0.98) if the mother was BCG vaccinated. From 3 to 13 mo, there were 7,028 vs. 6,791 events, IRR = 1.02 (95% CI: 0.97 to 1.07). CONCLUSION: This study did not find a nonspecific public health benefit of BCG on parent-reported infections. BCG may have reduced the incidence of infections in children of BCG-vaccinated mothers during the first 3 mo.

Oral Polio Vaccination and Hospital Admissions With Non-Polio Infections in Denmark: Nationwide Retrospective Cohort Study.

Background. Live vaccines may have nonspecific beneficial effects on morbidity and mortality. This study examines whether children who had the live-attenuated oral polio vaccine (OPV) as the most recent vaccine had a different rate of admissions for infectious diseases than children with inactivated diphtheria-tetanus-pertussis-polio-Haemophilus influenzae type b vaccine (DTaP-IPV-Hib) or live measles-mumps-rubella vaccine (MMR) as their most recent vaccine. Methods. A nationwide, register-based, retrospective cohort study of 137 403 Danish children born 1997-1999, who had received 3 doses of DTaP-IPV-Hib, were observed from 24 months (first OPV dose) to 36 months of age. Results. Oral polio vaccine was associated with a lower rate of admissions with any type of non-polio infection compared with DTaP-IPV-Hib as most recent vaccine (adjusted incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], .77-.95). The association was separately significant for admissions with lower respiratory infections (adjusted IRR, 0.73; 95% CI, .61-.87). The admission rates did not differ for OPV versus MMR. Conclusions. Like MMR, OPV was associated with fewer admissions for lower respiratory infections than having DTaP-IPV-Hib as the most recent vaccination. Because OPV is now being phased-out globally, further studies of the potential beneficial nonspecific effects of OPV are warranted.

Identification of important and potentially avoidable risk factors in a prospective audit study of neonatal deaths in a paediatric hospital in Vietnam.

AIM: Neonatal deaths (≤28 days) account for more than half of child mortality in Vietnam. Presumably most die in hospital, but data are scarce. This study aimed to identify risk factors of death among hospitalised neonates. METHODS: We prospectively studied all neonatal deaths and expected deaths (discharged alive after withdrawal of life-sustaining treatment) in a Vietnamese tertiary paediatric hospital during a 12-month period in 2009-2010. The medical files were audited classifying admission prognosis, discharge outcome, cause of death/expected death according to two classifications, and important and potentially avoidable risk factors during the hospital stay. RESULTS: Among 5763 neonates admitted, 235 deaths and 67 expected deaths were included. According to both classifications, major causes were congenital malformations, prematurity and severe infections. Six risk factors were identified in 85% (60/71) of the neonates with a relatively good prognosis: recognition or response to danger signs, internal transfers, nosocomial infections, sepsis management, access to usual equipment/staff, and family perception. CONCLUSION: Among 302 neonatal deaths/expected deaths, the major causes were congenital malformations, prematurity and severe infections. Six important and potentially avoidable risk factors could be addressed in the subgroup with relatively good admission prognosis, without implementing new technology or major organisational changes.

Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study.

BACKGROUND: Little is known about how chronic conditions other than prematurity, heart disease, and Down syndrome affect the risk and severity of hospitalization for respiratory syncytial virus (RSV). We assess the risk and severity of RSV hospitalization in children with chronic conditions in this register-based, population-based cohort study. METHODS: Data on RSV tests, maternal smoking, siblings, single parenthood, mode of delivery, gestational age at birth, major surgery, asthma diagnosis, chronic conditions, and hospitalization and discharge dates were obtained from the Danish RSV database, the National Patient and Birth Registries, and the Civil Registration System. STATISTICS: Cox regression models were used to estimate incidence rate ratios (IRRs) for RSV hospitalization between groups stratified by sex and date of birth. Duration of RSV hospitalization was analyzed in a linear regression and reported as geometric mean ratios. RESULTS: A total of 391 983 children aged 0-23 months were included in the analysis. A total of 10,616 (2.7%) had a diagnosis for chronic disease. IRRs (95% confidence intervals) for RSV hospitalization in children with any congenital or acquired chronic condition were 2.18 (2.01-2.36) and 2.25 (1.94-2.61), respectively. Several new risk factors for RSV hospitalization, including malformations, interstitial lung disease, neuromuscular disease, liver disease, chromosomal abnormalities, congenital immunodeficiencies, and inborn errors of metabolism, were identified. Duration of RSV hospitalization was increased in many chronic conditions. CONCLUSIONS: Chronic disease per se is an important risk factor for RSV hospitalization.

Prematurity, asphyxia and congenital malformations underrepresented among neonates in a tertiary pediatric hospital in Vietnam.

BACKGROUND: Estimated 17,000 neonates (≤ 28 days of age) die in Vietnam annually, corresponding to more than half of the child mortality burden. However, current knowledge about these neonates is limited. Prematurity, asphyxia and congenital malformations are major causes of death in neonates worldwide. To improve survival and long term development, these vulnerable neonates need access to the specialized neonatal care existing, although limited, in lower middle-income countries like Vietnam. The aim of this study was to describe these conditions in a specialized Vietnamese hospital, compared to a Danish hospital. METHODS: We performed a comparative observational study of all neonates admitted to a tertiary pediatric hospital in South Vietnam in 2009-2010. The data were prospectively extracted from the central hospital registry and included basic patient characteristics and diagnoses (International Classification of Diseases, 10th revision). Prematurity, asphyxia and designated congenital malformations (oesophageal atresia, gastroschisis, omphalocoele, diaphragmatic hernia and heart disease) were investigated. In a subgroup, the prematurity diagnosis was validated using a questionnaire. The hospitalization ratio of each diagnosis was compared to those obtained from a Danish tertiary hospital. The Danish data were retrieved from the neonatal department database for a ten-year period. RESULTS: The study included 5763 neonates (missing<1%). The catchment population was 726,578 live births. The diagnosis was prematurity in 7%, asphyxia in 2% and one of the designated congenital malformations in 6%. The diagnosis of prematurity was correctly assigned to 85% of the neonates, who were very premature or had very low birth weight according to the questionnaire, completed by 2196 neonates. Compared to the Danish Hospital, the hospitalization ratios of neonates diagnosed with prematurity (p<0.01), asphyxia (p<0.01) and designated congenital malformations (p<0.01- 0.04) were significantly lower. CONCLUSION: Our findings suggest the investigated diagnoses were underrepresented in the Vietnamese study hospital. In contrast, relatively mild diagnoses were frequent. These results indicate the use of specialized care may not be optimal. Pre-hospital selection mechanisms were not investigated and additional studies are needed to optimise utilisation of specialized care and improve neonatal survival.

Population based external validation of a European predictive model for respiratory syncytial virus hospitalization of premature infants born 33 to 35 weeks of gestational age.

Prospectively collected population-based data on 2529 Danish infants born at 33 to 35 weeks of gestation were used to validate an European predictive model of respiratory syncytial virus (RSV) hospitalization. The model was found to be robust with a diagnostic accuracy of 65.9% to distinguish between RSV-hospitalized versus non-RSV-hospitalized Danish infants born at 33 to 35 weeks of gestation.

Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study.

RATIONALE: Severe respiratory syncytial virus (RSV) infection is associated with asthma but the nature of this association is imperfectly understood. OBJECTIVES: To examine the nature of the association between severe RSV infection and asthma in a population-based sample of twins. METHODS: Data on hospitalization due to RSV infection was gathered for all twins born in Denmark between 1994 and 2000 (8,280 pairs) and linked to information on asthma obtained from hospital discharge registries and parent-completed questionnaires. Genetic variance components models and direction of causation models were fitted to the observed data. MEASUREMENTS AND MAIN RESULTS: RSV hospitalization and asthma were positively associated (r = 0.43), and genetic determinants for the two disorders overlapped completely. Modeling the direction of causation between RSV hospitalization and asthma showed that a model in which asthma "causes" RSV hospitalization fitted the data significantly better (P = 0.39 for deterioration in model fit) than a model in which RSV hospitalization "causes" asthma (P < 0.001 for deterioration in model fit), even when sex, birth weight, and maternal smoking during pregnancy were accounted for. CONCLUSIONS: RSV infection that is severe enough to warrant hospitalization does not cause asthma but is an indicator of the genetic predisposition to asthma.

Differential effects of risk factors on infant wheeze and atopic dermatitis emphasize a different etiology.

BACKGROUND: Atopic dermatitis (AD) often develops in infancy as the first manifestation of the atopic phenotype. Wheezing is also common in infancy, but it is less clear whether infant wheezing should be considered as an atopic phenotype. If infant wheeze and AD share a common aetiology, this would indicate that infant wheezing is an atopic phenotype. OBJECTIVE: To investigate whether potential risk factors for infant wheeze and AD have similar effects on these 2 phenotypes, indicating a common etiology. METHODS: A total of 34.793 mother-child pairs enrolled in the Danish National Birth Cohort were followed prospectively. Information on wheezing episodes, AD, and prenatal, perinatal, and postnatal risk factors was collected by interview at 12 and 30 weeks of gestation, at 6 and 18 months of age, and by linkage to the Danish Medical Birth Register. Data were analyzed by binary and polytomous logistic regression models. RESULTS: The following variables had significantly differential effects on infant wheezing and AD: parental hay fever, parental asthma, parental AD, sex, maternal age, maternal occupation, smoking during pregnancy, season of birth, birth weight, gestational age, head circumference, breast-feeding, number of older siblings, day care attendance, and pets in the home. CONCLUSION: The majority of risk factors had differential effects on infant wheeze and AD indicative of a different etiology. Infant wheezing does not seem to be etiologically linked to the epidemic of atopic disease, and infant wheezing should not be used as an indicator of the atopic phenotype.