Host RNA Expression Signatures in Young Infants with Urinary Tract Infection: A Prospective Study.

Early diagnosis of infections in young infants remains a clinical challenge. Young infants are particularly vulnerable to infection, and it is often difficult to clinically distinguish between bacterial and viral infections. Urinary tract infection (UTI) is the most common bacterial infection in young infants, and the incidence of associated bacteremia has decreased in the recent decades. Host RNA expression signatures have shown great promise for distinguishing bacterial from viral infections in young infants. This prospective study included 121 young infants admitted to four pediatric emergency care departments in the capital region of Denmark due to symptoms of infection. We collected whole blood samples and performed differential gene expression analysis. Further, we tested the classification performance of a two-gene host RNA expression signature approaching clinical implementation. Several genes were differentially expressed between young infants with UTI without bacteremia and viral infection. However, limited immunological response was detected in UTI without bacteremia compared to a more pronounced response in viral infection. The performance of the two-gene signature was limited, especially in cases of UTI without bloodstream involvement. Our results indicate a need for further investigation and consideration of UTI in young infants before implementing host RNA expression signatures in clinical practice.

Invasive group A streptococcal infections in children and adolescents in Denmark during 2022-23 compared with 2016-17 to 2021-22: a nationwide, multicentre, population-based cohort study.

BACKGROUND: A historic increase in paediatric invasive group A streptococcal (iGAS) infections was reported globally in 2022. iGAS infections can lead to severe manifestations (eg, pleural empyema, necrotising fasciitis, toxic shock syndrome, osteomyelitis, septic arthritis, and meningitis). We aimed to compare the incidence and severity of iGAS infections overall, for distinct clinical phenotypes, and for GAS emm variants in Denmark in 2022-23 with reference to the previous six seasons (ie, 2016-17, 2017-18, 2018-19, 2019-20, 2020-21, and 2021-22). METHODS: In this nationwide, multicentre, population-based cohort study, we included all children and adolescents in Denmark aged 0-17 years with a positive culture of GAS or GAS confirmed through PCR-based methods from otherwise sterile sites in 2022-23 and the previous six seasons from 2016-17 to 2021-22. For all seven seasons, data were obtained from week 21 to week 20 of the next year. Patients at all 18 paediatric hospital departments in Denmark were identified through the Danish Microbiology Database, in which iGAS isolates from sterile sites are prospectively registered, including emm typing. We obtained electronic medical health records for each patient admitted with a diagnosis of iGAS. We calculated the incidence of iGAS per 1 000 000 inhabitants aged 0-17 years in each season from week 21 to week 20 of the next year and the risk ratios (RRs) for incidence of iGAS, distinct disease manifestations, and emm variants in 2022-23 versus the three pre-COVID-19 seasons in 2016-17, 2017-18, and 2018-19 using Fisher's exact test and Pearson's χ2 test. FINDINGS: Among the Danish population of 1 152 000 children and adolescents aged 0-17 years, 174 with iGAS disease were included. 76 children and adolescents with iGAS during 2022-23 were identified; 31 (41%) of 76 were female and 45 (59%) were male. 98 children and adolescents with iGAS during 2016-17 to 2021-22 were identified; 41 (42%) of 98 were female and 57 (58%) were male. There was an increase in incidence of iGAS from mean 22·6 (95% CI 14·7-33·1) per 1 000 000 children and adolescents during 2016-17 to 2018-19 to 66·0 (52·0-82·6) per 1 000 000 during 2023-23 (RR 2·9, 95% CI 1·9-4·6; p<0·0001). During the COVID-19 pandemic in 2019-20, 2020-21, and 2021-22, the mean incidence of iGAS was 6·1 (95% CI 2·4-12·5) per 1 000 000 children and adolescents. In 2022-23, there was a 9·5-fold increase in emm-12 (95% CI 2·2-40·8; p=0·0002) and a 2·7-fold increase in emm-1 (1·3-5·5; p=0·0037). The most common clinical manifestations of iGAS in 2022-23 were soft-tissue infections, which increased by 4·5-fold (1·9-10·9; p=0·0003), and complicated pneumonia with parapneumonic effusion, which increased by 4·0-fold (1·4-11·4; p=0·0059), both compared with the three pre-COVID-19 seasons. Overall, there was no increased severity of iGAS in 2022-23 compared with the previous six seasons as measured by median duration of hospital stay (8 days, IQR 4-14 vs 9 days, 5-15; p=0·39), paediatric intensive care unit (PICU) admission (17 [22%] of 76 vs 17 [17%] of 98; p=0·53), duration of stay in PICU (4 days, IQR 2-10 vs 4 days, 2-11; p=0·84), or mortality (three [4%] of 76 vs three [3%] of 98; p=1·00). In 2022-23, there was a 3·6-fold (95% CI 1·8-7·3; p=0·0001) increase in children with a preceding upper respiratory tract infection and a 4·6-fold (1·5-14·1; p=0·0034) increase in children with a preceding varicella-zoster infection, both compared with the three pre-COVID-19 seasons. INTERPRETATION: In Denmark, the incidence of paediatric iGAS increased in 2022-23 compared with the three pre-COVID-19 seasons of 2016-17, 2017-18, and 2018-19. However, the course of iGAS disease in children and adolescents in 2022-23 was not more severe than in previous seasons. The high morbidity across all seasons highlights iGAS as a major invasive bacterial infection in children and adolescents. FUNDING: Innovation Fund Denmark.

Oral-only antibiotics for bone and joint infections in children: study protocol for a nationwide randomised open-label non-inferiority trial.

INTRODUCTION: Children with bone and joint infections are traditionally treated with intravenous antibiotics for 3-10 days, followed by oral antibiotics. Oral-only treatment has not been tested in randomised trials. METHODS AND ANALYSIS: Children (3 months to 18 years) will be randomised 1:1 with the experimental group receiving high-dose oral antibiotics and the control group receiving intravenous antibiotics with a shift in both groups to standard oral antibiotics after clinical and paraclinical improvement. Children in need of acute surgery or systemic features requiring intravenous therapy, including septic shock, are excluded. The primary outcome is defined as a normal blinded standardised clinical assessment 6 months after end of treatment. Secondary outcomes are non-acute treatment failure and recurrent infection. Outcomes will be compared by a non-inferiority assumption with an inferiority margin of 5%. ETHICS AND DISSEMINATION: The trial has the potential to reduce unnecessary hospitalisation and use of intravenous antibiotics in children with bone or joint infections. Due to the close follow-up, exclusion of severely ill children and predefined criteria for discontinuation of the allocated therapy, we expect the risk of treatment failure to be minimal. TRIAL REGISTRATION NUMBER: NCT04563325.

Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) occurs after infection with SARS-CoV-2 and its incidence is likely to depend on multiple factors, including the variant of the preceding SARS-CoV-2 infection and vaccine effectiveness. We aimed to estimate the incidence of MIS-C, and describe the clinical phenotype, following the delta variant of SARS-CoV-2 (B.1.617.2 and sublineages) according to vaccination status. We aimed to compare the incidence and clinical phenotype of MIS-C from our cohort during the pre-delta era. METHODS: This prospective, population-based cohort study included patients aged 0-17 years hospitalised with MIS-C in Denmark, according to the US Centers for Disease Control and Prevention case definition, from Aug 1, 2021, to Feb 1, 2022, a period dominated by the delta variant. We identified MIS-C cases via a nationwide research collaboration involving real-time data collection from all 18 paediatric departments. Aggregated number of SARS-CoV-2 infections by vaccination status was obtained from the Danish COVID-19 surveillance registries. The incidence of MIS-C was calculated using the estimated number of infected individuals by vaccination status. We calculated the incidence of MIS-C per 1 000 000 vaccinated and unvaccinated person-years, and estimated vaccine effectiveness as 1-incidence rate ratio using Poisson regression. Incidence and phenotype of MIS-C were compared with MIS-C cases from the first year of the pandemic. This study is registered at ClinicalTrials.gov, NCT05186597. FINDINGS: We identified 51 MIS-C cases among unvaccinated individuals and one in a fully vaccinated adolescent. The incidence of MIS-C was one in 3400 unvaccinated individuals (95% CI 2600-4600) with the delta variant and one in 9900 vaccinated individuals (95% CI 1800-390 000) with breakthrough infection. The estimated vaccine effectiveness against MIS-C after the delta variant was 94% (95% CI 55-99; p=0·0061) in individuals aged 5-17 years. The clinical phenotype during the delta wave was comparable to the pre-delta era. INTERPRETATION: We found the incidence and phenotype of MIS-C in unvaccinated children during the delta wave to be similar to the incidence during the first year of the pandemic. We found vaccine effectiveness to be high against MIS-C, which we suggest was due to protection from infection and, possibly, a decreased incidence of MIS-C after breakthrough infection. Knowledge of the incidence of MIS-C after different SARS-CoV-2 variants and the effect of vaccination might contribute to the elucidation of the extent to which MIS-C is a vaccine-preventable disease. FUNDING: National Ministry of Higher Education and Science and Innovation Fund Denmark.

Population-based Incidence of Myopericarditis After COVID-19 Vaccination in Danish Adolescents.

In this prospective nationwide multicenter study from Denmark, myopericarditis after Pfizer-BioNTech mRNA COVID-19 vaccination was identified in 13 males and 2 females between May 15 and September 15, 2021, among 133,477 vaccinated males and 127,857 vaccinated females 12-17 years of age, equaling 97 males and 16 females per million. In conclusion, the incidence of myopericarditis after COVID-19 vaccination among males appears higher than reports from the United States.

Fatal case of hospital-acquired hypernatraemia in a neonate: lessons learned from a tragic error.

A 3-week-old boy with viral gastroenteritis was by error given 200 mL 1 mmol/mL hypertonic saline intravenously instead of isotonic saline. His plasma sodium concentration (PNa) increased from 136 to 206 mmol/L. Extreme brain shrinkage and universal hypoperfusion despite arterial hypertension resulted. Treatment with glucose infusion induced severe hyperglycaemia. Acute haemodialysis decreased the PNa to 160 mmol/L with an episode of hypoperfusion. The infant developed intractable seizures, severe brain injury on magnetic resonance imaging and died. The most important lesson is to avoid recurrence of this tragic error. The case is unique because a known amount of sodium was given intravenously to a well-monitored infant. Therefore the findings give us valuable data on the effect of fluid shifts on the PNa, the circulation and the brain's response to salt intoxication and the role of dialysis in managing it. The acute salt intoxication increased PNa to a level predicted by the Edelman equation with no evidence of osmotic inactivation of sodium. Treatment with glucose in water caused severe hypervolaemia and hyperglycaemia; the resulting increase in urine volume exacerbated hypernatraemia despite the high urine sodium concentration, because electrolyte-free water clearance was positive. When applying dialysis, caution regarding circulatory instability is imperative and a treatment algorithm is proposed.

Prevalence of SARS-CoV-2-Antibodies in Danish Children and Adults.

In Denmark, severe acute respiratory syndrome coronavirus 2 antibodies were assessed in a cross-sectional study among 1033 children visiting pediatric departments and 750 blood donors in June 2020, using a point-of-care test. Antibodies were detected in 17 children (1.6%) and 15 blood donors (2.0%) (P = 0.58). In conclusion, children and adults were infected to a similar low degree.

[Clinical manifestations of Epstein-Barr virus infection in children and adolescents].

The most commonly known clinical manifestation of primary Epstein-Barr virus infection is infectious mononucleosis. In this review we cover the diagnostics and basic patho-physiology of Epstein-Barr virus infection and present the many clinical manifestations of the virus, including less well-known diseases such as hepatitis, auto-immune haemolytic anaemia, and neurological and immunological diseases. Our aim is to strengthen the clinicians' awareness and understanding of these conditions in order to improve diagnostics and avoid delay of treatment.

[Severe haemolytic anaemia and hepatitis in the course of Epstein-Barr virus infection].

Epstein-Barr virus (EBV) is globally prevalent and in adolescents mostly observed as infectious mononucleosis. Abnormal liver blood tests are common, whereas more serious hepatitis is less prevalent. Autoimmune haemolytic anaemia may also occur in the course of this infection. We report a case of a 15-year-old girl with cholestatic hepatitis and autoimmune haemolytic anaemia associated with EBV infection. The Donath-Landsteiner test was positive suggesting paroxysmal cold haemoglobinuria. She was treated with supportive care and discharged in recovery after three weeks.

[Rhabdomyolysis after isotretinoin treatment in a 17-year-old male].

Rhabdomyolysis is a rare, but known complication to treat-ment with systemic isotretinoin in patients with acne and can lead to severe kidney damage. In our case report a 17-year-old male, exercising moderately, developed rhab-domyolysis without kidney injury after two-month treatment with isotretinoin 20 mg daily. He complained of some muscle pain and was treated according to guidelines for rhabdomyolysis with no sequelae. Frequent monitoring of muscle complaints and control of serum creatine kinase in patients with affected liver and kidney function is essential.

EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement.

Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX neurotoxicity, we observed an electroencephalographic (EEG) with extreme delta brush. Extreme delta brush is an EEG pattern previously described in patients with NMDAR autoimmune encephalitis. The observations suggest that the mechanism of this neurotoxicity may be mediated by the NMDAR. Furthermore, extreme EEG delta brush should suggest a diagnosis of MTX associated subacute neurotoxicity.

A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data.

Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight, length, maternal age), birth characteristics (e.g. vacuum extraction, preterm delivery, birth order) and exposures during pregnancy (e.g. maternal: smoking, working, dietary supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain tumour risk. Agreement between interview and birth registry data ranged from moderate (Kappa=0.54; worked during pregnancy) to almost perfect (Kappa=0.98; birth weight). Neither anthropogenic factors nor birth characteristics were associated with childhood brain tumour risk. Maternal vitamin intake during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents.

[Epidural abscess secondary to sinusitis].

Approximately 0.5-2% of upper viral infections are com-licated by secondary acute bacterial sinusitis and may in rare cases evolve into more serious complications such as meningitis and intracranial abscess. Symptoms are often subtle and nonspecific as fever, headache, scalp tenderness, nausea and altered mental status. In this case report of a 12-year-old boy with an epidural abscess secondary to sinusitis we intend to increase the knowledge to these rare, but potentially life-threatening complications to ensure the optimal and timely treatment.

Brain tumors in children and adolescents and exposure to animals and farm life: a multicenter case-control study (CEFALO).

OBJECTIVES: The etiology of brain tumors in children and adolescents is largely unknown, and very few environmental risk factors have been identified. The aim of this study was to examine the relationship between pre- or postnatal animal contacts or farm exposures and the risk of childhood brain tumors (CBTs), since infectious agents may pose a risk factor and a proposed mechanism is transferral of infectious agents from animals to humans. METHODS: The case-control study conducted in Denmark, Norway, Sweden, and Switzerland included brain tumor cases diagnosed from 2004 to 2008 aged 7-19 years at diagnosis. Three hundred and fifty-two cases (83 % participation rate) were matched to 646 population-based controls (71 % participation rate). Conditional logistic regression was used to estimate odds ratios. RESULTS: Maternal farm residence during pregnancy was inversely related to all CBTs combined (adjusted odds ratio (aOR) = 0.40, 95 % confidence interval (CI) = 0.19-0.88), as was the child's farm residence but not statistically significantly so (aOR = 0.57, 95 % CI = 0.28-1.17). Exposure to animals was in general not related to CBT risk except postnatal contact with birds showing reduced aORs of all CBTs (0.67, 95 % CI = 0.46-0.97) and primitive neuroectodermal tumor (0.28, 95 % CI = 0.10-0.83). Sensitivity analyses focusing on early exposure of the child did not change the associations observed for the entire exposure period with the exception of exposure to goats and sheep which was associated with reduced risks of both all CBTs (aOR = 0.48, 95 % CI = 0.24-0.97) and astrocytomas (aOR = 0.29, 95 % CI = 0.10-0.87). CONCLUSION: Altogether, our data indicate an inverse association between the mother during pregnancy or the child living on a farm and CBT risk, which contrasts with the existing literature and merits further attention. With respect to exposure to animals, we did not observe any systematic pattern. This suggests that a potential protective effect of farm residence is mediated by some other factor than animal contact.

Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study.

BACKGROUND: It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents. METHODS: CEFALO is a multicenter case-control study conducted in Denmark, Sweden, Norway, and Switzerland that includes all children and adolescents aged 7-19 years who were diagnosed with a brain tumor between 2004 and 2008. We conducted interviews, in person, with 352 case patients (participation rate: 83%) and 646 control subjects (participation rate: 71%) and their parents. Control subjects were randomly selected from population registries and matched by age, sex, and geographical region. We asked about mobile phone use and included mobile phone operator records when available. Odds ratios (ORs) for brain tumor risk and 95% confidence intervals (CIs) were calculated using conditional logistic regression models. RESULTS: Regular users of mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors compared with nonusers (OR = 1.36; 95% CI = 0.92 to 2.02). Children who started to use mobile phones at least 5 years ago were not at increased risk compared with those who had never regularly used mobile phones (OR = 1.26, 95% CI = 0.70 to 2.28). In a subset of study participants for whom operator recorded data were available, brain tumor risk was related to the time elapsed since the mobile phone subscription was started but not to amount of use. No increased risk of brain tumors was observed for brain areas receiving the highest amount of exposure. CONCLUSION: The absence of an exposure-response relationship either in terms of the amount of mobile phone use or by localization of the brain tumor argues against a causal association.

Incidence of childhood central nervous system tumors in the Nordic countries.

BACKGROUND: The incidence rates of childhood central nervous system (CNS) tumors in the Nordic countries remain among the highest in the world. Large geographical and temporal variations in the incidence rates of CNS tumors have been reported. Increasing incidence rates would be a public health concern, as they might indicate increased exposure to environmental risk factors. METHODS: All 3,983 children 0-14 years of age registered with a primary CNS tumor in 1985-2006 in the national cancer registries of the Denmark, Finland, Norway, and Sweden were identified. Tumors were classified according to the International Classification of Childhood Cancer version 3 (ICCC-3). Join-point analysis was used to detect changes in trends and to estimate annual changes in incidence rates. RESULTS: The mean annual incidence rate of CNS tumors was 42 per million. No statistically significant change in time trends of incidence rates was observed during 1985-2006. Furthermore, the incidence by birth cohort was relatively stable during the study period. CONCLUSION: The incidence rates of childhood CNS tumors in the Nordic countries remain among the highest in the world. The stable incidence rates during the last 22 years indicate that major changes in environmental risk factors are unlikely.