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Abstract Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that emerged during the COVID-19 pandemic. Although recognized as an immune-mediated condition, the pathogenesis remains unresolved. Furthermore, the absence of a diagnostic test can lead to delayed immunotherapy. Using state-of-the-art mass-spectrometry proteomics, assisted by artificial intelligence (AI), we aimed to identify a diagnostic signature for MIS-C and to gain insights into disease mechanisms. We identified a highly specific 4-protein diagnostic signature in children with MIS-C. Furthermore, we identified seven clusters that differed between MIS-C and controls, indicating an interplay between apolipoproteins, immune response proteins, coagulation factors, platelet function, and the complement cascade. These intricate protein patterns indicated MIS-C as an immunometabolic condition with global hypercoagulability. Our findings emphasize the potential of AI-assisted proteomics as a powerful and unbiased tool for assessing disease pathogenesis and suggesting avenues for future interventions and impact on pediatric disease trajectories through early diagnosis.

Introduction Bronchiolitis is one of the most common reasons for hospital admissions in early childhood. As supportive treatment, some treatment guidelines suggest using nasal irrigation with normal saline (NS) to facilitate clearance of mucus from the airways. In addition, most paediatric departments in Denmark use nebulised NS for the same purpose, which can mainly be administered as inpatient care. However, no studies have ever directly tested the effect of saline in children with bronchiolitis.Methods and analysis The study is an investigator-initiated, multicentre, open-label, randomised, controlled non-inferiority trial and will be performed at six paediatric departments in eastern Denmark. We plan to include 300 children aged 0–12 months admitted to hospital with bronchiolitis. Participating children are randomised 1:1:1 to nebulised NS, nasal irrigation with NS or no saline therapy. All other treatment will be given according to standard guidelines.The primary outcome is duration of hospitalisation, analysed according to intention-to-treat analysis using linear regression and Cox regression analysis. By including at least 249 children, we can prove non-inferiority with a limit of 12 hours admission, alpha 2.5% and a power of 80%. Secondary outcomes are need for respiratory support with nasal continuous positive airway pressure or high-flow oxygen therapy and requirement of fluid supplements (either by nasogastric tube or intravenous).Ethics and dissemination This study may inform current practice for supportive treatment of children with bronchiolitis. First, if NS is found to be helpful, it may be implemented into global guidelines. If no effect of NS is found, we can stop spending resources on an ineffective treatment. Second, if NS is effective, but nasal irrigation is non-inferior to nebulisation, it may reduce the workload of nurses, and possible duration of hospitalisation because the treatment can be delivered by the parents at home.Trial registration number NCT05902702.

BackgroundEnteroviruses (EV) constitute a diverse group of viruses manifesting a broad spectrum of clinical presentations in humans ranging from mild skin manifestations to more severe central nervous system (CNS) infection. Severe infections are reported with increased frequency globally, albeit the burden of diseases and the evolution of circulating viruses is largely unknown. We aimed to systematically explore contemporary trends in hospitalizations attributed to EV infections using national hospitalization discharge data.MethodsWe utilized the Danish National Patient Register which holds information on all contacts to Danish hospitals. We covered eight full years (2015-2022). Length-of-stay and administrative procedure codes were used to distinguish hospital admissions from outpatient visits. We utilized burden of disease estimates and distribution statistics.ResultsWe identified 1029 hospitalizations and 1970 outpatient visits due to EV infections. The hospital admissions were primarily associated with CNS-infections (n=570, 55.4%) and skin (n=252, 24.5%), with variation over the studied period. The admitted patients were predominately children (43.8%) though patients were identified in all ages. The clinical manifestation was associated with age, with CNS infections dominating in the neonates and adults, and skin infections dominating in children 1-2 years (17.2%). Outpatient visits were predominantly observed among children 1-2 years (55.0%), presenting with skin symptoms (77.9%). We show a seasonal pattern of EV infections with summer/fall peaks and markedly impact on the EV hospitalization burden related to COVID-19 mitigation measures including national lockdown periods. 25% of hospital admissions occurred during 2020-2022.ConclusionEV infections caused both hospital admissions and outpatient visits in the period studied, predominately among children aged 1-2 years. Overall, skin infections dominated the outpatient visits, while the majority of hospital admissions were due to CNS infections. The pandemic period did not change the seasonal pattern of EV infections but notably lowered the number of admissions to hospital with CNS infection and raised the number of outpatient admissions with skin infection.

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.

Introduction Febrile urinary tract infection is one of the most common bacterial infections in children. Currently, recommended antibiotic duration is 10 days. However, recent evidence suggests that 90%–95% of children with febrile urinary tract infections are afebrile and clinically improved 48–72 hours after treatment initiation. Accordingly, individualised duration of antibiotic therapy, according to the recovery time, might be more beneficial than current recommendations, but no evidence exists.Methods and analysis An open-label randomised clinical trial equally randomising children aged 3 months to 12 years from eight Danish paediatric departments with uncomplicated febrile (≥38°C) urinary tract infection to either individualised or standard duration of antibiotic therapy. Children allocated to individualised duration of antibiotic therapy will terminate antibiotic therapy 3 days after clinical improvement with no fever, flank pain or dysuria. Children allocated to standard duration will receive 10 days of antibiotic therapy. Co-primary outcomes are non-inferiority for recurrent urinary tract infection or death within 28 days after the end of treatment (non-inferiority margin 7.5 percentage points) and superiority for the number of days with antibiotic therapy within 28 days after treatment initiation. Seven other outcomes will also be assessed. A total of 408 participants are needed to detect non-inferiority (one-sided alpha 2.5%; beta 80%).Ethics and dissemination This trial has been approved by the Ethics Committee (H-21057310) and the Data Protection Agency (P-2022-68) in Denmark. Regardless of the trial’s findings (whether positive, negative or inconclusive), the results will be compiled into one or more manuscripts for publication in international peer-reviewed scientific journals and presented at conferences.Trial registration number NCT05301023.

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.

In this real-world cohort study based on Danish nationwide registers, the cumulated proportion, relative risk (RR) of SARS-CoV-2 breakthrough infections, and vaccine effectiveness (VE) were investigated in adolescents aged 12–18 years following vaccination with the BNT162b2 vaccine compared to unvaccinated controls. Adolescents with and without vaccination with the first dose of BNT162b2 between 1 May and 30 September 2021 were included. Effect estimates include proportions with a positive SARS-CoV-2 RT-PCR test among vaccinated and unvaccinated, RR, and VE at three different time points. During Delta-dominance, VE was first 97.6% (95% CI 96.3–98.4), then 96.2% (95% CI 95.4–96.9) in the age group 12–15 and 95.1% (95% CI 94.1–96.0) followed by 95.5% (95% CI 94.8–96.1) in the age group 16–18 years, respectively. During Omicron dominance, VE was 5.8% (95% CI 4.6–7.0) in ages 12–15 years and 9.2% (95% CI 7.7–10.6) in ages 16–18 years. Thus, BNT162b2-vaccine protection was limited during the Omicron era.

This study investigates the impact of vaccination against SARS-CoV-2 on health outcomes and hospital contacts in children and adolescents aged 5–18 years infected with the SARS-CoV-2 Omicron variant, comparing previously vaccinated with unvaccinated. Using national register data, vaccinated and unvaccinated Danish children and adolescents with a positive SARS-CoV-2 test between 1 January and 31 March 2022 (Omicron dominance period) were included. The Prior Event Rate Ratio (PERR) was used to explore differences in hospital contacts (hospitalizations and emergency room (ER) visits), while Inverse Treatment Probability Weighted (IPW) risk ratios were used to explore the risk of severe health outcomes within six weeks following SARS-CoV-2 infection. Vaccinated 5–11-year-old girls had fewer visits to the ER compared to unvaccinated ones, PERR 0.92 (95% CI 0.84–1.00). Vaccinated 5–11-year-old boys had fewer hospitalizations (PERR 0.79 (0.64–0.99)) and more ER visits (PERR 1.13 (1.04–1.22)) compared to unvaccinated ones. An unadjusted and significant lower risk of febrile seizure among vaccinated 5–11-year-olds compared to unvaccinated ones was found (risk ratio 0.12 (0.04–0.39), p ≤ 0.01. No significant differences were found for severe conditions or for croup or pneumonia in either age group. The results indicate a modest protective effect of the vaccine in terms of hospital contacts, but no protective effect on health outcomes after SARS-CoV-2 Omicron infection in this population of Danish children and adolescents.

Purpose: The optimal choice of protocol for diagnostic imaging in children with tuberculosis (TB) is a contemporary challenge due to the war in Ukraine, which potentially can create a steep rise in TB cases in Western Europe. We aimed to gather all primary research comparing imaging modalities and their diagnostic accuracies for pulmonary findings in children with suspected or confirmed pulmonary tuberculosis (PTB). Method: We searched the databases PubMed and Embase using pre-specified search terms, for English- and non-English published and un-published reports from the period 1972 to 2022. We retrieved reports via citation search in excluded literature reviews and systematic reviews. Studies were eligible if most of the study population was between 0 and 18 years of age with confirmed or suspected PTB, and study participants had described diagnostic images from two or more different imaging modalities. Results: A total of 15 studies investigated conventional chest X-Ray (CXR) and computed tomography (CT) in diagnosing PTB in children. Nine studies investigated the number of participants in where CT or CXR confirmed the diagnosis of TB, and all of them, including a total of 1244 patients, reported that findings compatible with TB were more frequently detected on CT than CXR. Only two studies did not include radiological findings as part of their diagnostic criteria for PTB, and combined they showed that CT diagnosed 54/54 (100 %) children with confirmed PTB, while CXR diagnosed 42/54 (78 %). Two studies compared magnetic resonance imaging (MRI) with CXR and showed that MRI diagnosed more children with PTB than CXR. One study reported a higher positive predictive value (PPV), sensitivity and specificity for PTB findings for MRI than CXR. One study compared CXR with high-kilovolt (high-kV) CXR, finding compatible sensitivity and specificity regarding confirmation of PTB. Two studies compared ultrasound (US) with CXR and found that US had a higher diagnostic yield and more often correctly identified consolidations, mediastinal LAP, and pleural effusion. Conclusion: CT showed a higher diagnostic accuracy for PTB findings than CXR, MRI and US, and should be the imaging modality of first choice when available. MRI had a higher sensitivity and specificity than CXR for LAP, pleural effusion, and cavitation. US was complimentary in initial diagnostic work-up and follow up. A diagnostic strategy for PTB in children according to local availability and expertise is proposed, as no evidence from this systematic review shows otherwise, in acknowledgement of the expertise in high TB-burdened countries. CT can be performed when in doubt, due to the higher diagnostic yield.

Objectives To identify the risk factors for neonatal sepsis in Sub-Saharan Africa.Design Systematic review and meta-analysis.Data sources PubMed, Embase, Web of Science, African Index Medicus and ClinicalTrials.gov were searched for observational studies from January 2010 to August 2020.Setting Sub-Saharan Africa, at all levels of healthcare facilities.Participants ‘Neonates’ (

Improved methods are needed for diagnosing infectious diseases in children with cancer. Most children have fever for other reasons than bacterial infection and are exposed to unnecessary antibiotics and hospital admission. Recent research has shown that host whole blood RNA transcriptomic signatures can distinguish bacterial infection from other causes of fever. Implementation of this method in clinics could change the diagnostic approach for children with cancer and suspected infection. However, extracting sufficient mRNA to perform transcriptome profiling by standard methods is challenging due to the patient’s low white blood cell (WBC) counts. In this prospective cohort study, we succeeded in sequencing 95% of samples from children with leukaemia and suspected infection by using a low-input protocol. This could be a solution to the issue of obtaining sufficient RNA for sequencing from patients with low white blood cell counts. Further studies are required to determine whether the captured immune gene signatures are clinically valid and thus useful to clinicians as a diagnostic tool for patients with cancer and suspected infection.

In this register-based real-life cohort study, changes in symptom-specific hospital contacts among 12–18-year-olds following two doses of the BNT162b2 COVID-19 vaccine compared to unvaccinated peers were investigated. Using national register data, vaccinated and unvaccinated adolescents were sex and age-matched each week during the inclusion period from May to September 2021. Symptom-specific hospital contacts covering ICD-10 R diagnoses were assessed before first the vaccine dose and after the second vaccine dose. Taking previous rates of symptom-specific hospital contacts into account, differences between vaccinated and unvaccinated adolescents were found. For some hospital contacts, higher rates were seen among the vaccinated, and for others, higher rates were seen among the unvaccinated. Unspecific cognition symptoms may be important to monitor in vaccinated girls, and likewise for throat and chest pain in vaccinated boys within the first months post-vaccination. In perspective, symptom-specific hospital contacts after vaccination against COVID-19 must be assessed by taking the risk of infection and symptoms following COVID-19 infection into account.

Summary: Background: The purpose of this study was to investigate prevalence of self-reported symptom burden during the acute phase of SARS-CoV-2 infection and associated factors including sex differences. Methods: All Danish adolescents aged 15–18 years with laboratory confirmed SARS-CoV-2 infection between January 2020 and July 2021 were invited to participate. A survey covered the initial four weeks of SARS-CoV-2 infection and included questions regarding 17 symptoms associated with acute COVID-19, symptom burden and medical history. Statistical analyses included descriptive statistics and logistic regression. Findings: A total of 24,315 adolescents with SARS-CoV-2 infection were invited and 6630 (27.3%) completed the questionnaire. The median age was 17.6 years, and 58.4% (n = 3873) were female. No symptoms were reported by 33.8% (n = 2241), mild perceived symptom burden by 57.2%(n = 3775), and severe symptom burden by 9.0 % (n = 594). Two thirds (n = 2999) of the symptomatic participants reported a symptom duration of 1–10 days. The most prevalent symptoms included headaches 39.2% (n = 2597), a reduced sense of smell 36.2% (n = 2398), cough 31.6% (n = 2093), sore throat 31.1% (n = 2063), and a reduced sense of taste 31.1% (n = 2062). Adolescents at the age of 18 years had higher odds of reporting ≥6 symptoms OR1.47 (95%CI, 1.23–1.76), p

This study investigated self-reported short- and long-term symptoms among adolescents receiving the BNT162b2 (Pfizer/BioNTech) vaccine against SARS-CoV-2 and those who did not. A retrospective cohort study based on Danish national survey (collected between 20 July and 15 September 2021) and register data was conducted. Differences in short-term (two months) symptoms were explored using logistic regression adjusted for confounders. A total of 747 vaccinated (first dose n = 326; second dose n = 421) and 6300 unvaccinated adolescents were included in analyses of short-term symptoms and 32 vaccinated and 704 unvaccinated adolescents in long-term symptom analyses. In the first 14 days after the first and second vaccine dose the most reported symptoms included headache and muscle or joint symptoms. In both vaccinated and unvaccinated adolescents, the 15–19-year-olds reported significantly higher proportions of all symptoms compared to the 12–14-year-olds. After the second vaccine dose vaccinated 12–14-year-olds reported significantly more headache in adjusted analyses (OR 2.20 (95% CI 1.24; 3.90)). Among the 15–19-year-olds, significantly more vaccinated adolescents reported gastrointestinal symptoms (1.38 (1.06; 1.81)), headache (1.66 (1.24; 2.22)), and tiredness (1.44 (1.08; 1.93)). No differences were found in long-term symptoms. Vaccinated adolescents reported significantly more short-term symptoms including headache, tiredness, and gastrointestinal symptoms after the second vaccine dose than unvaccinated adolescents. Long-term symptom results should be interpreted with caution due to limited sample size.

Relapse of neonatal meningitis is most commonly caused by Escherichia coli. Management to prevent relapse varies and evidence is limited. We present four cases of relapsing neonatal E. coli meningitis in Denmark in 2016–2017 and review the current literature on this subject. During the primary episodes, our patients received cephalosporin for 3 weeks and gentamicin for the first 3 days. The only identified risk factor was delayed CSF sterilization in three of four cases and no repeated lumbar puncture. Relapse occurred after 2–28 days; one case with ventriculitis and one with empyema. Relapses were treated for 6–14 weeks with monotherapy. No children had an underlying disease predisposing to E. coli meningitis. There is generally a trend towards reducing invasive procedures, e.g., lumbar puncture and the length of intravenous antibiotics in pediatric infectious diseases, but our cases highlight a condition where the opposite might be needed.