Burden of disease and cost of illness of infants less than 6 months of age hospitalised with respiratory syncytial virus in Denmark - a 10-year national register-based study.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of hospitalisation in infants aged ≤ 6 months in Western countries. Nearly 1,500 infants under six months of age are hospitalised with RSV annually in Denmark. This nationwide study describes the healthcare resource utilisation and costs related to RSV hospitalisation in this vulnerable age group. METHODS: RSV cases were identified in the Danish National Patient Register. Infants were included if they at the age of 0-5 months had a (1) respiratory related hospital admission (duration > 12 h), (2) within 10 days of a positive RSV test, (3) between January 2013 and December 2022. Each case was matched with five individuals never diagnosed with RSV on age, sex, region of residence, birth (pre/full term), number of siblings < 7 years old, and parents' education. An episode of RSV was defined as the seven days prior to hospitalisation to 30 days after initial hospitalisation. Study outcomes included contacts with hospital and primary care, and total healthcare costs defined as the sum cost of hospital care, primary care, and prescription medicine. Cost and contacts attributable to RSV was calculated in a diff-in-diff framework, as the difference between case and reference group. RESULTS: The study population comprised of 8,428 RSV cases and 41,725 reference individuals. Cases generated 1.58 (p < 0.001) attributable inpatient contacts, 0.84 (p < 0.001) outpatient contacts, and 1.19 (p < 0.001) primary care contacts during their RSV episode. An additional 0.6 (p < 0.001) inpatient, 1.08 (p < 0.001) outpatient and 2.42 (p < 0.001) primary care contacts were attributed to RSV in the year following the RSV episode. Total cost of an RSV episode was EUR 2,997 (p < 0.001) with an additional EUR 1,428 (p < 0.001) in the following year. CONCLUSION: RSV hospitalisations of infants are associated with substantial healthcare utilisation and costs. The same pattern was observed in the year following the RSV episode. If the new RSV prevention options are introduced nationwide, the overall burden of RSV is expected to be substantially reduced in the future.

Treatment of Infants and Children With SARS-CoV-2 Monoclonal Antibodies: A European Case Series.

BACKGROUND: Although severe COVID-19 in children is rare, those with certain pre-existing health conditions are more prone to severe disease. Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are potent antiviral agents that reduce adverse clinical outcomes in adults, but are commonly not approved for use in pediatric patients. METHODS: We retrospectively evaluated mAb treatment in children <12 years of age or <40kg with SARS-CoV-2 infection between January 1, 2021, and March 7, 2022, in 12 tertiary care centers in 3 European countries. RESULTS: We received data from 53 patients from Austria, Denmark and Germany. Median age was 5.4 years [0-13.8, interquartile range (IQR) = 6.2], and median body weight was 20 kg (3-50.1, IQR = 13). The most frequent SARS-CoV-2 variant in this study, if known, was Omicron, followed by Delta and Alpha. Pre-existing conditions included immunodeficiency, malignancy, hematologic disease, cardiac disease, chronic lung disease, chronic liver disease, kidney disease and diabetes. Forty-two patients received sotrovimab (79%), 9 casirivimab/imdevimab (17%) and 2 bamlanivimab (4%). All but 1 patient survived. Median duration of hospital stay was 3 days (0-56, IQR = 6). Seven patients required treatment in an intensive care unit, and 5 required high-flow nasal cannula treatment. Potential side effects included neutropenia (6/53, 11%), lymphopenia (3/53, 6%), nausea or vomiting (2/53, 4%), rise of alanine transaminase (1/53, 2%) and hypotonia (1/53, 2%). CONCLUSIONS: MAb treatment was well tolerated by children in this cohort.

Lactate as a Screening Tool for Critical Illness in a Pediatric Emergency Department.

OBJECTIVES: Lactate has in some pediatric emergency departments (PEDs) gained acceptance as a screening tool for critical illness, with cut-off values of 2.0 to 2.5 mmol/L. We aimed to investigate if lactate could predict the need of acute resuscitation in patients in a PED. PATIENTS AND METHODS: This retrospective observational cohort study included patients aged 0 to 17 years admitted to the PED at Copenhagen University Hospital in Denmark from January 1, 2019 to January 1, 2021. Patients were included if they had lactate measured as part of their routine blood sampling because of acute PED evaluation. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess the ability of lactate to predict the need of acute resuscitation. In patients without need of acute resuscitation, we calculated the lactate upper limit as the 95th percentile, and significant predictors were included in a multiple linear regression model. RESULTS: A total of 1355 children were included. Fourteen (1%) children with a need of acute resuscitation had a median lactate of 1.7 mmol/L (interquartile range, 1.4-2.3) versus 1.6 mmol/L (interquartile range, 1.3-2.1) in children without need of resuscitation ( P > 0.05). The AUC for lactate to predict acute resuscitation was 0.56 (95% confidence interval, 0.54-0.59). In children without need of acute resuscitation, the 95th percentile of lactate was 3.2 mmol/L, and 392 (29.8%) had lactate greater than 2.0 mmol/L. Increasing age and venous sampling were associated with lower lactate. Lactate was not associated with sex, pediatric early warning score, or duration of hospital admission. The 95th percentile of lactate after inhaled beta-2-agonists was 5.0 mmol/L. CONCLUSIONS: In children evaluated in a PED, lactate achieved a low AUC, suggesting a poor ability of predicting acute resuscitation. In children without need of acute resuscitation, the 95th percentile for lactate was 3.2 mmol/L, higher than the generally accepted cut-off values. This is important to recognize to avoid concern in otherwise clinically stable children. Our data did not support the use of lactate as a screening tool for early recognition of critical illness in a PED.

Unexplained fever in children-Benefits and challenges of FDG-PET/CT.

AIM: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18 FDG-PET/CT) in patients where standard investigations were non-diagnostic. METHODS: We reviewed medical records of previously healthy children who had 18 FDG-PET/CT performed at Copenhagen University Hospital in 2015-2020 due to unexplained fever. RESULTS: Thirty-five of 819 paediatric 18 FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18 FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18 FDG-uptake, but 18 FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18 FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). CONCLUSION: 18 FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18 FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

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.

[COVID-19 among children and adolescents].

Children and adolescents infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are usually asymptomatic or have mild coronavirus disease (COVID-19) with low rates of hospitalization and death. Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe complication of SARS-CoV-2 infection. This paper reviews an excerpt of the literature on disease burden and complications following COVID-19 in children and adolescents aged 0-17 years, in addition to the effects and adverse drug reactions of BNT162b2 and mRNA-1273 vaccinations among children and adolescents aged 5-17 years.

[Varicella vaccination].

Chickenpox is generally considered a benign childhood disease. However, serious complications may arise. A safe and efficient vaccine is available, and universal chickenpox vaccination is already introduced in many countries. Denmark, among other countries, has been reluctant to introduce the vaccine due to insufficient information on disease burden and concerns regarding herpes zoster incidence and a potential age shift. In this review, we present current knowledge regarding the disease burden of chickenpox in Denmark and discuss perspectives on introducing the vaccine in Denmark.

Antimicrobial Susceptibility among Gram-Negative Isolates in Pediatric Patients in Europe from 2013-2018 Compared to 2004-2012: Results from the ATLAS Surveillance Study.

AIMS: Data on antimicrobial resistance (AMR) in the paediatric patient population are scarce. This study assessed the AMR rates and phenotype distribution of Gram-negative isolates in paediatric patients in Europe from 2004-2012 and 2013-2018. METHODS: Isolates that were collected were stratified by age groups (< 1, 1-5, 6-12, and 13-17 years) and regions (North-Western, Eastern and Southern Europe). Minimal inhibitory concentrations (broth microdilution) were interpreted according to European Committee on Antimicrobial Susceptibility Testing guidelines. Resistance rates and phenotype prevalence were identified for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Haemophilus influenzae. RESULTS: In the overall paediatric patient population (0-17 years), extended-spectrum beta-lactamase (ESBL) production significantly decreased (from 20.7% to 15.4%, P < 0.0001) in Escherichia coli, whereas it increased for Klebsiella pneumoniae (from 35.0% to 39.2%, P = 0.015). Carbapenem resistance was highest for Acinetobacter baumannii (32.3%) compared with Klebsiella pneumoniae (4.7%) and Pseudomonas aeruginosa (12.4%) in 2013-2018, and rates were significantly increased relative to 2004-2012. There was no change in resistance to beta-lactam antimicrobials for Haemophilus influenzae. The lowest resistance rates for most organism groups were observed in North-Western Europe. CONCLUSIONS: The results revealed a significant increase in Klebsiella pneumoniae isolates with an ESBL and carbapenem-resistance phenotype as well as in carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa from 2004-2012 to 2013-2018. Conversely, a decrease in ESBL E. coli was observed. Continued surveillance and awareness of resistance in these bacteria causing serious infections is crucial for improving treatment quality in paediatric patients.

Immunity to vaccine-preventable diseases among paediatric healthcare workers in Denmark, 2019.

BackgroundHealthcare workers (HCW) have been identified as index cases in disease outbreaks of vaccine-preventable diseases (VPD) in hospitals.AimWe investigated whether Danish paediatric HCW were protected against selected serious VPD.MethodsWe included 90% of staff members from two paediatric departments. All 555 HCW (496 women) supplied a blood sample for serology and filled in a questionnaire. Antibodies were measured with enzyme immunoassay against measles, mumps, rubella (MMR), varicella zoster, pertussis toxin and diphtheria toxin.ResultsProtective levels of IgG were found for measles (90.3%), mumps (86.5%), rubella (92.3%), varicella (98.6%) and diphtheria (80.5%). We found seropositivity for all three MMR components in 421 (75.9%) HCW, lowest in those younger than 36 years (63.3%). Only 28 (5%) HCW had measurable IgG to pertussis. HCW with self-reported immunity defined as previous infection or vaccination, had protective levels of IgG against measles, mumps, rubella and varicella in 87.4-98.8% of cases, not significantly higher than in those not reporting immunity. Previous history of disease had a high positive predictive value (PPV) of 96.8-98.8%. The PPV for previous vaccination ranged from 82.5% to 90.3%. In contrast, negative predictive values of self-reported history of disease and vaccination were remarkably low for all diseases.ConclusionThe immunity gaps found primarily in young HCW indicate a need for a screening and vaccination strategy for this group. Considering the poor correlation between self-reported immunity and seropositivity, efforts should be made to check HCW's immune status in order to identify those who would benefit from vaccination.

Barriers for vaccination of healthcare workers.

Outbreaks of vaccine preventable diseases (VPDs) in hospital settings remain a challenge even in countries with established (childhood-) vaccination programs. Healthcare workers (HCWs) with an updated vaccination card play an important role in reducing the risk of nosocomial spread of VPDs. Yet, in many places, HCWs report their immunization status to be unknown or not updated. In times of a global pandemic, the debate on vaccination of HCWs is as hot as ever; do HCWs have an increased responsibility to get vaccinated against VPDs? If so, how do we increase vaccination uptake rates among HCWs? Mandatory vaccination against VPDs for HCWs has been introduced in some countries, but it may cause ethical dilemmas and not be culturally acceptable everywhere. We looked at vaccination policies and HCWs' attitudes toward immunization against VPDs. We found that missing vaccine policies and lack of knowledge of VPDs, vaccination benefits, as well as inadequate organization around HCWs' immunizations were important barriers to have a complete vaccination record. A systematic approach to employees providing information of VPDs and vaccinations, going through their vaccination cards and offering antibody testing where appropriate or a shot of a missing vaccine could support staff to adhere to vaccination schemes.

[Malignant pertussis in a three-week-old girl].

Whooping cough is an infectious disease caused by Bordetella pertussis. Particularly children under the age of six months can be severely affected by the infection. Severe leukocytosis may lead to thrombosis and pulmonary hypertension and eventually circulatory failure and death. This a case report of a three-week-old girl with malignant pertussis, who due to respiratory insufficiency was mechanically ventilated, and her severe leucocytosis was treated with exchange blood transfusion. Whooping cough may partially be prevented with efficient vaccination programmes.

Self-reported immunity and opinions on vaccination of hospital personnel among paediatric healthcare workers in Denmark.

BACKGROUND: Denmark has no general recommendations for vaccination of healthcare workers (HCWs). We explored the self-reported immunity to varicella, measles, mumps, and rubella, reasons for receiving the influenza vaccine or not, and opinions on vaccination of HCWs against varicella, MMR, pertussis, diphtheria, and influenza among staff from departments with a high risk of exposure to infectious agents. METHODS: From May 2019 to August 2019, a structured questionnaire was distributed to clinical and non-clinical HCWs at a tertiary and a general paediatric department in Denmark. Self-reported immunity was defined as either previous infection or vaccination against the disease. RESULTS: Of 619 employed HCWs, 555 (90%) were included. A large proportion were unsure of or denied previous vaccination or infection with measles (20.1%), mumps (30.2%), rubella (21.4%), varicella (12.1%), pertussis (44.1%), and diphtheria (32.1%). Non-clinical personnel and employees born in 1974-1983 had the lowest level of self-reported immunity. Mandatory vaccination of non-immune HCWs was approved by 54-68.9% of participants, and any kind of vaccination (mandatory or as an offer at hospitals) was approved of up to 95.3% of all participants depending on the disease. During the season 2018/19, 214 (38.6%) HCWs received the influenza vaccine, including 20.3% of non-clinical staff, 34.8% of nurses and 56.5% of doctors (P < 0.001). Reasons for lack of vaccine uptake were mainly employees considering themselves rarely sick, the vaccine was not regarded as necessary, forgetfulness or lack of time. Only 37.8% was in favour of mandatory influenza vaccination. CONCLUSIONS: A large proportion of paediatric HCWs were not aware of their immune status against important vaccine-preventable diseases. >90% supported vaccination of HCWs, with two out of three supporting mandatory MMR, pertussis and diphtheria vaccination. Better information and an official immunisation policy of non-immune HCWs in Denmark is warranted.

Children Hospitalized With Varicella in Denmark: Sensitivity of the National Patient Register.

BACKGROUND: Varicella, common in childhood and most often self-limiting, may cause complications including bacterial superinfection, pneumonia and encephalitis. Universal childhood varicella vaccination has been introduced in several countries, but is controversial in Europe. In Denmark, varicella is not part of the national immunization program and there is no national surveillance of varicella. The primary aim of the study was to describe the epidemiology and clinical characteristics of children hospitalized with varicella in Denmark. The secondary aim was to validate the sensitivity and completeness of the Danish National Patient Register. METHODS: Active surveillance of children hospitalized with varicella was carried out at 4 pediatric departments. In the Danish National Patient Register, we identified all children discharged with an International Classification of Diseases, 10th revision code of varicella from the 4 departments. We used a capture-recapture analysis to estimate the "true" number of hospitalized children with varicella. RESULTS: By active surveillance, we identified 86 children eligible for clinical description. In 87% of cases, the children were 0-4 years of age. Complications were identified in 69% of patients, including 1 child with postvaricella cerebral angiopathy. In the National Patient register (NPR), we identified 125 children with a discharge diagnosis of varicella. By capture-recapture analysis, the sensitivity of the NPR was estimated to be 74%. CONCLUSIONS: Varicella can cause serious complications including cerebral angiopathy in children in Denmark. The NPR will be a useful tool for estimating hospitalization incidence, but will underestimate the true number of hospitalizations.

Best oral empirical treatment for pyelonephritis in children: Do we need to differentiate between age and gender?

BACKGROUND: Pyelonephritis is a common infection in childhood and may cause renal scarring. The aim was to determine an effective oral antibiotic treatment of first time pyelonephritis in children. METHODS: The study is a retrospective analysis of positive urine cultures collected at a Danish paediatric department from 2010-2013. Urine samples from 378 children aged 0-15.9 years, without renal anomalies and treated for first time pyelonephritis, were included. The urine pathogens and antimicrobial susceptibilities were analysed. RESULTS: The most common aetiologic agents found were Escherichia coli (85%), Klebsiella species and other Enterobacteriaecea (9.7%) and Enterococcus species (5.3%). Escherichia coli was significantly more common in girls than in boys (90% vs 74%, p < 0.001) and in children older than 6 months (89% vs 77%, p < 0.001). Children younger than 6 months had a higher prevalence of other Gram-negative rods (16% vs 7%, p < 0.001). These differences may be due to boys representing 63% of patients in the youngest age group compared to 16% of older children (p < 0.001). For all urine isolates, piv-mecillinam and amoxicillin-clavulanate had the lowest resistance rates of 6.9% and 7.2%, respectively, and 6% for both antimicrobials in patients older than 6 months. Uropathogens from boys above 6 months of age were more resistant to piv-mecillinam compared to girls (25% vs 2.4%, p < 0.001). CONCLUSION: This study recommends piv-mecillinam or amoxicillin-clavulanate as empirical treatment of first time pyelonephritis in Danish children from 6 months of age. Age and gender of patients should be taken into consideration when initiating empirical treatment.

Clinical characteristics and laboratory findings in Danish children hospitalized with primary Epstein-Barr virus infection.

BACKGROUND: Epstein-Barr virus (EBV) positive infectious mononucleosis (IM) is a common disease in adolescents. However, IM is often considered a rare disease in early childhood. We aimed to describe the classical presentation of adolescent EBV-associated IM compared to EBV infection at younger age. METHODS: All immunocompetent children hospitalized at Hvidovre University Hospital, Copenhagen between 2002 and 2013, who presented with clinical features that prompted a laboratory test for EBV, and who tested positive by presence of EBV-specific antibodies, heterophile antibodies or a positive EBV PCR were included (n = 95). RESULTS: Children aged 1-2 years were the age group most commonly hospitalized with acute EBV infection (27% of the cohort), followed by teenagers aged 14-15 years (23%). Fever, cervical lymphadenopathy, tonsillitis and fatigue were the most common physical findings overall. Dividing the children into three age groups (0-4 years, 5-10 years and 11-15 years) revealed that the oldest age groups significantly more often suffered from headache, tonsillitis, sore throat, abdominal pain and nausea. Young children typically presented with a runny nose, fever, fatigue and cervical adenitis. Compared with children under 5, children aged 5-15 years more often showed lymphocytosis (84% vs 62%), elevated alanine aminotransferase (77% vs 33%) and lactate dehydrogenase (79% vs 44%). CONCLUSION: EBV infection is common in young children, and children less than 3 years of age constitute the largest group of hospitalizations for acute EBV infection. EBV-associated IM should be suspected in febrile children of all ages with tonsillitis, lymphadenopathy, lymphocytosis and elevated liver enzymes.

Absence of novel human parvovirus (PARV4) in Danish mothers and children.

BACKGROUND: The recently discovered human parvovirus 4 (PARV4) is found most frequently in injection drug users, HIV-positive patients, and in haemophiliacs. Studies from Ghana report the finding of PARV4 in plasma from 2 to 12% of children without acute infection, and in nasal secretions and faecal samples. Studies of PARV4 in children from industrialized countries are few. OBJECTIVES: We aimed to describe the occurrence of PARV4 in a population-based birth cohort of 228 Danish mothers and their healthy children who previously participated in a study of respiratory tract infections in infancy. STUDY DESIGN: Children were included over a whole calendar year and were monitored through monthly home visits through the first year of life. Plasma samples for the present study were available from 228 mothers, 176 newborns, and 202 12-months-old children. All samples were analysed for the presence of PARV4 antibodies by enzyme immunoassay, and samples with detectable antibodies were in addition studied by real-time PCR. RESULTS: One (0.4%) of 228 mothers had PARV4 IgG exceeding the cut-off absorbance level and another had borderline IgG reactivity. No mother among these two had an acute infection, as they were IgM and PARV4 DNA negative. All blood samples from newborns and one-year-old children had IgG and IgM reactivity below cut-off. CONCLUSIONS: PARV4 is rare in Danish mothers and infants. Further studies are needed, in both rural and urban settings, to investigate the epidemiology and clinical significance of this novel human parvovirus.

Low Prevalence of Parvovirus 4 in HIV-infected Children in Denmark.

Parvovirus 4 (PARV4) has been associated with HIV infection in adults. We examined plasma samples from 46 HIV-infected 0-year-old to 16-year-old children for the presence of PARV4. Four children (8.7%) had detectable PARV4 IgG and 1 had IgM. The result of PARV4 polymerase chain reaction was found to be negative in all patients. PARV4 seropositivity was associated with low CD4 count but not with HIV viral load.