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.

Diabetic ketoacidosis and severe hypertriglyceridaemia in a child.

Diabetic ketoacidosis (DKA) in children with severe hypertriglyceridaemia (S-HTG) is infrequent. This case report presents a seven-year-old girl without a family history of dyslipidaemia with moderate DKA, lipaemic plasma, retinal lipaemia, and P-triglyceride 185 mmol/l. The course was uneventful on standard treatment and lipids normalized. She had abdominal pain but no biochemical or ultrasound evidence of pancreatitis. S-HTG affected laboratory analysis; CO2 could not be analyzed, and there was haemolysis and uncertain electrolyte results with P-Na+ 125 mmol/l, i.e. pseudo hyponatraemia, despite ultracentrifugation.

Herpes simplex virus infection among neonates suspected of invasive bacterial infection: a population-based cohort study.

OBJECTIVE: To estimate the incidence of neonatal herpes simplex virus (HSV) infection and the number of neonates with suspected invasive bacterial infection (IBI) needed to treat (NNT) with acyclovir to ensure prompt treatment of invasive HSV infections. DESIGN: A nationwide population-based cohort study. SETTING: All neonatal and paediatric emergency departments in Denmark from 1 January 2010 to 31 December 2019. PATIENTS: Neonates aged 0-28 days with HSV infection. MAIN OUTCOME MEASURES: The main outcome measures were incidence and NNT. The NNT was calculated based on neonates with invasive HSV infection whose onset symptoms resembled IBI and the estimated number of Danish neonates who received antibiotics for suspected IBI. RESULTS: Fifty-four neonates with HSV infection were identified, that is, an incidence of 9 per 100 000 live births. Twenty presented with symptoms resembling IBI, all within the first 14 days of life. Of 18 (78%) neonates, 14 had elevated C reactive protein, 14 of 19 (74%) had elevated alanine aminotransferase and 11 of 17 (65%) had thrombocytopaenia. The estimated NNTs with empiric acyclovir at postnatal ages 0-3, 4-7 and 8-14 days were 1139 (95% CI 523 to 3103), 168 (95% CI 101 to 726) and 117 (95% CI 48 to 198), respectively. CONCLUSIONS: The incidence of neonatal HSV infection was higher than in previous decades; however, the estimated NNT with empiric acyclovir was high. Therefore, we propose not to treat all neonates suspected of IBI with empiric acyclovir, as current European guidelines suggest. However, HSV should be considered in neonates with signs of infection, especially after the third postnatal day and in neonates with high alanine aminotransferases and thrombocytopaenia.

Hospital admissions and need for mechanical ventilation in children with respiratory syncytial virus before and during the COVID-19 pandemic: a Danish nationwide cohort study.

BACKGROUND: The incidence of respiratory syncytial virus (RSV) increased in several countries after the relaxation of COVID-19 restrictions. We aimed to investigate the age-related risk of RSV-associated hospital admissions and need for mechanical ventilation during the RSV resurgence in summer and autumn 2021 compared with the four RSV seasons preceding the COVID-19 pandemic. We also aimed to describe the clinical complications necessitating mechanical ventilation. METHODS: This population-based cohort study included patients aged 0-17 years admitted to hospital with RSV in Denmark during the RSV resurgence in summer and autumn 2021, and the four pre-COVID-19 RSV seasons (2016-17, 2017-18, 2018-19, and 2019-20). We retrieved data on RSV-associated hospital admissions from the Danish National Patient Registry and demographic and clinical details of children who received mechanical ventilation through prospective real-time data collection in 2021-22 and retrospective data collection for the 2016-17 to 2019-20 RSV seasons from all eight paediatric and neonatal intensive care units in Denmark. Risk factors for severe RSV disease were as defined as age younger than 3 months or severe comorbidities. We calculated the risk of RSV-associated hospital admissions per 100 000 population in each RSV season from week 21 to week 20 of the following year. We also calculated the risk rate of receiving mechanical ventilation per 100 000 population and 1000 RSV-associated hospital admissions during each RSV season from week 21 to week 20 of the following year. We calculated risk ratios (RRs) for hospital admission and mechanical ventilation by dividing the risk rate of hospital admission and mechanical ventilation in 2021-22 by annual mean risk rates in the four pre-COVID-19 RSV epidemics (2016-17 to 2019-20). We compared RRs using Fisher's exact test. We compared complications leading to intubation between children with and without risk factors for severe RSV disease. The study is registered at ClinicalTrials.gov, NCT05186597. FINDINGS: Among 310 423 Danish children aged younger than 5 years, the mean number of RSV-associated hospital admissions increased from 1477 (SD 226) in the 2016-17 to 2019-20 RSV seasons to 3000 in the 2021-22 RSV season (RR 2·0 [95% CI 1·9-2·1]). 54 children with RSV received mechanical ventilation in 2021-22 compared with 15-28 annually in the 2016-17 to 2019-20 RSV seasons (2·3 [1·6-3·3]). The highest increase in hospital admissions and need for mechanical ventilation occurred among children aged 24-59 months (4·1 [3·6-4·7] for hospital admission; 4·6 [1·7-12·6] for mechanical ventilation). Among children admitted to hospital, the risk of mechanical ventilation was similar in 2021-22 and the four pre-COVID-19 seasons (risk rate 14·3 per 1000 RSV-associated hospital admissions [95% CI 10·4-19·3] vs 12·9 [10·1-16·1]; RR 1·1 [95% CI 0·8-1·6]). Across all RSV seasons studied, among children younger than 3 months or those with severe comorbidities, respiratory failure due to bronchiolitis led to mechanical ventilation in 69 (79%) of 87 children. Of 46 children with no risk factors for severe RSV, 40 (87%) received mechanical ventilation due to additional complications, including neurological (n=16; 35%), cardiac (n=1; 2%), and pulmonary complications (n=23; 50%; eg, wheeze responsive to bronchodilator therapy, severe bacterial co-infections, and pneumothorax). INTERPRETATION: In Denmark, RSV disease did not seem to be more severe for the individual child during the RSV resurgence in 2021 following relaxation of COVID-19 restrictions. However, hospital admissions were higher among older children, possibly due to a postponed first RSV infection or no recent reinfection. Older children without risk factors for severe RSV disease had atypical complications that led to intubation. If new RSV-preventive interventions for healthy infants delay first RSV infection, a higher number of older children might be admitted to hospital due to atypical clinical phenotypes, rather than classical bronchiolitis. FUNDING: National Ministry of Higher Education and Science and the Innovation Fund Denmark.

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.

[Tubulointerstitial nephritis and uveitis syndrome].

Tubulointerstitial nephritis and uveitis (TINU) syndrome in children is an uncommon, underreported condition. Onset of renal and ocular symptoms is often not simultaneous with nephritis which may precede uveitis by several months. A variable treatment response and a propensity for relapse characterize the syndrome. This is a case report of a previously healthy 14-year-old boy with TINU syndrome, emphasizing the need for long-term interdisciplinary treatment and monitoring. Also, the importance of repetitive screening of patients with uveitis for renal disease and ophthalmological evaluation of children with nephritis is emphasized.