Bacterial Colonisation of the Nasal and Nasopharyngeal Cavities in Children: The Generation R Study

Humans are surrounded by microorganisms: viruses, bacteria, fungi and parasites. We can divide these organisms into the following four categories: innocent, beneficial, harmful and dangerous. Most of the times, microorganisms are not harmful and are therefore referred to as non-pathogenic. Innocent microorganisms cause no harm nor do they provide benefits. Benefi cial microorganisms even provide a significant advantage for humans by aiding digestion or preventing pathogenic microorganisms to cause infection via colonisation resistance. By colonising the respiratory and/or gastro-intestinal tract, these organisms prevent pathogenic microorganisms to settle and cause harm. Pathogens causing harm in certain cases, but not per definition, are grouped into the harmful category. However, microbes that fall into the dangerous category comprise organisms that cause morbidity and mortality in humans even in those with an intact immune system

Risk factors for otitis media in children with special emphasis on the role of colonization with bacterial airway pathogens: the Generation R study

Acute otitis media is the most frequent diagnosis in children visiting physicians’ offices. Risk factors for otitis media have been widely studied. Yet, the correlation between bacterial carriage and the development of otitis media is not entirely clear. Our aim was to study in a population-based prospective cohort the risk factors for otitis media in the second year of life with special emphasis on the role of colonization with Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The study was embedded in the Generation R Study. Data on risk factors and doctor-diagnosed otitis media were obtained by midwives, hospital registries and postal questionnaires in the whole cohort (n = 7,295). Nasopharyngeal swabs were obtained at the age of 1.5, 6 and 14 months in the focus cohort (n = 1,079). Of these children, 2,515 (47.2%) suffered at least one period of otitis media in their second year of life. The occurrence of otitis media during the follow-up period in the first 6 months of life and between 6 and 12 months of age was associated with the risk of otitis media in the second year of life (aOR, 1.83 95% CI 1.24–2.71 and aOR 2.72, 95% CI 2.18–3.38, respectively). Having siblings was associated with an increased risk for otitis media in the second year of life (aOR 1.42, 95% CI 1.13–1.79). No associations were found between bacterial carriage in the first year of life and otitis media in the second year of life. In our study, otitis media in the first year of life is an independent risk factor for otitis media in the second year of life. Surprisingly, bacterial carriage in the first year of life did not add to this risk. Moreover, no association was observed between bacterial carriage in the first year of life and otitis in the second year of life

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children From Wild-type to Population Immunity:A Prospective Multicenter Cohort Study With Real-time Reporting

BACKGROUND: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. METHODS: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. RESULTS: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. CONCLUSIONS: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections.</p

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children From Wild-type to Population Immunity:A Prospective Multicenter Cohort Study With Real-time Reporting

BACKGROUND: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. METHODS: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. RESULTS: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. CONCLUSIONS: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections.</p

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.</p

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.</p

Risk Factors for Severe Pediatric Invasive Group A Streptococcal Disease

Importance: An increase in pediatric cases of invasive group A streptococcus (iGAS) disease was noted in the Netherlands starting in early 2022. GAS disease can range from mild to life-threatening invasive infections. Clinical and public health decisions rely on timely and detailed reporting of clinical data. Objective: To determine risk factors associated with severe pediatric iGAS, defined as requiring admission to an intensive care unit and/or death, and to analyze pediatric iGAS incidence, presentations, and outcome between pre-COVID-19 pandemic (January 2015 to March 2020), COVID-19 pandemic (April 2020 to December 2021), and post-COVID-19 pandemic (January 2022 to June 2024) periods.Design, Setting, and Participants: This observational, retrospective and prospective cohort study in 20 hospitals (tertiary and nontertiary) in the Netherlands was conducted from January 2015 to June 2024, with real-time reporting of data on the study website since January 2022. Children aged 0 to 17 years with iGAS (positive culture or polymerase chain reaction test and/or clinical presentation) were included. Exposure:iGAS infection. Main Outcome and Measures: The primary outcome was risk factors for severe iGAS; secondary outcomes included iGAS incidence rate and clinical phenotypes prior, during, and after the COVID-19 pandemic. Risk factors for severity and mortality were analyzed using univariable and multivariable logistic regression analyses, and incidence rate ratios (IRRs) between pre-COVID-19 and postCOVID-19 pandemic periods were calculated using Poisson regression. Results: Of 617 children included, 351 (56.9%) were aged 0 to 4 years. For the 192 participants with detailed data collection, median (IQR) age was 4.2 (1.7-7.1) years and 91 (47.4%) were male. iGAS cases decreased during the COVID-19 pandemic and increased significantly in the post-COVID-19 period (IRR, 2.93; 95%, 2.46-3.49), as compared with the pre-COVID-19 pandemic period. By late 2023, the incidence of iGAS returned to pre-COVID-19 pandemic levels. Factors associated with increased risk of severe disease included a post-COVID-19 pandemic diagnosis (odds ratio [OR], 3.49; 95% CI, 2.31-6.26), pulmonary involvement (OR, 8.64; 95% CI, 5.50-13.55), streptococcal toxic shock syndrome (STSS; OR, 11.71; 95% CI, 4.39-31.18), and meningitis or encephalitis (OR, 4.38; 95% CI, 4.39-31.18). Clinical factors associated with increased risk of severe disease were reduced consciousness (OR, 7.61; 95% CI, 1.84-34.41), dyspnea (OR, 9.89; 95% CI, 3.04-32.14), abnormal auscultation (OR, 6.32; 95% CI, 2.18-18.32), and elevated C-reactive protein (OR, 6.32; 95% CI, 2.18-18.32), while estimated glomerular filtration rate was associated with a decreased risk (OR, 0.64; 95% CI, 0.49-0.84). Disease severity increased in post-COVID-19-pandemic cases, with higher mortality (13 of 294 cases [4.4%] vs 3 of 218 cases [1.4%]) and intensive care admission rates (113 of 294 cases [38.4%] vs 34 of 218 cases [15.6%]), as compared with pre-COVID-19 pandemic cases. Severity of pulmonary iGAS was similar in both periods. In the post-COVID-19 pandemic period, there was a significant increase in the incidence of pulmonary infections (IRR, 5.04; 95% CI, 3.27-7.97) , STSS (IRR, 10.30; 95% CI, 3.88-35.60), meningitis or encephalitis (IRR, 12.30; 95% CI, 4.14-52.70), and necrotizing fasciitis (IRR, 26.10; 95% CI, 5.14-475.00). Conclusions and Relevance: In this cohort study, risk factors for a complicated course of iGAS in children included pulmonary or central nervous system involvement, STSS, reduced consciousness or pulmonary clinical signs, elevated CRP, and decreased eGFR. Awareness of these risk factors is important to improve timely recognition of at-risk cases and improve clinical outcomes.</p