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.

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.

The introduction of allergenic foods and the development of reported wheezing and eczema in childhood: the Generation R study.

OBJECTIVE: To examine whether the timing of introduction of the allergenic foods cow's milk, hen's egg, peanuts, tree nuts, soy, and gluten is associated with eczema and wheezing in children 4 years of age or younger. DESIGN: Population-based prospective cohort study from fetal life until young adulthood. SETTING: Rotterdam, the Netherlands, from April 2002 through January 2006. PARTICIPANTS: A total of 6905 preschool children participating in the Generation R study. MAIN EXPOSURE: Timing of introduction of cow's milk, hen's egg, peanuts, tree nuts, soy, and gluten collected by questionnaires at 6 and 12 months of age. MAIN OUTCOME MEASURES: Information on the outcomes eczema and wheezing were obtained by questions from the age-adapted version of the "International Study of Asthma and Allergies in Childhood" core questionnaire and questionnaire data on parentally reported physician diagnosis for eczema. RESULTS: Of 6905 children, wheezing was reported in 31% at age 2 years and in 14% at ages 3 and 4 years. Eczema was reported in 38%, 20%, and 18% of children at the ages of 2, 3, and 4 years, respectively. The introduction of cow's milk, hen's egg, peanuts, tree nuts, soy, and gluten before the age of 6 months was not significantly associated with eczema or wheezing at any age after adjustment for potential confounders (P > .10 for all comparisons). The results did not alter after stratification according to the child's history of cow's milk allergy and parental history of atopy. CONCLUSION: This study does not support the recommendation for delayed introduction of allergenic foods after age 6 months for the prevention of eczema and wheezing.

Natural antibodies against several pneumococcal virulence proteins in children during the pre-pneumococcal-vaccine era: the generation R study.

The currently available pneumococcal vaccines do not protect against all serotypes of Streptococcus pneumoniae. A shift toward nonvaccine serotypes causing colonization and invasive disease has occurred, and studies on protein-based vaccines have been undertaken. We assessed the association between specific antibodies against pneumococcal virulence proteins and colonization and respiratory tract infections (RTIs). Additionally, we assessed the extent to which colonization induces a humoral immune response. Nasopharyngeal swabs collected from children at 1.5, 6, 14, and 24 months of age were cultured for pneumococcus. Serum samples were obtained at birth and at 6, 14, and 24 months (n = 57 children providing 177 serum samples). Data were collected prior to the pneumococcal vaccine era. IgG, IgA, and IgM levels against 17 pneumococcal protein vaccine candidates were measured using a bead-based flow cytometry technique (xMAP; Luminex Corporation). Information regarding RTIs was questionnaire derived. Levels of IgG against all proteins were high in cord blood, decreased in the first 6 months and increased again thereafter, in contrast to the course of IgA and IgM levels. Specific antibodies were induced upon colonization. Increased levels of IgG against BVH-3, NanA, and SP1003 at 6 months, NanA, PpmA, PsaA, SlrA, SP0189, and SP1003 at 14 months, and SlrA at 24 months were associated with a decreased number of RTIs in the third year of life but not with colonization. Maternal antipneumococcal antibodies did not protect against pneumococcal colonization and infection. Certain antibodies against pneumococcal virulence proteins, some of which are induced by colonization, are associated with a decreased number of RTIs in children. This should be taken into account in future pneumococcal vaccine studies.

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.

The inverse correlation between Staphylococcus aureus and Streptococcus pneumoniae colonization in infants is not explained by differences in serum antibody levels in the Generation R Study.

Colonization rates of Streptococcus pneumoniae and Staphylococcus aureus are inversely correlated in infants. Several studies have searched for determinants of this negative association. We studied the association between antipneumococcal antibodies with Staphylococcus aureus colonization and the association between antistaphylococcal antibodies with pneumococcal colonization in healthy children in the pneumococcal vaccine era. In the first year of life, no association between maternal IgG levels and colonization was seen. In addition, no association between the IgG and IgA levels in the child versus colonization status was seen.

Correlation of bacterial colonization status between mother and child: the Generation R Study.

Determinants of bacterial colonization in children have been described. In the Generation R Study, a population-based cohort study, we determined whether the colonization statuses of mothers and children are correlated. Such a correlation was observed for Staphylococcus aureus and Haemophilus influenzae. Direct transmission, genetic susceptibility and/or unidentified environmental factors may play a role here.

Role of Staphylococcus aureus nasal colonization in atopic dermatitis in infants: the Generation R Study.

OBJECTIVE: To study the association between Staphylococcus aureus nasal colonization and atopic dermatitis (AD) in infancy. DESIGN: Population-based prospective cohort study of pregnant women and their children. SETTING: This project was embedded in the Generation R Study. PARTICIPANTS: A total of 1079 postnatal Dutch infants/children participated in the focus cohort. Main Exposures Nasal swabs for S aureus cultivation were taken at ages 1.5, 6, and 14 months. Main Outcome Measure Questionnaires that pertain to AD and confounders (birth weight, gestational age, sex, and parental eczema) were completed prenatally and postnatally. The outcome was AD in the first and second years of life. RESULTS: A first positive culture for S aureus at age 6 months was associated with AD prevalence in the first and second years of life (adjusted odds ratio [aOR], 2.13; 95% confidence interval [CI], 1.17-3.87; and aOR, 2.88; 95% CI, 1.60-5.19, respectively) and also with severity (aOR, 3.27; 95% CI, 1.30-8.03). Moreover, frequent colonization in the first year of life (>/=2 times) held a 4.29-fold (95% CI, 1.03- to 17.88-fold) risk of moderate to severe AD in the second year of life. CONCLUSION: Colonization with S aureus at age 6 months and frequent colonization in the first year of life are associated with AD and its severity in young children.

Dynamics and determinants of Staphylococcus aureus carriage in infancy: the Generation R Study.

Serial nasal swabs were collected at the ages of 1.5, 6, and 14 months from 443 infants in the Generation R Study. The objective was to study the dynamics and determinants of Staphylococcus aureus nasal carriage in the first year of life. The prevalence of S. aureus carriage decreased in the first year of life, from 52.1% at the age of 1.5 months to 12.9% at 14 months. Persistent carriage, defined as continuous carriage of the same S. aureus strain at the three sampling moments, was rarely detected in early infancy.

Short communication: CD4 counts of HIV-infected pregnant women and their infected children--implications for PMTCT and treatment programmes.

A considerable proportion of pregnant women and their infected children are likely to be eligible for anti-retroviral treatment. The antenatal-postnatal divide needs to be bridged with respect to the follow-up of both HIV-infected women and their exposed infants.