Exhaled Breath Condensate in Childhood Asthma: A Review and Current Perspective

Exhaled breath condensate (EBC) was introduced more than two decades ago as a novel, non-invasive tool to assess airway inflammation. This review summarizes the latest literature on the various markers in EBC to predict asthma in children. Despite many recommendations and two comprehensive Task Force reports, there is still large heterogeneity in published data. The biggest issue remains a lack of standardization regarding EBC collection, preservation, processing, and analysis. As a result, published studies show mixed or conflicting results, questioning the reproducibility of findings. A joint, multicenter research study is urgently needed to address the necessary methodological standardization

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

Epidemiology and management of nontuberculous mycobacterial disease in people with cystic fibrosis, the Netherlands

BACKGROUND: Nontuberculous mycobacteria (NTM) are opportunistic, difficult to treat pathogens. With increasing prevalence of NTM infections in people with cystic fibrosis (pwCF) and the improved life expectancy, the burden is expected to grow. METHODS: We assessed the epidemiology and management of NTM isolation and disease in pwCF in the Netherlands using a survey and retrospective, case-controlled data from the Dutch CF Registry. We determined the isolation prevalence, treatment and outcomes from 2013-2019. RESULTS: NTM isolation prevalence increased from 1.0% to 3.6% (2013-2019). This was a single NTM isolation in 53.7% of the adults and 60.0% of the children. M. abscessus and M. avium complex (MAC) were most frequent (47.1 and 30.9%). Of the treated pwCF, 48.5% attained culture conversion of M. abscessus; 54.5% for MAC. Children with an NTM isolation showed more infections with S. maltophilia and/or A. fumigatus (p < 0.001) compared to controls. In the year prior to NTM isolation, children in the NTM group had a lower mean FEV1% predicted (81.5 ± 16.7 vs. 88.6 ± 15.3, p = 0.024), while adults in the NTM group had more IV antibiotic days compared to controls (60 vs. 17, p = 0.047). In the following years, FEV1% predicted declined faster in pwCF with NTM than the control group (children: -3.8% vs. -1.6%, p = 0.023; adults: -0.7% and 0.4%, ns). CONCLUSIONS: The isolation prevalence of 3.6%, poor treatment outcomes and associated lung function decline emphasize that NTM pulmonary disease (NTM-PD) is a significant health issue among pwCF in the Netherlands. Its prevention and treatment require increased attention

Non-invasive biomarkers in paediatric asthma

Asthma is the most common chronic respiratory disease in children and adults. However, asthma is a heterogeneous disease, which makes an adequate and timely diagnosis challenging, particularly in preschool children. Wheezing is one of the most common respiratory symptoms in preschool children: 40% of young children suffer from these symptoms. However, in the majority of wheezing preschool children (70%) these symptoms are transient. It is currently hardly possible to adequately predict which wheezing children will eventually develop asthma. This results in both underdiagnosis and overdiagnosis of true asthma. Moreover, it is unclear which wheezing children will benefit from asthma treatment, which results in both undertreatment and overtreatment with (anti-inflammatory) asthma medication. This thesis investigated the usefulness of non-invasive biomarkers in the prediction of asthma and the prediction of a clinical treatment response in wheezing preschool children. For this purpose, this thesis focused on exhaled breath analysis and assessment of the gut microbiome. The findings from this thesis will improve the applicability of these newly developed non-invasive biomarkers, which might lead to improved diagnostic algorithms, better monitoring of disease, and improved treatment decision making

Exhaled Breath Analysis for Investigating the Use of Inhaled Corticosteroids and Corticosteroid Responsiveness in Wheezing Preschool Children

Exhaled breath analysis has great potential in diagnosing various respiratory and non-respiratory diseases. In this study, we investigated the influence of inhaled corticosteroids (ICS) on exhaled volatile organic compounds (VOCs) of wheezing preschool children. Furthermore, we assessed whether exhaled VOCs could predict a clinical steroid response in wheezing preschool children. We performed a crossover 8-week ICS trial, in which 147 children were included. Complete data were available for 89 children, of which 46 children were defined as steroid-responsive. Exhaled VOCs were measured by GC-tof-MS. Statistical analysis by means of Random Forest was used to investigate the effect of ICS on exhaled VOCs. A set of 20 VOCs could best discriminate between measurements before and after ICS treatment, with a sensitivity of 73% and specificity of 67% (area under ROC curve = 0.72). Most discriminative VOCs were branched C11H24, butanal, octanal, acetic acid and methylated pentane. Other VOCs predominantly included alkanes. Regularised multivariate analysis of variance (rMANOVA) was used to determine treatment response, which showed a significant effect between responders and non-responders (p &lt; 0.01). These results show that ICS significantly altered the exhaled breath profiles of wheezing preschool children, irrespective of clinical treatment response. Furthermore, exhaled VOCs were capable of determining corticosteroid responsiveness in wheezing preschool children