Lilly M. Verhagen’s research while affiliated with Radboud University Medical Centre (Radboudumc) and other places

Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL; P = 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.

Background. Bacillus Calmette-Guerin (BCG) vaccination has been hypothesised to reduce SARS-CoV-2 infection, severity, and/or duration via trained immunity induction. Methods. Healthcare workers (HCWs) in 9 Dutch hospitals were randomised to BCG or placebo vaccination (1:1) in March/April 2020 and followed for one year. They reported daily symptoms, SARS-CoV-2 test results, and healthcare-seeking behaviour via a smartphone application, and donated blood for SARS-CoV-2 serology at two time points. Results. 1,511 HCWs were randomised and 1,309 analysed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio=0.95; 95% confidence interval 0.76-1.21; p=0.732). Only three participants required hospitalisation for COVID-19. The proportions of participants with asymptomatic, mild, or mild-to-moderate infections, and the mean infection durations, did not differ between randomisation groups. Unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes either. The percentage of participants with seroconversion (7.8% versus 2.8%; p=0.006) and mean anti-S1 antibody concentration (13.1 versus 4.3 IU/ml; p=0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months post-vaccination. Conclusions. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (on a scale from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection.

Background: Suboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level. Methods: We systematically searched MEDLINE, Embase, and Web of Science (1990-2021) for pharmacokinetic studies of first-line antituberculosis drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-recommended paediatric doses. Determinants of AUC0-24 and Cmax were assessed with linear mixed-effects models. Results: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means (95% CIs) of steady-state AUC0-24 were summarised for isoniazid (18.7 [15.5-22.6] h·mg·L-1), rifampicin (34.4 [29.4-40.3] h·mg·L-1), pyrazinamide (375.0 [339.9-413.7] h·mg·L-1), and ethambutol (8.0 [6.4-10.0] h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all antituberculosis drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0-24. Conclusion: This study provides the most comprehensive estimates of plasma exposures to first-line antituberculosis drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Background Many studies support the protective effect of breastfeeding on respiratory tract infections. Although infant formulas have been developed to provide adequate nutritional solutions, many components in human milk contributing to the protection of newborns and aiding immune development still need to be identified. In this paper we present the methodology of the “Protecting against Respiratory tract lnfections through human Milk Analysis” (PRIMA) cohort, which is an observational, prospective and multi-centre birth cohort aiming to identify novel functions of components in human milk that are protective against respiratory tract infections and allergic diseases early in life. Methods For the PRIMA human milk cohort we aim to recruit 1000 mother–child pairs in the first month postpartum. At one week, one, three, and six months after birth, fresh human milk samples will be collected and processed. In order to identify protective components, the level of pathogen specific antibodies, T cell composition, Human milk oligosaccharides, as well as extracellular vesicles (EVs) will be analysed, in the milk samples in relation to clinical data which are collected using two-weekly parental questionnaires. The primary outcome of this study is the number of parent-reported medically attended respiratory infections. Secondary outcomes that will be measured are physician diagnosed (respiratory) infections and allergies during the first year of life. Discussion The PRIMA human milk cohort will be a large prospective healthy birth cohort in which we will use an integrated, multidisciplinary approach to identify the longitudinal effect human milk components that play a role in preventing (respiratory) infections and allergies during the first year of life. Ultimately, we believe that this study will provide novel insights into immunomodulatory components in human milk. This may allow for optimizing formula feeding for all non-breastfed infants.

Background Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related disease, but little is known about children living in settings with high tuberculosis and HIV burden. This study reflects clinical data on South African children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We collected clinical data of children aged younger than 13 years with laboratory confirmed SARS-CoV-2 presenting to Tygerberg Hospital, Cape Town between 17th of April and 24th of July 2020. Results Hundred and fifty-nine children (median age 48·0 months (interquartile range, IQR 12·0-106·0)) were included. Hospitalized children (n=62), median age of 13·5 months (IQR 1·8-43·5) were younger than children not admitted (n=97), median age 81·0 months (IQR 34·5-120·5, p< 0·01). Thirty-three of 159 (20·8%) children had pre-existing medical conditions. Fifty-one of 62 (82·3%) hospitalized children were symptomatic; lower respiratory tract infection was diagnosed in 21/51 (41·2%) and 11/16 (68·8%) children younger than 3 months of age. Respiratory support was required in 25/51 (49·0%) children; 13/25 (52·0%) children were younger than 3 months. One child was HIV infected and 11/51 (21·2%) were HIV exposed uninfected and 7/51 (13·7%) children had a recent or new diagnosis of tuberculosis. Conclusion Children less than 1 year of age hospitalized with SARS-CoV-2 in Cape Town frequently required respiratory support, the access to oxygen may be limited in some LMICs which could potentially drive morbidity and mortality. HIV infection was uncommon but a relationship between HIV exposure, tuberculosis and SARS-CoV-2 should be explored.

Introduction The simultaneous increased prevalence of atopic diseases and decreased prevalence of infectious diseases might point to a linkbetween the two entities. Past work mainly focused on either atopic diseases or recurrent infections. We aim to investigatewhetherrisk factorsfor atopicdiseases(i.e. asthma, allergic rhinitis, atopic dermatitis and/orfood allergy)differ from risk factors for recurrent respiratory tract infections (RRTIs) in children. Methods Cross‐sectional data were used from 5517 children aged 1‐18 years who participated in an Electronic Portal for children between 2011 and 2019. Univariable/multivariable logistic regression analyses were performed to determine risk factors forany atopic disease and RRTIs. Results Children aged ≥5 years were more likely to have any atopic disease (adjusted Odds Ratio, OR, 1.50‐2.77)and less likely to have RRTIs (OR 0.68‐0.84) compared to children aged <5 years. Female sex (OR 0.72; 95% CI 0.63‐0.81), low birth weight (OR 0.74; 95% CI 0.57‐0.97) and dog ownership (OR 0.79; 95% CI 0.66‐0.95) reduced the odds of any atopic disease, but not ofRRTIs.Day care attendance (OR 1.22; 95% CI 1.02‐1.47) was associated with RRTIs, but not with atopic diseases. Afamily history of asthma, allergic rhinitis, atopic dermatitis and RRTIs was significantly associated with the same entity in children, with OR varying from 1.58 (95% CI 1.35‐1.85) in allergic rhinitis to 2.20 (95% CI 1.85‐2.61) in asthma. Conclusion Risk factors for atopic diseases are distinct from risk factors for RRTIs, suggesting that the changing prevalence of both entities is not related to shared risk factors. This article is protected by copyright. All rights reserved.