Public health impact and return on investment of Belgium's pediatric immunization program.

Objective: We evaluated the public health impact and return on investment of Belgium's pediatric immunization program (PIP) from both healthcare-sector and societal perspectives. Methods: We developed a decision analytic model for 6 vaccines routinely administered in Belgium for children aged 0-10 years: DTaP-IPV-HepB-Hib, DTaP-IPV, MMR, PCV, rotavirus, and meningococcal type C. We used separate decision trees to model each of the 11 vaccine-preventable pathogens: diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, measles, mumps, rubella, Streptococcus pneumoniae, rotavirus, and meningococcal type C; hepatitis B was excluded because of surveillance limitations. The 2018 birth cohort was followed over its lifetime. The model projected and compared health outcomes and costs with and without immunization (based on vaccine-era and pre-vaccine era disease incidence estimates, respectively), assuming that observed reductions in disease incidence were fully attributable to vaccination. For the societal perspective, the model included productivity loss costs associated with immunization and disease in addition to direct medical costs. The model estimated discounted cases averted, disease-related deaths averted, life-years gained, quality-adjusted life-years gained, costs (2020 euros), and an overall benefit-cost ratio. Scenario analyses considered alternate assumptions for key model inputs. Results: Across all 11 pathogens, we estimated that the PIP prevented 226,000 cases of infections and 200 deaths, as well as the loss of 7,000 life-years and 8,000 quality-adjusted life-years over the lifetime of a birth cohort of 118,000 children. The PIP was associated with discounted vaccination costs of €91 million from the healthcare-sector perspective and €122 million from the societal perspective. However, vaccination costs were more than fully offset by disease-related costs averted, with the latter amounting to a discounted €126 million and €390 million from the healthcare-sector and societal perspectives, respectively. As a result, pediatric immunization was associated with overall discounted savings of €35 million and €268 million from the healthcare-sector and societal perspectives, respectively; every €1 invested in childhood immunization resulted in approximately €1.4 in disease-related cost savings to the health system and €3.2 in cost savings from a societal perspective for Belgium's PIP. Estimates of the value of the PIP were most sensitive to changes in input assumptions for disease incidence, productivity losses due to disease-related mortality, and direct medical disease costs. Conclusion: Belgium's PIP, which previously had not been systematically assessed, provides large-scale prevention of disease-related morbidity and premature mortality, and is associated with net savings to health system and society. Continued investment in the PIP is warranted to sustain its positive public health and financial impact.

A molecular understanding of citrate adsorption on calcium oxalate polyhydrates.

Calcium oxalate precipitation is a common pathological calcification in the human body, whereby crystallite morphology is influenced by the chelating properties of biological ions such as citrate. It has been suggested that citrate could steer oxalate formation towards its dihydrated form and away from the monohydrated form, which was identified as a major cause for disease. To assess the influence of the citrate ion on the resulting calcium oxalate, surface energies were calculated at the dispersion-corrected density functional level of theory for both monohydrated and dihydrated calcium oxalate. Different adsorption geometries were considered by varying the attacking angle of citrate as well as by considering the citrate ion on top of an adsorbed water layer or penetrating the water layer. The obtained results were compared to ab initio molecular dynamics simulations and experimental scanning electron microscope images. A strong preference for citrate adsorption on calcium oxalate dihydrate was observed, suggesting medical applications for the treatment of such pathological calcifications.

Activation of epithelial and inflammatory pathways in adolescent elite athletes exposed to intense exercise and air pollution.

RATIONALE: Participation in high-intensity exercise in early life might act as stressor to the airway barrier. OBJECTIVES: To investigate the effect of intense exercise and associated exposure to air pollution on the airway barrier in adolescent elite athletes compared with healthy controls and to study exercise-induced bronchoconstriction (EIB) in this population. METHODS: Early-career elite athletes attending 'Flemish-Elite-Sports-Schools' (12-18 years) of 4 different sport disciplines (n=90) and control subjects (n=25) were recruited. Presence of EIB was tested by the eucapnic voluntary hyperventilation (EVH) test. Markers at mRNA and protein level; RNA-sequencing; carbon load in airway macrophages were studied on induced sputum samples. RESULTS: 444 genes were differentially expressed in sputum from athletes compared with controls, which were related to inflammation and epithelial cell damage and sputum samples of athletes contained significantly more carbon loaded airway macrophages compared with controls (24%, 95% CI 20% to 36%, p<0.0004). Athletes had significantly higher substance P (13.3 pg/mL, 95% CI 2.0 to 19.2) and calprotectin (1237 ng/mL, 95% CI 531 to 2490) levels as well as IL-6, IL-8 and TNF-α mRNA levels compared with controls (p<0.05). The incidence of EIB in athletes was 9%. The maximal fall in forced expiratory volume in 1 s (%) after EVH test in athletes was significantly associated with prior PM10 and PM2.5 exposure. CONCLUSION: Early-career elite athletes showed increased markers of air pollution exposure, epithelial damage and airway inflammation compared with controls. Acute exposure to increased air pollution PM10 levels was linked to increased airway hyper-reactivity. TRIAL REGISTRATION NUMBER: NCT03587675.

The burden and surveillance of RSV disease in young children in Belgium-expert opinion.

Infections with respiratory syncytial virus (RSV) can cause severe disease. In young children, RSV is the most common cause of lower respiratory tract illness and life-threatening infections most commonly occur in the first years of life. In adults, elderly and immunocompromised people are most vulnerable. Recently there has been an acceleration in the development of candidate RSV vaccines, monoclonal antibodies and therapeutics which are expected to become available in Europe within the next 2-10 years. Understanding the true burden of childhood RSV disease will become very important to support public health authorities and policy makers in the assessment of new therapeutic opportunities against RSV disease. A systematic literature search was performed to map local data on the burden of RSV disease and to evaluate available RSV surveillance systems. A group of 9 paediatric infectious diseases specialists participated in an expert panel. The purpose of this meeting was to evaluate and map the burden associated with RSV infection in children, including patient pathways and the epidemiological patterns of virus circulation in Belgium. Sources of information on the burden of RSV disease in Belgium are very limited. For the outpatient setting, it is estimated that 5-10% of young patients seen in primary care are referred to the hospital. Around 3500 children between 0 and 12 months of age are hospitalized for RSV-bronchiolitis every year and represent the majority of all hospitalizations. The current Belgian RSV surveillance system was evaluated and found to be insufficient. Knowledge gaps are highlighted and future perspectives and priorities offered. CONCLUSION: The Belgian population-based RSV surveillance should be improved, and a hospital-led reporting system should be put in place to enable the evaluation of the true burden of RSV disease in Belgium and to improve disease management in the future. WHAT IS KNOWN: • RSV bronchiolitis is a very important cause of infant hospitalization. • The burden of disease in the community is poorly studied and underestimated. WHAT IS NEW: • This expert opinion summarizes knowledge gaps and offers insights that allow improvement of local surveillance systems in order to establish a future-proof RSV surveillance system.

Blood transcriptomics to facilitate diagnosis and stratification in pediatric rheumatic diseases - a proof of concept study.

BACKGROUND: Transcriptome profiling of blood cells is an efficient tool to study the gene expression signatures of rheumatic diseases. This study aims to improve the early diagnosis of pediatric rheumatic diseases by investigating patients' blood gene expression and applying machine learning on the transcriptome data to develop predictive models. METHODS: RNA sequencing was performed on whole blood collected from children with rheumatic diseases. Random Forest classification models were developed based on the transcriptome data of 48 rheumatic patients, 46 children with viral infection, and 35 controls to classify different disease groups. The performance of these classifiers was evaluated by leave-one-out cross-validation. Analyses of differentially expressed genes (DEG), gene ontology (GO), and interferon-stimulated gene (ISG) score were also conducted. RESULTS: Our first classifier could differentiate pediatric rheumatic patients from controls and infection cases with high area-under-the-curve (AUC) values (AUC = 0.8 ± 0.1 and 0.7 ± 0.1, respectively). Three other classifiers could distinguish chronic recurrent multifocal osteomyelitis (CRMO), juvenile idiopathic arthritis (JIA), and interferonopathies (IFN) from control and infection cases with AUC ≥ 0.8. DEG and GO analyses reveal that the pathophysiology of CRMO, IFN, and JIA involves innate immune responses including myeloid leukocyte and granulocyte activation, neutrophil activation and degranulation. IFN is specifically mediated by antibacterial and antifungal defense responses, CRMO by cellular response to cytokine, and JIA by cellular response to chemical stimulus. IFN patients particularly had the highest mean ISG score among all disease groups. CONCLUSION: Our data show that blood transcriptomics combined with machine learning is a promising diagnostic tool for pediatric rheumatic diseases and may assist physicians in making data-driven and patient-specific decisions in clinical practice.

Guided Gradual Egg-Tolerance Induction in Hen's Egg Allergic Children Tolerating Baked Egg: A Prospective Randomized Trial.

Background: Over the last few years, studies have shown that the majority of egg allergic children tolerate baked egg (e.g., cake), and that consuming baked egg accelerates the resolution of egg allergy. However, few prospective studies demonstrate the step-wise reintroduction of egg at home after developing baked egg tolerance. Although this could have a positive impact on the children's quality of life and nutrition. Additionally, research supporting the theoretical concept that heating in the presence or absence of wheat causes reduced allergenicity of egg proteins is limited. Objective: To investigate the clinically most favorable duration of gradual egg-tolerance induction in baked egg tolerant children at home, with regard to complete raw egg tolerance. Methods: Baked egg tolerant children above 12 months of age were randomly assigned to a short- or long arm protocol. In the short arm, egg-tolerance induction was studied over 18 months compared to 30 months in the long arm. Children were guided through this protocol involving the step-wise introduction of increasingly allergenic forms of egg starting with baked egg offered as cake, followed by hard-boiled egg, omelet/waffle/pancake, soft-boiled egg, and finally raw egg. We hereby designed this protocol based on the influence of thermal processing in the presence or absence of wheat on egg proteins, as investigated by ELISA, SDS-PAGE, and immunoblotting. At inclusion, children either passed an in-hospital cake challenge or had ovomucoid sIgE ≤1.2 kUA/L, which was considered safe for introduction at home. Results: Gel electrophoresis revealed that the ovalbumin band became weaker with heating, while the ovomucoid band remained stable. In accordance, the IgE-binding to ovalbumin decreased with extensive heating, as opposed to ovomucoid. However, heating in the presence of wheat led to a decreased IgE reactivity to ovomucoid. Of the 78 children in the intention-to-treat group, 39 were randomized to each arm. Fifty-eight children reached the raw egg tolerance endpoint, of which 80% were in the short arm and 69% in the long arm. Within the short arm, the median time to raw egg tolerance was 24 months (95% CI, 21-27 months) compared to 30 months (95% CI, 28-32 months) in the long arm (p = 0.005). No grade IV reactions or cases of eosinophilic esophagitis were observed. The short arm was considered to be non-inferior to the long arm. Conclusion: Our gradual short arm protocol appears to be safe and allows clinicians to guide baked egg tolerant children toward raw egg tolerance at home. The allergenicity of the egg proteins was affected by heating temperature and duration, as well as the presence of wheat.

Explaining the formation of a plateau in rotavirus vaccine impact on rotavirus hospitalisations in Belgium.

BACKGROUND: Observational data on the reduction in hospitalisations after rotavirus vaccine introduction in Belgium suggest that vaccine impact plateaued at an unexpectedly high residual hospitalisation rate. The objective of this analysis was to identify factors that influence real-world vaccine impact. METHODS: Data were collected on hospitalisations in children aged ≤ 5 years with rotavirus disease from 11 hospitals since 2005 (the RotaBIS study). The universal rotavirus vaccination campaign started late in 2006. A mathematical model simulated rotavirus hospitalisations in different age groups using vaccine efficacy and herd effect, influenced by vaccine coverage, vaccine waning, and secondary infection sources. The model used optimisation analysis to fit the simulated curve to the observed data, applying Solver add-in software. It also simulated an 'ideal' vaccine introduction maximising hospitalisation reduction (maximum coverage, maximum herd effect, no waning), and compared this with the best-fit simulated curve. Modifying model input values identified factors with the largest impact on hospitalisations. RESULTS: Compared with the 'ideal' simulation, observed data showed a slower decline in hospitalisations and levelled off after three years at a higher residual hospitalisation rate. The slower initial decline was explained by the herd effect in unvaccinated children. The higher residual hospitalisation rate was explained by starting the vaccine programme in November, near the rotavirus seasonal peak. This resulted in low accumulated vaccine coverage during the first rotavirus disease peak season, with the consequential appearance of secondary infection sources. This in turn reduced the herd effect, resulting in a diminished net impact. CONCLUSIONS: Our results indicate that countries wishing to maximise the impact of rotavirus vaccination should start vaccinating well ahead of the rotavirus seasonal disease peak. This maximises herd effect during the first year leading to rapid and high reduction in hospitalisations. Secondary infection sources explain the observed data in Belgium better than vaccine waning.

Belgian Consensus Recommendations to Prevent Vitamin K Deficiency Bleeding in the Term and Preterm Infant.

Neonatal vitamin K prophylaxis is essential to prevent vitamin K deficiency bleeding (VKDB) with a clear benefit compared to placebo. Various routes (intramuscular (IM), oral, intravenous (IV)) and dosing regimens were explored. A literature review was conducted to compare vitamin K regimens on VKDB incidence. Simultaneously, information on practices was collected from Belgian pediatric and neonatal departments. Based on the review and these practices, a consensus was developed and voted on by all co-authors and heads of pediatric departments. Today, practices vary. In line with literature, the advised prophylactic regimen is 1 or 2 mg IM vitamin K once at birth. In the case of parental refusal, healthcare providers should inform parents of the slightly inferior alternative (2 mg oral vitamin K at birth, followed by 1 or 2 mg oral weekly for 3 months when breastfed). We recommend 1 mg IM in preterm <32 weeks, and the same alternative in the case of parental refusal. When IM is perceived impossible in preterm <32 weeks, 0.5 mg IV once is recommended, with a single additional IM 1 mg dose when IV lipids are discontinued. This recommendation is a step towards harmonizing vitamin K prophylaxis in all newborns.

Closing schools for SARS-CoV-2: a pragmatic rapid recommendation.

Background: In Belgium, schools closed during the first lockdown in March 2020, with a partial reopening in May. They fully reopened in September. During the summer, infections started to increase in the general population, speeding up in September. Some measures were taken to limit social contacts but those were insufficient to mitigate the exponential rise of infections in October. Children were still receiving all lessons at school at that time and it was questioned whether this position was tenable. We systematically compared the benefits and harms of closing primary and secondary schools and developed a recommendation. Methods: A multidisciplinary panel, including school pupils and teachers, educational experts, clinicians and researchers, produced this recommendation in compliance with the standards for trustworthy rapid guidelines. The recommendation is based on data collected through national surveillance or studies from Belgium, and supported by a rapid literature review. Results: Closing schools during the first lockdown probably resulted in a large learning delay and possibly led to more cases of child abuse. We are uncertain about the effect on the infection rate, hospitalisations, transmission rates, mental health of children, teachers and parents. The panel concluded that the balance of benefits and harms of closing schools clearly shifts against closing schools. Detrimental effects are even worse for vulnerable children. This recommendation is affected by the local virus circulation. Conclusion: The guideline panel issues a strong recommendation against closing schools when the virus circulation is low to moderate, and a weak recommendation against closing schools when the virus circulation is high. It does not apply when the school system cannot function due to lack of teachers, too many children who are at home or a shortage of support services. As the results of international studies are consistent with Belgian study results, this recommendation may also be relevant internationally.

The Type and Concentration of Inoculum and Substrate as Well as the Presence of Oxygen Impact the Water Kefir Fermentation Process.

Eleven series of water kefir fermentation processes differing in the presence of oxygen and the type and concentration of inoculum and substrate, were followed as a function of time to quantify the impact of these parameters on the kinetics of this process via a modeling approach. Increasing concentrations of the water kefir grain inoculum increased the water kefir fermentation rate, so that the metabolic activity during water kefir fermentation was mainly associated with the grains. Water kefir liquor could also be used as an alternative means of inoculation, but the resulting fermentation process progressed slower than the one inoculated with water kefir grains, and the production of water kefir grain mass was absent. Substitution of sucrose with glucose and/or fructose reduced the water kefir grain growth, whereby glucose was fermented faster than fructose. Lacticaseibacillus paracasei (formerly known as Lactobacillus paracasei), Lentilactobacillus hilgardii (formerly known as Lactobacillus hilgardii), Liquorilactobacillus nagelii (formerly known as Lactobacillus nagelii), Saccharomyces cerevisiae, and Dekkera bruxellensis were the main microorganisms present. Acetic acid bacteria were present in low abundances under anaerobic conditions and only proliferated under aerobic conditions. Visualization of the water kefir grains through scanning electron microscopy revealed that the majority of the microorganisms was attached onto their surface. Lactic acid bacteria and yeasts were predominantly associated with the grains, whereas acetic acid bacteria were predominantly associated with the liquor.

Real-time versus thermal desorption selected ion flow tube mass spectrometry for quantification of breath volatiles.

RATIONALE: Selected ion flow tube mass spectrometry (SIFT-MS) is versatile, rapidly provides result output and determines a wide range of volatiles, making it suitable for biomedical applications. When direct sampling into the SIFT-MS instrument is impractical, combining thermal desorption (TD) and SIFT-MS might offer a solution as it allows sample storage on sorbent tubes for later analysis. This work compares off-line TD SIFT-MS and real-time SIFT-MS for the quantification of selected breath volatiles. METHODS: Ten healthy non-smoking individuals provided 60 breath samples per method. For off-line analysis, breath was collected onto sorbent tubes via a breath sampler provided with filtered inspiratory air. After TD, samples were re-collected in Tedlar bags which were then connected to the SIFT-MS instrument. For real-time analysis, breath was sampled directly into the instrument. In both cases the analytical method included a total of 155 product ions, and 14 selected volatiles were quantified. The agreement between the methods was assessed using Pearson correlation coefficients and Bland-Altman plots. RESULTS: Overall, correlations between real-time and off-line analysis were moderate to very strong (r = 0.43-0.92) depending on the volatile of interest, except for 2,3-butanedione and styrene. The difference between real-time and off-line measured breath concentrations (average bias) ranged between -14.57 and 20.48 ppbv. For acetone and isoprene, it was 251.53 and 31.9 ppbv, respectively. CONCLUSIONS: Real-time SIFT-MS and off-line TD SIFT-MS for quantification of selected breath volatiles did not show optimal agreement. Analyzing a multitude of analytes in breath via direct exhalation into a SIFT-MS instrument for real-time analysis is challenging. On the other hand, off-line analysis using a breath collection device also has its issues such as possible sample losses due to selective absorption depending on the sorbent used or during desorption and transfer to the instrument. Despite these drawbacks, both methods were moderately well correlated.

The Influence of Superabsorbent Polymers and Nanosilica on the Hydration Process and Microstructure of Cementitious Mixtures.

Superabsorbent polymers (SAPs) are known to mitigate the development of autogenous shrinkage in cementitious mixtures with a low water-to-cement ratio. Moreover, the addition of SAPs promotes the self-healing ability of cracks. A drawback of using SAPs lies in the formation of macropores when the polymers release their absorbed water, leading to a reduction of the mechanical properties. Therefore, a supplementary material was introduced together with SAPs, being nanosilica, in order to obtain an identical compressive strength with respect to the reference material without additives. The exact cause of the similar compressive behaviour lies in the modification of the hydration process and subsequent microstructural development by both SAPs and nanosilica. Within the present study, the effect of SAPs and nanosilica on the hydration progress and the hardened properties is assessed. By means of isothermal calorimetry, the hydration kinetics were monitored. Subsequently, the quantity of hydration products formed was determined by thermogravimetric analysis and scanning electron microscopy, revealing an increased amount of hydrates for both SAP and nanosilica blends. An assessment of the pore size distribution was made using mercury intrusion porosimetry and demonstrated the increased porosity for SAP mixtures. A correlation between microstructure and the compressive strength displayed its influence on the mechanical behaviour.

Lessons Learned from Long-Term Assessment of Rotavirus Vaccination in a High-Income Country: The Case of the Rotavirus Vaccine Belgium Impact Study (RotaBIS).

INTRODUCTION: The rotavirus (RV) vaccine Belgium Impact Study (RotaBIS) evaluated the vaccine effect on RV-related hospital care in children up to 5 years old over a period of 13 years. Different forces were identified that influence the reduction in hospital care. Our analysis aims to report on the current RotaBIS dataset and explore through model simulation whether, how, and when the results could have been improved. METHODS: As performed in previous assessments, this analysis evaluated RV-related events per year, per age group, RV nosocomial infections, hospitalization duration, and herd effect. It subsequently identified results that were surprising or unexpected. To know whether those data could have been improved through specific interventions, we developed a model with the forces acting on the disease transmission and the vaccine effect on RV-related hospital care. Scenario analysis of the forces should explain the current findings and identify ways to optimize the results. RESULTS: The RotaBIS data show that annual RV-related hospital cases (n = 1345 pre-vaccination) dropped by 70% (95% confidence interval [CI] 66-74%) by year 5 (n = 395) after vaccine introduction, and by 84% (95% CI 79-89%) by year 10 (n = 217). The herd effect during the first year was limited to 14% extra gain. During the last 5 years, small disease increases were seen biennially. The simulation model indicates that higher vaccine coverage of the major transmitters during the peak season of the first year of vaccination could have reduced RV-related hospital care by nearly 90% at 5 and 10 years after vaccine introduction owing to a higher herd effect. The smaller peaks observed in recent years would have been dramatically reduced. CONCLUSION: The current RotaBIS data show a maintained reduction, around 76%, in RV hospitalization cases. Simulations show that these results could have been improved to an important extent with a more optimal initiation of the vaccination program. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01563146 and NCT01563159.

Diagnosing enterovirus meningitis via blood transcriptomics: an alternative for lumbar puncture?

BACKGROUND: Meningitis can be caused by several viruses and bacteria. Identifying the causative pathogen as quickly as possible is crucial to initiate the most optimal therapy, as acute bacterial meningitis is associated with a significant morbidity and mortality. Bacterial meningitis requires antibiotics, as opposed to enteroviral meningitis, which only requires supportive therapy. Clinical presentation is usually not sufficient to differentiate between viral and bacterial meningitis, thereby necessitating cerebrospinal fluid (CSF) analysis by PCR and/or time-consuming bacterial cultures. However, collecting CSF in children is not always feasible and a rather invasive procedure. METHODS: In 12 Belgian hospitals, we obtained acute blood samples from children with signs of meningitis (49 viral and 7 bacterial cases) (aged between 3 months and 16 years). After pathogen confirmation on CSF, the patient was asked to give a convalescent sample after recovery. 3' mRNA sequencing was performed to determine differentially expressed genes (DEGs) to create a host transcriptomic profile. RESULTS: Enteroviral meningitis cases displayed the largest upregulated fold change enrichment in type I interferon production, response and signaling pathways. Patients with bacterial meningitis showed a significant upregulation of genes related to macrophage and neutrophil activation. We found several significantly DEGs between enteroviral and bacterial meningitis. Random forest classification showed that we were able to differentiate enteroviral from bacterial meningitis with an AUC of 0.982 on held-out samples. CONCLUSIONS: Enteroviral meningitis has an innate immunity signature with type 1 interferons as key players. Our classifier, based on blood host transcriptomic profiles of different meningitis cases, is a possible strong alternative for diagnosing enteroviral meningitis.

The Sustained Rotavirus Vaccination Impact on Nosocomial Infection, Duration of Hospital Stay, and Age: The RotaBIS Study (2005-2012).

INTRODUCTION: The benefits of rotavirus (RV) vaccination in developed countries have focused on reductions in mortality, hospitalization and medical visits, and herd protection. We investigated other aspects related to RV-induced nosocomial infection, duration of hospital stay, age shift, and sustained vaccine impact (VI) over time. METHOD: RotaBIS (Rotavirus Belgian Impact Study; ClinicalTrials.gov identifier, NCT01563146) annually collects retrospective data on hospitalization linked to RV testing in children up to 5 years old from 11 pediatric wards located all over Belgium. Data from 2005 to 2012 have been split in pre- (2005-2006) and post-vaccination (2007-2012) period. Information was collected on age, gender, RV test result, nosocomial infection caused by RV and duration of hospital stay. RESULTS: Over the 6-year period after the introduction of the RV vaccine, an 85% reduction in nosocomial infections was observed (221 in 2005 to 33 in 2012, p < 0.001). A significant reduction of almost 2 days in average duration of hospital stay per event was observed overall (7.62 days in 2005 to 5.77 days in 2012, p < 0.001). The difference is mainly explained by the higher reduction in number of nosocomial infections. A pronounced age shift (+24%, p < 0.01) of RV nosocomial infection to infants ≤2 months old was observed, increasing with length of post-vaccination period. VI was maintained over the follow-up (±79% VI per birth cohort). A decrease was seen depending on age, 85% (95% CI 76-91%) in the youngest to 63% (95% CI 22-92%) in the oldest age group. CONCLUSION: The higher reduction in nosocomial infection may affect the overall average duration of hospital stay for RV infection. No change in VI by birth cohort, but a reduction by age group was observed. These findings could be important for decision-makers considering the introduction of universal mass RV vaccination programs. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01563146. FUNDING: GlaxoSmithKline Biologicals SA (Rixensart, Belgium).

Medium- to Long-Term Impact of Rotavirus Vaccination on Hospital Care in Belgium: A 7-Year Follow-Up of the Rotavirus Belgium Impact Study (RotaBIS).

INTRODUCTION: Rotavirus (RV) vaccination was introduced in Belgium in 2006. With the high uptake it had (>85%), a sharp decline in hospitalizations was observed during the first years after vaccine introduction. The objective of this study was to investigate whether this decline was maintained and to simulate projections. METHODS: The Rotavirus Belgium Impact Study allowed an analysis of the RV vaccine impact amongst children in 11 hospitals in Belgium over a 9-year period (2005-2013) with 2 years pre- and 7 years post-vaccine introduction. Results were compared by year and by subsequent birth cohort aging up to 5 years. The two different analysis methods helped dismantling the different (direct and indirect) effects of vaccine protection to simulate future hospitalization trends. RESULTS: During the whole observation period, 40,552 RV detection tests were performed of which 5832 were positive (14.4%). After RV vaccine introduction, a significant reduction in number of tests performed (-38%) was combined with a dramatic drop in numbers of positive tests (-76.6%). The decreases were spectacular during the first two years of vaccine introduction; after that period, the decrease flattened. Cross-sectional comparison with cohort data showed that the initial drop was heavily influenced by the herd effect of the vaccine. Cohort analysis demonstrated a low rate of residual disease over time, suggesting another infection source other than the child population. CONCLUSION: The residual disease will be maintained in the community when a same vaccination strategy is continued over time, starting vaccination of children only at 6 weeks' time. FUNDING: GlaxoSmithKline Biologicals SA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01563146.

Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age.

INTRODUCTION: Annual seasonal influenza epidemics are particularly dangerous for the very young, the elderly and chronically ill individuals, in whom infection can cause severe morbidity, hospitalization and death. Existing, nonadjuvanted influenza vaccines exhibit a suboptimal immunogenicity and efficacy in immunologically naive subjects such as young children. METHODS: This phase II, randomized clinical trial was conducted to evaluate the antibody and cell-mediated responses to a trivalent influenza vaccine administered without adjuvant (TIV) or adjuvanted with MF59 (ATIV) in previously nonvaccinated children less than 3 years of age. RESULTS: The MF59-adjuvanted vaccine was well tolerated, and induced higher titers of hemagglutination inhibition antibodies able to recognize strains different from the one used in the vaccine (heterovariant) than TIV. The presence of the adjuvant MF59 induced a larger expansion of vaccine-specific CD4 T cells. Interestingly, the adjuvant MF59 did not modify the cytokine profile of the elicited T cells, characterized by the production of IL-2 and TNF-α, and did not bias the response toward either Th1 or Th2. The advantage of ATIV over TIV was more pronounced for the virus strains that had not circulated in the years that preceded this study and for the heterovariant strains. CONCLUSION: These data highlight the relevant role played by the oil-in-water adjuvant MF59 in enhancing the immunogenicity of inactivated influenza vaccines in immunologically naive individuals.

Nutritional status of children hospitalized for parapneumonic effusion.

BACKGROUND & AIMS: Among children hospitalized for pneumonia, those with parapneumonic effusion (PPE) are at particular risk for nutritional deterioration. This study aimed to 1) investigate the evolution of the nutritional status during hospitalization and at outpatient follow-up; 2) determine clinical risk factors for weight loss during hospitalization; 3) describe the nutritional interventions for these children. METHODS: Retrospective chart review (January '07 - September '12) of 56 children with pneumonia, complicated by PPE in two Belgian hospitals for data on body weight and height at admission (t0) and discharge (t1), and two weeks (t2) and one month (t3) after discharge. Length of hospitalization (LoS), length of stay in paediatric intensive care (LoSPICU) and maximal in-hospital weight loss (tmax) were calculated and nutritional interventions were recorded. RESULTS: The median (range) age was 3.5 (1.0-14.8) years. Weight or height was lacking in five (8.9%) children at t0 and in 28 (50%) at t1; 21.4% was weighed only once during hospitalization. At tmax, respectively 17/44 and 5/44 children lost ≥ 5% and ≥ 10% of their weight. Median (range) LoS and LoSPICU were 18.0 (10-41) and 4.0 (0-23) days. One-fourth received a nutritional intervention. Weight for height at admission (WFH(t0)) significantly predicted maximal weight loss (ß (95% CI) = -0.34 (-2.0--0.1); p = 0.03). At t2 and t3, 13/32 and 5/22 of the children with available follow-up data did not reach WFH(t0), whilst in 4/35 and 5/26 body weight remained ≥ 5% under the weight(t0). CONCLUSIONS: One-third of children with pneumonia complicated by PPE and monitored for weight and height, lost ≥ 5% of their body weight during hospitalization. One-fourth did not reach initial WFH one month after discharge. Those with a higher WFH at admission were at higher risk of weight loss. More attention for monitoring of weight loss and the nutritional policy during and after hospitalization is warranted.