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Background: The purpose of this investigation was to analyse the ophthalmic follow-up care of former pre-term and full-term born infants aged 4 to 10 years in the clinical practice and the comparison to the recommendations of the national ophthalmic guidelines., Methods: For the prospective Wiesbaden Prematurity Study (WPS), 503 infants were examined: 239 former pre-term infants (PT) with gestational age (GA) ≤ 32 weeks and 264 former full-term born infants (FT) with a GA ≥ 37 weeks aged 4 to 10 years. Ophthalmic examination was performed including refractive measurements and orthoptic examination. Anisometropia was defined as a difference of ≥ 1 D spherical equivalent. Data was assessed if an ophthalmological examination was performed after hospital discharge, and how many times the ophthalmologist was contacted within the last 12 months., Results: Overall, strabismus and anisometropia were present in 18 and 10% of all PT, and in 2 and 5% of all FT infants, respectively. In infants aged 4 to 6 years, 65% of all former PT and 42% of all former FT had ophthalmological contacts within the last year (p = 0.002). 15% of the pre-term infants with strabismus did not have an ophthalmological examination within the last year. The parents of three former pre-term infants reported that they never had an ophthalmologic examination after hospital discharge., Conclusion: Two-thirds of the former pre-term infants participated in a screening examination at the age of 4 to 6 years in the last year according to their parents, which is recommended by the guidelines for the care of former pre-term infants. There is still room for improvement to provide best ophthalmological care for this vulnerable population that have high risk for strabismus and amblyopia., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht. Die Studie wurde nicht finanziell unterstützt., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Value assessment of vaccination programs against serogroup B invasive meningococcal disease (IMD) is on the agenda of public health authorities. Current evidence on the burden due to IMD is unfit for pinning down the nature and magnitude of the full social and economic costs of IMD for two reasons. First, the concepts and components that need to be studied are not agreed, and second, measures of the concepts that have been studied are weak and inconsistent. Thus, the economic evaluation of the available serogroup B meningococcal (MenB) vaccines is difficult. The aims of this DELPHI study are to: (1) agree on the concepts and components determining the burden of MenB diseases that need to be studied; and (2) seek consensus on appropriate methods and study designs to measure quality of life (QoL) associated with MenB induced long-term sequelae in future studies., Methods: We designed a DELPHI questionnaire based on the findings of a recent systematic review on the QoL associated with IMD-induced long-term sequelae, and iteratively interviewed a panel of international experts, including physicians, health economists, and patient representatives. Experts were provided with a controlled feedback based on the results of the previous round., Results: Experts reached consensus on all questions after two DELPHI rounds. Major gaps in the literature relate (i) to the classification of sequelae, which allows differentiation of severity levels, (ii) to the choice of QoL measures, and (iii) to appropriate data sources to examine long-term changes and deficits in patients' QoL., Conclusions: Better conceptualisation of the structure of IMD-specific sequelae and of how their diverse forms of severity might impact the QoL of survivors of IMD as well as their family network and care-providers is needed to generate relevant, reliable and generalisable data on QoL in the future. The results of this DELPHI panel provide useful guidance on how to choose the study design, target population and appropriate QoL measures for future research and hence, help promote the appropriateness and consistency in study methodology and sample characteristics.

Protection by meningococcal group A, C, W and Y (MenACWY) vaccines against four meningococcal disease-causing serogroups is increasingly important because of changing epidemiologic patterns of meningococcal disease, including recent meningococcal serogroup W outbreaks/disease clusters. The MenACWY vaccine conjugated to tetanus toxoid (MenACWY-TT) has been extensively evaluated across the age spectrum (age ≥6 weeks) in randomized Phase II and III and in postmarketing studies. Results support the robust immunogenicity of MenACWY-TT across ages and coadministration with other vaccines. The safety profile is similar regardless of age, primary versus booster vaccination, or concomitant administration; local (swelling, pain, redness) and systemic (fever, fatigue, headache, drowsiness, loss of appetite, irritability) reactogenicity events are most common. These data support use of MenACWY-TT to protect against MenACWY disease.

Purpose: The objective of this study was to investigate the relationship between visual acuity, peripapillary retinal nerve fibre layer (pRNFL), retinal thickness at the fovea and other factors with the neurologic status of former preterm children., Methods: In this cross-sectional hospital based study in a maximum care tertiary centre, detailed anthropometric and ophthalmological data of former preterm children ranging from 4 to 10 years of age with a gestational age (GA) ≤32 weeks were assessed. Analyses of the correlation between pRNFL and foveal thickness, as well as visual acuity (VA) parameters at 4-10 years of age, with neurological development were evaluated at 2 years of age by Bayley Scales II of Infant Development, including Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI)., Results: Data were available for 106 former preterm children. Univariate analysis revealed a correlation between PDI with pRNFL thickness (B = 0.43; p = 0.013), VA (B = -29.2; p < 0.001), GA (B = 2.7; p = 0.002), retinopathy of prematurity (ROP; B = -16.3; p < 0.001) and intraventricular haemorrhages (IVH; B = -22.9; p < 0.001) but not with strabismus or foveal thickness. In the multivariable analysis, the association remained for visual acuity and IVH, but not for pRNFL thickness or ROP. Mental Developmental Index (MDI) was associated with visual acuity (B = -34.3; p = 0.001), GA (B = 2.53; p = 0.02) and IVH (B = -15.4; p = 0.02), the latter also in the multivariable analysis., Conclusion: This study revealed an association between PDI at 2 years of age and lower visual acuity later in childhood. However, there was no correlation between retinal morphology and neurologic outcome in former preterm children after adjusting for several potential confounders., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation., Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations., Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge., Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Competing Interests: Markus Knuf: LKP und PI bei Impfstudien. Beratertätigkeit für GSK, Pfizer, Sanofi, MSD, SPMSD, Baxter, Novartis, AstraZeneca, Medimmune u. a. Präsentationen während Industrie-Symposien. Die o. g. Tätigkeiten nimmt der Autor als Dienstaufgabe wahr. Er erhält persönlich keine Honorare von Firmen. Es besteht diesbezüglich auch keine Zielvereinbarung mit seinem Dienstherren. Fred Zepp served as independent Chairman of the DSMB (Data Safety Moniotoring Board) during the clinical development of Sanofi Pasteurʼs quadrivalent Influenza Vaccine with infants and toddlers.

Measles, mumps, rubella and varicella are viral infections which can implicate seriously long-term sequelae of infected individuals or even the unborn child. Vaccines against the individual diseases have long been available. Global measles vaccination is estimated to have prevented more than 20million deaths during 2000-2015. During the same time period, measles incidence decreased from 146 to 36 cases per million populations. Today vaccinations against measles, mumps, rubella and varicella are now carried out mainly with combination vaccines. These are today known as immunogenic and safe. MMRV had similar immunogenicity and overall safety profiles to MMR administered with or without varicella vaccine. This issue provides a review of the different vaccines, mode of administration, catch up immunization and postexposure prophylaxis as well as contraindications and adverse effects of the immunization against measles, mumps, rubella, and varicella. The article presents an overview of important information of preventing these diseases with a focus on the existing combination vaccines., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background Context: In patients with mucopolysaccharidosis (MPS), glycosaminoglycan deposits in the dura mater and supporting ligaments cause spinal cord compression and consecutive myelopathy, predominantly at the craniocervical junction. Disease characteristics of craniocervical stenosis (CCS) in patients with MPS differ profoundly from other hereditary and degenerative forms. Because of high periprocedural morbidity and mortality, patients with MPS pose a substantial challenge to the inexperienced medical care provider. As literature remains scarce, we present our experience with a large cohort of patients with MPS treated for CCS without atlanto-occipital instrumentation., Purpose: The present study aimed to describe a safe and least traumatic approach for treating CCS in children with MPS, avoiding primary instrumentation., Study Design: This is a prospective follow-up (cohort) study., Patient Samples: We report 15 consecutive patients with CCS related to MPS, who were treated with stand-alone cervical decompression., Outcome Measures: Myelopathy was assessed using magnetic resonance imaging (MRI), somatosensory evoked potentials, and clinical evaluation. Cervical instability was evaluated using plain x-ray and MRI. The disability status is quantified using either the Karnofsky or Lansky Performance Score., Methods: We describe 15 consecutive patients treated with craniocervical decompression. Data were collected prospectively. The mean follow-up is 6 years (5 standard deviation). The technique and treatment principles are described., Results: The overall clinical outcome in this patient cohort is good (mean Karnofsky Performance Score of 80). No patient developed signs of C0-C1-C2 instability or progressive myelopathy. Restenosis occurred in seven patients, requiring a total of eight reoperations., Conclusions: Surgery in patients with MPS is associated with high morbidity and mortality of up to 4.2%. Because of the unique nature of the disease, recurring stenosis is inevitable. To shorten the procedure time and simplify the anticipated reoperation, we provide data that craniocervical decompression is feasible without the necessity of primary osteosynthesis. In the absence of craniocervical instability, decompression surgery without occipitocervical stabilization yields good postoperative results and challenges the long-standing paradigm of prophylactic craniocervical fixation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We evaluated antibody persistence up to 68 months (M) post-vaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) or a licensed monovalent MenC conjugate vaccine (MenC-CRM 197 ) and subsequent booster responses to MenACWY-TT in healthy European children., Methods: In the initial study (NCT00674583), healthy children, 2-10 years of age, were randomized to receive a single dose of either MenACWY-TT or MenC-CRM 197 . In the follow-up study, we present the persistence at 32, 44, 56, and 68 M post-vaccination, overall and stratified by age (2-5 and 6-10 years), and the immunogenicity and safety of MenACWY-TT administered to all study participants at M68 post-primary vaccination., Results: At M68, 33.3% (age group 2-5 years) and 47.1% (age group 6-10 years) of the children vaccinated with MenACWY-TT, and 50.0% (age group 2-5 years) and 75.9% (age group 6-10 years) vaccinated with MenC-CRM 197 retained titers ≥1:8 for MenC, as assessed by a serum bactericidal assay using rabbit complement (rSBA). In the MenACWY-TT recipients, the percentages of children retaining rSBA titers ≥1:8 for MenA, MenW, and MenY were 81.7%, 47.3% and 66.7% in age group 2-5 years and 91.8%, 58,8% and 76.5% in age group 6-10 years, respectively. The booster dose induced robust responses (100% for all serogroups) and was well-tolerated., Conclusions: Antibody persistence (rSBA titers ≥ 1:8) for serogroups A, W and Y was observed in more than 50.0% of the children 68 M after receiving one dose of MenACWY-TT; for MenC, antibody persistence was observed in more than one third of MenACWY-TT and more than half of MenC-CRM 197 recipients. Vaccination with a booster dose of MenACWY-TT induced robust immune responses for all serogroups., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Infants with history of prematurity (<37 weeks gestation) and low birth weight (LBW, <2500 g) are at high risk of infection due to functional immaturity of normal physical and immunological defense mechanisms. Despite current recommendations that infants with history of prematurity/LBW should receive routine immunization according to the same schedule and chronological age as full-term infants, immunization is often delayed., Methods: Here we summarize 10 clinical studies and 15 years of post-marketing safety surveillance of GSK's hexavalent vaccine (DTPa-HBV-IPV/Hib), a combined diphtheria-tetanus-acellular-pertussis-hepatitis-B-inactivated-poliovirus-Haemophilus influenzae-type-b (Hib) conjugate vaccine, when administered alone, or co-administered with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with history of prematurity/LBW in clinical trials., Results: At least 92.5% of infants with history of prematurity/LBW as young as 24 weeks gestation in clinical studies were seropositive to all vaccine antigens after 3-dose primary vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine, with robust immune responses to booster vaccination. Seropositivity rates and antibody concentrations to hepatitis B and Hib appeared lower in infants with history of prematurity/LBW than term infants. Between 13-30% of medically stable infants with history of prematurity developed apnea after vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine; usually after dose 1. The occurrence of post-immunization cardiorespiratory events appears to be influenced by the severity of any underlying neonatal condition. Most cardiorespiratory events resolve spontaneously or require minimal intervention. GSK's hexavalent DTPa-HBV-IPV/Hib vaccine was well tolerated in co-administration regimens., Conclusion: GSK's hexavalent DTPa-HBV-IPV/Hib vaccine alone or co-administered with other pediatric vaccines has a clinically acceptable safety and immunogenicity profile when used in infants with history of prematurity/LBW for primary and booster vaccination. Additional studies are needed in very premature and very LBW infants. However, currently available data support using GSK's hexavalent DTPa-HBV-IPV/Hib vaccine to immunize infants with history of prematurity/LBW according to chronological age., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Limited data exist collating most of the associated factors for strabismus in one analysis. The aim of this study was to assess the prevalence of strabismus and to analyse associated factors in former preterm and full-term infants., Methods: In this cross-sectional study, 239 former preterm infants with gestational age (GA) ≤ 32 weeks and 264 former full-term born infants with GA ≥ 37 weeks underwent detailed ophthalmologic examination in the age of 4-10 years and perinatal data assessment for risk factor analysis. Ophthalmologic examinations included cover testing, best corrected visual acuity, cycloplegic objective refraction, slit lamp as well as fundus examinations. For association analysis with strabismus, the following data was collected and included in multivariable analysis: sex, age at examination, anisometropia, myopic and hyperopic refractive error (≥ 3 dioptres), astigmatism, birth weight percentile, gestational age, retinopathy of prematurity occurrence, maternal age at childbirth, mother smoking, breastfeeding < 3 months, artificial ventilation, intraventricular bleeding, and other perinatal adverse events., Results: Overall, 4/264 (2%) full-term infants, 15/125 (12%) preterm-infants with GA 29-32 weeks without ROP, 13/59 (22%) preterm infants with GA ≤ 28 weeks without ROP and 14/55 (26%) with GA ≤ 32 weeks with retinopathy of prematurity were affected by strabismus. In the multivariable regression model strabismus was associated with GA (OR = 0.84 per week; p = 0.001), hyperopic refractive error (OR = 4.22; p = 0.002) and astigmatism (OR = 1.68; p = 0.02)., Conclusion: This investigation highlights that low gestational age and refraction of the eye are independent risk factors for strabismus, while the other factors show less independent influence.

Purpose: To compare corneal aberrations in former preterm infants to that of full-term infants., Methods: A prospective cross-sectional study was carried out measuring the corneal shape with Scheimpflug imaging in former preterm infants of gestational age (GA) ≤32 weeks and full-term infants with GA ≥37 weeks now being aged between 4 to 10 years. The main outcome measures were corneal aberrations including astigmatism (Zernike: Z2-2; Z22), coma (Z3-1; Z31), trefoil (Z3-3; Z33), spherical aberration (Z40) and root-mean square of higher-order aberrations (RMS HOA). Multivariable analysis was performed to assess independent associations of gestational age groups and of retinopathy of prematurity (ROP) occurrence with corneal aberrations adjusting for sex and age at examination., Results: A total of 259 former full-term and 226 preterm infants with a mean age of 7.2 ± 2.0 years were included in this study. Statistical analysis revealed an association of extreme prematurity (GA ≤28 weeks) with higher-order and lower-order aberrations of the total cornea. Vertical coma was higher in extreme prematurity (P < 0.001), due to the shape of the anterior corneal surface, while there was no association with trefoil and spherical aberration. ROP was not associated with higher-order aberrations when adjusted for gestational age group., Conclusions: This study demonstrated that specific corneal aberrations were associated with extreme prematurity rather than with ROP occurrence.

Purpose: The aim of the study was to investigate peripapillary retinal nerve fibre layer thickness (RNFLT) in former preterm infants and full-term neonates using spectral-domain optical coherence tomography (SD-OCT)., Methods: The prospective, controlled, cross-sectional, hospital-based study in a tertiary centre with maximum care examined 503 infants with a former gestational age (GA) of ≥37 and ≤32 weeks now aged between 4 and 10 years. In total, we analysed 432 participants with successful circular peripapillary RNFLT OCT measurements. Main outcome measures were RNFLT correlations to GA, birth weight, occurrence of retinopathy of prematurity (ROP), perinatal adverse events as well as functional correlation., Results: Global RNFLT was thinner in infants with GA ≤28 weeks compared with infants with GA between 29 and 32 weeks (p=0.024), and to full-term neonates (p=0.007) independent of the occurrence of ROP. Multivariable analysis revealed that RNFLT was positively associated with higher birth weight and GA. Furthermore, a decrease of RNFLT was related to reduced visual function in all peripapillary sectors., Conclusions: The main factors for retinal nerve fibre layer thinning are low birth weight and low GA. In addition, decreased RNFLT was associated with reduced visual function. This demonstrates that preterm infants are at high risk for peripapillary RNFL damage associated with reduced visual function., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: To analyse macular retinal and choroidal layer thickness in former preterm and full-term infants and to assess associated perinatal influence factors and functional correlation., Methods: This prospective controlled, cross-sectional, hospital-based study in a tertiary center of maximum care examined former preterm infants with a gestational age (GA) ≤ 32 weeks and full-term neonates currently aged 4 to 10 years. We investigated data from 397 infants, analysing total foveal retinal thickness and six distinct macular retinal layer and choroidal layer measurements via spectral-domain optical coherence tomography. Multivariable linear regression analysis was performed to investigate associations of layer thickness with GA and retinopathy of prematurity (ROP)., Results: Total retinal thickness in the fovea was thicker in former preterm infants with GA ≤ 28 weeks and in those with GA between 29-32 weeks compared to full-term infants independently of ROP. Occurrence of ROP was also associated with increased foveal thickness. Ganglion cell layer together with inner plexiform layer (GCL+IPL) was thinner in infants with GA ≤ 28 weeks than in full-term infants at 1000 and 2000μm distance from the fovea, but no association with ROP was present. Similar results were found for the photoreceptor layer. Total foveal retinal thickness was associated with low visual function., Conclusion: This study identified low gestational age and ROP occurrence as main determinants for foveal thickening. Furthermore, thinned GCL+IPL measurements were associated with lower gestational age. This study highlights the prognostic value of these maturity parameters influencing retinal morphology, which may affect visual function.

Purpose: To compare the axial length and anterior segment alterations in preterm infants with and without retinopathy of prematurity with those of full-term infants., Methods: The Wiesbaden Prematurity Study investigated 503 participants of former gestational age ≤32 weeks and gestational age ≥37 weeks now being aged 4 to 10 years. This study included 485 participants in the prospective controlled cross-sectional, hospital-based study with successful Pentacam Scheimpflug imaging. Anterior segment parameters, axial length measurements, and associated factors were analyzed., Results: Corneal thickness did not differ between former preterm and full-term infants. Significant differences were found between preterm and full-term infants now aged ≤7 years for spherical equivalent, astigmatism, corneal diameter, and axial length. In preterm infants aged ≥8 years compared with full terms of the same age, we found a significant difference only in the corneal diameter. In multivariable analysis of the corneal diameter, we detected an association with birth weight and perinatal adverse events. Astigmatism correlated with birth weight and laser treatment, anterior chamber depth with birth weight, laser treatment and age at examination, and axial length with birth weight and age at examination., Conclusions: This study demonstrated altered axial length and anterior segment morphology in former preterm infants, especially in the first years of life. In addition, we observed that preterm infants seemed to catch up, so that the differences in ocular growth in terms of spherical equivalent, astigmatism, and axial length decreased within the first 8 years of life.

Objective  The aim of our study was to evaluate the occurrence of viral infections in infants with suspected late-onset bacterial sepsis in a neonatal intensive care unit. Methods  In a prospective study, infants with suspected late-onset bacterial sepsis underwent viral testing alongside routine blood culture sampling. Using a multiplex reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay, nasopharyngeal aspirates were analyzed for adenovirus, respiratory syncytial virus (RSV), influenza virus A and B, H1N1 virus, parainfluenza virus 1 to 4, metapneumovirus, coronavirus, and picornavirus. Stools were examined for adenovirus, rotavirus, norovirus, and enterovirus. Results  Between August 2010 and March 2014, data of 88 infants with 137 episodes of suspected late-onset bacterial sepsis were analyzed. Six infants were diagnosed with a respiratory viral infection (2 × RSV, 4 × picornavirus). Blood culture-proven bacterial sepsis was detected in 15 infants. Neither viral-bacterial coinfections nor polymerase chain reaction positive stool samples were found. Conclusion  Respiratory viruses can be detected in a considerable number of neonates with suspected late-onset bacterial sepsis. In contrast, gastrointestinal viral or enterovirus infections appear uncommon in such cases., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Purpose: The aim of the study was to investigate peripapillary choroidal thickness in former preterm and full-term infants with spectral-domain optical coherence tomography (SD-OCT)., Methods: Subanalysis of infants with successful peripapillary choroidal thickness measurements of a prospective, controlled, cross-sectional, hospital-based study in a tertiary center of maximum care. The study examined 503 infants aged 4 to 10 years at the time of examination. Infants were divided into different groups: group 1 born with gestational age (GA) ≥37 weeks, group 2 born with GA between 29 and 32 weeks without ROP (retinopathy of prematurity), group 3 born with GA ≤28 weeks without ROP, and group 4 born with GA ≤32 weeks and presence of ROP., Results: Peripapillary choroidal measurements were available for 388 of 503 participants. No significant differences were found among the four groups for global peripapillary choroidal thickness. Multivariable analysis revealed no association with low GA, birth weight, ROP occurrence, perinatal adverse events, and logMAR visual acuity. Only infants born small for GA (SGA) revealed peripapillary choroidal thinning in the superior (P = 0.033) and nasal (P = 0.024) sectors compared with infants born appropriate for GA (AGA). Infants SGA had lower visual acuity than AGA infants (0.03 ± 0.07 logMAR SGA versus 0.01 ± 0.05 logMAR AGA; P = 0.029)., Conclusions: Our results indicate that prematurity itself does not affect choroidal thickness in the peripapillary region. Only infants born SGA revealed peripapillary choroidal thinning compared with AGA infants. Our data indicate that fetal growth restriction leads to choroidal long-term alterations in the peripapillary region.

Targeting antigen combined with adjuvants to hepatic antigen-presenting cells (APCs) is essential for the induction of intrahepatic T cellular immunity controlling and resolving viral infections of the liver. Intravenous injection of antigen-loaded nanoparticles is a promising approach for the delivery of antigens to liver APCs. Accordingly, polymeric nanocapsules (NCs) synthesized exclusively of hepatitis C virus non-structural protein 5A (NS5A) and the adjuvant monophosphoryl lipid A (MPLA) adsorbed to the nanocapsule surface were developed. Aim of the present study was the evaluation of the in vitro and in vivo behavior of MPLA-functionalized NS5A-NCs regarding the interaction with liver dendritic cells (DCs) and the potential to induce intrahepatic immune responses in a mouse model. Maturation of DCs was significantly increased by application of NS5A+MPLA-NCs compared to non-functionalized NS5A-NCs promoting a vigorous expression of CD40, CD80, CD86 and a strong secretion of the Th1-related cytokine IL-12. NS5A-NCs were preferentially deposited in DCs and Kupffer cells residing in the liver after intravenous administration. Immunization with NS5A-NCs induced intrahepatic antigen-specific CD4(+) T cellular immune responses determined by the secretion of IFNγ and IL-2. Furthermore, supplementation with MPLA induced significant levels of NS5A-specific antibodies. The application of polymeric nanocapsules synthesized exclusively out of antigen avoids the risk of unintended side effects caused by additional carrier substances. Functionalization with adjuvants like MPLA and the efficient targeting to liver-resident APCs inherits the potential for application of antigen nanocapsules in further vaccination approaches against pathogens affecting the liver., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This report describes the case of a 10-month-old infant, who was delivered to our hospital by the emergency physician intubated and in an unclear unconscious state. The father reported that the child had fallen from the couch to the ground. The consulted ophthalmologist reported venous stasis in both eyes including intraretinal and preretinal bleeding in all four quadrants, a diffuse vitreous hemorrhage in the right eye and temporal retinal wrinkling in both eyes. Based on these particular clinical findings a shaken baby syndrome was suspected. This report demonstrates the importance of recognizing and correctly interpreting the typical ophthalmological signs of physical child abuse in order to detect and prevent further mistreatment of children; moreover, the increasing importance of photographic documentation and histological work-up of the findings for forensic reasons are emphasized.

Background: Representative, population-based epidemiologic data for gastroenteritis caused by rotavirus (RV) are rare. RV vaccines were first licensed in Europe in 2006 and recommended in 5 western federal states in 2008 or thereafter. This study establishes a baseline for assessing the impact of vaccination and delineates the RV disease burden in Germany today., Methods: Nationwide data obtained from hospitals for children 0 to 10 years of age and transferred to the Federal Statistical Office were analyzed retrospectively. Acute gastroenteritis cases because of RV were identified by the International Classification of Diseases code (ICD-10) combined with the referring diagnosis-related group code. Coding quality was validated by random sampling the patient records (n=1003). Crude and age-standardized rates per 100,000 person-years were calculated. The rate ratios of seasonal effects and recommended immunization adjusted for year, federal state and age were estimated using Poisson regression., Results: Between 2005 and 2010, 5,843,730 children were hospitalized; 520,606 cases were hospitalized because of acute gastroenteritis. RV caused 152,636 of these cases or an age-standardized rate of 302 hospitalizations per 100,000 person-years. Rates were slightly higher in boys than girls, decreased with age, and differed by federal state, year and season. Rate ratios decreased in those western federal states that recommended immunization and were inversely associated with vaccine doses sold., Conclusions: With an average of 25,440 children hospitalized yearly, RV infection has a great impact on the German healthcare system. Our findings indicate that RV immunization will lead to a decline in in-patient treatment and associated costs.

Background: This case report describes an extremely rare Candida lens abscess in a premature infant (gestational age 24 weeks at birth)., Case Report: After birth the infant suffered from Candida sepsis which was successfully treated with an antifungal medication. The patient was referred at the age of 6 months because of greyish alterations in the pupils but an absence of other symptoms. The examination with the patient under general anesthesia revealed a grey pupillary membrane and behind it a whitish swollen lens. A lensectomy was performed. The vitreous body was inconspicuous. Candida albicans was identified microbiologically., Conclusions: In preterm infants dissemination of pathogens into the lens through the vascular coat of the lens is possible, which after regression of the coat is no longer accessible to systemic treatment and may thus be manifested as delayed abscess formation.

Objective: Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1/tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC., Methods: Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC (n = 16) were compared with healthy subjects (n = 20)., Results: Compared with monocytes from healthy controls, LPS showed a more prominent gene expression pattern in patients with TSC (CCL24, CXCL10, IL-6, IL-10, and IL-1B). Proinflammatory reactions against LPS were modulated by rapamycin. With LPS + rapamycin monocytes from patients with TSC showed gene expression patterns different from healthy subjects. Furthermore, developmental differences were discernible in patients with TSC, compared with gene expression levels for patients 0 to 5 years to those 6 to 11 years of age, the latter with marked expression of IL-6 IL-1A, IL-1B, RIPK2, but also IL-10., Conclusion: The effects of LPS, even more of LPS with rapamycin on monocytes from patients with TSC suggested that inflammatory processes are distinct from those in healthy subjects. Furthermore, reaction to rapamycin indicates age-related gene expression levels. Our findings offer a model to decipher the unknown and varying gene expression pattern induced by rapamycin., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Interleukin-27 (IL-27) has been described to be highly expressed during the very first days after birth, but secretion of IL-27 by dendritic cells during the course of childhood has not been described., Findings: In our present study we enrolled children (n = 55) in the range from 1 day of to 18 years of age and asked for a small whole blood sample. The capacity of dendritic cells to produce IL-27 during childhood was measured after whole blood culture with or without inflammatory stimuli. Results support recent findings of high IL-27 levels after birth and lowest levels in adults. Interestingly, we detected an interim peak production level at early adolescence., Conclusion: These data hint to prominent roles of IL-27 at the very start of post-natal life. Furthermore, a link has been given to so far not described immunological events during puberty.

In 2011, intranasally administered live attenuated influenza vaccine (LAIV) was approved in the EU for prophylaxis of seasonal influenza in 2-17-year-old children. Our objective was to estimate the potential epidemiological impact and cost-effectiveness of an LAIV-based extension of the influenza vaccination programme to healthy children in Germany. An age-structured dynamic model of influenza transmission was developed and combined with a decision-tree to evaluate different vaccination strategies in the German health care system. Model inputs were based on published literature or were derived by expert consulting using the Delphi technique. Unit costs were drawn from German sources. Under base-case assumptions, annual routine vaccination of children aged 2-17 years with LAIV assuming an uptake of 50% would prevent, across all ages, 16 million cases of symptomatic influenza, over 600,000 cases of acute otitis media, nearly 130,000 cases of community-acquired pneumonia, nearly 1.7 million prescriptions of antibiotics and over 165,000 hospitalisations over 10 years. The discounted incremental cost-effectiveness ratio was 1,228 per quality-adjusted life year gained from a broad third-party payer perspective (including reimbursed direct costs and specific transfer payments), when compared with the current strategy of vaccinating primarily risk groups with the conventional trivalent inactivated vaccine. Inclusion of patient co-payments and indirect costs in terms of productivity losses resulted in discounted 10-year cost savings of 3.4 billion. In conclusion, adopting universal influenza immunisation of healthy children and adolescents would lead to a substantial reduction in influenza-associated disease at a reasonable cost to the German statutory health insurance system. On the basis of the epidemiological and health economic simulation results, a recommendation of introducing annual routine influenza vaccination of children 2-17 years of age might be taken into consideration.

Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza. We evaluated the immunogenicity, safety, and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents. This was a randomized, single-blind, multicenter study with a total of 666 healthy subjects aged 6 months-17 y in one of 3 vaccination groups, each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59. A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations. Antibody titers were assessed by hemagglutination inhibition (HI) and microneutralization assays obtained on days 1, 22, 43, 366, and 387 (3 weeks post booster). Safety was monitored throughout the study. One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50% MF59 (3.75&#95;halfMF59) or 7.5 μg of A/H1N1 antigen formulated with 100% MF59 (7.5&#95;fullMF59) induced an HI titer ≥1:40 in >70% of children in the 1-<3, 3-8, and 9-17 y cohorts; however, 2 vaccinations with nonadjuvanted 15 μg A/H1N1 antigen were needed to achieve this response in the 1-<3 and 3-8 y cohorts. Among children aged 6-11 months, 1 dose of 7.5&#95;fullMF59 resulted in an HI titer ≥1:40 in >70% while 2 doses of 3.75&#95;halfMF59 were required to achieve this result. All vaccines were well tolerated. Our findings support the immunogenicity and safety of the 3.75&#95;halfMF59 (2 doses for children <12 months) and 7.5&#95;fullMF59 vaccine formulations for use in children and adolescents aged 6 months to 17 y The use of the 3.75&#95;halfMF59 could have the benefit of antigen and adjuvant sparing, increasing the available vaccine doses allowing vaccination of more people.

Objectives: This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects., Methods: Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months)., Results: A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event., Conclusions: An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Vaccines against pandemic A/H1N1 influenza should provide protective immunity in children, because they are at greater risk of disease than adults. This study was conducted to identify the optimal dose of an MF59®-adjuvanted, egg-derived, A/H1N1 influenza vaccine for young children., Methods: Children 6-11 months (N = 144) and 12-35 months (N = 186) of age received vaccine formulations containing either 3.75 μg antigen with half the standard dose of MF59 or 7.5 μg antigen with a standard dose of MF59, or a nonadjuvanted formulation containing 15 μg antigen (children 12-35 months only). Participants were given 2 primary vaccine doses 3 weeks apart, followed by 1 booster dose of MF59-adjuvanted seasonal influenza vaccine 1 year later. Immunogenicity was assessed by hemagglutination inhibition and microneutralization assays., Results: All vaccine formulations were highly immunogenic and met all 3 European licensure criteria after 2 doses. MF59-adjuvanted vaccines met all licensure criteria after 1 dose in both age cohorts, while nonadjuvanted vaccine did not meet all criteria after 1 dose in children 12-35 months. A single booster dose was highly immunogenic, and stable antibody persistence was observed in response to all vaccines. All vaccines were well tolerated., Conclusions: In this study, a single dose of 3.75 μg antigen with half the standard dose of MF59 was shown to be optimal, providing adequate levels of immediate and long-term antibodies in pediatric subjects 6-35 months of age. These data demonstrated that MF59 adjuvant allowed for reduced antigen content and promoted significant long-term antibody persistence in children, with a satisfactory safety profile.

Background and Aim: For patients with polyglandular autoimmune syndrome (PGA), data pertaining to familial clustering and quality of life are missing. Therefore, we performed a prospective and controlled study to collect this information., Patients and Methods: Clinical and serological evaluation of 75 consecutively recruited patients with PGA (mean age 47,5 ± 15,3 years; 65,3% women) and their 108 relatives (mean age 33,13 ± 20,08 years; 65,7% women) was performed. Three validated questionnaires for psychosocial evaluation (quality of life short form 36 [SF-36], hospital anxiety and depression scale [HADS] and the Gießener Beschwerdebogen [GBB]) were answered by patients and relatives., Results: 47 (62%) patients with PGA had type 1 diabetes and autoimmune thyroid disease. 56 (52%) of their relatives had an autoimmune disease whereas Hashimoto's thyroiditis and type-A-gastritis were the most prevalent endocrine and non-endocrine components. Thyroid peroxidase autoantibodies were most prevalent in patients and involved relatives. Compared to a German reference group, all scales of the SF-36 were markedly decreased in patients and involved relatives (p < 0.001). Anxiety and depression scales were pathologically increased in patients and relatives (p < 0.001). Also, all GBB scales were elevated for patients and relatives (p < 0.001). Patients with both glandular and non-glandular autoimmune diseases showed the most pathological psychosocial results., Conclusion: Familial clustering is high in patients with PGA. Quality of life and psychosocial status are poor in patients and involved relatives. Multidisciplinary management of the multiplex families in specialized centers is warranted., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Influenza vaccines contain Influenza A and B antigens and are adjusted annually to match the characteristics of circulating viruses. In Germany, Influenza B viruses belonged to the B/Yamagata lineage, but since 2001, the antigenically distinct B/Victoria lineage has been co-circulating. Trivalent influenza vaccines (TIV) contain antigens of the two A subtypes A(H3N2) and A(H1N1), yet of only one B lineage, resulting in frequent vaccine mismatches. Since 2012, the WHO has been recommending vaccine strains from both B lineages, paving the way for quadrivalent influenza vaccines (QIV)., Methods: Using an individual-based simulation tool, we simulate the concomitant transmission of four influenza strains, and compare the effects of TIV and QIV on the infection incidence. Individuals are connected in a dynamically evolving age-dependent contact network based on the POLYMOD matrix; their age-distribution reproduces German demographic data and predictions. The model considers maternal protection, boosting of existing immunity, loss of immunity, and cross-immunizing events between the B lineages. Calibration to the observed annual infection incidence of 10.6% among young adults yielded a basic reproduction number of 1.575. Vaccinations are performed annually in October and November, whereby coverage depends on the vaccinees' age, their risk status and previous vaccination status. New drift variants are introduced at random time points, leading to a sudden loss of protective immunity for part of the population and occasionally to reduced vaccine efficacy. Simulations run for 50 years, the first 30 of which are used for initialization. During the final 20 years, individuals receive TIV or QIV, using a mirrored simulation approach., Results: Using QIV, the mean annual infection incidence can be reduced from 8,943,000 to 8,548,000, i.e. by 395,000 infections, preventing 11.2% of all Influenza B infections which still occur with TIV (95% CI: 10.7-11.8%). Using a lower B lineage cross protection than the baseline 60%, the number of Influenza B infections increases and the number additionally prevented by QIV can be 5.5 times as high., Conclusions: Vaccination with TIV substantially reduces the Influenza incidence compared to no vaccination. Depending on the assumed degree of B lineage cross protection, QIV further reduces Influenza B incidence by 11-33%.

Nonadherence to recommended pneumococcal conjugate vaccine (PCV) schedules may have implications for protection against pneumococcal disease. In this commentary, we have assessed adherence to the recommended dosing schedules (the completion of the primary PCV and booster series) in different European countries. We found that adherence with the PCV schedule was lower than that for diphtheria-tetanus-acellular pertussis (DTaP) and that higher adherence was observed in countries where PCV vaccination is recommended and funded. Adherence with the booster dose is often lower than that with the primary series completion, and it is often given after the recommended age. These data highlight the need to encourage timely vaccination of children with PCV, in line with local immunization schedules. There is no single solution to improve adherence; actions need to be tailored to the context of individual countries through initiatives at the national, regional, and local levels and should target different stakeholders., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Background: In Germany, the outbreak of the novel pandemic 2009 influenza A(H1N1) virus A(H1N1)pdm09 caused a wave of high activity between November 2009 and January 2011. The aim of this study was to investigate the prevalence of 19 respiratory pathogens in children hospitalized for lower respiratory tract infections during the winter influenza seasons of 2009/2010 and 2010/2011 and to observe a possible impact of influenza A(H1N1)pdm09 on the epidemiology of other epidemic viruses., Materials and Methods: Specimens were nasopharyngeal aspirates which had been collected from children admitted to the participating hospitals in the area of Mainz, Wiesbaden, and Kiel, Germany, with acute community-acquired lower respiratory tract infections. The specimens were subjected to a previously described multiplex reverse transcription PCR assay to detect the following microorganisms: enterovirus, influenza virus types A and B, respiratory syncytial virus (RSV), parainfluenzavirus types 1-4, adenovirus, Mycoplasma pneumoniae, Chlamydophila pneumoniae, rhinovirus, human metapneumovirus (hMPV), coronavirus OC43 and 229E, influenza A(H1N1)pdm09, Bordetella pertussis, Bordetella parapertussis, and Legionella pneumophila., Results: A total of 3,998 clinical specimens were collected from July 2009 to March 2011, of which 296 were positive for A(H1N1)pdm09. An epidemic of seasonal influenza A or B was not observed in the 2009/2010 season, but a minor epidemic of seasonal influenza B was observed in January/February 2011. Influenza A(H1N1)pdm09 coincided with the absence of the seasonal influenza A of former years. The RSV and hMPV epidemics of 2009/2010 erupted several weeks later than expected based on data collected in the PID-ARI-Network during the past 10 years, whereas in the 2010/2011 influenza season they occurred as expected., Conclusions: The emergence of the novel influenza A(H1N1)pdm09 virus may have been influenced the epidemiology of other epidemic viruses, such as the RSV and hMPV. No epidemic of seasonal influenza was observed in the 2009/2010 influenza season.

Unlabelled: The burden of influenza is unevenly distributed, with more severe outcomes in children aged <5 years than older children and adults. In spite of this, immunisation policies for young children are far from universal. This article provides an overview of the published evidence on the burden of influenza in children worldwide, with a particular interest in the impact of pandemic influenza in 2009-2010 (caused by the H1N1pdm09 virus). In an average season, up to 9.8 % of 0- to 14-year olds present with influenza, but incidence rates can be markedly higher in younger children. Children aged <5 years have greater rates of hospitalisation and complications than their older counterparts, particularly if the children have co-existing illnesses; historically, this age group have had higher mortality rates from the disease than other children, although during the 2009-2010 pandemic the median age of those who died of influenza was higher than in previous seasons. Admissions to hospital and emergency departments appear to have been more frequent in children with H1N1pdm09 infections than during previous seasonal epidemics, with pneumonia continuing to be a common complication in this setting. Outcomes in children hospitalised with severe disease also seem to have been worse for those infected with H1N1pdm09 viruses compared with seasonal viruses. Studies in children confirm that vaccination reduces the incidence of seasonal influenza and the associated burden, underlining the importance of targeting this group in national immunisation policies., Conclusions: Children aged <5 years are especially vulnerable to influenza, particularly that caused by seasonal viruses, and vaccination in this group can be an effective strategy for reducing disease burden.

Background: Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany., Methods: A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion., Results: In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children., Conclusions: Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.

There is a lack of knowledge concerning the frequency and significance of respiratory viral infections that occur in the neonatal intensive care unit. In the present study, all neonates with suspected nosocomial bacterial sepsis were screened for a panel of respiratory viruses. Respiratory viral infections were detected in 10% of these cases. This was comparable with the frequency of a blood-culture-proven sepsis.

Background: The main target groups for influenza vaccination are the elderly, the chronically ill, infants, and toddlers. Influenza vaccines are needed that suit the immunological particularities of each of these age and risk groups. Recent years have seen the approval of influenza vaccines that are more immunogenic than before, but whose use in Germany is limited by the restriction of reimbursement to a small number of vaccines., Methods: The Medline database was selectively searched for pertinent literature., Results: The suboptimal immunogenicity of conventional influenza vaccines that contain inactivated viral cleavage products and subunits can be markedly improved by the use of squalene-based adjuvant systems, by the integration of viral antigens in virosomal particles, or by intradermal administration. The vaccination of elderly persons with a vaccine containing the adjuvant MF59 was found to lower the risk of hospitalization for influenza or pneumonia by 25% compared to vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the adjuvant ASO3 was found to be associated with an up to 17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a virosomal vaccine lowered the frequency of laboratory-confirmed influenza in vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%)., Conclusion: The newer vaccines possess improved efficacy when used for primary and booster immunization in certain age and risk groups, and they are superior in this respect to conventional vaccines based on viral cleavage products and subunits. The risk/benefit profiles of all currently available vaccines vary depending on the age group or risk group in which they are used.

Unlabelled: In Europe, the introduction of monovalent meningococcal serogroup C (MenC) conjugate vaccines has resulted in a significant decline in MenC invasive disease. However, given the potential for strain evolution and increasing travel to areas of high endemicity, protection against additional serogroups is needed. In this study, the immunogenicity, measured by a serum bactericidal activity assay using rabbit complement (rSBA), and the safety of a quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) were compared to that of a licensed monovalent MenC conjugate vaccine (MenC-CRM₁₉₇) in children 2-10 years of age. Children were randomised (3:1) to receive a single dose of either MenACWY-TT or MenC-CRM₁₉₇. Non-inferiority of the immunogenicity of MenACWY-TT versus MenC-CRM₁₉₇ in terms of rSBA-MenC vaccine response was demonstrated. Exploratory analyses suggested that rSBA-MenC geometric mean titres adjusted for pre-vaccination titres were lower in children vaccinated with MenACWY-TT compared to MenC-CRM₁₉₇. Nevertheless, at 1 month post-vaccination, ≥99.3 % of the children who received MenACWY-TT had rSBA titres ≥1:128 for each of the four vaccine serogroups, which is the more conservative correlate of protection. The reactogenicity and safety profile of MenACWY-TT was clinically acceptable and no serious adverse events considered related to vaccination were reported throughout the study., Conclusion: When administered to European school-age children, MenACWY-TT has a clinically acceptable safety profile and, when compared with MenC-CRM₁₉₇, the potential to broaden protection against meningococcal disease caused by serogroups A, W-135 and Y while maintaining protection against MenC. This study has been registered at www.clinicaltrials.gov NCT00674583.

Tonsillotomy and tonsillectomy are most frequently performed interventions during childhood. There is a need for a critical assessment of indication by using selected criteria. The collaboration of pediatricians and ENT surgeons is essential. Tonsillotomy in children < 6 years of age is associated with lower rates of postoperative bleeding.

Background: Long-term persistence of immune response and safety of an H5N1 prepandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based adjuvant system) was evaluated using various prime-boost schedules that mimicked potential pandemic scenarios (NCT00430521)., Methods: Five hundred and twelve healthy adults aged 18-60 years received primary vaccination with one or two doses (0, 21 days schedule) of the A/Vietnam/1194/2004 H5N1 vaccine followed by a booster dose (A/Vietnam/1194/2004 or A/Indonesia/05/2005 strain) six or twelve months later across eight randomized groups. Immunogenicity results by hemagglutination inhibition [HI] assay, microneutralization assay, and the cell-mediated immune response (CMI) are reported here for the four groups boosted at Month 12., Results: A one-dose-adjuvanted primary administration followed 12 months later by a single-adjuvanted booster dose containing a heterologous vaccine strain met or exceeded all US and European criteria for both strains. Increasing the interval between the first and second dose (from 21 days to 12 months) resulted in stronger cross-reactive immune responses against the A/Indonesia/05/2005 strain. The HI antibody response against the two strains persisted for 6 months after the booster dose irrespective of the booster vaccine's strain. The neutralizing antibody responses and the CMI observed in the study population paralleled the HI immune response. Overall, the vaccine had a clinically acceptable safety profile., Conclusion: The H5N1 vaccine in this study allowed for flexibility in the time interval between primary and booster vaccination and the use of a heterologous strain without impacting the strength of the humoral and cellular immune response to both vaccine strains., (© 2012 Blackwell Publishing Ltd.)

This article reports the case of a 14-year-old boy who was presented in the case conference with symptoms of decreased visual acuity, scintillating scotomas and photophobia. Physical examination revealed right facial paralysis, parotid gland swelling, high fever and poor general condition. Ophthalmoscopy revealed anterior and posterior uveitis including macular edema and chorioretinal infiltrates. Angiography revealed a dense pattern of hyperfluorescent lesions and these observations resulted in the diagnosis of Heerfordt syndrome. Under systemic prednisolone therapy, symptoms were reduced and visual acuity recovered.

The present extension study, conducted in children originally vaccinated at 12-14 mo or 3-5 y of age, assessed antibody persistence and immune memory induced by an investigational tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT). In the original study, participants were randomized to receive one dose of MenACWY-TT or licensed age-appropriate meningococcal control vaccines. Fifteen months post-vaccination, all participants underwent serum sampling to evaluate antibody persistence and participants previously vaccinated as toddlers received a polysaccharide challenge to assess immune memory development. Exploratory comparisons showed that (1) All children and ≥ 92.3% of the toddlers maintained serum bactericidal (rSBA) titers ≥ 1:8 at 15 mo post MenACWY-TT vaccination; statistically significantly higher rSBA geometric mean titers (GMTs) were observed compared with control vaccines. (2) At one month after polysaccharide challenge, all toddlers primed with MenACWY-TT or with the monovalent serogroup C conjugate vaccine had rSBA titers ≥ 1:8 and ≥ 1:128 for serogroup C and similar rSBA-GMTs; rSBA-GMTs for serogroups A, W-135 and Y were statistically significantly higher in toddlers primed with MenACWY-TT compared with the control vaccine. Thus, a single dose of MenACWY-TT induced persisting antibodies in toddlers and children and immune memory in toddlers. This study has been registered at www.clinicaltrials.gov NCT00126984.

Community-acquired pneumonia (CAP) is a common cause of morbidity among children in developed countries and accounts for an incidence of 10-40 cases per 1000 children in the first 5 years of life. Given the clinical, social and economic importance of CAP, there is general agreement that prompt and adequate therapy is essential to reduce the impact of the disease. The aim of this discussion paper is to consider critically the available data concerning the treatment of uncomplicated pediatric CAP and to consider when, how and for how long it should be treated. This review has identified the various reasons that make it difficult to establish a rational approach to the treatment of pediatric CAP, including the definition of CAP, the absence of a pediatric CAP severity score, the difficulty of identifying the etiology, limited pharmacokinetic (PK)/pharmacodynamic (PD) studies, the high resistance of the most frequent respiratory pathogens to the most widely used anti-infectious agents and the lack of information concerning the changes in CAP epidemiology following the introduction of new vaccines against respiratory pathogens. More research is clearly required in various areas, such as the etiology of CAP and the reasons for its complications, the better definition of first- and second-line antibiotic therapies (including the doses and duration of parenteral and oral antibiotic treatment), the role of antiviral treatment and on how to follow-up patients with CAP. Finally, further efforts are needed to increase vaccination coverage against respiratory pathogens and to conduct prospective studies of their impact.

Unlabelled: Two doses of a varicella-containing vaccine in healthy children <12 years are suggested to induce better protection than a single dose. Persistence of immunity against measles, mumps, rubella, and varicella as well as varicella breakthrough cases were assessed 3 years after two-dose measles, mumps, rubella, and varicella (MMRV) vaccination or concomitant MMR (Priorix™) and varicella (Varilrix™) vaccination. Four hundred ninety-four healthy children, 12-18 months old at the time of the first dose, received either two doses of MMRV vaccine (GlaxoSmithKline Biologicals) 42-56 days apart (MMRV, N = 371) or one dose of MMR and varicella vaccines administered simultaneously at separate sites, followed by another MMR vaccination 42-56 days later (MMR + V, N = 123). Three hundred-four subjects participated in 3-year follow-up for persistence of immunity and occurrence of breakthrough varicella (MMRV, N = 225; MMR + V, N = 79). Antibodies were measured by ELISA (measles, mumps, rubella) and immunofluorescence (varicella). Contacts with individuals with varicella or zoster and cases of breakthrough varicella disease were recorded. Three years post-vaccination seropositivity rates in subjects seronegative before vaccination were: MMRV-measles, 98.5% (geometric mean titer [GMT] = 3,599.6); mumps, 97.4% (GMT = 1,754.5); rubella, 100% (GMT = 51.9); varicella, 99.4% (GMT = 225.5); MMR + V-measles, 97.0% (GMT = 1,818.8); mumps, 93.8% (GMT = 1,454.6); rubella, 100% (GMT = 53.8); and varicella, 96.8% (GMT = 105.8). Of the subjects, 15-20% reported contact with individuals with varicella/zoster each year. After 3 years, the cumulative varicella breakthrough disease rate was 0.7% (two cases) in the MMRV group and 5.4% (five cases) in the MMR + V group., Conclusion: Immunogenicity of the combined MMRV vaccine was sustained 3 years post-vaccination. (208136/041/NCT00406211).

Background: Nine randomized controlled clinical trials, including approximately 26,000 children aged 6 months to 17 years, have evaluated the efficacy of live attenuated influenza vaccine (LAIV) against culture-confirmed influenza illness compared with placebo or trivalent inactivated influenza vaccine (TIV). The objective of the current analysis was to integrate available LAIV efficacy data in children aged 2-17 years, the group for whom LAIV is approved for use., Methods: A meta-analysis was conducted using all available randomized controlled trials and a fixed-effects model. Cases caused by drifted influenza B were analyzed as originally classified and with all antigenic variants classified as dissimilar., Results: Five placebo-controlled trials (4 were 2-season trials) and 3 single-season TIV-controlled trials were analyzed. Compared with placebo, year 1 efficacy of 2 doses of LAIV was 83% (95% CI: 78, 87) against antigenically similar strains; efficacy was 87% (95% CI: 78, 93), 86% (95% CI: 79, 91), and 76% (95% CI: 63, 84) for A/H1N1, A/H3N2, and B, respectively. Classifying B variants as dissimilar, efficacy against all similar strains was 87% (95% CI: 83, 91) and 93% (95% CI: 83, 97) against similar B strains. Year 2 efficacy was 87% (95% CI: 82, 91) against similar strains. Compared with TIV, LAIV recipients experienced 44% (95% CI: 28, 56) and 48% (95% CI: 38, 57) fewer cases of influenza illness caused by similar strains and all strains, respectively. LAIV efficacy estimates for children from Europe, the United States, and Middle East were robust and were similar to or higher than those for the overall population., Conclusions: In children aged 2-17 years, LAIV demonstrated high efficacy after 2 doses in year 1 and revaccination in year 2, and greater efficacy compared with TIV. This meta-analysis provides precise estimates of LAIV efficacy among the approved pediatric age group., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Induction of immunologic memory was assessed following primary vaccination with 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV)., Methods: Infants were randomized (1:1) to receive 3 doses of PHiD-CV or 7vCRM (7-valent CRM197-conjugated pneumococcal conjugate vaccine [PCV]) at 2, 3, and 4 months of age followed by 23-valent pneumococcal polysaccharide vaccine (23vPS) booster dose at 11 to 14 months of age. Pneumococcal geometric mean antibody concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers were measured., Results: Postprimary immune responses were consistent with those in previous PHiD-CV and 7vCRM studies. Following 23vPS boosting, vaccine serotype-specific antibody GMCs increased 6.5- to 33.3-fold and 4.8- to 32.2-fold versus prebooster in the PHiD-CV and 7vCRM groups, respectively. Postbooster OPA titers increased 2.8- to 38.8-fold and 2.6- to 58.9-fold, respectively. Postbooster antibody GMCs exceeded postprimary levels but, for some serotypes, postbooster OPA geometric mean titers were lower than postprimary in both groups. An additional dose of the same PCV received for priming was administered to 52 children aged 46 to 50 months, resulting in higher responses versus postprimary vaccination for all serotypes, but not always higher than post-23vPS booster., Conclusions: Induction of immunologic memory following PHiD-CV priming was confirmed. Additional PCV boosting in 4-year-olds did not provide strong evidence of hyporesponsiveness induced by previous 23vPS boosting. However, our results did not rule out depletion of the memory B cell pool following 23vPS vaccination, resulting in subsequent attenuated immune responses, and therefore support the use of PCV rather than 23vPS for booster vaccination in the second year of life.

Introduction: The hemagglutination inhibition (HI) titer of 1:40, which has been recognized as an immunologic correlate corresponding to a 50% reduction in the risk of contracting influenza, is based on studies in adults. Neither seasonal nor challenge-based correlates have been evaluated in children., Methods: A total of 4707 influenza vaccine-naive healthy children 6 to 72 months old were randomized in a ratio of 2:2:1 to receive 2 doses of MF-59-adjuvanted influenza vaccine (Novartis Vaccines), trivalent inactivated influenza vaccine subunit (trivalent inactivated influenza vaccine control, GSK), or a saline placebo during the 2007 to 2008 and 2008 to 2009 influenza seasons. The second dose was given 30 days after dose 1. Clinical influenza-like illnesses cases identified by active surveillance were confirmed by reverse transcription polymerase chain reaction testing for influenza. Vaccine immunogenicity 50 days after dose 1 was evaluated in a subset of 777 children., Results: Immunogenicity and efficacy results for H3N2 were evaluated against the Prentice criteria, which confirmed that the immunogenicity results warranted estimation of an immunologic correlate. We then used the Dunning model fitting the H3N2 antibody titers at day 50 and the influenza cases observed in the immunogenicity subset to estimate a correlate of protection. This analysis revealed that a cutoff HI titer of 1:110 was associated with the conventional 50% clinical protection rate against infection during the entire season, and titers of 1:215, 1:330, and 1:629 predicated protection rates of 70%, 80%, and 90%, respectively. The conventional adult HI titer of 1:40 was only associated with 22% protection., Conclusions: The use of the 1:40 HI adult correlate of protection is not appropriate when evaluating influenza vaccines in children. Although a cutoff of 1:110 may be used to predict the conventional 50% clinical protection rate, a titer of 1:330 would predict an 80% protective level, which would seem to be more desirable from a public health perspective.

Background: The efficacy of inactivated influenza vaccines is known to be poor in infants and young children., Methods: We studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay., Results: Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups., Conclusions: Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).