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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Background Recently, emergence of a higher proportion of serotype 3 in children with parapneumonic pleural effusion/empyema (PPE/PE) were observed in Germany despite general immunization with 13-valent pneumococcal conjugate vaccine (PCV13) since 2009. The impact of PCV13 on the overall incidence of PPE/PE in children is unclear. Methods Annual incidence of PPE/PE in children were determined using secondary health care data for 2009–2018, provided by the Barmer statutory health insurer, serving about 11% of the German population. Temporal trends of the annual incidence were modelled applying generalized additive models. Results Overall incidence of PPE/PE in children ( ≤18 years) in the ten-year observation period was 18.17 per 100,000. The 0–1 year olds showed the highest incidence (43.09 per 100 000). PPE/PE incidence decreased from 2009 until 2013 (nadir 2013 was 15.36; 95% CI: 13.41–17.31). Since 2013, the data show an annual increase. The nadir of incidence for the 2–5 year olds (15.85; 95% CI: 11.27–20.43) and the 6–18 year olds (12.29; 95% CI: 10.23–14.36) was also in 2013, whereas for the 0–1 year olds it was found in 2014 (32.66; 95% CI: 23.79–41.54). The GAM across all age groups showed a nearly U-shaped curve between time and incidence of PPE/PE by calendar year (p-non-linear = 0.0017). The model confirms the nadir in the year 2013. Discussion We found a nonlinear temporal trend of PPE/PE incidence in children with a decrease from 2009 to 2013 and a subsequent increase until 2018. The former might be explained by a quasi elimination of serotype 1, the latter by an increase in the proportion of serotype 3 as demonstrated in German surveillance data of pediatric PPE/PE cases generated during the same observation period.

Vaccine 38(3), 570-577 (2020). doi:10.1016/j.vaccine.2019.10.056, Published by Elsevier, Amsterdam

Varicella is a common vaccine-preventable disease that usually presents as a mild disorder but can lead to severe complications. Before the implementation of universal varicella vaccination (UVV) in some European countries, the burden of varicella disease was broadly similar across the region. Despite this, countries adopted heterogeneous varicella vaccination strategies. UVV is currently recommended in 12 European countries. Known barriers to UVV implementation in Europe include (1) a perceived low disease burden and low public health priority; (2) cost-effectiveness and funding availability; (3) concerns related to a shift in varicella disease and incidence of herpes zoster and (4) safety concerns related to measles, mumps, rubella and varicella-associated febrile seizures after the first dose. Countries that implemented UVV experienced decreases in varicella incidence, hospitalizations and complications, showing overall beneficial impact. Alternative strategies targeting susceptible individuals at higher risk of complications have been less effective. This article discusses ways to overcome the barriers to move varicella forward as a truly vaccine preventable disease.

Background Vaccination during pregnancy can protect both the expecting mother and the unborn and newborn child from infectious diseases. Methods This review is based on publications retrieved by a selective literature search on the immunological particularities of infectious diseases affecting pregnant women, unborn children, and neonates, with particular attention to the guidelines of the German Standing Committee on Vaccinations (Standige Impfkommission, STIKO) and the pertinent guidelines. Results Vaccination during pregnancy protects the expecting mother from a severe course of a number of different infectious diseases. Vaccination with inactivated vaccines against influenza, tetanus, and pertussis is effective, safe, and well tolerated. Women who are pregnant or of child-bearing age should be immunized against tetanus according to the STIKO recommendations. All pregnant women from the second trimester onward should receive an inactivated quadrivalent influenza vaccine. The immunity acquired after vaccination with an acellular pertussis vaccine is present only for a limited time. In a cohort study involving 72,781 pregnant women, pertussis vaccination during pregnancy was found to yield 91% protection against pertussis for their subsequently born children in the first three months of life. Further types of vaccine can also be given during pregnancy if indicated. Additional reasonable measures to protect the health of mother and child include the vaccination of other persons in close contact as well as the closure of relevant vaccination gaps among young adults, particularly women of child-bearing age. Treating physicians play a crucial role in encouraging vaccine acceptance by their patients. Conclusion Maternal immunization is a safe and effective strategy for giving neo - nates passive immune protection against life-threatening infections by the vertical transmission of maternal antibodies until they are able to build up their own adaptive immunity.

Parapneumonic pleural effusion and pleural empyema (PPE/PE) are complications of community-acquired pneumonia. The objective of this study was to analyze prehospital antibiotic therapy (PH-ABT) of children with PPE/PE and investigate its effects on clinical outcome and pathogen detection.Prospective nationwide active surveillance in Germany between October 2010 and June 2018. Children and adolescents18 years of age with pneumonia-associated PE or PPE requiring drainage or with persistence of PPE/PE7 days were included.A total of 1724 children with PPE/PE were reported, of whom 556 children (32.3% of 1719 with available data) received PH-ABT. Children with PH-ABT had a shorter median hospital length of stay (15 vs. 18 days, P0.001), a longer time from onset of symptoms until hospital discharge (25 vs. 23 days, P = 0.002), a lower rate of intensive care unit admission (58.3% vs. 64.4%, P = 0.015) and fewer infectious complications (5.9% vs. 10.0%; P = 0.005). Bacterial pathogens in blood or pleural fluid culture were detected in 597 (34.5%) of 1513 children. Positive culture results were less frequent in children with than without PH-ABT (81/466 [17.4%] vs. 299/1005 [29.8%]; P0.001), whereas detection rates in pleural fluid samples by polymerase chain reaction were similar (91/181 [50.3%] vs. 220/398 [55.3%]; P = 0.263).In children with PPE/PE, PH-ABT significantly reduced the overall rate of bacterial pathogen detection by culture, but not by polymerase chain reaction. PH-ABT was associated with a lower rate of infectious complications but did not affect the overall duration of disease. We therefore speculate that the duration of PPE/PE is mainly a consequence of an infection-induced inflammatory process, which can only partially be influenced by antibiotic treatment.

Background: Investigating the role of children in the COVID-19 pandemic is pivotal to prevent the virus spreading. In most cases, children infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) develop non-specific symptoms or are asymptomatic. Therefore, the infection rate among this age group remains unclear. Seroprevalence studies, including clinical questionnaires, may contribute to our understanding of the time course and clinical manifestations of SARS-CoV-2 infections. Methods: SARS-CoV-2-KIDS is a longitudinal, hospital-based, multicentre study in Germany on the seroprevalence of anti-SARS-CoV-2 immunoglobulin G, as determined by an Enzyme-Linked Immunosorbent Assay in children (aged ≤17 years). A study-specific questionnaire provided additional information on clinical aspects. Findings: This analysis included 10,358 participants recruited from June 2020 to May 2021. The estimated anti-SARS-CoV-2 seroprevalence increased from 2·0% (95% confidence interval (95% CI) 1·6, 2·5) to 10·8% (95% CI 8·7, 12·9) in March 2021, without major change afterwards and was higher in children with migrant background (on average 6·6% vs. 2·8%). In the pandemic early stages, children under three years were 3·5 (95% CI 2·2, 5·6) times more likely to be seropositive than older children, with the levels equalising in later observations. History of self-reported respiratory tract infections or pneumonia was associated with seropositivity (OR 1·8 (95% CI 1·4, 2·3);2·7 (95% CI 1·7, 4·1)). Interpretation: The majority of children in Germany do not have detectable SARS-CoV-2 IgG. To some extent, this may reflect the effect of differing containment measures implemented in the federal states. Detection levels might have been greater in certain age groups or migrant background. Lifting containment measurements is likely to cause a general increase in respiratory tract infections, which already pose a challenge to paediatric medical care during regular winter seasons. This challenge might become critical with additional infections caused by SARS-CoV-2.

This evidence‐based clinical guideline provides consensus‐recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus‐based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non‐infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG‐replacement therapy. Summary and consensus‐recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG‐replacement therapy. Special aspects of concomitant impaired T‐cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA‐4‐, and LRBA‐deficiency).

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition with impairment of cytotoxic T-cells and natural killer cells. Causes in infants are mostly hereditary immune defects as well as various infectious triggering factors, amongst these cytomegalovirus (CMV). Vertical CMV transmission may occur in utero, during birth, and by breast feeding. Usually, a CMV infection transmitted via breast milk is symptomatic only in very immature preterm infants. We report on a late preterm infant born after 35 + 5 weeks of gestation with a birth weight of 1840 g, being admitted to our intensive care unit at the age of 9 weeks with acute enteritis and severe dehydration. After a prolonged recovery, the infant developed a sepsis-like condition with hyperpyrexia, hepatosplenomegaly, and pancytopenia. Combination with high ferritin levels (2809 μg/l), hypertriglyceridaemia (481 mg/dl), elevated soluble IL-2 receptor (sCD25, 9120 U/ml), and reduced perforin expression allowed diagnosis of HLH, caused by an acute CMV infection. Since connatal CMV infection had been ruled out earlier, we report the rare case of secondary HLH triggered by a postnatally acquired symptomatic CMV infection in an immunocompetent infant, most likely transmitted via breast milk. The infant was successfully treated with ganciclovir without need for immunosuppressive therapy.

Universal varicella vaccination for 1-year-old children was introduced in Germany in 2004. We investigated changes in the incidence and type of varicella-associated neurologic complications in children during the first 7 years after universal vaccination recommendation.A surveillance study was conducted based on patients17 years of age with an International Classification of Diseases (10th Revision) discharge diagnosis of varicella, annually reported by 22-29 pediatric hospitals in Bavaria, Germany, 2005 to 2011. Annual incidences were estimated and linear trend across years was assessed by Poisson regression models.Of a total of 1263 varicella-associated pediatric hospitalizations, 228 children (18.1%) had neurologic complications (median age 4 years, interquartile range 2-7; 56% male). The most frequent neurologic complications were febrile convulsion (32.0% of 228 children, median age 3.0 years), varicella encephalitis or meningitis (28.9%; median age 4.5 years), syncope (13.2%; median age 7.0 years) and cerebral convulsion (11.0%; median age 4.0 years). Other complications included ataxia (3.1%), facial nerve palsy (2.6%) and cerebral vasculitis/infarction (1.8%). Neurologic complications showed a continuous decrease between 2005 and 2011, from an incidence of 2.8 (95% confidence interval: 2.1-3.6) per 100,000 children17 years of age to 1.2 (95% confidence interval: 0.7-2.1; P0.001). In particular, a marked decline was observed among children up to 7 years of age, mainly because of a decrease in the number of febrile convulsions and encephalitis or meningitis.The incidence of varicella-associated neurologic complications in children decreased approximately by 60% during the first 7 years following the recommendation for universal vaccination.

Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age 70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P

Pediatric pulmonology 52(4), 540-547 (2017). doi:10.1002/ppul.23562, Published by Wiley-Liss, New York, NY [u.a.]

Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community-acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunization for infants.Children18 years of age hospitalized with pneumonia-associated PPE/PE necessitating pleural drainage or persisting7 days were reported to the German Surveillance Unit for Rare Diseases in Childhood between October 2010 and June 2017. All bacteria detected in blood or pleural fluid (by culture/PCR) were included, with serotyping for Streptococcus pneumoniae.The median age of all 1447 PPE/PE patients was 5 years (interquartile range 3-10). In 488 of the 1447 children with PPE/PE (34%), 541 bacteria (40 species) were detected. Aerobic gram-positive cocci accounted for 469 of 541 bacteria detected (87%); these were most frequently Streptococcus pneumoniae (41%), Streptococcus pyogenes (19%) and Staphylococcus aureus (6%). Serotype 3 accounted for 45% of 78 serotyped S. pneumoniae strains. Annual PPE/PE incidence varied between 14 (95%CI 12-16) and 18 (95%CI 16-21) PPE/PE per million children. Incidence of S. pneumoniae PPE/PE decreased from 3.5 (95%CI 2.5-4.6) per million children in 2010/11 to 1.5 (95%CI 0.9-2.4) in 2013/14 (p 0.002), followed by a re-increase to 2.2 (95%CI 1.5-3.2) by 2016/17 (p 0.205).In the era of widespread PCV immunization, cases of paediatric PPE/PE were still caused mainly by S. pneumoniae and, increasingly, by S. pyogenes. The re-increase in the incidence of PPE/PE overall and in S. pneumoniae-associated PPE/PE indicates ongoing changes in the bacterial aetiology and requires further surveillance.

BACKGROUND Limited data on the influenza burden in pediatric outpatients are available, especially regarding direct comparison of the cocirculating (sub)types A(H1N1)pdm09, A(H3N2) and B. METHODS Children 1-5 years of age, unvaccinated against influenza and presenting with febrile acute respiratory infections (ARIs), were enrolled in 33 pediatric practices in Germany from 2013 to 2015 (January-May). Influenza was confirmed by multiplex polymerase chain reaction from pharyngeal swabs and (sub)typed. RESULTS In 805 children with ARI, influenza was the most frequently detected respiratory virus (n = 305; 37.9%). Of 217 influenza patients included, 122 (56.2%) were infected with A(H3N2), 56 (25.8%) with A(H1N1)pdm09 and 39 (18.0%) with B. Median age was 3.7 years [interquartile range (IQR), 2.1-4.8]; 11% had underlying conditions. Median fever duration was 4 days (IQR, 3-5), and the disease duration was 9 days (IQR, 7-12). Most frequent diagnoses were pharyngitis (26%), bronchitis (18%) and acute otitis media (10%). Children received mainly antipyretics (86%) and adrenergic nasal drops/spray (53%); 9% received antibiotics and 3% oseltamivir. Thirty-six percent required at least 1 additional practice visit; 1% was hospitalized. Median absences from childcare were 5 days (IQR, 3-7); parents lost 4 workdays (IQR, 2-6). Symptoms, severity and impact on the family were largely unrelated to (sub)type. However, patients with A(H1N1)pdm09 had fewer underlying conditions (P = 0.017), whereas patients with B more often had pharyngitis (P = 0.022), acute otitis media (P = 0.012) and stenosing laryngotracheitis (P = 0.007). CONCLUSIONS Influenza was the most frequently detected viral pathogen in outpatient children with febrile, mostly uncomplicated ARI. In this setting, clinical manifestations and severity were similar across the (sub)types prevalent during the postpandemic seasons.

A 4-year-old Turkish girl of consanguineous parents was hospitalized for the evaluation of headaches and recurrent febrile episodes of unknown origin. Her medical history was unremarkable except for a few episodes of uncomplicated oral thrush. Meningitis was diagnosed, and Candida albicans was the only pathogen identified by polymerase chain reaction and culture. Despite systemic antifungal multidrug therapy, a prolonged course of 16 months of therapy was necessary to clear C. albicans from the cerebrospinal fluid. Molecular genetic analysis revealed a homozygous caspase recruitment domain 9 (CARD9) mutation (Q295X), which was reported to predispose to chronic mucocutaneous candidiasis. Immunologic workup excluded predisposing B-cell and T-cell defects. In addition, T cells producing interleukin-17 were repeatedly measured within the normal range. Analyses of neutrophils demonstrated normal nicotinamide adenine dinucleotide phosphate oxidase activity in response to various stimuli including Staphylococcus aureus and C. albicans. Additional neutrophilic functional testing, however, showed a decreased cytotoxicity to nonopsonized C. albicans, indicating an impaired killing mechanism against Candida spp. independent from the production of reactive oxygen species by the nicotinamide adenine dinucleotide phosphate oxidase system. Because this defect was only demonstrated in the absence of opsonins, it might especially predispose to chronic C. albicans infections in the central nervous system where opsonin concentrations are usually low. We, therefore, suggest that due to an additional neutrophil dependent defect CARD9 deficiency predisposes not only to chronic mucocutaneous candidiasis, but also to invasive chronic Candida infections, especially of the central nervous system.

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.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.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.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.

Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use 2 distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized C albicans was found to be dependent on complement receptor 3 (CR3) and the signaling proteins phosphatidylinositol-3-kinase and caspase recruitment domain-containing protein 9 (CARD9), but was independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The second mechanism for the killing of opsonized C albicans was strictly dependent on Fcγ receptors, protein kinase C (PKC), and reactive oxygen species production by the NADPH oxidase system. Each of the 2 pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensable for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency, or chronic granulomatous disease.

Varicella in oncology patients can result in serious complications. We analyzed trends in hospitalization rates and characteristics of pediatric oncology and non-oncology patients hospitalized with varicella during the first 7 years after introduction of routine varicella vaccination. Our data included children

Hypophosphatasia (HPP) is a heterogeneous rare inborn error of bone and mineral metabolism caused by mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). These mutations result in a decreased level of TNAP activity and increased levels of its substrates, including inorganic pyrophosphate, pyridoxal-5′-phosphate and phosphoethanolamine. Clinical presentations are highly variable, ranging from stillbirth and absence of mineralization in severe disease to mild dental problems or osteopenia in adulthood. Further clinical symptoms include defective bone mineralization with bone deformities, recurrent fractures, chronic non-bacterial osteomyelitis, craniosynostosis, neonatal seizures, nephrocalcinosis, muscular hypotonia, failure to thrive and dental abnormalities with premature exfoliation of teeth and caries. Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease but patients with mild phenotypes (adult form or Odonto-HPP) usually do not have a limitation in their life expectancy. Although TNAP is a ubiquitous enzyme, mostly known for its crucial role during mineralization of bone and teeth, its exact biological role in different human organs is still unclear, and the pathophysiology of symptoms due to TNAP deficiency in HPP are not understood in detail. Since inflammation and tissue destruction of the musculoskeletal system may occur in HPP, TNAP may also play an important role in controlling inflammatory processes. Recent investigations provide evidence that TNAP is also essentially involved in the development of the central nervous system and might contribute to multiple functions of the human brain. HPP can be diagnosed on clinical, biochemical and radiological criteria, and genetic testing confirms the diagnosis and is useful for genetic counseling. Since clinical symptoms are highly variable, patients should be followed up by a multidisciplinary team having experience in HPP treatment. Up to now, no curative treatment of HPP is available. Therefore, symptomatic treatment in particular with regard to pain, seizures and other metabolic phenomena is most important. However, recently, enzyme replacement therapy with a bone-targeted recombinant human TNAP molecule has been reported to improve bone mineralization, respiratory function and physical activity in severely affected infants with HPP, and further clinical trials are ongoing. Hopefully, this and other new therapeutic strategies may improve the prognosis and quality of life of patients with HPP and may contribute to our understanding of bone metabolism in general.

International audience; OBJECTIVE: To assess the impact of household smoking and palivizumab prophylaxis on the risk of respiratory syncytial virus (RSV) hospitalisation in late-preterm (32-35 weeks' gestational age) infants. METHODS: Familial smoking and other RSV risk factor data from the FLIP, FLIP-2 and IMpact studies and datasets from France, Germany and Italy, together with palivizumab prophylaxis data from the FLIP-2 and IMpact studies, were analysed using cross-correlation and Bayesian meta-analytical modelling employing Markov Chain Monte Carlo sampling. RESULTS: There were 2.35 times (95% confidence interval [CI] 1.37-4.02) as many hospitalisations amongst infants from smoking compared with those from non-smoking families. Among non-prophylaxed infants, there were 2.53 times (95% CI 1.27-4.94) as many RSV hospitalisations from smoking than from non-smoking families and that excess hospitalisation was reduced to 1.03 times (95% CI 0.38-2.99) amongst prophylaxed infants. Familial smoking correlates significantly (p \textless 0.01) with other RSV risk factors: positive correlation with number of school-age siblings, history of family atopy, family wheeze and gestational age; negative correlation with birth weight and breast feeding. CONCLUSIONS: Late-preterm infants from smoking families appear to be at heightened risk for severe RSV infection requiring hospitalisation of which the risk may be reduced with RSV prophylaxis.

International audience; Objective: To investigate the association between birth weight and respiratory syncytial virus (RSV) hospitalisation during the first year of life in 33°–356 weeks’ gestational age (wGA) infants.Study design: Pooled analysis of data (n = 1218) from Spain, Germany, France and Italy.Result: RSV hospitalised infants overall had a significantly higher birth weight than non-hospitalised infants (2.24 versus 2.14 kg; p \textless 0.001) for both males (2.25 versus 2.18 kg; p = 0.049) and females (2.22 versus 2.11 kg, p = 0.007). The effect was significant only in 34 wGA infants (33 wGA: hospitalised 1.95 kg versus non-hospitalised 1.95 kg, p = 0.976; 34 wGA: 2.26 versus 2.14 kg, p = 0.007; 35 wGA: 2.37 versus 2.29 kg, p = 0.070), particularly female 34 wGA infants (female: 2.24 versus 2.08 kg, p = 0.019; male: 2.27 versus 2.20, p = 0.191). Birth weight was shown to be an independent risk factor for RSV hospitalisation.Conclusions: In 33–35 wGA infants, a higher birth weight appeared independently associated with an increased risk of RSV hospitalisation.

Diffusion-weighted MRI (DWI) is helpful for detection of brain abscess and pelvic abscess in adults. In the present study, we evaluated the diagnostic performance of DWI in children and young adults with abdominal and soft tissue abscess formations.Seventeen patients (11 females, aged 13 ± 6 years) with suspected abdominal or soft-tissue abscess underwent routine MRI including free-breathing DWI and contrast-enhanced T1w imaging. Seventeen random age-matched patients with non-purulent abdominal fluid collections served as controls. Mean apparent diffusion coefficent (ADC) was measured for abscess, muscle, liver, spleen and kidney tissue as well as for cerebrospinal fluid, urine and free abdominal fluid.All fluid collections were identified on diffusion-weighted images. Thirteen of 14 confirmed abscess formations showed an ADC1.0 × 10(-3) mm(2)/s with a mean value of 0.80 ± 0.38 mm(2)/s. One tuberculous soft-tissue abscess had a higher ADC of 1.85 × 10(-3) mm(2)/s. Ring enhancement on T1w imaging was seen in three non-purulent fluid collections. There were no false-positive findings in the control group.Diffusion-weighted MRI is highly sensitive for abscess and may add specificity to contrast-enhanced T1w imaging of ring-enhancing fluid collections. DWI with free-breathing rapid image acquisition and without the need of intravenous contrast application constitutes a particularly useful choice in pediatric imaging.

Owing to their low reactogenicity, confirmed efficacy and availability in combination vaccines, acellular pertussis (aP)-inactivated poliovirus (IPV) combined vaccines are now included in various national immunization programs worldwide. We provide an overview of 16 years of clinical experience with a diphtheria (D), tetanus (T), aP, IPV and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus protein (PRP~T) combined vaccine (DTaP–IPV//PRP~T — Pentaxim, Sanofi Pasteur, France). Good immunogenicity has been demonstrated after primary vaccination with Pentaxim, regardless of the population ethnicity and primary vaccination schedule. A booster vaccination in the second year of life also resulted in a high immune response for each antigen. Furthermore, 10 years of national surveillance in Sweden has demonstrated the effectiveness of Pentaxim in controlling pertussis. As is the case for other aP-containing combined vaccines, Pentaxim is well tolerated, with the safety profile being better than for whole-cell pertussiscontaining combination vaccines for primary and booster vaccinations.

Owing to their low reactogenicity, confirmed efficacy and availability in combination vaccines, acellular pertussis (aP)-inactivated poliovirus (IPV) combined vaccines are now included in various national immunization programs worldwide. We provide an overview of 16 years of clinical experience with a diphtheria (D), tetanus (T), aP, IPV and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus protein (PRP∼T) combined vaccine (DTaP-IPV//PRP∼T - Pentaxim, Sanofi Pasteur, France). Good immunogenicity has been demonstrated after primary vaccination with Pentaxim, regardless of the population ethnicity and primary vaccination schedule. A booster vaccination in the second year of life also resulted in a high immune response for each antigen. Furthermore, 10 years of national surveillance in Sweden has demonstrated the effectiveness of Pentaxim in controlling pertussis. As is the case for other aP-containing combined vaccines, Pentaxim is well tolerated, with the safety profile being better than for whole-cell pertussis-containing combination vaccines for primary and booster vaccinations.

Background Safety of a sixth consecutive dose of acellular pertussis vaccine in adolescents was assessed in a 2-armed, randomized study. Methods Adolescents who had received 5 doses of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (6-dose group) received 1 dose of reduced 5-component acellular pertussis vaccine combined with tetanus toxoid and reduced diphtheria toxoid (Tdap). Adolescents who had received a primary series of 3 doses of whole-cell pertussis and 1 acellular or whole-cell pertussis booster received 1 dose of Tdap vaccine (5-dose group). Results Of 214 participants, 176 (82%) reported an injection-site reaction with pain (80%), erythema (22%), and swelling (19%) most frequently reported. A systemic reaction was reported by 169 of 214 (79%) with myalgia (66%), headache (42%), malaise (39%), and fever (9%) most frequently reported. The overall rate of solicited reactions was lower in the 6-dose group than in the 5-dose group (for injection-site reactions: 76.1% vs. 89.7%; for systemic reactions 72.6% vs. 86.6%). Significant differences were observed for injection-site pain, erythema, and for grade 1 or grade 2 increases in arm circumference. Fever, myalgia, and headache were reported at a significantly lower rate in the 6-dose group. Swelling >10 cm was observed in 5 patients (2%), 4 in the 5-dose group. Conclusions Tdap vaccine was safe when given to adolescents who had received 5 prior doses of acellular pertussis vaccine.

Varicella is an acute febrile, highly infectious disease. We describe the incidence and types of neurologic complications in children up to 16 years old. Hospitalized varicella cases were prospectively captured by active nationwide surveillance through the German Pediatric Surveillance Unit for Rare Diseases from January 2003 to December 2004. Neurologic complications occurred in 232 (25.4%) of 918 hospitalized children with varicella, and were the most frequent reason for hospitalization. The median age was 4.2 years (interquartile range 2.5-5.9). The median duration of hospital stay was 6 days (interquartile range 3-11). Neurologic complications were more frequent (P=0.054) in immunocompetent (32%) than immunocompromised (4%) children. The most frequent diagnoses comprised acute cerebellar ataxia in 72 (31.0%), febrile convulsion in 69 (29.7%), meningoencephalitis in 52 (22.4%), cerebral convulsions in 21 (9.1%), syncope in 9 (3.9%), and cerebral vasculitis/infarction in 6 (2.6%) of all children with neurologic complications. Twenty-eight (12%) demonstrated sequelae (18 with ataxia, four with epilepsy, two with hemiparesis, three with cerebral nerve palsy, and one with dysesthesia). Three patients died. The yearly incidence of neurologic varicella-associated hospitalizations was estimated at 2.4 neurologic complications per 100,000 children, corresponding to about one neurologic complication in 2000 varicella cases.

Infections play an important role in childhood. For Germany, few data are available on the epidemiology of infectious diseases such as otitis media and pneumonia in children. We therefore described the prevalence, first episode proportions and recurrence of these childhood infection diseases in selected regions of Germany in children up to 6 years of age. The analysis was based on data from the LISA Study, a prospective population-based birth cohort study including 3,097 full-term infants. Information was collected by parent questionnaire. The first episode proportions for the first 6 years of life were high for otitis media (66.7%; 95%CI 0.65-0.69) and pneumonia (13.5%; 95%CI 0.12-0.15). The annual first episode proportions for otitis media ranged from 7.3% to 25.6% and for pneumonia from 1.4% to 3.4%; both peaked during the second year. The average number of otitis media episodes was 2.2 (SD 2.0) episodes per child within the first 2 years. During the first 2 years of life, hospitalisations due to otitis and pneumonia occurred in up to 7.8 per thousand and 3.0 per thousand of the children, respectively. On average, 50.6% of the children with otitis media were treated with antibiotics during the first year of life. In conclusion, this analysis shows that infectious diseases, especially otitis media, are very frequent childhood diseases in Germany. Thus, parents and physicians should not per se worry about a high frequency of otitis media during early childhood.

Aim of the study To evaluate the immunogenicity, safety and reactogenicity of a seven-valent pneumococcal conjugate vaccine (PCV7) when given concomitantly with a fully liquid DTaP–IPV–HBV–Hib combination vaccine. Methods Two hundred and sixty-six healthy infants in France (n = 136) and Germany (n = 130) were randomized to receive DTaP–IPV–HBV–Hib and PCV7 (test group) at the age of 2, 3 and 4 months (primary series) and 12–15 months (booster dose), or to receive DTaP–IPV–HBV–Hib at the same time points but PCV7 at the ages of 5, 6, 7 and 13–16 months (control group). Antibody levels to all vaccine antigens were measured before dose 1, 1 month after dose 3, at the time of booster, and 1 month later. Safety data were collected after each vaccine dose. Results Two hundred and fifty-seven infants (test group, 131; control group, 126) completed the primary immunization series and two hundred and forty-five received the booster dose (test group, 125; control group, 120). Depending on the serotype, 92.8–100% of subjects in the test group achieved antibody levels ≥0.15 μg/mL for PCV7 antigens at 5 months of age, and 89.7–99.1% of them antibody levels ≥0.50 μg/mL 1 month after booster. For DTaP–IPV–HBV–Hib, there was no statistically significant difference between the two groups in the proportion of infants that achieved pre-defined seroprotective levels for each antigen at 5 months and 1 month after booster. Frequency of local and systemic reactions was similar in both groups except for fever above 38.0 °C, which was more frequent in the test group after dose 1, 2 or 4. Fever >39.0 °C was only reported from three children in each group. Conclusion The PCV7 vaccine was highly immunogenic, well tolerated, and safe when coadministered with the DTPa–IPV–HBV–Hib vaccine at 2, 3, and 4 months of age and a booster dose at 12–15 months. In this study, PCV7 did not show any relevant influence on the immunogenicity and safety of the concurrently administered DTPa–IPV–HBV–Hib vaccine.

In a 2-year-long active surveillance conducted in all German pediatric hospitals, the incidence of hospitalization because of herpes zoster and the clinical picture of complications in children were assessed. Herpes zoster resulted in hospitalization of 244 children, 78 of whom were considered to be immunocompromised. Zoster ophthalmicus (n=29), meningoencephalitis (n=22), and zoster oticus (n=23) (11 cases had Ramsay Hunt syndrome) accounted for 59% of all complications (n=115). The incidence of hospitalization suggests that at least 1 in every 100 children with herpes zoster is hospitalized and that at least 1 in every 250 immunocompetent children with herpes zoster is hospitalized with complications.

Background Administration of two doses of hepatitis A (HA) vaccine to children ≥2 years of age has been shown to be protective. The present study assessed whether HA vaccine can be administered as early as 6 months of age and whether it can be administered concomitantly with a hexavalent (HV) vaccine at this age. Methods In an open label, randomized, parallel group study, the liquid HV vaccine (HEXAVAC ® ) (diphtheria, tetanus, 2-component acellular pertussis, inactivated poliomyelitis vaccine, Haemophilus influenzae type b conjugated to tetanus protein and hepatitis B) was administered at 2, 4, 6, and 12 months of age to all children. HA vaccine (VAQTA ® ) was given at 7 and 13 months in the separate administration group (Group 1) and at 6 and 12 months in the concomitant administration group (Group 2). Serum samples were obtained at 2, 7, 12, and 14 months in Group 1 and at 2, 7, 12, and 13 months in Group 2. The primary immunogenicity outcomes were the seroconversion rates for HA 1 month after the second dose of HA vaccine in initially seronegative subjects, and the seroconversion rates for each HV antigen 1 month after the third dose of the HV vaccine (both at 7 months of age). Results HA seropositivity rates 1 month after the second dose were 100% in both groups, regardless of initial serostatus. The responses to each HV antigen 1 month after the third dose were similar in both groups. The vaccines were generally well tolerated in both groups regardless of vaccine(s) administered. Conclusions A schedule of two doses of HA vaccine, 6 months apart beginning at 6 months of age is highly immunogenic and well tolerated when administered alone or concomitantly with HV vaccine at 6 and 12 months of age.

We report on a 3-year-old boy presenting with left-sided eyelid myocloni due to an intracranial abscess harboring Haemophilus paraphrophilus. This is the first description of an intracranial infection with this pathogen in a child.

Background Latent Cytomegalovirus (CMV) infection accelerates immunosenescence in elderly with reactivations reported in Rheumatoid Arthritis (RA) and abnormal responses towards CMV in Juvenile Idiopathic Arthritis (JIA). Objectives Considering the signs of premature T-cell immunosenescence in arthritis patients, the known effect of CMV latency on speeding up many of these signs in an age-dependent manner and the role of CMV on IFNγ-mediated inflammation in healthy elderly and RA, we hypothesized that latent CMV infection accelerates TCR repertoire restriction, loss of CD28, peripheral T-cell proliferation and aberrant IFNγ responses in arthritis patients. Study design Unspecific and CMVpp65-specific IFNγ responses were investigated in peripheral CD8+ T-cells in RA or JIA patients and healthy, age-matched controls. Results Despite higher prevalence and concentrations of IgG-anti-CMV, arthritis patients showed lower unspecific IFNγ production, lower CD69-mediated activation and lower CD8+ T-cell proliferation. CMV-seropositive RA patients showed higher intracellular IFNγ production and increased proportions of CD28-CD8+ T-cells after specific CMVpp65 long-term stimulation which was not altered by in vitro blockade of TNFα or IL-6. A skewed TCR repertoire towards oligoclonality and less polyclonality was found in JIA. Discussion CMVpp65-specific IFNγ production with expansion of CD28-CD8+ T-cells suggests an efficient control of latent CMV regardless of immunosuppressive therapy or in vitro blockade of TNFα or IL-6 in CMV-seropositive arthritis patients. Increased IgG-anti-CMV antibody concentrations and increased proportions of intracellular IFNγ-producing CMVpp65-specific CD8+ T-cells in long-term cultures propose a possibly role of endogenous CMV reactivations boosting antibody levels and a higher possibly CMV-driven IFNγ-mediated inflammatory potential of CD8+ T-cells in arthritis patients.

Hypophosphatasia (HPP) is a rare monogenetic and multisystemic disease with involvement of different organs, including bone, muscle, kidney, lung, gastrointestinal tract and the nervous system. The exact metabolic mechanisms of the effects of TNAP deficiency in different tissues are not understood in detail. There is no approved specific treatment for HPP; therefore symptomatic treatment in order to improve the clinical features is of major interest. Enzyme replacement therapy (ERT) is a relatively new type of treatment based on the principle of administering a medical treatment replacing a defective or absent enzyme. Recently ERT with a bone targeted recombinant human TNAP molecule has been reported to be efficient in ten severely affected patients and improved survival of life threatening forms. These results are very promising especially with regard to the skeletal phenotype but it is unclear whether ERT also has beneficial effects for craniosynostosis and in other affected tissues in HPP such as brain and kidney. Long-term data are not yet available and further systematic clinical trials are needed. It is also necessary to establish therapeutic approaches to help patients who are affected by less severe forms of HPP but also suffer from a significant reduction in quality of life. Further basic research on TNAP function and role in different tissues and on its physiological substrates is critical to gain a better insight in the pathogenesis in HPP. This and further experiences in new therapeutic strategies may improve the prognosis and quality of life of patients with all forms of HPP.

To reduce the number of injections needed to comply with paediatric vaccination requirements, a liquid, hexavalent vaccine (DTaP-IPV-PRP-T-HBs; Hexavac; Aventis Pasteur MSD) has been developed for primary and booster vaccination of infants and toddlers. In extensive clinical studies, Hexavac has been shown to be highly immunogenic. Seroconversion or seroprotective titres of antibodies against all antigens were achieved in the majority of infants following a primary series of three doses administered at 1-2-month intervals from 2 months of age. Hexavac also induced immunologic memory, as evidenced by the anamnestic response to booster vaccination at 12-18 months of age. These responses were comparable with those seen following concomitant administration of Pentavac (DTaP-IPV//PRP-T) and monovalent hepatitis B vaccine (H-B-Vax II), and were also within the ranges observed for other relevant licensed vaccines. Clinical studies comparing the immunogenicity of Hexavac administered at either 2, 3 and 4 months or 2, 4 and 6 months demonstrated that it can be used by either vaccination schedule. A further study also supported the use of primary doses of Hexavac at 3 and 5 months with a booster at 12 months of age. Hexavac demonstrated a good reactogenicity and tolerability profile. The most frequently reported adverse events after both primary and booster doses were local reactions of redness and swelling/induration and a systemic response of mild fever, irrespective of the vaccine used for priming. Hexavac provided immunity against six important childhood diseases with a single injection at each visit.

Objectives.To evaluate the safety and immunogenicity of Biken acellular pertussis vaccine in combination with diphtheria and tetanus toxoid (Biken DTaP) vaccine administered to children 4 to 6 years of age who had previously received four doses of Biken DTaP.Methods.580 children were enrolled to rec

OBJECTIVE To compare the immunogenicity and safety of a trivalent tetanus-diphtheria (low toxoid content)-inactivated poliomyelitis vaccine, Td-IPV (Revaxis; Pasteur Merieux), with a tetanus-diphtheria (low toxoid content) vaccine, Td (Td-Impfstoff Merieux; Pasteur Merieux), when administered as a booster to children age 6 to 9 years. METHODS A group of 301 children were randomized and vaccinated with Td-IPV (n = 150) or Td (n = 151) in this open, controlled, multicenter trial. Serum specimens were obtained before and 28 days after vaccination. Safety was assessed for up to 28 days postvaccination by parental diary cards. Solicited local and systemic reactions were recorded for 7 days after vaccination. RESULTS Seroprotection (enzyme-linked immunosorbent assay titer, > or =0.10 IU/ml) against tetanus and diphtheria was induced by either Td-IPV or Td in all subjects. Tetanus and diphtheria geometric mean titer were higher after Td (34.0 and 5.74 IU/ml) than after Td-IPV (15.9 and 4.38 IU/ml). All subjects boosted with Td-IPV were seroprotected against each type of poliovirus (neutralizing antibody titer, > or =5/dilution). The most frequently reported solicited local and systemic symptoms were pain triggered by movement of the arm (54% vs. 39.1%) and headache (17.3% vs. 7.3%), after Td-IPV and Td, respectively. All other events were similar between the two groups. Reactions were generally mild and all were temporary. CONCLUSIONS A booster dose of Td-IPV induced in all children seroprotection against tetanus, diphtheria and poliomyelitis. The overall safety profile of the two vaccines was acceptable.

Among 1158 preterm infants of 29-35 weeks' gestational age, respiratory syncytial virus (RSV) -related hospitalizations (RSV-H) occurred in 4.2% during the first year of life. Four independent factors influenced the risk for RSV-H: neurologic problems (odds ratio [OR], 3.6), male gender (OR, 2.8), presence of an older sibling (OR, 1.7) and discharge from October to December (OR, 1.7). The estimated risk of RSV-H varied between 1% (no risk factor present) and 30% (4 risk factors present).

OBJECTIVE: To compare the polymerase chain reaction (PCR) results with conventional culture results for the diagnosis of Bordetella pertussis infections. METHODS: PCR and culture were performed in the course of a large vaccine efficacy trial in Germany on specimens taken from 7153 children less-than-or-equal2 years of age with cough illness lasting >6 days, and laboratory results were compared with clinical data also obtained from the patients. Calcium alginate nasopharyngeal swabs were taken for culture and clinical data were obtained from patients. Swabs were inoculated on charcoal horse blood agar plates containing cephalexin, and then discarded. The agar plates were preincubated for 2 days at the physician's office and then shipped to the culture laboratory at the University Children's Hospital in Munich, Germany, for diagnosis of B. pertussis and B. parapertussis infections. In this laboratory, Dacron swabs for PCR were taken from each culture by a wide sweep over the culture. Swabs for PCR were stored in NaCl and sent weekly to the PCR laboratory at the University Children's Hospital in Basel, Switzerland, for PCR diagnosis of B. pertussis infections. RESULTS: B. pertussis was identified by culture in 3% (213/7153) and by PCR in 7.6% (546/7153) of the specimens. Therefore, PCR increased the identification rate of subjects with B. pertussis infection 2.6-fold. Clinical characteristics were considered according to the type of laboratory findings: group 1 consisted of 209 culture-positive and PCR-positive subjects, and group 2 of 337 culture-negative but PCR-positive subjects. Group 2 subjects were significantly more likely to have mild or atypical clinical symptoms of whooping cough than were group 1 subjects. By analyzing the PCR results of group 2 subjects semiquantitatively, it could be shown that the degree of PCR positivity correlated with the severity of the clinical symptoms of whooping cough in the patient. CONCLUSIONS: PCR identified many pertussis cases with mild or atypical clinical symptoms that were not identified by culture. Semiquantification of PCR products revealed that the less positive the PCR result, the higher was the failure rate in diagnosing pertussis by culture, and, in addition, the less typical were the clinical symptoms in the patient.

Since hepatitis A virus (HAV) infection during childhood is mostly asymptomatic, only seroprevalence studies can provide reliable information on incidence of HAV infection in children. The prevalence of anti-HAV antibodies was determined in sera taken in 2008 to 2010 from 1,645 children aged 0–17 years and in sera taken in 2010–2011 from 400 adult blood donors in Germany. For examination of trend over time, 715 sera collected between 1999 and 2006 from children at the age of 0–17 years within the federal state Thuringia were included. Antibody testing was carried out using the test kits ETI-AB-HAVK PLUS and ETI-HA-IGMK PLUS from DiaSorin. In children, the overall prevalence of antibodies was 10.8 %. After the seroprevalence declined from 8.8 % among the 0–2 year-olds to 2.4 % among the 3–4 year-olds, there was a significant increase to 20.5 % in the group of the 15–17 year-olds. Boys had with 12.7 % a significantly higher seroprevalence of anti-HAV antibodies compared to 8.8 % among girls. In adult blood donors, there was a HAV seroprevalence of 19.3 %. The likelihood of past infection or immunization within the age groups of children from 0 to 12 years differed significantly from that of adults. In conclusion, in Germany, only a small number of HAV infections occur in children, especially up to the age of 12 years. The proportion of susceptible children is greater than the proportion of susceptible adults. Thus, during outbreaks, the rate of infection among children would usually be higher than the rate among adults.

Hypophosphatasia (HPP) is a heterogeneous rare, inherited disorder of bone and mineral metabolism caused by different mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease. TNAP deficiency, however, may also result in neurological symptoms such as neonatal seizures. The exact biological role of TNAP in the human brain is still not known and the pathophysiology of neurological symptoms due to TNAP deficiency in HPP is not understood in detail. In this report, we describe the clinical features and functional studies of a patient with severe perinatal HPP which presented with rapidly progressive encephalopathy caused by new compound heterozygous mutations in the ALPL gene which result in a functional ALPL "knock out", demonstrated in vitro. In contrast, an in vitro simulation of the genetic status of his currently asymptomatic parents who are both heterozygous for one mutation, showed a residual in vitro AP activity of above 50%. Interestingly, in our patient, the fatal outcome was due to progressive encephalopathy which was refractory to antiepileptic therapy including pyridoxine, rather than hypomineralization and respiratory insufficiency often seen in HPP patients. The patient's cranial MRI showed progressive cystic degradation of the cortex and peripheral white matter with nearly complete destruction of the cerebrum. To our knowledge, this is the first MRI-based report of a deleterious neurological clinical outcome due to a progressive encephalopathy in an infant harboring a functional human ALPL "knock out". This clinical course of disease suggests that TNAP is involved in development and may be responsible for multiple functions of the human brain. According to our data, a certain amount of residual TNAP activity might be mandatory for normal CNS function in newborns and early childhood.

Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000 + 2T → G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.

BACKGROUND Rotavirus (RV) vaccination with the first generation vaccine (Rotashield) has been associated with intussusception (IS). Reliable age specific baseline incidence data for children ≤6 months of age in particular is fundamental for further post marketing monitoring of potential effects of recently introduced new RV vaccines. METHODS IS incidence was estimated by a 2-source capture-recapture calculation (CRC) based on ESPED (German Paediatric Surveillance Unit) reports and on hospital discharge records for 2006 and 2007. ESPED as well as hospital records were validated according to the Brighton Collaboration's Group definition for definite IS. PATIENTS Children that have been treated for IS in a hospital in one of two states of Germany (North-Rhine Westphalia and Bavaria). RESULTS The annual IS incidence for infants

Cytokines have been shown to modulate the respiratory burst of polymorphonuclear leukocytes and monocytes from normal controls. We have examined whether monocytes from children with chronic granulomatous disease (CGD) can be primed by cytokines other than interferon-gamma (IFN gamma), which has been demonstrated to improve the production of reactive oxygen species in vivo and in vitro. Monocytes isolated from peripheral blood were cultured without and with IFN gamma (500 U/mL), tumor necrosis factor-alpha (500 U/mL), interleukin-1 beta (IL-1 beta) (100 U/mL), and IL-3 (100 U/mL). After 3 days of culture, the phorbolmyristate acetate (2 ng/mL) and the formyl- methionyl-leucyl-phenylalanine (0.1 mumol/L)-stimulated superoxide- production was determined in a microtiter system. In nearly all of the 14 patients examined (5 autosomal, 5 X-chromosomal, and 4 of unknown inheritance), an improvement of superoxide production could be demonstrated. The most impressive effect with the cytokines newly tested was seen with monocytes from autosomal CGD patients treated with IL-3 and stimulated by phorbolmyristate acetate. In single patients cultivation of monocytes with IL-6 and granulocyte-macrophage colony- stimulating factor resulted in only slight improvement of superoxide production. Our findings indicate that cytokines other than IFN gamma can positively modulate the defective respiratory burst in CGD and that each patient reacts with an individual pattern to different cytokines.

The primary objective of this epidemiological surveillance study was to estimate the incidence of intussusception (IS) associated with hospitalisation in children

Since 2004, general varicella vaccination has been recommended for all children 11-14 months of age in Germany. The objective of this study was to examine vaccination coverage in children and factors associated with parental acceptance during the first years after recommendation. In a regional surveillance area, cross-sectional parent surveys were conducted in 2006, 2007 and 2008 in random samples (n=600) of children aged 18-36 months; data were obtained for 372, 364 and 352 children, respectively. Parents were questioned on their child's varicella disease history, and on varicella vaccination status as recorded in the child's vaccination booklet. Overall coverage increased from 38% in 2006 to 51% in 2007 and stagnated at 53% in 2008; in susceptible children (without previous varicella disease until vaccination or time of survey) coverage was 42%, 61% and 59%, respectively. Recommendation by the paediatrician as reported by the parents increased from 48% (2006) to 57% (2007) and 60% (2008), and was the main independent factor associated with parental acceptance. In 32-35% of unvaccinated children parents had not yet decided whether to vaccinate against varicella. Additional programmes targeting paediatricians' and parents' acceptance of varicella vaccination are needed to achieve the WHO-defined goal of at least 85% coverage.