Heterogeneity of treatment effect of vilobelimab in COVID-19: a secondary analysis of a randomised controlled trial.

In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward's hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed (p = 0.998). For HC, no significant classes were found (p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (ß), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes (p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07-0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients.

Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients.

BACKGROUND: Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. RESULTS: From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2-168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5-156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5-21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9-152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25. CONCLUSIONS: This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trial registration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420.

Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO2/FiO2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

The anti-C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID-19.

Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX-1) in patients with severe coronavirus disease 2019 (COVID-19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical formation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and secondary outcomes appeared in favor of vilobelimab. We now report the pharmacokinetic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID-19 pneumonia confirmed by real-time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20-45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03-200.89, p = 0.0006). The suppression was maintained on day 8 (p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID-19.

Determinants of Long-term protection after hepatitis B vaccination in infancy: a meta-analysis.

BACKGROUND: The duration of protection after hepatitis B vaccination in early infancy is unclear and may be related to vaccination schedule, dosage, vaccine type and population characteristics. Factors potentially influencing waning immunity were assessed. METHODS: A systematic review was performed. The main outcomes were prevalence of anti-hepatits B antibodies ≥ 10 mIU/mL after primary or booster vaccination. Factors potentially influencing protection were assessed in an adjusted random-effects meta-analysis model by age for both outcomes. Results of both meta-analyses were combined in a prognostic model. RESULTS: Forty-six studies reporting on the anti-hepatits B antibodies ≥ 10 mIU/mL 5 to 20 years after primary immunization and 29 on booster response were identified. The adjusted meta-analyses identified maternal carrier status (odds ratio [OR]: 2.37 [1.11; 5.08]), lower vaccine dosage than presently recommended (OR: 0.14 [0.06; 0.30]) and gap time between last and preceding dose of the primary vaccine series (OR: 0.44 [0.22; 0.86]) as determinants for persistence of anti-hepatits B antibodies ≥ 10. A lower vaccine dosage was also associated with failure to respond to booster (OR: 0.20 [0.10; 0.38]). The prognostic model predicted long-term protection of 90% [77%; 100%] at the age of 17 years for offspring of noncarrier mothers vaccinated with a presently recommended dose and vaccination schedule. CONCLUSIONS: Based on meta-analyses, predictors of waning immunity after hepatitis B vaccination in infancy could be identified. A prognostic model for long-term protection after hepatitis B vaccination in infancy was developed.

Impact of maternal carrier status on immunologic markers for protection after hepatitis B vaccination in infancy: a meta-analysis.

Better protection against hepatitis B infection in offspring of carrier mothers has been postulated because of a booster effect by close maternal contact. Empirical evidence, however, is inconclusive. Immunologic markers for protection against hepatitis B are anti-HBs ≥ 10 mIU/ml or response to booster in case anti-HBs had fallen below 10 mIU/ml. The objective of this paper was to asses whether immunologic markers suggest a higher protection after hepatitis B vaccination in offspring of carrier mothers. A systematic review was performed in order to identify all studies in offspring of carrier and non-carrier mothers reporting the proportions of individuals with anti-HBs ≥ 10 mIU/ml after infant hepatitis B vaccination with a presently recommended dose in children aged 5 years or older or response to a booster dose in case anti-HBs was below 10 mIU/ml. Associations between carrier status and the proportions of anti-HBs ≥ 10 mIU/ml or booster response were analysed by random effects models with adjustment for age and potential confounders. We identified 19 studies providing proportions of anti-HBs ≥ 10 mIU/ml with explicit information regarding the maternal carrier status. These studies reported 3245 children of carrier mothers aged up to 20 years and 4602 children of non-carrier mothers aged up to 14 years. Antibody titres ≥ 10 mIU/ml were detected in 75.8% of children of carrier and 63.6% of non-carrier mothers. A random effects model with adjustment for confounding yielded an odds ratio of 2.43 (95% CI 1.24-4.75) suggesting a markedly higher probability of anti-HBs ≥ 10 mIU/ml in offspring of carrier compared to non-carrier mothers. The distribution of proportions of individuals with post booster increase of anti-HBs titres ≥ 10 mIU/ml stratified by age at booster (≤ 10 years and >10 years) showed no differences between offspring of carrier and non carrier mothers up to the age of 10 years and only marginal differences thereafter. In conclusion the proportions of anti-HBs ≥ 10 mIU/ml were clearly higher in offspring of carrier mothers years after infant vaccination but there appeared to be no clinically relevant difference in response to booster. It is unclear to which extent higher proportions of breakthrough infections contribute to the higher proportions of protective antibody titres in offspring of carrier mothers.

HIV/AIDS related knowledge among school-going adolescents from the Middle East and North Africa.

The aim of this secondary analysis was to present cross-national data about HIV/AIDS related knowledge among 13- to 15-year-old school-going adolescents from the Middle East and North Africa. Data from 23673 school-going adolescents from seven countries (Jordan, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Tunisia and United Arab Emirates) that undertook the Global School-Based Student Health Survey between 2004 and 2008 were analysed. HIV/AIDS related knowledge varied significantly between countries and gender. Research for this sensitive topic is scarce in this region. In addition, schools could be among the many key players for HIV/AIDS education.

General ultrasound screening reduces the rate of first operative procedures for developmental dysplasia of the hip: a case-control study.

OBJECTIVES: To assess the effectiveness of general ultrasound screening to prevent first operative procedures of the hip. STUDY DESIGN: We conducted a case-control study in a population in which general ultrasound screening supplementing clinical screening is recommended and offered free of charge for all children. Participation in ultrasound screening before week 7 as recommended in Germany was the exposure of interest. Case ascertainment was based on active surveillance in orthopedic hospitals. The case definition was: first operative procedure for developmental dysplasia of the hip (closed reduction, open reduction, or osteotomy) in children >9 weeks old and <5 years old and born between 1996 and 2001. Control subjects from the same birth cohorts were recruited in telephone surveys. RESULTS: Cases of first operative procedures for developmental dysplasia of the hip (n = 446) were compared with 1173 control subjects for ultrasound screening. Effectiveness of ultrasound screening to prevent first operative procedures for developmental dysplasia of the hip was estimated as 52% (95% CI, 32-67). Effectiveness did not vary substantially for closed and open reductions and osteotomy. CONCLUSIONS: General ultrasound screening reduces the rate of operative procedures for developmental dysplasia of the hip; the impact on developmental dysplasia of the hip. Treatment rates and avascular necrosis need further assessment to balance the benefit against potential overtreatment and adverse effects.

Immunogenicity of pneumococcal conjugate vaccines in infants after two or three primary vaccinations: a systematic review and meta-analysis.

Pneumococcal conjugate vaccines have been successfully used in infant vaccination programs. While most countries have used vaccination schedules with three primary immunisations and one booster dose, some countries have implemented schedules with only two primary immunisations and a booster dose. This systematic review aims to summarize evidence on immunogenicity of pneumococcal conjugate vaccines in infants comparing two and three primary immunisations before a booster dose is given. We systematically reviewed papers published between 1999 and 2011. Results from individual studies were pooled in a meta-analysis with the difference in proportion of children achieving serotype-specific ELISA antibody levels of ≥0.35 µg/ml. We estimated that about 10% less children achieve ELISA antibody levels of ≥0.35 µg/ml after two primary immunisations compared to three primary immunisations for most of serotypes included in one of the licensed pneumococcal conjugate vaccines. This difference in proportion was higher for serotypes 6B and 23F, where -49.4% (-66.0; -32.9%) and -26.9% (-37.2%; -16.6%) less children achieved protective antibody levels. These results support the notion that the majority of children are protected by two primary immunisations with pneumococcal conjugate vaccines in the first year of life. However, for serotypes 6B and 23F protection may be reduced.

Post-pandemic seroprevalence of pandemic influenza A (H1N1) 2009 infection (swine flu) among children <18 years in Germany.

BACKGROUND: We determined antibodies to the pandemic influenza A (H1N1) 2009 virus in children to assess: the incidence of (H1N1) 2009 infections in the 2009/2010 season in Germany, the proportion of subclinical infections and to compare titers in vaccinated and infected children. METHODOLOGY/PRINCIPAL FINDINGS: Eight pediatric hospitals distributed over Germany prospectively provided sera from in- or outpatients aged 1 to 17 years from April 1(st) to July 31(st) 2010. Vaccination history, recall of infections and sociodemographic factors were ascertained. Antibody titers were measured with a sensitive and specific in-house hemagglutination inhibition test (HIT) and compared to age-matched sera collected during 6 months before the onset of the pandemic in Germany. We analyzed 1420 post-pandemic and 300 pre-pandemic sera. Among unvaccinated children aged 1-4 and 5-17 years the prevalence of HI titers (≥1∶10) was 27.1% (95% CI: 23.5-31.3) and 53.5% (95% CI: 50.9-56.2) compared to 1.7% and 5.5%, respectively, for pre-pandemic sera, accounting for a serologically determined incidence of influenza A (H1N1) 2009 during the season 2009/2010 of 25,4% (95% CI : 19.3-30.5) in children aged 1-4 years and 48.0% (95% CI: 42.6-52.0) in 5-17 year old children. Of children with HI titers ≥1∶10, 25.5% (95% CI: 22.5-28.8) reported no history of any infectious disease since June 2009. Among vaccinated children, 92% (95%-CI: 87.0-96.6) of the 5-17 year old but only 47.8% (95%-CI: 33.5-66.5) of the 1-4 year old children exhibited HI titers against influenza A virus (H1N1) 2009. CONCLUSION: Serologically determined incidence of influenza A (H1N1) 2009 infections in children indicates high infection rates with older children (5-17 years) infected twice as often as younger children. In about a quarter of the children with HI titers after the season 2009/2010 subclinical infections must be assumed. Low HI titers in young children after vaccination with the AS03(B)-adjuvanted split virion vaccine need further scrutiny.

Is low birth weight in the causal pathway of the association between maternal smoking in pregnancy and higher BMI in the offspring?

A number of cross-sectional and prospective studies suggested a priming effect of maternal smoking in pregnancy on offspring's obesity. It has been hypothesized that this association might be explained by low birth weight and subsequent catch-up growth in the causal pathway. We therefore examined the role of birth weight in children exposed versus not exposed to cigarette smoking in utero on later body mass index (BMI). Using data of 12,383 children and adolescents (3-17 years of age) recorded in a German population-based survey (KiGGS), we assessed mean body mass index standard deviation scores (BMI-SDS) in different birth weight SDS categories, stratified for children with smoking and non-smoking mothers. We calculated spline regression models with BMI-SDS as outcome variable, cubic splines of birth weight SDS, and potential confounding factors. Children whose mothers had been smoking during pregnancy had lower birth weight SDS and higher BMI-SDS at interview compared to children of non-smoking mothers. However, we observed a linear association between birth weight SDS and BMI-SDS in crude analyses for both groups. Similarly, almost linear effects were observed in adjusted spline regression analyses, except for children with very low birth weight. The respective 95% confidence bands did not preclude a linear effect for the whole birth weight SDS distribution. Our findings suggest that low birth weight is unlikely to be the main cause for the association between intrauterine nicotine exposure and higher BMI in later life. Alternative mechanisms, such as alterations in the noradrenergic system or increased food efficiency, have to be considered.

Growth in utero and body mass index at age 5 years in children of smoking and non-smoking mothers.

BACKGROUND: High birth weight is associated with overweight later in life, while tobacco exposure in utero is associated with low birth weight, but with later risk of overweight. AIMS: To examine whether body mass index (BMI) z-scores of children at age 5 are associated with measurements of mid-abdominal diameter (MAD) in utero comparing smoking and non-smoking mothers. STUDY DESIGN: Growth in utero was recorded as MAD in mm per days of gestational age (MAD for gestational age) at 17, 25, 33 and 37 weeks of gestation in 561 infants whose mothers participated in a population-based study in Scandinavia (1986-1988). OUTCOME MEASURES: The offspring's BMI z-score at 5 years was used as a dependent variable, and MAD for gestational age as well as birth weight divided by gestational age in days were included as explanatory variables in separate linear regression models. Maternal BMI was considered as a potential confounder. RESULTS: At 17 and 25 weeks gestation there were no relevant differences in MAD for gestational age between smokers and non-smokers. At 33 and 37 weeks gestation, children of smoking mothers had less increase in MAD than children of non-smoking mothers. In adjusted models, MAD for gestational age in week 33 and 37 was positively associated with BMI z-score at 5 years of age among children of both smoking and non-smoking mothers. CONCLUSIONS: In this study overweight in children exposed to tobacco smoking in utero was apparently not mediated through foetal growth retardation, followed by enhanced fat accretion after birth.

Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis.

BACKGROUND: The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates. METHODS: We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors. RESULTS: Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro. CONCLUSIONS: These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property.

Efficacy of 7-valent pneumococcal conjugate vaccination in Germany: An analysis using the indirect cohort method.

Efficacy of 7-valent pneumococcal conjugate vaccination has been shown in randomized controlled trials using 4 dose vaccination schedules in children under 2 years of age. A case-control study from the US showed considerable protection from IPD for reduced vaccination schedules and even some protection from only one dose. In Germany, delayed and incomplete vaccination is a major issue. We assessed efficacy of PCV7 using data on cases of IPD from active surveillance and applying the indirect cohort design proposed by Broome, comparing cases of IPD with a vaccine serotype with cases with a non-vaccine serotype. Efficacy of at least one dose of PCV7 was estimated to be 88.3% (95% CI: 64.0-96.6). Estimates of efficacy for one, two, and three doses in the first 7 months of life were 78.1% (3.4-96.1), 89.8% (20.6-100.0), and 94.6% (69.7-99.5) respectively. Our study adds to evidence of good protection from IPD by reduced vaccination schedules with PCV7, e.g. with two doses as primary series, in a setting where a high proportion of children receives vaccination delayed.

Prenatal and postnatal tobacco exposure and behavioral problems in 10-year-old children: results from the GINI-plus prospective birth cohort study.

BACKGROUND: Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear. OBJECTIVE: We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally. METHODS: We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as "normal," "borderline," or "abnormal" according to the subscales "emotional symptoms," "conduct problems," "hyperactivity/inattention," "peer-relationship problems," and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires. RESULTS: Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4-3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9-4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9-1.9). These results could not be explained by confounding by parental education, father's employment, child's time spent in front of computer or television screen, being a single father or mother, or mother's age. CONCLUSIONS: Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.

Effect of heptavalent pneumococcal conjugate vaccination on invasive pneumococcal disease in preterm born infants.

BACKGROUND: Evidence for protection of preterm born infants from invasive pneumococcal disease (IPD) by 7-valent pneumococcal conjugate vaccination (PCV7) is relatively sparse. Data from randomized trials is based on relatively small numbers of preterm born children. METHODS: We report data from active prospective surveillance of IPD in children in Germany. The cohorts of preterm born children in 2000 and 2007 and the respective whole birth cohorts are compared regarding occurrence of IPD. RESULTS: After introduction of PCV7 we observed a reduction in the rate of IPD in preterm born infants comparing the 2000 and 2007 birth cohort. The rate of IPD among the whole birth cohorts was reduced from 15.0 to 8.5 notifications per 100,000 (P < .001). The impact among the preterm birth cohort was comparable: A reduction in notification rate from 26.1 to 16.7 per 100,000 comparing the 2000 with the 2007 preterm birth cohort (P = .39). Preterm born infants with IPD were either unvaccinated or vaccinated delayed or incomplete. CONCLUSIONS: This adds to evidence that PCV7 also protects preterm born infants effectively from IPD. Preterm born infants should receive pneumococcal vaccination according to their chronological age.

Association between peer relationship problems and childhood overweight/obesity.

AIMS: To assess the association between peer relationship problems and childhood overweight and obesity. METHODS: Data on 4718 preschool children were obtained at the obligatory school entry health examination in Bavaria. Parentally reported peer relationship problems ('normal', 'borderline' or 'abnormal') were assessed from the Strengths and Difficulties Questionnaire. Overweight and obesity were defined according to age- and gender-specific BMI cut-off points. Multivariate logistic regression analysis was performed to control potential confounders. RESULTS: The prevalence of overweight and obesity was higher among children with 'borderline' or 'abnormal' peer relationship problems compared to 'normal' children. The association of 'abnormal' peer relationship problems was still significant in the final logistic regression model for girls [odds ratio (OR) for overweight 2.0; 95% confidence interval (CI): 1.4-3.0; OR for obesity 2.6; 95% CI: 1.3-5.0]. Among boys the adjusted odds ratio were lower and no longer significant. CONCLUSION: The significantly increased prevalence of overweight and obesity among preschool children with peer relationship problems could not be explained by confounding. It seems evident that there is a relevant co-morbidity of peer relationship problems and obesity in pre-school children pointing to the need of interventions focusing on both physical as well as psychosocial health.

Reduction in the incidence of invasive pneumococcal disease after general vaccination with 7-valent pneumococcal conjugate vaccine in Germany.

General vaccination with the 7-valent pneumococcal conjugate vaccine was recommended in Germany in July 2006 for all children <2 years. The proportion of reported invasive pneumococcal disease (IPD) caused by vaccine serotypes before vaccine introduction was considerably lower than in the US. We report data from nationwide surveillance of IPD in children with two reporting sources, pediatric hospitals and microbiological laboratories in Germany. Incidence rates with regard to age groups and pneumococcal serotypes are based on capture recapture estimates combining the two reporting sources. Between July 1, 1997 and June 30, 2003, 2680 cases (an average 447 yearly cases) of IPD were observed in children <16 years in Germany compared to 223 cases between July 1, 2007 and June 30, 2008. A significant reduction in overall incidence (4/100,000-3.2/100,000) was attributed to significant reductions in children younger than 2 years (20.0/100,000-11.0/100,000). While the incidence of all serotypes included in the vaccine was reduced in the age group <2 years, the incidence of non-vaccine serotypes remained stable. These data show a first success of the pneumococcal vaccination program in Germany. Further changes in incidence and serotype distribution of IPD are subject to future surveillance.

Association of serotype of Streptococcus pneumoniae with risk of severe and fatal outcome.

BACKGROUND: Invasive pneumococcal disease (IPD) in children may manifest as bacteremia/sepsis, bacteremic pneumonia, or meningitis, with serious outcomes that include hospitalization, neurologic sequelae, or death. The risk of severe or fatal outcome of disease is associated with host-related factors, such as age or comorbid conditions. Furthermore, there is an ongoing discussion about organism-related factors, such as the pneumococcal serotype. METHODS: Data on 494 children aged <16 years hospitalized for IPD between 1997 and 2003 in pediatric hospitals in Germany were analyzed. Serotype specific case-fatality rates and rates of severe outcome were compared using standardized mortality ratios (SMR). The risk of severe or fatal outcome for the serotype with the highest case-fatality rate was further analyzed using multivariate logistic regression adjusting for age younger than 1 year, meningitis, sex, and immunocompromised status as potential confounders. RESULTS: The overall case-fatality rate was 5.3% and the rate of severe outcome was 17.0%. Serotype 7F had the highest case-fatality rate (14.8%, SMR 3.1), followed by serotypes 23F (8.3%, SMR 1.7) and 3 (8.3%, SMR 1.7). The highest rate of severe outcome was also observed for 7F (40.7%, SMR 2.4). Multivariate analysis showed an odds ratio of 4.3 (1.3-14.7) for fatal outcome and 4.0 (1.6-10.4) for severe outcome comparing 7F to all other serotypes. CONCLUSIONS: In this study population, serotype 7F accounted for a higher risk of severe and fatal outcome than other serotypes of Streptococcus pneumoniae. In describing the epidemiology of IPD, the serotype-specific risk for severe or fatal outcome is an important complement to other serotype-specific aspects like incidence and antibiotic resistance pattern.