The pediatric Glasgow coma scale (pGCS) is a consciousness score that, although widely applied, r... more The pediatric Glasgow coma scale (pGCS) is a consciousness score that, although widely applied, requires skill to apply. The AVPU scale uses four simple categories (Alert; Verbal response; response to Pain; Unresponsive), but has not been studied in a large pediatric population. We compared the performance of the AVPU and pGCS scales in a large pediatric cohort in an acute, prehospital setting. In a six-month-long prospective cohort study, AVPU and pGCS scores were determined by emergency physicians in children less than 10 years of age at their first prehospital encounter. We included 302 children (median age 2.3 years) with a broad spectrum of diagnoses. Data were complete for 287 children. AVPU and pGCS scores showed good a correlation in the extreme categories A and U (positive predictive values of 98% and 100%, respectively). Corresponding pGCS scores for each AVPU category were as follows: 11-15 for A; 5-15 for V; 4-12 for P; and 3-5 for U. The positive predictive value to detect patients with pGCS ≥ 8 for AVPU category V was 100%. We demonstrated good correlation of simple and fast consciousness AVPU scoring to the standard pGCS in a large cohort of pediatric patients in a prehospital setting. The AVPU category "V" identifies patients with a pGCS of or exceeding 8 and, therefore, identifies children at low risk requiring more invasive procedures or intensive care treatment. Key words: Glasgow coma scale (GCS); Alert-verbal-pain-unresponsive-score; AVPU-score; consciousness assessment; children, pediatric emergency.
Objective. To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with a... more Objective. To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune manifestations. Patients with sterile osteitis were analysed to develop diagnostic criteria. Methods. A total of 89 patients with non-bacterial inflammatory bone lesions were observed for a median of 49 months. History, diagnostic imaging, laboratory and histological data were obtained. Mutation analysis in the genes PSTPIP1 and PSTPIP2 was performed. Results. Patients had an onset of disease at a median age of 10 yrs [interquartile range (IQR) 7.5-12] and suffered a median period of 21 (IQR 9-52) months with a median of three foci per patient. Twenty percent of all the patients demonstrated associated autoimmune disorders, particularly of the skin and bowel. The majority of bone lesions were located in the vertebrae and metaphyses. Slight-to-moderate elevation of inflammation values were found in all the patients and antinuclear antibodies were elevated in 30%. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective in 85% of the patients. HLA-B27 and Human Leukocyte Antigen-DR (HLA-DR)-classification did not differ from the general population. Autoimmune diseases in 40% of all the families, multiply affected family members, linkage to 18q21 and mouse models strongly indicate a genetic basis for NBO. We observed three different courses of disease regarding the duration of complaints, rate of complications and associated autoimmune manifestations leading to a new classification of NBO.
Metabolic factors acting during limited and sensitive time periods of pre- and postnatal developm... more Metabolic factors acting during limited and sensitive time periods of pre- and postnatal development can induce lasting effects on health and disease risk in later life up to old age, including later obesity risk, which is referred to as early metabolic programming of long-term health. Three meta-analyses of observational studies found that obesity risk at school age was reduced with early breastfeeding compared to formula feeding. We assumed that breastfeeding protects against later obesity by reducing the occurrence of high weight gain in infancy and that one causative factor is the lower protein content of human milk compared to usual infant formulas (the "early protein hypothesis"). We are testing this hypothesis in the European Childhood Obesity Project, a double-blind, randomized clinical trial enrolling 1,678 infants in five countries (Belgium, Germany, Italy, Poland, Spain). We have randomized healthy infants born at term to receive for the first year infant formul...
Vaccine effectiveness (VE) was determined with a case-cohort approach using Cox regression. Cases... more Vaccine effectiveness (VE) was determined with a case-cohort approach using Cox regression. Cases with confirmed systemic Hib infections in children born from 1 August 2000 to 31 December 2004 were ascertained through two independent nationwide active surveillance systems. A representative cohort of 1303 children born in the same time frame was randomly sampled in a nationwide immunisation survey. Thirty cases were eligible for VE calculation; 19 were unvaccinated and 11 vaccinated with hexavalent vaccines. VE was 68.4% (95% CI: 19.0-87.6) for incomplete primary series and 90.4% (95% CI: 70.6-96.8) for the full primary series. For full immunisation VE was 100.0% (95% CI: 52.7-100.0). Hexavalent vaccines show a high effectiveness against invasive Hib disease in Germany.
Advances in Experimental Medicine and Biology, 2009
Some 30 years ago, Günter Dörner proposed that exposure to hormones, metabolites and neurotransmi... more Some 30 years ago, Günter Dörner proposed that exposure to hormones, metabolites and neurotransmitters during limited, sensitive periods of early development exert programming effects on disease risk in human adults. Early programming of long term health has since received broad scientific support and attention. For example, evidence increases for programming effects of infant feeding choices on later obesity risk. Meta-analyses of observational studies indicate that breast feeding reduces the odds ratio for obesity at school age by about 20%, relative to formula feeding, even after adjustment for biological and sociodemographic confounding variables. We hypothesized that breast feeding protects against later obesity by reducing the likelihood of high weight gain in infancy, and that this protection is caused at least partly by the lower protein supply with breast milk relative to standard infant formulae (the "Early Protein Hypothesis"). These hypotheses are tested in the European Childhood Obesity Project, a randomized double blind intervention trial in more than 1,000 infants in five European countries (Belgium, Germany, Italy, Poland, Spain). Formula fed infants were randomized to receive during the first year of life infant formulae and follow-on-formulae with higher or lower protein contents. Follow-up at 2 years of age shows that lower protein supply with formula normalizes early growth relative to a breast fed reference group and to the WHO growth reference. These results demonstrate that modification of infant feeding practice has an important potential for long-term health promotion and should prompt a review of the recommendations and policies for infant formula composition.
Since 2004, general varicella vaccination has been recommended for all children 11-14 months of a... more 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.
To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune m... more To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune manifestations. Patients with sterile osteitis were analysed to develop diagnostic criteria. A total of 89 patients with non-bacterial inflammatory bone lesions were observed for a median of 49 months. History, diagnostic imaging, laboratory and histological data were obtained. Mutation analysis in the genes PSTPIP1 and PSTPIP2 was performed. Patients had an onset of disease at a median age of 10 yrs [interquartile range (IQR) 7.5-12] and suffered a median period of 21 (IQR 9-52) months with a median of three foci per patient. Twenty percent of all the patients demonstrated associated autoimmune disorders, particularly of the skin and bowel. The majority of bone lesions were located in the vertebrae and metaphyses. Slight-to-moderate elevation of inflammation values were found in all the patients and antinuclear antibodies were elevated in 30%. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective in 85% of the patients. HLA-B27 and Human Leukocyte Antigen-DR (HLA-DR)-classification did not differ from the general population. Autoimmune diseases in 40% of all the families, multiply affected family members, linkage to 18q21 and mouse models strongly indicate a genetic basis for NBO. We observed three different courses of disease regarding the duration of complaints, rate of complications and associated autoimmune manifestations leading to a new classification of NBO. Clinical analysis of our cohort leads us to define NBO as a distinct disease entity with three clinical presentations: acute NBO, chronic recurrent multifocal osteomyelitis or persistent chronic NBO. Diagnostic criteria were proposed to differentiate NBO from diseases with similar clinical presentation.
Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was obse... more Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was observed in the United Kingdom, which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis (DTaP) Hib vaccines. A study in Germany based on approximately 2 years of follow-up, estimated vaccine effectiveness (VE) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high. To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake. Cases with confirmed systemic Hib infections in children born between June 1, 1996 and December 31, 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002. A representative subcohort of 667 children born in the same time frame was randomly sampled in a nationwide vaccine coverage survey. VE was determined with a case-cohort approach of Cox regression with time-dependent covariates. Thirty-six cases of Hib disease were reported. Of these, 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated. Of the 10 vaccinated cases, 4 had received an incomplete primary series (1-2 doses), and 6 had received the full primary series (3 doses), 3 of whom also received the booster dose. VE of combination vaccines against invasive Hib infection was 89.6% [95% confidence interval (CI), 67.0-96.7] for an incomplete primary series, 96.7% (95% CI 87.7-99.1) for a full primary series and 98.5% (95% CI 94.5-99.6) for a booster dose (irrespective of priming). Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany.
In Germany, Haemophilus influenzae type b (Hib), polio and hepatitis B (HBV) vaccines have been c... more In Germany, Haemophilus influenzae type b (Hib), polio and hepatitis B (HBV) vaccines have been combined with diphtheria, tetanus and acellular pertussis vaccines. We examined whether the use of combination vaccines has improved the timing of these vaccinations. Vaccination information was obtained from representative nationwide telephone interviews about 2701 children born from 1996 through 2003 in Germany. We assessed up-to-date vaccination as the percentage of children vaccinated by 3, 5 and 15 months for the first dose, full primary series and full immunization, respectively. We compared results over periods when different combination vaccines were used. We also compared median age at first dose, full priming and full immunization for children receiving different types of combination vaccines. During the study period, monovalent vaccines were replaced by higher-valent combination vaccines. With the change from mono- to 4-, 5- and 6-valent vaccines, up-to-date vaccination increased for Hib, polio and HBV. Median age at immunization improved by 0.5 month for Hib, 0.4 month for polio and 0.9 month for HBV at the first dose and 2.2 months for Hib, 3.2 months for polio and 1.4 months for HBV at full immunization when comparing hexavalent with monovalent vaccines. Median age for 4-5-valent vaccines was intermediate. The difference between monovalent and 6-valent vaccines remained significant after stratifying/adjusting for the effect of birth cohorts. Combination vaccines are usually advocated for reducing the number of injections. In Germany, however, the use of combination vaccines has also significantly improved timeliness of immunizations.
Protein intake has been directly associated with kidney growth and function in animal and human o... more Protein intake has been directly associated with kidney growth and function in animal and human observational studies. Protein supply can vary widely during the first months of life, thus promoting different kidney growth patterns and possibly affecting kidney and cardiovascular health in the long term. To explore this further, we examined 601 healthy 6-month-old formula-fed infants who had been randomly assigned within the first 8 weeks of life to a 1-year program of formula with low-protein (LP) or high-protein (HP) contents and compared them with 204 breastfed (BF) infants. At 6 months, infants receiving the HP formula had significantly higher kidney volume (determined by ultrasonography) and ratios of kidney volume to body length and kidney volume to body surface area than did infants receiving the LP formula. BF infants did not differ from those receiving the LP formula in any of these parameters. Infants receiving the HP formula had significantly higher serum urea and urea to creatinine ratios than did LP formula and BF infants. Hence, in this European multicenter clinical trial, we found that a higher protein content of the infant formula increases kidney size at 6 months of life, whereas a lower protein supply achieves kidney size indistinguishable from that of healthy BF infants. The potential long-term effects of a higher early protein intake on long-term kidney function needs to be determined.
BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significan... more BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC. Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease. Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants. Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.
In a 2-year-long active surveillance conducted in all German pediatric hospitals, the incidence o... more 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.
Objective: The interplay of genetic and nutritional regulation of the insulin-like growth factor-... more Objective: The interplay of genetic and nutritional regulation of the insulin-like growth factor-I axis in children is unclear. Therefore, potential gene-nutrient effects on serum levels of the IGF-I axis in a formula feeding trial were studied. Design: European multicenter randomized clinical trial of 1090 term, formula-fed infants assigned to receive cow's milk-based infant and follow-on formulae with lower (LP: 1.25 and 1.6 g/100 mL) or higher (HP: 2.05 and 3.2 g/100 mL) protein contents for the first 12 months of life; a comparison group of 588 breastfed infants (BF) was included. Eight single nucleotide polymorphisms (SNPs) of the IGF-1-(rs6214, rs1520220, rs978458, rs7136446, rs10735380, rs2195239, rs35767, and rs35766) and two of the IGFBP-3-(rs1496495, rs6670) gene were analyzed. Serum levels of total and free IGF-I, IGFBP-3 and the molar ratio IGF-1/IGFBP-3 at age 6 months were regressed on determined SNPs and feeding groups in 501 infants. Results: IGF-1-SNPs rs1520220, rs978458, and rs2195239 significantly increased total-IGF-I and molar-ratio IGF-I/IGFBP-3 by~1.3 ng/mL and~1.3 per allele, respectively; compared to LP infants concentration and molar-ratio were increased in HP by~1.3 ng/mL and~1.3 and decreased in BF infants by~0.6 ng/mL and~0.6, respectively. IGFBP-3 was only affected by the BF group with~450 ng/mL lower levels than the LP group. No gene-feeding-group interaction was detected for any SNP, even without correction for multiple testing. Conclusions: Variants of the IGF-1-gene play an important role in regulating serum levels of the IGF-I axis but there is no gene-protein-interaction. The predominant nutritional regulation of IGF-I and IGFBP-3 gives further evidence that higher protein intake contributes to metabolic programming of growth.
The primary objective of this epidemiological surveillance study was to estimate the incidence of... more The primary objective of this epidemiological surveillance study was to estimate the incidence of intussusception (IS) associated with hospitalisation in children <1, <2 and <17 years of age in Germany. We analysed primary and secondary ICD-10 discharge diagnoses for IS (K56.1) and procedure codes for desinvagination from 28 paediatric hospitals in Bavaria, Germany, to identify children hospitalised in 2005 or 2006 due to IS. A total of 518 children with an ICD-10 code for IS were reported: 123 (23.7%) of the children were <1 year of age, 267 (51.5%) were 1-3 years old and 128 (24.8%) older than 3 years of age. IS was the primary ICD-10 diagnosis in 382 (74%) children, including 231 (60%) children with a procedure code for desinvagination. In 136 (26%) children, IS was reported as a secondary ICD-10 diagnosis, including 38 (28%) with a desinvagination procedure code. The yearly incidence of IS in children <1 year of age was estimated as 72/100,000 overall and as 43/100,000 for those with an additional procedural code for desinvagination. Patients solely with an ICD-10 code for IS are often suspected cases, based on clinical presentation. The combination of the ICD-10 code for IS and a procedure code for desinvagination provides a more specific and clinically relevant case definition, thereby offering a useful tool for long-term surveillance of the incidence of IS.
In Germany, a low coverage with hepatitis B and measles vaccines and a considerable delay in admi... more In Germany, a low coverage with hepatitis B and measles vaccines and a considerable delay in administration of all recommended vaccines were previously apparent. Whether there have been improvements and whether there are regional differences within Germany is not known. Using representative nationwide telephone interviews on 2,701 children born 1996-2003, we assessed vaccination coverage for the first dose or full primary series (2/3 doses, depending on vaccine used) at 24 months of age. The proportions vaccinated with the first dose, full priming and full immunisation (2/3 doses plus booster in the 2nd year of life) until the end of the recommended age (3, 5 and 15 months, respectively, for diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib) and hepatitis B vaccines (DTPPolioHibHep), and 15 for the first measles, mumps and rubella dose (MMR) were used as indicators of compliance with national guidelines. Coverage for polio, Hib and hepatitis B vaccines increased, while coverage for the first MMR dose remained constantly low at about 70%. Vaccination coverage differed substantially among the German states and was highest for the new states. Compliance with national guidelines increased from 2.5% to 15% for the full primary DTPPolioHibHep series, from 16.2% to 44.7% for the first MMR dose and from 1.0% to 19.3% for the full immunisation with all recommended vaccines (DTPPolioHibHepMMR). Vaccination coverage at 24 months and compliance with national guidelines has improved for most vaccines in Germany. However, improving coverage for measles, mumps, rubella and eliminating the regional disparities remain a major challenge for the public health sector.
From the *GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neu... more From the *GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany; Ludwig-Maximilians-University of Munich, Institute of Medical Data Management, Biometrics and Epidemiology, Munich, Germany; Utrecht ...
Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very li... more Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for which RTX was used and to describe the applied therapeutic regimens, the observed efficacy, as well as potential immunological side effects. The need to develop standard treatment guidelines for future trials should be discussed. Sixty-five patients were included. Nineteen patients suffered from systemic lupus erythematosus, 13 from vasculitic disorders, 12 from hematological autoimmune diseases, 5 from mixed connective tissue disorders, 4 from juvenile idiopathic arthritis, and 9 had other autoimmune diseases. Adverse, infusion-related events were reported in 12/65 (18%) patients. Considering laboratory and clinical parameters, 13 patients (22%) were in complete remission, 31 (52%) were in partial remission, 6 (10%) were unchanged and 10 (17%) had progressed after 6 months. In 46% of the patients, the steroid dose could be more than halved. IgG, IgM and IgA decreased from normal levels prior to RTX therapy to below normal levels at 6 months in 2/22 (9%), 10/21 (48%), and 4/22 (18%) patients, respectively. Immunoglobulin deficiency or prolonged CD20 depletion was reported in eight patients after an observation period longer than 12 months. RTX therapy led to a perceivable reduction in disease activity. However, long-term immunological alterations may occur in more than 10% of the patients. Guidelines and protocols for off-label therapy are desirable to document reasonable follow-up data. Controlled prospective studies for RTX therapies in children with standardised therapeutic and diagnostic protocols are urgently needed.
The pediatric Glasgow coma scale (pGCS) is a consciousness score that, although widely applied, r... more The pediatric Glasgow coma scale (pGCS) is a consciousness score that, although widely applied, requires skill to apply. The AVPU scale uses four simple categories (Alert; Verbal response; response to Pain; Unresponsive), but has not been studied in a large pediatric population. We compared the performance of the AVPU and pGCS scales in a large pediatric cohort in an acute, prehospital setting. In a six-month-long prospective cohort study, AVPU and pGCS scores were determined by emergency physicians in children less than 10 years of age at their first prehospital encounter. We included 302 children (median age 2.3 years) with a broad spectrum of diagnoses. Data were complete for 287 children. AVPU and pGCS scores showed good a correlation in the extreme categories A and U (positive predictive values of 98% and 100%, respectively). Corresponding pGCS scores for each AVPU category were as follows: 11-15 for A; 5-15 for V; 4-12 for P; and 3-5 for U. The positive predictive value to detect patients with pGCS ≥ 8 for AVPU category V was 100%. We demonstrated good correlation of simple and fast consciousness AVPU scoring to the standard pGCS in a large cohort of pediatric patients in a prehospital setting. The AVPU category "V" identifies patients with a pGCS of or exceeding 8 and, therefore, identifies children at low risk requiring more invasive procedures or intensive care treatment. Key words: Glasgow coma scale (GCS); Alert-verbal-pain-unresponsive-score; AVPU-score; consciousness assessment; children, pediatric emergency.
Objective. To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with a... more Objective. To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune manifestations. Patients with sterile osteitis were analysed to develop diagnostic criteria. Methods. A total of 89 patients with non-bacterial inflammatory bone lesions were observed for a median of 49 months. History, diagnostic imaging, laboratory and histological data were obtained. Mutation analysis in the genes PSTPIP1 and PSTPIP2 was performed. Results. Patients had an onset of disease at a median age of 10 yrs [interquartile range (IQR) 7.5-12] and suffered a median period of 21 (IQR 9-52) months with a median of three foci per patient. Twenty percent of all the patients demonstrated associated autoimmune disorders, particularly of the skin and bowel. The majority of bone lesions were located in the vertebrae and metaphyses. Slight-to-moderate elevation of inflammation values were found in all the patients and antinuclear antibodies were elevated in 30%. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective in 85% of the patients. HLA-B27 and Human Leukocyte Antigen-DR (HLA-DR)-classification did not differ from the general population. Autoimmune diseases in 40% of all the families, multiply affected family members, linkage to 18q21 and mouse models strongly indicate a genetic basis for NBO. We observed three different courses of disease regarding the duration of complaints, rate of complications and associated autoimmune manifestations leading to a new classification of NBO.
Metabolic factors acting during limited and sensitive time periods of pre- and postnatal developm... more Metabolic factors acting during limited and sensitive time periods of pre- and postnatal development can induce lasting effects on health and disease risk in later life up to old age, including later obesity risk, which is referred to as early metabolic programming of long-term health. Three meta-analyses of observational studies found that obesity risk at school age was reduced with early breastfeeding compared to formula feeding. We assumed that breastfeeding protects against later obesity by reducing the occurrence of high weight gain in infancy and that one causative factor is the lower protein content of human milk compared to usual infant formulas (the "early protein hypothesis"). We are testing this hypothesis in the European Childhood Obesity Project, a double-blind, randomized clinical trial enrolling 1,678 infants in five countries (Belgium, Germany, Italy, Poland, Spain). We have randomized healthy infants born at term to receive for the first year infant formul...
Vaccine effectiveness (VE) was determined with a case-cohort approach using Cox regression. Cases... more Vaccine effectiveness (VE) was determined with a case-cohort approach using Cox regression. Cases with confirmed systemic Hib infections in children born from 1 August 2000 to 31 December 2004 were ascertained through two independent nationwide active surveillance systems. A representative cohort of 1303 children born in the same time frame was randomly sampled in a nationwide immunisation survey. Thirty cases were eligible for VE calculation; 19 were unvaccinated and 11 vaccinated with hexavalent vaccines. VE was 68.4% (95% CI: 19.0-87.6) for incomplete primary series and 90.4% (95% CI: 70.6-96.8) for the full primary series. For full immunisation VE was 100.0% (95% CI: 52.7-100.0). Hexavalent vaccines show a high effectiveness against invasive Hib disease in Germany.
Advances in Experimental Medicine and Biology, 2009
Some 30 years ago, Günter Dörner proposed that exposure to hormones, metabolites and neurotransmi... more Some 30 years ago, Günter Dörner proposed that exposure to hormones, metabolites and neurotransmitters during limited, sensitive periods of early development exert programming effects on disease risk in human adults. Early programming of long term health has since received broad scientific support and attention. For example, evidence increases for programming effects of infant feeding choices on later obesity risk. Meta-analyses of observational studies indicate that breast feeding reduces the odds ratio for obesity at school age by about 20%, relative to formula feeding, even after adjustment for biological and sociodemographic confounding variables. We hypothesized that breast feeding protects against later obesity by reducing the likelihood of high weight gain in infancy, and that this protection is caused at least partly by the lower protein supply with breast milk relative to standard infant formulae (the "Early Protein Hypothesis"). These hypotheses are tested in the European Childhood Obesity Project, a randomized double blind intervention trial in more than 1,000 infants in five European countries (Belgium, Germany, Italy, Poland, Spain). Formula fed infants were randomized to receive during the first year of life infant formulae and follow-on-formulae with higher or lower protein contents. Follow-up at 2 years of age shows that lower protein supply with formula normalizes early growth relative to a breast fed reference group and to the WHO growth reference. These results demonstrate that modification of infant feeding practice has an important potential for long-term health promotion and should prompt a review of the recommendations and policies for infant formula composition.
Since 2004, general varicella vaccination has been recommended for all children 11-14 months of a... more 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.
To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune m... more To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune manifestations. Patients with sterile osteitis were analysed to develop diagnostic criteria. A total of 89 patients with non-bacterial inflammatory bone lesions were observed for a median of 49 months. History, diagnostic imaging, laboratory and histological data were obtained. Mutation analysis in the genes PSTPIP1 and PSTPIP2 was performed. Patients had an onset of disease at a median age of 10 yrs [interquartile range (IQR) 7.5-12] and suffered a median period of 21 (IQR 9-52) months with a median of three foci per patient. Twenty percent of all the patients demonstrated associated autoimmune disorders, particularly of the skin and bowel. The majority of bone lesions were located in the vertebrae and metaphyses. Slight-to-moderate elevation of inflammation values were found in all the patients and antinuclear antibodies were elevated in 30%. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective in 85% of the patients. HLA-B27 and Human Leukocyte Antigen-DR (HLA-DR)-classification did not differ from the general population. Autoimmune diseases in 40% of all the families, multiply affected family members, linkage to 18q21 and mouse models strongly indicate a genetic basis for NBO. We observed three different courses of disease regarding the duration of complaints, rate of complications and associated autoimmune manifestations leading to a new classification of NBO. Clinical analysis of our cohort leads us to define NBO as a distinct disease entity with three clinical presentations: acute NBO, chronic recurrent multifocal osteomyelitis or persistent chronic NBO. Diagnostic criteria were proposed to differentiate NBO from diseases with similar clinical presentation.
Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was obse... more Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was observed in the United Kingdom, which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis (DTaP) Hib vaccines. A study in Germany based on approximately 2 years of follow-up, estimated vaccine effectiveness (VE) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high. To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake. Cases with confirmed systemic Hib infections in children born between June 1, 1996 and December 31, 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002. A representative subcohort of 667 children born in the same time frame was randomly sampled in a nationwide vaccine coverage survey. VE was determined with a case-cohort approach of Cox regression with time-dependent covariates. Thirty-six cases of Hib disease were reported. Of these, 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated. Of the 10 vaccinated cases, 4 had received an incomplete primary series (1-2 doses), and 6 had received the full primary series (3 doses), 3 of whom also received the booster dose. VE of combination vaccines against invasive Hib infection was 89.6% [95% confidence interval (CI), 67.0-96.7] for an incomplete primary series, 96.7% (95% CI 87.7-99.1) for a full primary series and 98.5% (95% CI 94.5-99.6) for a booster dose (irrespective of priming). Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany.
In Germany, Haemophilus influenzae type b (Hib), polio and hepatitis B (HBV) vaccines have been c... more In Germany, Haemophilus influenzae type b (Hib), polio and hepatitis B (HBV) vaccines have been combined with diphtheria, tetanus and acellular pertussis vaccines. We examined whether the use of combination vaccines has improved the timing of these vaccinations. Vaccination information was obtained from representative nationwide telephone interviews about 2701 children born from 1996 through 2003 in Germany. We assessed up-to-date vaccination as the percentage of children vaccinated by 3, 5 and 15 months for the first dose, full primary series and full immunization, respectively. We compared results over periods when different combination vaccines were used. We also compared median age at first dose, full priming and full immunization for children receiving different types of combination vaccines. During the study period, monovalent vaccines were replaced by higher-valent combination vaccines. With the change from mono- to 4-, 5- and 6-valent vaccines, up-to-date vaccination increased for Hib, polio and HBV. Median age at immunization improved by 0.5 month for Hib, 0.4 month for polio and 0.9 month for HBV at the first dose and 2.2 months for Hib, 3.2 months for polio and 1.4 months for HBV at full immunization when comparing hexavalent with monovalent vaccines. Median age for 4-5-valent vaccines was intermediate. The difference between monovalent and 6-valent vaccines remained significant after stratifying/adjusting for the effect of birth cohorts. Combination vaccines are usually advocated for reducing the number of injections. In Germany, however, the use of combination vaccines has also significantly improved timeliness of immunizations.
Protein intake has been directly associated with kidney growth and function in animal and human o... more Protein intake has been directly associated with kidney growth and function in animal and human observational studies. Protein supply can vary widely during the first months of life, thus promoting different kidney growth patterns and possibly affecting kidney and cardiovascular health in the long term. To explore this further, we examined 601 healthy 6-month-old formula-fed infants who had been randomly assigned within the first 8 weeks of life to a 1-year program of formula with low-protein (LP) or high-protein (HP) contents and compared them with 204 breastfed (BF) infants. At 6 months, infants receiving the HP formula had significantly higher kidney volume (determined by ultrasonography) and ratios of kidney volume to body length and kidney volume to body surface area than did infants receiving the LP formula. BF infants did not differ from those receiving the LP formula in any of these parameters. Infants receiving the HP formula had significantly higher serum urea and urea to creatinine ratios than did LP formula and BF infants. Hence, in this European multicenter clinical trial, we found that a higher protein content of the infant formula increases kidney size at 6 months of life, whereas a lower protein supply achieves kidney size indistinguishable from that of healthy BF infants. The potential long-term effects of a higher early protein intake on long-term kidney function needs to be determined.
BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significan... more BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC. Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease. Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants. Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.
In a 2-year-long active surveillance conducted in all German pediatric hospitals, the incidence o... more 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.
Objective: The interplay of genetic and nutritional regulation of the insulin-like growth factor-... more Objective: The interplay of genetic and nutritional regulation of the insulin-like growth factor-I axis in children is unclear. Therefore, potential gene-nutrient effects on serum levels of the IGF-I axis in a formula feeding trial were studied. Design: European multicenter randomized clinical trial of 1090 term, formula-fed infants assigned to receive cow's milk-based infant and follow-on formulae with lower (LP: 1.25 and 1.6 g/100 mL) or higher (HP: 2.05 and 3.2 g/100 mL) protein contents for the first 12 months of life; a comparison group of 588 breastfed infants (BF) was included. Eight single nucleotide polymorphisms (SNPs) of the IGF-1-(rs6214, rs1520220, rs978458, rs7136446, rs10735380, rs2195239, rs35767, and rs35766) and two of the IGFBP-3-(rs1496495, rs6670) gene were analyzed. Serum levels of total and free IGF-I, IGFBP-3 and the molar ratio IGF-1/IGFBP-3 at age 6 months were regressed on determined SNPs and feeding groups in 501 infants. Results: IGF-1-SNPs rs1520220, rs978458, and rs2195239 significantly increased total-IGF-I and molar-ratio IGF-I/IGFBP-3 by~1.3 ng/mL and~1.3 per allele, respectively; compared to LP infants concentration and molar-ratio were increased in HP by~1.3 ng/mL and~1.3 and decreased in BF infants by~0.6 ng/mL and~0.6, respectively. IGFBP-3 was only affected by the BF group with~450 ng/mL lower levels than the LP group. No gene-feeding-group interaction was detected for any SNP, even without correction for multiple testing. Conclusions: Variants of the IGF-1-gene play an important role in regulating serum levels of the IGF-I axis but there is no gene-protein-interaction. The predominant nutritional regulation of IGF-I and IGFBP-3 gives further evidence that higher protein intake contributes to metabolic programming of growth.
The primary objective of this epidemiological surveillance study was to estimate the incidence of... more The primary objective of this epidemiological surveillance study was to estimate the incidence of intussusception (IS) associated with hospitalisation in children <1, <2 and <17 years of age in Germany. We analysed primary and secondary ICD-10 discharge diagnoses for IS (K56.1) and procedure codes for desinvagination from 28 paediatric hospitals in Bavaria, Germany, to identify children hospitalised in 2005 or 2006 due to IS. A total of 518 children with an ICD-10 code for IS were reported: 123 (23.7%) of the children were <1 year of age, 267 (51.5%) were 1-3 years old and 128 (24.8%) older than 3 years of age. IS was the primary ICD-10 diagnosis in 382 (74%) children, including 231 (60%) children with a procedure code for desinvagination. In 136 (26%) children, IS was reported as a secondary ICD-10 diagnosis, including 38 (28%) with a desinvagination procedure code. The yearly incidence of IS in children <1 year of age was estimated as 72/100,000 overall and as 43/100,000 for those with an additional procedural code for desinvagination. Patients solely with an ICD-10 code for IS are often suspected cases, based on clinical presentation. The combination of the ICD-10 code for IS and a procedure code for desinvagination provides a more specific and clinically relevant case definition, thereby offering a useful tool for long-term surveillance of the incidence of IS.
In Germany, a low coverage with hepatitis B and measles vaccines and a considerable delay in admi... more In Germany, a low coverage with hepatitis B and measles vaccines and a considerable delay in administration of all recommended vaccines were previously apparent. Whether there have been improvements and whether there are regional differences within Germany is not known. Using representative nationwide telephone interviews on 2,701 children born 1996-2003, we assessed vaccination coverage for the first dose or full primary series (2/3 doses, depending on vaccine used) at 24 months of age. The proportions vaccinated with the first dose, full priming and full immunisation (2/3 doses plus booster in the 2nd year of life) until the end of the recommended age (3, 5 and 15 months, respectively, for diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib) and hepatitis B vaccines (DTPPolioHibHep), and 15 for the first measles, mumps and rubella dose (MMR) were used as indicators of compliance with national guidelines. Coverage for polio, Hib and hepatitis B vaccines increased, while coverage for the first MMR dose remained constantly low at about 70%. Vaccination coverage differed substantially among the German states and was highest for the new states. Compliance with national guidelines increased from 2.5% to 15% for the full primary DTPPolioHibHep series, from 16.2% to 44.7% for the first MMR dose and from 1.0% to 19.3% for the full immunisation with all recommended vaccines (DTPPolioHibHepMMR). Vaccination coverage at 24 months and compliance with national guidelines has improved for most vaccines in Germany. However, improving coverage for measles, mumps, rubella and eliminating the regional disparities remain a major challenge for the public health sector.
From the *GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neu... more From the *GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany; Ludwig-Maximilians-University of Munich, Institute of Medical Data Management, Biometrics and Epidemiology, Munich, Germany; Utrecht ...
Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very li... more Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for which RTX was used and to describe the applied therapeutic regimens, the observed efficacy, as well as potential immunological side effects. The need to develop standard treatment guidelines for future trials should be discussed. Sixty-five patients were included. Nineteen patients suffered from systemic lupus erythematosus, 13 from vasculitic disorders, 12 from hematological autoimmune diseases, 5 from mixed connective tissue disorders, 4 from juvenile idiopathic arthritis, and 9 had other autoimmune diseases. Adverse, infusion-related events were reported in 12/65 (18%) patients. Considering laboratory and clinical parameters, 13 patients (22%) were in complete remission, 31 (52%) were in partial remission, 6 (10%) were unchanged and 10 (17%) had progressed after 6 months. In 46% of the patients, the steroid dose could be more than halved. IgG, IgM and IgA decreased from normal levels prior to RTX therapy to below normal levels at 6 months in 2/22 (9%), 10/21 (48%), and 4/22 (18%) patients, respectively. Immunoglobulin deficiency or prolonged CD20 depletion was reported in eight patients after an observation period longer than 12 months. RTX therapy led to a perceivable reduction in disease activity. However, long-term immunological alterations may occur in more than 10% of the patients. Guidelines and protocols for off-label therapy are desirable to document reasonable follow-up data. Controlled prospective studies for RTX therapies in children with standardised therapeutic and diagnostic protocols are urgently needed.
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Papers by Veit Grote