Burkhard Simma

Unifying Candidate Gene and GWAS Approaches in Asthma

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

Tracheostomy in children

We reviewed the records of 108 patients who had a tracheostomy performed over a 10-year period from July 1979 to April 1989. Median age at tracheostomy was 6 months (1 week–15 years). Indications for surgery were acquired subglottic stenosis (31.4%), bilateral vocal cord paralysis (22.2%), congenital airway malformations (22.2%) and tumours (11.1%). No epiglottis and no emergency situation had to be managed by tracheostomy. Operation was uneventful in all, but 8 patients (7.4%) developed a pneumothorax in the postoperative period. Twenty-one (19.5%) had severe complications during the cannulation period (tube obstruction in 11 patients with cardiorespiratory arrest in 4; dislocation of the tube in 6 patients). Fifteen patients (13.8%) had severe complications after decannulation (2 had a cardiorespiratory arrest); all 15 had to be recannulated. At the end of the study period 85 patients (78.7%) were successfully decannulated with a median period of tracheostomy of 486 days (8 days–6.6 years). The median hospital stay was 159 days (13 days–2.7 years). All patients could be discharged. Eight patients (7.4%) died but no death was related to tracheostomy. In summary the mortality rate is lower than reported in previous reviews and tracheostomy is a safe operation even in small children but cannula-related complications may lead to life-threatening events. The management of tracheostomized small children and infants in a highly staffed and monitored intensive care unit has allowed better handling of complications and has resulted in a reduction in cannula-related deaths.

T cell activation and cytokine release in streptococcal toxic shock-like syndrome

A 5-year-old girl with streptococcal toxic shock-like syndrome during varicella infection had high levels of tumor necrosis factor alpha and interleukin-6 but no interleukin-1 or interleukin-2 in the serum. Intravenous administration of gamma-globulin coincided with clinical improvement and with reduction of the levels of tumor necrosis factor alpha and interleukin-6. The data suggest that streptococcal pyrogenic exotoxins trigger synthesis of tumor necrosis factor alpha and interleukin-6 in vivo; intravenously administered gamma-globulin may down-regulate the cytokine response.

Hyperhomocysteinemia in Children Treated with Antiepileptic Drugs Is Normalized by Folic Acid Supplementation

Summary:  Purpose: To assess the prevalence of hyperhomocysteinemia in pediatric patients treated with antiepileptic drugs (AEDs) and to evaluate the effect of folic acid supplementation on plasma total homocysteine (tHcy) concentrations in hyperhomocysteinemic patients.

Total homocysteine, folate, and cobalamin, and their relation to genetic polymorphisms, lifestyle and body mass index in healthy children and adolescents.

We investigated total homocysteine (tHcy) concentrations and relations between tHcy and folate, cobalamin (Cbl), genetic polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTHFR 1793G>A), blood pressure (BP), body mass index (BMI), cholesterol, triglycerides, sports activities, family and individual history of cardiovascular disease (CVD) and lifestyle issues in 264 healthy children and adolescents (2–17 y). THcy concentrations significantly increased while folate and Cbl decreased with age without gender differences. Age, folate and Cbl were significant predictors for tHcy concentrations. THcy was higher but within normal ranges in MTHFR 677TT homozygotes (10.6%) and carriers of the MTHFR 1793A allele (8%). Only two individuals (0.8%), both with low tHcy concentrations, were homozygous for MTHFR 1793AA. THcy concentration correlated positively with creatinine, triglycerides, BMI and systolic BP and was not related to cholesterol, sports activities and family history of CVD.In conclusion, tHcy concentrations in this pediatric population were significantly influenced by age, folate and Cbl concentrations. No gender differences for tHcy, folate or Cbl concentrations were observed. Both the MTHFR 677TT genotype and the MTHFR 1793A allele were not associated with hyperhomocysteinemia. The prevalence of the MTHFR 1793AA genotype was too low for meaningful interpretation.

Different FCER1A polymorphisms influence IgE levels in asthmatics and non-asthmatics.

Recently, three genome‐wide association studies (GWAS) demonstrated FCER1A, the gene encoding a ligand‐binding subunit of the high‐affinity IgE receptor, to be a major susceptibility locus for serum IgE levels. The top association signal differed between the two studies from the general population and the one based on an asthma case–control design. In this study, we investigated whether different FCER1A polymorphisms are associated with total serum IgE in the general population and asthmatics specifically.

Congenital Cystic Lung Disease: Diagnostic and Therapeutic Considerations

Congenital lung cysts such as congenital cystic adenomatoid malformation, pulmonary sequestration, congenital lobar emphysema, and bronchogenic cysts are rare but fascinating anomalies of lung development. While there are many similarities in terms of their presenting features, there are particular differences between the diagnostic groups that are important to highlight, especially in relationship to approaches to imaging and long-term outcome. A case of each entity is presented with an emphasis on the contemporary approach to diagnostic investigations and therapeutic options.

Changes in left ventricular function in shocked newborns

Objective: To assess whether the change in cardiac output after volume replacement is due to elevation of stroke volume or heart rate and to determine the effect of mechanical ventilation on the hemodynamic situation. Design: Prospective study. Setting: A ten-bed neonatal intensive care unit (level III) at a university hospital. Patients: 15 consecutive newborns with blood pressure below the 10th percentile related to age and weight. Interventions: Volume replacement with Ringers lactate 20 ml/kg body weight. Measurements and results. Before and after volume replacement, arterial pressure recordings, blood gas analysis, and an echocardiographic study were carried out. Left ventricular and aortic diameters were measured by the two-dimensional M-mode technique and velocity time integral of aortic flow by the pulsed color Doppler technique. From these data, stroke volume and cardiac output were calculated. Cardiac output (703 ± 204 vs 826 ± 166 ml/min, p < 0.005) and cardiac index (267 ± 69 vs 302 ± 55 ml/min per kg body weight, p < 0.01) changed significantly due to an appreciable elevation in stroke volume (5.2 ± 1.7 vs 5.8 ± 1.7 ml, p < 0.05), whereas heart rate was unaltered (140 ± 12 vs 142 ± 20 beats/min; NS). The change in blood pressure (32 ± 5 vs 38 ± 8 mm Hg, p < 0.01) was also significant. Cardiac index before and after volume replacement showed a significant inverse correlation with the severity of respiratory disease expressed as alveolar-arterial oxygen difference (A-aDO2) (A-aDO2 vs cardiac index before volume replacement: r = − 0.77, p < 0.001; after volume replacement: r = − 0.73, p < 0.005) or oxygenation index (oxygenation index vs cardiac index before volume replacement: r = − 0.73, p < 0.005; after volume replacement: r = − 0.73, p < 0.005). Changes in left ventricular diastolic diameter, left ventricular systolic diameter, and fractional shortening were not significant. Conclusions: These results indicate that the major regulator of left ventricular output in newborns with hypovolemic or cardiogenic shock is stroke volume and not heart rate and that cardiac output depends on the severity of the respiratory disease.

Nasal Continuous Positive Airway Pressure (n-CPAP) Does Not Change Cardiac Output in Preterm Infants

Our objective was to study how invasive mechanical ventilation impairs cardiac output (CO) in children and adults. Although the application of continuous positive airway pressure (CPAP) is widely practiced in neonatal intensive care, its hemodynamic consequences have not yet been investigated. A prospective study to assess the hemodynamic effects was conducted in 21 preterm infants < 1500 g using two-dimensional M-mode and pulsed Doppler echocardiography during and 1 hour after discontinuation of nasal CPAP (n-CPAP). Gestational age was 28.0 +/- 1.9 weeks (mean +/- standard deviation); birthweight, 1000 +/- 238 g; age at study entry, 200 +/- 155 hours; total maintenance fluid, 154 +/- 42 mL/kg/day; and n-CPAP level, 4.4 +/- 0.9 cm H(2)O. None of the infants received inotropic support, and n-CPAP did not cause any significant difference in the parameters measured: stroke volume, 3.1 +/- 1.0 mL (with n-CPAP) versus 3.1 +/- 1.0 mL (without n-CPAP); cardiac output, 487 +/- 156 mL/minute versus 500 +/- 176 mL/minute; left ventricular diastolic diameter, 1.22 +/- 0.15 cm versus 1.24 +/- 0.14 cm; fractional shortening, 0.30 +/- 0.05% versus 0.29 +/- 0.04%; and aortic velocity-time integral, 8.64 +/- 1.80 cm versus 8.70 +/- 1.65 cm. The n-CPAP level did not influence CO; n-CPAP (up to 7 cm H (2)O) has no echocardiographically detectable hemodynamic effect in preterm infants. Our data imply there is no need to withhold n-CPAP support to prevent circulatory compromise in these infants.

CD14 C-159T and toll-like receptor 4 Asp299Gly polymorphisms in surviving meningococcal disease patients.

Background Carriage of Neisseria meningitidis occurs approximately in 10% of the population, onset of invasive meningococcal disease (IMD) cannot be predicted and differs between ages. It remains unclear, which host factors determine invasion of the bloodstream by the bacteria. Innate immunity has a very important role in the first recognition of invading pathogens. The functional single nucleotide polymorphisms (SNPs) CD14 C-159T and toll-like receptor 4 (TLR4) Asp299Gly have been associated with the risk of gram-negative infections. However, their role in development of IMD still remains unclear. Our aim was to investigate the influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of IMD. Methodology/Principal Findings It was a retrospective case control study. Surviving Austrian meningococcal disease patients were enrolled by sending buccal swabs for DNA analysis. 185 cases with a proven meningococcal infection and 770 healthy controls were enrolled. In surviving meningococcal disease patients DNA analysis of CD14 C-159T and TLR 4 Asp299Gly polymorphisms was performed, as they are part of the innate immune response to bacterial determinants. CD14 C-159T and TLR4 Asp299Gly SNPs were not significantly associated with the presence of IMD when compared to healthy controls. The odds ratio for CD14 C-159T SNP was 1.14 (95% confidence interval (CI) 0.91–1.43; p = 0.266). In TLR4 Asp 299 Gly SNP the odds ratio was 0.78 (CI 0.47–1.43; p = 0.359). Conclusion/Significance We could not observe a significant influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of developing IMD in surviving meningococcal disease patients. To our knowledge, this is the first study investigating the influence of the CD14 C-159T SNP on the susceptibility to IMD.