Bridgette L. Jones

Defining Risk Factors for Red Man Syndrome in Children and Adults

Background: Red man syndrome (RMS) is a well-known adverse reaction that occurs in pediatric patients receiving vancomycin, yet reported prevalence is varied, and characteristics and risk factors are not well understood. Our objective was to determine the prevalence, characteristics and risk factors for RMS in pediatric patients receiving vancomycin, including contributing genetic factors. Methods: A multicenter retrospective study of 546 subjects (0.5–21 years) who received at least 1 dose of intravenous vancomycin was conducted. Demographic and symptom data were collected through chart review and parent/nurse report. Genotype analysis included 10 single nucleotide polymorphisms in the histamine pathway. Results: RMS was observed in 77 (14%) subjects receiving vancomycin. Forty percent of subjects with RMS symptoms developed rash, pruritis and flushing, without hypotension. Antecedent antihistamine use was identified as a risk factor for RMS (P < 0.001). Multivariate regression analysis identified age > 2 years (P = 0.008), previous RMS (P < 0.001), vancomycin dose (P = 0.02) and vancomycin concentration (P = 0.017) as RMS risk factors, whereas African American race was protective (P = 0.011). We observed an apparent association between RMS and a single nucleotide polymorphism in the diamine oxidasegene (P = 0.044); however, no associations were revealed by multifactor dimensionality reduction analysis. Conclusions: RMS is a common adverse event in children receiving vancomycin. Identified risk factors are Caucasian ethnicity, age≥ 2 years, previous RMS history, vancomycin dose ≥ 10 mg/kg, vancomycin concentration ≥ 5 mg/mL and antecedent antihistamine use. Known genetic variants in histamine metabolism or receptors do not appear to be substantial contributors to risk of RMS.

Development of biomarkers to optimize pediatric patient management: what makes children different?

Despite the frequent utilization of biomarkers in medical practice, there is a relative paucity of information regarding validated pediatric biomarkers. Frequently, biomarkers found to be efficacious in adults are extrapolated to the pediatric clinical setting without considering that the pathogenesis of many diseases is distinctly different in children, and ontogeny directly influences disease evolution and therapeutic response in children. New and innovative approaches are necessary to provide reliable, validated biomarkers that can be used to improve and advance pediatric medical care.

Assessment of Histamine Pharmacodynamics by Microvasculature Response of Histamine Using Histamine Iontophoresis Laser Doppler Flowimetry

T pharmacodynamics and potency of orally administered H1 antagonists are routinely investigated using bioassays that measure edema and suppression of the cutaneous wheal-and-flare response following administration of histamine by either the intradermal or epicutaneous (ie, skin prick test) route. Epicutaneous histamine (EH) has been used successfully to characterize the onset, maximum activity, and duration of antihistamine effect relative to drug dose in both adults and children and presently is considered to be the “gold standard” for assessing antihistamine pharmacodynamics (PD). Assessment of wheal-and-flare magnitude following EH testing has been shown to correlate with dermal concentrations of H1 receptor antagonists and relief of symptoms of allergic rhinitis. Although this technique has been widely used clinically because of its presumed simplicity, EH has significant limitations when used as a quantitative biomarker to assess histamine PD. In contrast, histamine iontophoresis with laser Doppler (HILD) flowimetry has been proposed as a more accurate and robust method for assessing histamine PD. As with EH, HILD has been used to assess histamine response in the skin and to study the PD of antihistamines in adults. EH has several limitations such as operator subjectivity in assessing the wheal-and-flare response, inability to continuously assess response, invasive nature of the procedure, and inability to administer a fixed dose of histamine. HILD allows a fixed dose of histamine to be delivered into the skin noninvasively, and blood flow response is measured in an objective manner, which is also continuous and dynamic. A comparison of the relative attributes and limitations of EH and HILD would suggest that this latter method may provide a more robust method to assess antihistamine pharmacokinetic-pharmacodynamic relationships, but head-to-head evaluations have not been performed. The objective of this study was to conduct a controlled, concurrent evaluation of EH and HILD and to compare the 2 methods in a population of healthy adult volunteers.

Genetic variation within the histamine pathway among patients with asthma – a pilot study

Abstract Objective: Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine-related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway, and determine their association with asthma and HRH1 mRNA expression. Methods: We enrolled children and adults (n = 93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for nine known SNPs in the HDC, HRH1, HRH4, HNMT and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher’s exact test and Chi-square test were used to determine differences in allele, genotype and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p < 0.05. Results: No difference was observed in genotype/allele frequency for the nine SNPs between subjects with and without asthma. The HNMT-1639C/-464C/314C/3′UTRA haplotype was more frequently observed in those without asthma than those with asthma (p = 0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p = 0.04). Conclusions: Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings.

Detecting gene expression in buccal mucosa in subjects with asthma versus subjects without asthma

Differences in mRNA expression for inflammatory markers have been observed between subjects with asthma vs. controls and in relation to corticosteroid response. However, these studies utilized methods (e.g., bronchoscopy) that are too invasive to be used routinely in children and in the clinic. The primary purpose of this study was to determine the feasibility of obtaining RNA of adequate quantity and quality from buccal mucosa of children and adults for gene expression studies. Secondly, this study aimed to determine whether gene expression patterns in buccal mucosa are similar to those that have been observed in respiratory epithelium.

Characterization of delayed liquid gastric emptying in children by the 13C-acetate breath test

The (13)C-acetate breath test represents a potential alternative to conventional scintigraphy to measure liquid gastric emptying (GE). The purpose of this study was to compare the (13)C-acetate breath test to gastric scintigraphy in children with functional dyspepsia. Simultaneous assessment of GE was performed in 28 children (9-17 years of age) using a liquid test meal that was double labeled with (13)C-acetate and (99 m)Technetium. (13)CO(2) versus time profiles were fit using traditional pharmacokinetic analyses. For each subject, GE half-life [Formula: see text] determined by scintigraphy was plotted against parameters determined from the (13)C-acetate breath test. Linear regression was used to explore the associations between the tests. Complete (13)CO(2) versus time profiles were available for 25 subjects. There was no association between the scintigraphy GE T½ and the(13)CO(2) half-exhalation time. However, significant associations were observed between the gastric half-emptying time as determined by scintigraphy and two of the breath test parameters: the enrichment of (13)CO(2) present in breath samples at 60 min (DOB(60)) (r = -0.52, p = 0.01) and the area under the curve from 0 to 60 min (AUC(0-60 min)) (r = -0.54; p < 0.01). The (13)C-acetate breath test has the potential to serve as a rapid, technically simple and inexpensive means to assess liquid GE in children with functional dyspepsia and possibly serve as a pharmacodynamic surrogate in studies of prokinetic drugs in children.

Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma

Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease.

Variability of Histamine Pharmacodynamic Response in Children With Allergic Rhinitis

Histamine iontophoresis with laser Doppler monitoring (HILD) is a robust and dynamic surrogate for histamine microvasculature response. We characterized histamine pharmacodynamics in children using HILD. HILD was performed in 54 children with allergic rhinitis. A non‐compartmental analysis and non‐linear mixed‐effects model with a linked effect PK/PD model was used to provide estimates for area under the effect curve (AUEC), maximal response over baseline (EffmaxNT), and time of EffmaxNT (Tmax). Data were placed in sub‐groups by visualization of time vs. response relationships. ANOVA and regression analyses were used for sub‐group comparisons. Three histamine response phenotypes were identified. One group demonstrated a hyper‐responsive phenotype (higher Tmax, EffmaxNt and AUEC, P < .01). AUEC and EffmaxNT were more strongly associated in this group (r2 = 0.86) than the entire cohort (r2 = 0.64). These data demonstrate a hyper‐responsive histamine phenotype via HILD. This finding is important to future pharmacologic studies of antihistamines.

Mixed modeling and sample size calculations for identifying housekeeping genes.

Normalization of gene expression data using internal control genes that have biologically stable expression levels is an important process for analyzing reverse transcription polymerase chain reaction data. We propose a three-way linear mixed-effects model to select optimal housekeeping genes. The mixed-effects model can accommodate multiple continuous and/or categorical variables with sample random effects, gene fixed effects, systematic effects, and gene by systematic effect interactions. We propose using the intraclass correlation coefficient among gene expression levels as the stability measure to select housekeeping genes that have low within-sample variation. Global hypothesis testing is proposed to ensure that selected housekeeping genes are free of systematic effects or gene by systematic effect interactions. A gene combination with the highest lower bound of 95% confidence interval for intraclass correlation coefficient and no significant systematic effects is selected for normalization. Sample size calculation based on the estimation accuracy of the stability measure is offered to help practitioners design experiments to identify housekeeping genes. We compare our methods with geNorm and NormFinder by using three case studies. A free software package written in SAS (Cary, NC, U.S.A.) is available at http://d.web.umkc.edu/daih under software tab.

Understanding the biology of disease in underserved children with asthma: The missing piece of the health disparity puzzle

African American children are disproportionately affected by asthma compared with non-Hispanic white children. Recent data from the Centers for Disease Control and Prevention indicate that asthma prevalence rates (10.3% vs 7.8%) remain higher among nonHispanic black children than non-Hispanic white children, and non-Hispanic black children are almost 3 times as likely to die of asthma as non-Hispanic white children.1 Studies have also found that African American children have more frequent and burdensome asthma symptoms and use emergency department (ED) care more frequently than white children.2 Socioeconomic factors (eg, family income, medical insurance type, parental educational level) have been associated with observed asthma-related disparities experienced by racial/ethnic minority groups. However, socioeconomic factors have not accounted for the entirety of gaps in asthma outcomes between racial groups.3,4 Even when numerous socioeconomic factors are taken into account, the disparity remains in African American children bearing more disease-related burden than white children.3 Intrinsic biological differences that may or may not be affected by socioeconomic factors differ among racial groups with asthma.5 For example, even among children of similar socioeconomic backgrounds, African American children with asthma tend to have more allergic disease.6 These data suggest that other factors related to actual disease pathophysiologic mechanisms may differ by race, which may be influenced by nonsocioeconomic factors, such as genetic ancestry. Asthma is now recognized as a heterogeneous disease composed of phenotypes that differ in pathophysiologic factors, natural history, and response to therapeutic interventions. Methods to better identify phenotype classifications that are meaningful in guiding management strategies are being explored. Recently, statistical cluster analysis techniques have been used to identify differences among patients with asthma in classification of asthma phenotypes. Statistical clustering has been described as “the process of partitioning individual items into successively smaller and smaller numbers of similar groups.”7 The purpose of cluster analysis techniques is to identify similarities within a group of a heterogeneous items or individuals to allow more homogeneous subgroups to be formed. Statistical clustering analyses among children and adults with asthma have used variables such as clinical symptoms (eg, symptom frequency), biomarkers (eg, eosinophil count, exhaled nitric oxide), disease trajectory (eg, age at onset,