The effect of age on whole blood interferon-gamma release assay response among children investigated for latent tuberculosis infection.

OBJECTIVE: To evaluate the effect of age upon QuantiFERON-TB Gold-In-Tube (QFT-IT) assay outcome among children examined for latent tuberculosis infection (LTBI). STUDY DESIGN: A cross-sectional study was conducted among 761 children (mean age ± SD: 7.84 ± 4.68 years) evaluated for LTBI. Participants were examined with both tuberculin skin test and QFT-IT (Cellestis, Australia) and categorized into 4 age groups. Multivariate logistic and linear regressions were used to evaluate the association between selected demographic and patient characteristics upon the qualitative and quantitative QFT-IT outcomes. Agreement between the tuberculin skin test and QFT-IT within groups was evaluated with the κ statistic. RESULTS: QFT-IT indeterminate results occurred more frequently among young children (8.1%; P < .0001) and children (2.7%; P = .025) than adolescents (0.7%). Among QFT-IT positive patients, infants had higher mean (± SD) interferon-gamma (IFNγ) concentration than adolescents. QFT-IT positive (vs negative) outcome was associated with origin from a high tuberculosis endemicity setting (AOR = 4.54; 95% CI, 3.22-6.25) and lack of previous Bacille Calmette Guerin immunization (AOR = 2.70; 95% CI, 1.89-3.85), but not patient age (AOR = 0.96; 95% CI, 0.92-0.99). However, among QFT-IT positive patients, the IFNγ concentration was inversely associated with patient age (P = .009) and positively with mitogen response (P = .0002). Agreement between tests was not significantly different between younger and older children in the different risk groups. CONCLUSIONS: Qualitative QFT-IT assay results are not affected by patient age. However, indeterminate results occur more frequently among younger children. Among patients with LTBI the quantitative QFT-IT result (ie, IFNγ) is inversely associated with patient age.

Chemokines in respiratory viral infections: focus on their diagnostic and therapeutic potential.

Chemokines are small chemoattractant cytokines involved in cell trafficking and activation. Despite the general nonspecific nature of chemokine activity in certain instances, specific chemokine expression patterns have been associated with specific disease states. In the field of respiratory viral infection, evidence suggests that response to viral invasion is regulated by a distinct chemokine expression profile involving more CC chemokines than CXC chemokines. Moreover, among the CC chemokines, CCL3 and CCL5 appear to be most commonly implicated in viral respiratory disease. Most data available in this field have been derived from in vitro studies, as well as studies conducted in animal models with limited evidence obtained in settings of actual human disease. In the present review, we focus on the diagnostic, prognostic, and therapeutic potential of virus-induced chemokine activity as reflected by studies conducted in actual disease states, either in animal models or humans. We further discuss whether these data advocate chemokines as a realistic clinical tool for the management of viral infection.

Button battery ingestion: the Greek experience and review of the literature.

OBJECTIVES: Foreign body ingestion is a common cause of admission in the pediatric emergency room. In the past, button batteries accounted for less than 2% of the foreign bodies ingested by small children, but in the last 2 decades, they show a rapidly increased frequency. The aim of the present study was to evaluate the potential risk after button battery ingestion in relation with the clinical manifestations and to perform a treatment-observation protocol in accordance with the international procedure. METHODS AND RESULTS: In a prospective observational analysis from November 2007 through February 2008, 31 cases of button battery ingestion were recorded by the Greek Poison Information Center. The interval between the accidental ingestion and first medical contact ranged from 5 minutes to 10 days. After initial evaluation including clinical examination and radiological localization of the foreign body, all cases were treated as outpatients. Reported complications included "black stools" in 9% and diarrhea in 3% of cases. In 1 case, the battery was endoscopically removed. CONCLUSIONS: The role of primary care physicians in informing the public about the potential danger of button battery digestion is crucial. Pediatricians should educate the parents about this hazard, as part of the routine guidelines for childproofing at home. Once again, prolepsis is the best policy.

Therapeutic implications of chemokine-mediated pathways in atherosclerosis: realistic perspectives and utopias.

Current perspectives on the pathogenesis of atherosclerosis strongly support the involvement of inflammatory mediators in the establishment and progression of atherosclerostic lesions. Chemokine-mediated mechanisms are potent regulators of such processes by orchestrating the interactions of inflammatory cellular components of the peripheral blood with cellular components of the arterial wall. The increasing evidence supporting the role of chemokine pathways in atherosclerosis renders chemokine ligands and their receptors potential therapeutic targets. In the following review, we aim to highlight the special structural and functional features of chemokines and their receptors in respect to their roles in atherosclerosis, and examine to what extent available data can be applied in disease management practices.

Interleukin 8 and cardiovascular disease.

Since the establishment of the inflammatory basis of atherosclerosis, several pro- or anti-inflammatory agents have been examined as potential mediators of the biochemical pathways of lesion formation. Interleukin (IL)-8 was first characterized in 1987. Since then, knowledge regarding its role in leucocyte trafficking and activation has advanced rapidly, especially in the field of cardiovascular disease. In the scientific literature, there is sufficient evidence to support beyond any doubt the involvement of IL-8 in the establishment and preservation of the inflammatory micro-environment of the insulted vascular wall. However, how the information derived from in vitro studies and animal models can be applied in clinical practice has yet to be determined. In the present review, the available evidence regarding the role of IL-8 in cardiovascular disease is presented, and future perspectives are discussed.

Genetic diversity of CX3CR1 gene and coronary artery disease: new insights through a meta-analysis.

A significant portion of current medical research is devoted to the pursuit of genetic markers that can be used to identify disease or predict susceptibility to disease. In such a quest many investigators hypothesized that genetic variations that alter signalling pathways involved in atherosclerosis affect susceptibility to coronary artery disease (CAD). Fractalkine (FKN) is a small cytokine involved in monocyte chemotaxis and activation. Two single nucleotide polymorphisms, V249I and T280M, have been identified in the receptor coding sequence of FKN. The polymorphisms alter ligand-receptor affinity and are believed to influence an individual's susceptibility to atherosclerosis. Several investigators have tested the latter hypothesis with inconsistent results. In order to clarify the effect of the two polymorphisms on susceptibility to CAD we performed a meta-analysis, using pooled data retrieved from seven case-control studies. In total, 2000 CAD patients and 2841 subjects without evidence of cardiovascular disease were included in the meta-analysis. The 280M allele was associated with a reduced risk for CAD in the heterozygous state. Consequently, this effect was attributed to the only 280M-containing haplotype: I(249)M(280). The latter haplotype was found to be significantly more frequent in the control population's gene pool. Although we do not believe that the retrieved odds ratios render the T280M polymorphism a candidate genetic marker for clinical applications, we do believe that the above genotype-phenotype interaction is indicative of the strong associations between FKN-induced pathways and CAD.

Genetic diversity of the host and severe respiratory syncytial virus-induced lower respiratory tract infection.

Respiratory syncytial virus (RSV)-induced lower respiratory tract disease is a common problem in children and adults in Western societies. The clinical range of RSV infection from asymptomatic to respiratory distress syndrome is believed to be the outcome of viral and host immunity interactions. Genes associated with immune response are of particular interest regarding genetic predisposition to severe RSV infection. Several investigators have sought to identify genetic markers for high-risk patients, and more than 20 independent studies in the medical literature assess the impact of genetic variations-mostly single nucleotide polymorphisms-on the clinical presentation of RSV-induced disease. Several candidate gene loci have been tested in association studies based on the concept that a particular allele is a significant risk factor for a phenotype of interest. Despite the wealth of information available, we are still far from evolving a practical and cost-effective screening tool; certain flaws in association studies first need to be overcome. The development of haplotype-based analysis for candidate loci across the genome, along with advances in biostatistics and bioinformatics, would facilitate the assessment of the relative contribution of genetic markers to disease susceptibility in RSV infection.

RANTES promoter gene polymorphisms and susceptibility to severe respiratory syncytial virus-induced bronchiolitis.

BACKGROUND: Severe respiratory syncytial virus (RSV) infection is characterized by enhanced chemokine activity. Several studies have linked increased regulated on activation, normal T cell expressed and secreted (RANTES) expression with severe RSV disease. Three single nucleotide polymorphisms, -28C/G, -403G/A, and In1.1T/C in the RANTES gene, have been correlated with the gene's transcriptional activity. In the present study, we explored the possible correlation of the genetic variability of the RANTES gene with the clinical manifestation of RSV disease. METHODS: DNA samples were obtained from 106 children hospitalized for RSV bronchiolitis, in a 2-year period. One hundred twenty sex-matched healthy adults, without a history of severe lower respiratory tract infections, formed the control group. RESULTS: No association was established between -28C/G polymorphism and RSV-induced bronchiolitis, mainly because of its extreme rarity in the studied population. No statistically significant differences were observed in cases and controls regarding genotype and allele frequencies of each of the In.1.1T/C and -403G/A polymorphisms. By contrast, the -28C/C-403G/AIn1.1T/T combined genotype was significantly more common in cases than in controls. CONCLUSIONS: Our results indicate an association between a common genotype with severe RSV infection. This observation supports the previously reported results indicating RANTES as an important mediator of RSV infection.

T280M variation of the CX3C receptor gene is associated with increased risk for severe respiratory syncytial virus bronchiolitis.

BACKGROUND: Recent data suggest that immunologic response during respiratory syncytial virus (RSV) infection is partially modified through interaction of viral G glycoprotein with the host's chemokine receptor, CX3CR1. We hypothesized that two nonsynonymous, single-nucleotide polymorphisms of the CX3CR1 gene (CX3CR1-V249I and CX3CR1-T280M) that disrupt the affinity of CX3CR1 for its natural ligand (fractalkine) could also affect the G glycoprotein-CX3CR1 pathway. METHODS: To test the hypothesis, DNA samples were obtained from 82 children hospitalized for RSV bronchiolitis in a 1-year period. One hundred twenty sex-matched healthy adults, without a history of severe lower respiratory tract infections, formed the control group. RESULTS: Epidemiologic data showed an increase in the RSV infection rate during the late winter season, with a peak rate in early spring. Genotyping revealed predominance of the 280M-containing genotypes (M/M or T/M) in cases compared with controls (37.8% versus 20.8%, respectively; odds ratio, 2.03; 95% confidence interval, 1.1-3.9; P = 0.025), demonstrating an association between the common CX3CR1-T280M variations and increased risk of severe RSV bronchiolitis. CONCLUSIONS: Our findings support the hypothesis of the pivotal role of the G glycoprotein CX3CR1 pathway in the pathogenesis of RSV bronchiolitis and propose CX3CR1 as a potential therapeutic target.