Zdzisława Kycler

The hyperimmunoglobulin E syndrome - clinical manifestation diversity in primary immune deficiency

The hyper-IgE syndromes are rare, complex primary immunodeficiencies characterized by clinical manifestation diversity, by particular susceptibility to staphylococcal and mycotic infections as well as by a heterogeneous genetic origin. Two distinct entities - the classical hyper-IgE syndrome which is inherited in an autosomal dominant pattern and the autosomal recessive hyper-IgE syndrome have been recognized. The autosomal dominant hyper-IgE syndrome is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities which are not observable in the recessive type. In the majority of affected patients with autosomal dominant hyper-IgE syndrome a mutation in the signal transducer and the activator of the transcription 3 gene has been identified, leading to an impaired Th17 cells differentiation and to a downregulation of an antimicrobial response. A mutation in the dedicator of the cytokinesis 8 gene has been identified as the cause of many cases with autosomal recessive hyper-IgE syndrome and, in one patient, a mutation in tyrosine kinase 2 gene has been demonstrated. In this paper, the authors provide a review of the clinical manifestations in the hyper-IgE syndromes with particular emphasis on the diversity of their phenotypic expression and present current diagnostic guidelines for these diseases.

Health-related quality of life in Polish adolescents with Hymenoptera venom allergy treated with venom immunotherapy

Introduction Venom allergy, though rare, may seriously influence health-related quality of life (HRQoL). There is a paucity of research on HRQoL of adolescents and young adults with Hymenoptera venom allergy. The aim was to assess the level of HRQoL and to evaluate its independent predictors in Polish adolescents and young adults treated with venom immunotherapy. Material and methods A multicenter cross-sectional study based on the Vespid Allergy Quality of Life Questionnaire (VQLQ) adapted for Polish adolescents was used. The study sample included 87 patients (14-21 years) studied at different stages of venom immunotherapy (VIT). Statistical analysis was done with multivariate linear regression. Results Anxiety level was higher in patients with 4th grade of Muellers classification (anaphylactic shock) than in those with 3rd grade (B = 0.84, 95% CI = 0.07-1.61, p = 0.03). Caution increased along with an increase of anxiety of adolescents treated with VIT (B = 0.54, 95% CI = 0.39-0.68, p < 0.01). Level of limitations increased with increasing caution of adolescents (B = 0.63, 95% CI = 0.35-0.91, p < 0.01). Discomfort increased along with a rise of caution of patients (B = 0.38, 95% CI = 0.22-0.55, p < 0.01). Similarly, it increased with an increase of their feeling of limitations (B = 0.37, 95% CI = 0.23-0.51, p < 0.01). The level of discomfort in adolescents treated with VIT was lower in those who were treated with conventional protocol in comparison to those treated with rush or ultra-rush ones (B = –0.47, 95% CI = –0.90 - –0.03, p = 0.04). Conclusions Severity of anaphylactic reaction is an independent determinant of anxiety level in adolescents treated with VIT. The VIT protocol affects HRQoL of treated patients.

Neurotrophin serum concentrations and polymorphisms of neurotrophins and their receptors in children with asthma

BACKGROUND In the recent years numerous studies have analysed the effects of neurotrophins on allergic inflammation in airway diseases reporting increased neurotrophin levels locally in the airways as well as in serum of asthmatic patients. We aimed to investigate if levels of neurotrophins in serum of asthmatic children are influenced by the genotype of functional variants within genes encoding analysed neurotrophins and their specific receptors. METHODS In the study we included 98 children diagnosed with asthma. Genotyping of 9 polymorphisms located in neurotrophins genes and their receptors genes was done with use of TaqMan SNP genotyping assays or PCR-RFLP. The serum levels of four neurotrophins (BDNF, NGF, NTF3, NTF4) were analysed during exacerbation of asthma symptoms with use of DuoSet ELISA Development Kit (R&D). RESULTS The two patients with the genetic variant A/A of NTRK1 (rs6334) showed significantly higher NGF serum concentrations (113.4 and 218.1 pg/mL) as compared to the mean NGF serum concentrations in the total group of patients (34.8 pg/mL). We also observed a significant epistatic interactions between variants of NGF rs6330 and NTRK1 rs6334 that influenced NGF serum level (P = 0.0004). Analysis of four neurotrophins serum levels in relation to different genotypes of analysed neurotrophins genes showed no significant differences among analysed asthmatic children. CONCLUSIONS Our results suggest that, among analysed neurotrophins, NGF serum levels may be influenced by the genotype of NTRK1 gene individually as well as in the interaction with NGF functional genetic variant suggesting their involvement in allergic inflammation in asthma. Serum levels of the other neurotrophins do not seem to be affected by the variants in the analysed genes.

Multilocus Analysis of Candidate Genes Involved in Neurogenic Inflammation in Pediatric Asthma and Related Phenotypes: A Case–Control Study

Objectives. Asthma is a heterogenous complex disorder caused by chronic inflammation of the airways. The key issue in genetic association studies of complex disorders is the identification of multiple low-risk genes that individually have little impact on the phenotype, but in combination account for the clinical manifestation of asthma. Since neurogenic inflammation is emerging as a candidate factor in the pathogenesis of asthma, the aim of the study was to investigate whether genetic variants of neurotrophin genes are associated with asthma disease severity or asthma-related phenotypes in a pediatric population. Methods. We genotyped 27 polymorphisms located in neurotrophin genes, using TaqMan SNP genotyping assays or Polymerase Chain Reaction - Restriction Fragments Lengths Polymorphism (PCR-RFLP) in 200 children diagnosed with asthma and 226 controls. Interactions between 27 polymorphic loci and asthma-related phenotypes were determined using the Multifactor Dimensionality Reduction (MDR) method. Results. In single marker analysis, we observed an association of MAP3K1 gene polymorphisms (rs702689 and rs889312) with asthma. We also observed that four Single Nucleotide Polymorphisms (SNPs) were associated with severe asthma. Analysis stratified by asthma-related phenotype revealed an association between atopy and NGFR (rs3785931), while BDNF (rs7124442), NTRK2 (rs1212171), NGFR (rs2072446), and FYN (rs3730353) variants were associated with increased exhaled nitric oxide (exNO). In addition, gene–gene interaction analysis revealed a significant epistatic interaction between MAPK (rs889312) and NGF (rs11102930) variants in asthma susceptibility. Conclusions. Our results suggest that genetic variants of MAP3K1 and NGF genes involved in the regulation of neurogenic inflammation may contribute to asthma, possibly via enhanced NGF expression and MAPK signaling pathway activation.

Pulmonary Lymphomatoid Granulomatosis in Griscelli Syndrome Type 2

Griscelli syndrome type 2 (GS2) is a rare autosomal-recessive disorder associated with a RAB27A gene mutation, and clinically manifesting as hypopigmentation, disseminated chronic encephalitis, and severe immunological disorders characterized by an accelerated hematological phase, also referred to as hemophagocytic syndrome (HS), or hemophagocytic lymphohistiocytosis (HLH). The authors report the diagnosis of GS2 in an 11-year-old girl with hypopigmentation, immunodeficiency, hepatosplenomegaly, severe neurological impairments, and fatal multiorgan failure. In this patient a diagnosis of pulmonary lymphomatoid granulomatosis (LG), an Epstein-Barr virus (EBV)-related lymphoproliferative disorder, was established from radiological and histological findings. Although EBV-related malignancies are common in immunocompromised patients, this is the first report of a diagnosis of pulmonary LG in a patient with GS2.

Interleukin 1β polymorphism and serum level are associated with pediatric asthma

Interleukin‐1 is a pro‐inflammatory cytokine found in two forms (α and β). The α form is mainly cell‐bound, whereas IL‐1β is primarily secreted by macrophages in response to immune system stimulation. We hypothesized that polymorphic variants of interleukin 1 genes may play a role in childhood asthma risk. The aim of this study was to investigate if IL‐1α and β polymorphism is associated with asthma in a pediatric population and if the genotype affects its serum level.

Gastroesophageal reflux is not associated with short-term variability of parasympathetic activity in children

PURPOSE A lower parasympathetic activity was described in patients with the gastroesophageal reflux disease. We aimed to determine whether gastroesophageal reflux (GER) episodes are associated with a short-term parasympathetic tone variability in children. METHODS In order to address this question we performed simultaneous 24-h esophageal multichannel intraluminal impedance-pH and electrocardiographic monitoring in 16 children (age range 6-18 years), including 8 with asthma and 2 with gastroesophageal reflux disease. After describing duration, height, and acidity of 483 GER episodes we also measured parasympathetic-related heart rate variability parameters in 4 time periods: preceding, containing, following GER, and in-between GERs (control). High frequency (HF) power and root-mean square differences of successive R-R intervals (r-MSSD) were assessed in 2.5-min and 1-min periods, respectively. RESULTS We did not identify the searched short-term parasympathetic tone changes. CONCLUSIONS In conclusion, GER episodes and their characteristics were not associated with short-term variability of parasympathetic activity in children.

521 Serum NT-3 and NT-4 Levels are Associated with Clinical Severity in Asthmatic Children

Background Neuronal modulation of inflammation and airway hyperresponsiveness has been well described in asthma and neurotrophins provide the link between inflammation and neuronal dysfunction. In humans, elevated BDNF, NGF and NT-3 levels have been found in bronchoalveolar lavage fluid (BALF) following allergen provocation. Moreover, BDNF levels are significantly higher in untreated asthmatic patients in comparison to those treated with inhaled glucocorticoids and non asthmatic controls. It has also been shown that allergic inflammation increases local all 4 neurotrophins production that are important mediators of eosinophil survival in BALF. The aim of this study was to analyze if levels of neurotrophins in serum of asthmatic pediatric patients are altered in the course of disease (exacerbation and asymptomatic period) and therefore may serve as potential biomarkers for disease activity or symptoms severity. Methods In the study we included 98 children diagnosed with asthma. The blood was collected twice: during exacerbation and in the asymptomatic period. The serum levels of 4 neurotrophins (BDNF, NGF, NT-3, NT-4) were analyzed with use of DuoSet ELISA Development Kit (R&D). Statistical analysis was performed with Statistica v. 9.0. Results Analysis revealed no significant differences in neurotrophins levels in serum between asthmatic patients during asthma exacerbation and asymptomatic period. However, we found that serum levels of NT-3 and NT4 correlate with disease severity, being significantly lower in mild asthmatics as compared to patients with moderate and severe asthma (P < 0.01). Conclusions Our results suggest that neurotrophins levels do not seem to correlate with the clinical symptoms activity in the course of asthma, however 2 of them (NT-3 and NT-4) correlate with disease severity.

Clinical immunology Bronchiectasis in children with primary immune deficiency diseases

Background: Primary immune deficiencies are a common cause of bronchiectasis in children. Aim of the study: The aim of this study was to evaluate the incidence and characteristic radiological findings of bronchiectasis in children with primary immune deficiencies. Material and methods: A retrospective review of medical records and pulmonary imaging (chest radiographs and high resolution computed tomography scans) of forty-one patients with primary immune deficiency diseases, aged between 6 months and 18 years was undertaken. Results: Based on high resolution computer tomography (HRCT) imaging, the diagnosis of bronchiectasis was established in 5 patients (12.2%), with Bruton’s agammaglobulinemia (XLA), common variable immunodeficiency (CVID) and the hyperimmunoglobulin E syndrome (HIES). In 3 children (7.2%), two with IgG subclass deficiencies (IgGsD) and in one with HIES, pre-bronchiectasis was demonstrated. The HRCT features of bronchiectasis were predominatingly detected in the basilar segments of the lower lobes, followed by the right middle lobe and the lingula. The median age of 5 children with bronchiectasis visualized in HRCT imaging was 13 years. Pyogenic bacteria were recovered in the respiratory tract of all the children with bronchiectasis, with Streptococcus pneumoniae most frequently identified. Conclusions: Bronchiectasis is a frequent pulmonary complication and should be actively looked for in children with primary immune deficiencies and lung infections.