High fetal bisphenol A exposure enhances IL22 secretion: A proinflammatory cytokine.

BACKGROUND: Bisphenol A (BPA) is an industrial product, widely used in human consumed types of equipment that can be transmitted orally, by inhalation or through dermal absorption and is detectable in many body fluids including cord blood. A correlation between BPA concentration in maternal serum and cord blood has been demonstrated previously, suggesting a possible transfer of BPA via the transplacental path. OBJECTIVE: Our objective is to determine the impact of cord blood BPA level on cytokine responses. METHODS: In this cross-sectional study, healthy pregnant women who delivered healthy newborns followed by the Obstetrics and Gynecology Department between September 2016 to June 2017 were enrolled. Cord blood samples were obtained and BPA and IL4, IL5, IL10, IL17, IL22, IFN gama and TGF beta levels were studied by ELISA. RESULTS: Among 197 deliveries, 176 of them were included in the study. Due to lack of cut-off value, BPA levels were stratified as percentiles. No statistically significant difference was detected in comparison of cytokine levels based on BPA concentrations below and above the 25th and 50th percentiles. Significantly higher IL22 levels (p = 0.007) and increased ratio of IL22/TGFß (p = 0.04) were detected in those with BPA level above 75th percentile (>19.16 ng/ml) compared to the below group. CONCLUSIONS: This in vivo real-life study demonstrated that very high BPA levels in cord blood of expectant mothers enhances IL22 secretion in cord blood which is a proinflammatory cytokine. Studies evaluating long term immunological effects on those highly exposed newborns are necessitated.

Immune mechanisms induced by sublingual immunotherapy in allergic respiratory diseases.

Allergic respiratory diseases (ARDs) are still a major burden on global public health. Sublingual immunotherapy (SLIT) is a mode of allergen immunotherapy (AIT) which involves administration of the allergen under the tongue, and benefits from tolerogenic properties of the oral mucosa. Studies revealed reduced levels of eosinophilia and eosinophil-dominated inflammation in airways of both animals and humans after SLIT. SLIT was also suggested to lower basophil responsiveness and innate lymphoid cell-2 function in blood samples collected from patients with ARD. Moreover, apart from shifting pathogenic type 2 (TH2) to a type 1 (TH1) and protective regulatory (Treg) polarization of helper T-cell immune response, antibody isotype switch from IgE to IgG1, IgG2, IgG4 and IgA was also reported in patients with ARD receiving SLIT. Today, the literature on SLIT-mediated activities is still scarce and more studies are required to further enlighten the mechanisms utilized by SLIT for the induction of tolerance. The aim of this review is to summarize the current knowledge about the immune-regulatory mechanisms induced by SLIT against ARDs.

Maintained disease control and steroid-sparing effect of subcutaneous immunotherapy in allergic rhinitis and asthma.

BACKGROUND: Allergen immunotherapy is the only currently available treatment strategy that modifies the immune response to the causative allergen and induces clinical improvement and a steroid-sparing effect. OBJECTIVE: In this real-life study, we aimed to evaluate and compare the efficacy of subcutaneous immunotherapy (SCIT) with one allergen or multiple allergens in children and adults with asthma and/or allergic rhinitis in terms of disease control and a steroid-sparing effect. METHODS: Demographics, the initial inhaled corticosteroid (ICS) and/or intranasal corticosteroid (INS) dose, and other drugs of patients receiving SCIT for at least 12 months were recorded. Data on the final dose/use of ICS/INS and asthma and/or allergic rhinitis control were gathered. RESULTS: Of 104 patients included, 57.1% and 64.5% of patients with asthma and allergic rhinitis, respectively, were able to discontinue ICS and INS after SCIT. The median time to INS and ICS dose reduction was 6 months. SCIT with one allergen or multiple allergens effectively reduced the ICS and INS dose and led to control of asthma and allergic rhinitis, with no significant difference between the groups. When the efficacy of SCIT was compared in children and adults, there was no significant difference in terms of a steroid-sparing effect or the control of asthma and allergic rhinitis. SCIT was effective in both children and adult patients. CONCLUSIONS: In this real-life observational study, we have demonstrated a marked steroid-sparing effect while maintaining control of asthma and allergic rhinitis in children and adults treated with one allergen or multiple allergens.

Predictive risk factors for relapse after cessation of inhaled corticosteroids in well-controlled childhood asthma.

BACKGROUND: There is limited data for predicting the risk of exacerbations following the cessation of inhaled corticosteroids (ICS) in well controlled childhood asthma. In current study, clinical, functional and inflammatory parameters at the time of ICS withdrawal were investigated in that respect. METHODS: Forty children asymptomatic for at least 3 months on low dose ICS's were enrolled and ICS were discontinued in summer. At enrolment symptom/medication diary, pulmonary function parameters, methacholine provocation testing, peripheral blood eosinophilia, serum total and allergen-specific IgE levels and skin prick testing were performed. In a subgroup of patients, phytohemaglutinin induced secretion of IL-5, IL-13, IFN-γ and IL-10 from blood mononuclear cells were measured. Patients were assessed with symptom/medication diary and pulmonary function test every 2 months for 6 months. RESULTS: Eighteen of 37 patients experienced recurrence of acute asthma symptoms. In patients with acute attack (group I), changes in rhinitis symptom scores at 2nd month vs. baseline were statistically higher. In addition, group I had significantly higher rhinitis symptom scores compared to group II at fourth-month visit. Patients with acute exacerbation revealed a significant decrease in FEV1% at 2nd month compared to baseline. Moreover, group I showed significantly lower FEF 25-75% compared to group II at 2nd month. Baseline bronchial hyper-responsiveness with methacholine was found to be an independent risk factor for asthma exacerbation. CONCLUSIONS: The findings of this study identified baseline bronchial hyperreactivity, higher rhinitis symptom scores and gradual decrease in pulmonary function parameters during follow-up as risk factors for subsequent exacerbation of asthma.

Altered serum antibody levels in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.

Objectives: This study aimed to extend the literature by analyzing immunoglobulin (Ig) A, IgE, IgG, IgG2, IgG3, and IgM antibody levels in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) patients. Patients and methods: This study retrospectively analyzed the antibody test results of 20 pediatric patients (10 males, 10 females; mean age: 2.5±1.5 years; range, 0.5 to 5.4 years) with and without flare who were initially evaluated for a number of underlying diseases due to periodic fever/infectious symptoms but then diagnosed with PFAPA between January 2015 and December 2020. Antibody levels were determined by chemiluminescence microparticle immunoassay. The results were retrospectively compared with a group of healthy children after the PFAPA diagnosis was confirmed. Results: The chemiluminescence microparticle immunoassay revealed 35%, 65%, 20%, 86.6%, and 55% of PFAPA cases with low serum levels of IgA, IgG, IgG2, IgG3, and IgM respectively, while 56.2% had high IgE levels. Moreover, low serum levels of at least two antibody classes or subclasses were reported in 80% of the PFAPA children. While cases with low IgG serum levels were with the highest incidence rates among the low IgG3 PFAPA patient population, both high IgE and low IgM cases were common in the rest of the patients. Conclusion: Our results suggest an association between PFAPA and low serum antibody levels, particularly of IgG3. Future studies are needed to confirm our conclusion.

Risk factors for persistence of asthma in children: 10-year follow-up.

OBJECTIVE: Risk factors related to the outcome of childhood asthma are not yet well established. We aimed to investigate the long-term outcome for children with asthma to determine the risk factors in predicting persistence of disease. METHODS: Sixty-two children with asthma were evaluated retrospectively at the end of a 10-year follow-up. Patients were asked to complete a questionnaire requesting clinical information, and underwent physical examination, skin prick testing, a pulmonary function test and bronchial provocation testing. Immunologic parameters evaluated were allergen-specific IgE and IgG4 levels, and allergen-induced generation of CD4(+)CD25(+) cells. RESULTS: Mean age at final assessment was 15.9 ± 3.6 years, and duration of follow-up was 10.30 ± 1.27 years. Fifty percent of patients outgrew their asthma during the 10-year follow-up period. All the non-atopic patients outgrew their disease during the study period, whereas 67% of atopic patients did not. We identified two risk factors independently related to the persistence of symptoms: presence of bronchial hyper-responsiveness and presence of rhinitis. Atopic children who were in remission demonstrated significantly higher allergen-induced CD4(+)CD25(+) T cells compared to healthy controls. CONCLUSIONS: Atopy, presence of rhinitis, positive and presence of bronchial hyper-reactivity are important risk factors for the persistence of asthma in children. Allergen-induced CD4(+)CD25(+) T cells were higher in the atopic children who outgrew their disease, implicating an immunological mechanism of asthma remission in children.

Is calprotectin a marker of tobacco smoke related inflammation?: a pilot study in children.

CONTEXT: Environmental tobacco smoke (ETS) related inflammation has an anorexigenic effect through affecting the release of appetite-modulating mediators, leptin and ghrelin. Elevated serum calprotectin levels are found in a variety of inflammatory conditions. OBJECTIVE: To study the relation between ETS and body mass index (BMI), as well as serum levels of leptin, ghrelin and calprotectin. MATERIALS AND METHODS: A cross-sectional study was performed by searching the smoking status of parents. After filling in the questionnaires, parents were phoned and children were invited to supply fasting blood samples in order to measure serum levels of leptin, ghrelin and calprotectin, and to calculate their BMIs. Participant children were divided into Group 1 (n = 51), those who are not exposed to and Group 2 (n = 46), exposed to indoor ETS. RESULTS: There were no statistical difference in BMI, leptin and ghrelin levels between Group 1 and Group 2 (p values are 0.85, 0.87 and 0.42, respectively), but serum calprotectin levels were statistically higher in Group 2 (p = 0.003). DISCUSSION AND CONCLUSION: In this study serum levels of calprotectin were found to be higher in children with indoor ETS exposure where no relation was detected with BMI and serum levels of leptin and ghrelin. Increased serum levels of calprotectin might be an indicator of inflammation related to ETS exposure.

A novel approach in allergen-specific immunotherapy: combination of sublingual and subcutaneous routes.

BACKGROUND: Subcutaneous allergen-specific immunotherapy (SIT) has an early onset of action, whereas repeated injections and safety concerns have limited its use in the pediatric age group. Meanwhile, the improved safety profile of the sublingual route has been accepted as an alternative despite its relatively late onset of action. OBJECTIVE: We sought to improve the efficacy and safety of SIT with a combination of the subcutaneous route in the build-up phase and sublingual maintenance in comparison with the sublingual or subcutaneous routes alone. METHODS: Fifty-one house dust mite-sensitized children with mild-to-moderate asthma were randomized into one of 4 groups to receive either (1) subcutaneous immunotherapy (SCIT), (2) sublingual immunotherapy (SLIT), (3) SCIT plus SLIT, or (4) pharmacotherapy. Clinical parameters were evaluated at baseline and months 1, 4, 12, and 18. Allergen-specific immunoglobulin levels and allergen-induced IL-5, IL-10, IL-13, IL-17, TGF-ß, and IFN-γ levels were evaluated as well. RESULTS: In the SCIT and SCIT plus SLIT groups, the number of asthma attacks and inhaled corticosteroid dosage decreased compared with baseline values at the months 4, 12, and 18 but only at month 12 in the SLIT group. The improvement in visual analog scores for rhinitis was significant only in the SCIT plus SLIT group. Increases in the levels of regulatory and T(H)1 cytokines were observed both in the SCIT and SLIT groups, with some differences in dynamics. Antigen-specific IgG(4) levels increased in the SCIT and SCIT plus SLIT groups but not in the SLIT group. Clinical symptom scores were correlated positively with IL-5 levels and negatively with antigen-specific IgG(4), IFN-γ, and TGF-ß levels. CONCLUSION: Our novel regimen of immunotherapy, SCIT plus SLIT, appeared promising in that it successfully combined the advantages of the 2 alternatives: rapid onset and potency in SCIT and safety and avoidance of injections in SLIT.

Cutaneous Allergic reactions to pine processionary caterpillar (Thaumetopoea Pityocampa): a complicated cutaneous reaction in an infant and review of the literature.

BACKGROUND: Thaumetopoea Pityocampa (TP) are frequent in the Mediterranean region especially affecting forest workers in pinewood areas. The common symptoms include swelling, rash or burns like any form of dermatitis. The reactions can be triggered by mechanical, chemical or allergic factors and the `allergic` reaction is caused by sensitization to a hair protein named `thaumetopoein`. This protein triggers the IgE mediated reaction resulting in the mast cell degranulation causing urticaria. Different kinds of allergic reactions like urticaria or anaphylaxis have been reported previously commonly in adults, especially in forest workers while severe reactions without direct contact are rare in pediatric population. CASE: A 28 month old healthy boy was admitted to Near East University Pediatric Allergy and Immunology Outpatient Clinic in March with complaints of pain, hyperemia and swelling on the left hand. His complaints had started the day before his admission just after walking around in their garden which is surrounded by pine trees. On admission, his physical examination revealed serious edema and hyperemia on his left hand limiting his finger movements with a few bullae on the skin. His temperature was 38 C and the other vital parameters were normal. Based on hyperemia, swelling and high acute phase reactants he was hospitalized with the differential diagnosis of soft tissue inflammation and cellulitis. The case was treated with iv antihistamines, systemic steroids and antibiotics. CONCLUSIONS: Pine processionary (PP) is an important irritant and allergen especially in endemic areas like Cyprus which is a Mediterranean Country. It must be kept in mind in case of local or generalized urticaria, dermatitis, bullae and other allergic reactions even if there had been no direct contact with PP. Systemic involvement with fever and elevated acute phase reactants in infancy may necessitate hospitalization and intravenous treatment. Hereby, we reported an infant who presented with fever in addition to severe cutaneous lesions following the exposure to TP without direct contact. This is the first case reported from North Cyprus.

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021.

Introduction: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI. Results: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174). Conclusions: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries.

Serum immunoglobulin levels as a predictive factor for a better outcome of non-atopic childhood asthma.

Childhood asthma is a heterogeneous condition with different phenotypes. Hereby, we aimed to study impact of serum immunoglobulin levels on clinical phenotypes and outcome of asthma. Seventy-eight children (M: 26, F: 52) aged less than 10 yrs (mean = 8.56 ± 3.23 yrs) and diagnosed as mild-moderate persistent asthma, followed up for at least 1 yr were included into the study. Asthmatic children were divided into two groups based on serum immunoglobulin levels at admission and were evaluated with respect to demographic data, allergic sensitization, symptom scores, medication usage, pulmonary functions, and non-specific bronchial hyper-reactivity. The age at onset of symptoms (40.88 ± 32.02 vs. 23.04 ± 26.97 months) was significantly younger in children with hypogammaglobulinemia (n = 28) compared to normogammaglobulinemia group (n = 50) (p = 0.016). Mean follow-up duration was 3.8 ± 2.1 yrs. Atopic sensitization rate was higher in those with normal immunoglobulin levels (81.2% vs. 17.9%), (p < 0.0001). Normal serum immunoglobulin levels were associated with atopic asthma (OR, 4.5; 95% confidence interval (CI): 2.0-10.1). For the prediction of atopic asthma, having normal immunoglobulin levels yielded predictive values of: sensitivity = 88.6%, specificity = 71.8%, positive predictive value = 81.1%, negative predictive value = 82.1%. Furthermore, percentages of atopic dermatitis and allergic conjunctivitis, elevated serum total IgE levels, eosinophilia, and bronchial hyper-reactivity were more common in normogammaglobulinemia with asthma group (p = 0.040, p = 0.003, p = 0.024, p = 0.030, p = 0.040, respectively). Although marked reductions in asthma scores and inhaled corticosteroid usage were observed in both groups over time, the rate of decline was significantly higher and earlier in hypogammaglobulinemia group (p = 0.0001, p = 0.004, respectively). In conclusion, asthmatic children with hypogammaglobulinemia presented at an earlier age, with lower rates of atopy, and earlier clinical improvement accompanied with earlier discontinuation of inhaled corticosteroids than children with normal immunoglobulin levels. Our data demonstrated that in children currently named as early-onset non-atopic asthma, hypogammaglobulinemia might be accompanying, providing evidence for a different phenotype of childhood asthma.

Osteoporosis: an ignored complication of CVID.

BACKGROUND: Multiple factors in common variable immunodeficiency (CVID) might interfere with optimal growth and maturation and potentially compromise bone health. METHODS: We aimed to evaluate bone mineral density (BMD) of patients with CVID using dual energy X-ray absorptiometry (DEXA) and investigate risk factors associated with decreased bone density. RESULTS: Twenty-two patients were included (M: 16, F: 6) with a mean age of 15.6 ± 9.0 yr. DEXA revealed osteopenia in 6/22 (27.3%) and osteoporosis in 9/22 (40.9%) at lumbar spine and osteopenia in 7/19 (37%) and osteoporosis in 3/19 (16%) at femoral neck sites. The age of subjects with osteoporosis was significantly higher than those without (21.6 ± 8.0 vs. 9.0 ± 5.7 yr; p < 0.0001). BMD z-scores were significantly lower in patients with bronchiectasis compared with those without (p = 0.03). Patients with osteoporosis at femoral neck site had lower forced expiratory volume in 1 s (FEV(1) ) (p = 0.024), FEV(1) /forced vital capacity (FVC) (p < 0.0001), PEF (p = 0.008), and FEF 25-75 (p = 0.013) values compared with the patients with normal BMD z-scores. Low serum 25(OH) vitamin D levels were detected in 13/22 patients and low dietary calcium intake in 17/22 patients. BMD z-scores at femoral neck were lower in patients with low B-cell percentage (p = 0.03). BMD z-score at lumbar spine was correlated with folate (r = +0.63, p = 0.004) and serum immunoglobulin G levels (r = +0.430, p = 0.04). CONCLUSION: Osteoporosis appeared as an emerging health problem of patients with CVID, the risk increasing with older age and poorer lung function. Nutritional, biochemical, and immunologic factors appeared to take part in decreased BMD. Insight into the mechanisms of osteoporosis in CVID is crucial to develop preventive strategies.

Altered tonsillar toll-like receptor (TLR)-1 and TLR-2 expression levels between periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA), and group A beta-hemolytic streptococcal (GAßHS) recurrent tonsillitis patients.

INTRODUCTION: Tonsillar microenvironment is thought to contribute to innate immune dysregulation responsible for the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) because of beneficial effects of tonsillectomy on treatment of the syndrome. Accordingly previous studies reported altered lymphocyte frequency, cytokine level and microbial composition in PFAPA tonsils. The aim of our study is to monitor expression levels of pro-inflammatory cell surface Toll-like receptors (TLRs) which have important role in induction of inflammation and maintaining tissue haemostasis. MATERIALS AND METHODS: Seven patients with PFAPA syndrome, and eight patients with group A beta-hemolytic streptococcal (GAßHS) recurrent tonsillitis were included in our study. Tonsillar expression levels of TLR-1, -2, -4, -5, and -6 were monitored by immunohistochemistry (IHC). Expression levels were scored using semi-quantitative analysis method and were statistically analyzed by Two-Way Repeated Measures Analysis of Variance test. RESULTS: IHC analysis demonstrated expression of all TLRs in tonsillar surface epithelium (SE) and lymphoid interior (LI) except for TLR-6 which was not present in the former. There has not been any statistically significant difference in TLR expression levels between PFAPA and GAßHS tonsils, except for TLR-1 and TLR-2 which were higher on LI and lower on SE of PFAPA tonsils, respectively, than that of the GAßHS samples. CONCLUSIONS: Altered TLR expression levels may be involved in PFAPA pathogenesis. Future studies with higher patient number, uninflamed tonsils and cellular markers are required to further enlighten the role of TLRs in the development of syndrome.

Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors.

We evaluated 131 children (M=88, F=43) with hypogammaglobulinemia. Data was analyzed mainly for delineating predictor factors for outcome. The distance from the lower limit of normal (-2SD) for any single measurement of immunoglobulins (Ig) was calculated and transformed into Ig scores. Mean age and duration of follow-up were 5.06 ± 4.05 and 3.7 ± 3.03 years, respectively. The diagnoses were: 22 CVID, 16 IgA deficiency, 33 transient hypogammaglobulinemia of childhood (THC), 3 selective IgM deficiency and 57 unclassified hypogammaglobulinemia (UCH). Low IgA scores (<-0.124) at presentation were indicative of subsequent development of IgA deficiency or CVID, whereas low IgM score (<-0.038) pointed towards more severe and persistent phenotypes. Combination of low IgM score between 2 and 5 years, impaired antibody response and low B cell counts enabled us to predict persistence of hypogammaglobulinemia beyond 5 years (specificity=90.5% and PPV=94.9%) and chronic lung disease (sensitivity=90.4% and specificity=68.3%). The set of criteria including low IgM scores, impaired antibody response and low B cell counts provided a high predictive value in detecting those with persistent hypogammaglobulinemia.

Neonatal BCG vaccination induces IL-10 production by CD4+ CD25+ T cells.

To determine the optimal time of Bacillus Calmette-Guerin (BCG) vaccination for induction of Th1 immunity, we measured the interferon (IFN)-γ and interleukin (IL)-10 secretion in purified protein derivative (PPD)-stimulated peripheral blood mononuclear cell (PBMC) cultures in newborns vaccinated at birth or 2nd month of life. Moreover, role of CD4(+) CD25(+) T cells was studied by depletion assay at 8th month. Nineteen term and healthy newborns were randomized into two groups: Group I composed of 10 newborns vaccinated with BCG at birth and the remaining 9 (group II) at 2nd month of life. PBMCs were isolated at birth, 2nd and 8th months of age, and PPD-stimulated IL-10, 5 and IFN-γ secretion were assessed. The same measurements were repeated for IL-10 and IFN-γ after the depletion of CD4(+) CD25(+) T cells at the 8th month. Children vaccinated at birth demonstrated higher PPD-stimulated IFN-γ and IL-10 levels at 2 months of age when compared to non-vaccinated ones (p = 0.038 and p = 0.022, respectively), whereas at 8 months, no significant differences were detected between the two groups. Moreover, CD4(+) CD25(+)-depleted T-cell cultures resulted in lower PPD-stimulated IL-10 levels in those vaccinated at birth when compared to non-depleted condition at the 8th month (p < 0.001). BCG at birth upregulated PPD-stimulated IFN-γ secretion at the 2nd month and remained still detectable at 8 month after the vaccination, whereas those vaccinated at the 2nd month of life lacked that increase in IFN-γ response at the same time-point. Furthermore, depletion assays suggest that CD4(+) CD25(+) T cells are involved in PPD-stimulated IL-10 secretion in response to BCG vaccination.

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.

BACKGROUND: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. OBJECTIVE: To elucidate mechanisms underlying different forms of HIES. METHODS: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. RESULTS: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. CONCLUSION: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

Planning and approach to allergen-specific immunotherapy in polyallergic patients.

Allergy immunotherapy (AIT) is currently the only disease-modifying treatment for allergic-respiratory diseases. Polysensitization may increase the severity of current disease resulting in subsequent asthma development in patients with allergic rhinitis. Due to the absence of general recommendations for the practical approach to polysensitized patients, clinical management is not standardized. The correlation between sensitizations and clinical symptoms, elimination of possible pollen cross-reactivities and principles of homologous allergen groups will guide the allergists to deduce the most relevant allergens for AIT. In the highlight of the previously proposed approach strategies to polyallergic patients, hereby we propose a revised practical stepwise approach based on the current European Medicine Agency (EMA) guidelines. However, more supporting data from well-designed, controlled, future studies are needed to improve clinical management recommendations for AIT in polyallergic patients.

Headliner in Physiology and Management of Childhood Asthma: Hypothalamic-Pituitary-Adrenal Axis.

Asthma is the most common chronic inflammatory disease of children. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy which are the most effective, commonly used treatment of persistent asthma. Mostly, studies on the relationship between asthma and cortisol have focused on side effects of treatment. Recently, asthmatic patients not treated with ICS have been reported to have an attenuated activity and/or responsiveness of their Hypothalamic-Pituitary- Adrenal (HPA) axis. Moreover, it has been proposed that asthma worsening with stress may be due to a dysfunctional HPA axis, or cortisol insensitivity due to chronic psychological stress through impaired glucocorticoid receptor expression or function. Although long-term ICS treatment might produce adrenal suppression or iatrogenic Cushing syndrome, improvement of adrenal function has also been detected in some of asthmatic cases. Thus, the response scheme of HPA axis still contains undiscovered features in asthma. The management of asthma can be improved by increasing knowledge on the role of HPA axis in asthma pathophysiology. The risk for side effects of ICS can be minimized through increased awareness, early recognition of at-risk patients and regular patient follow-up. This review was written to draw attention to the role of HPA axis in both asthma and its treatment and to illustrate a follow up algorithm of HPA axis in the management of asthma.

Association of cord blood bisphenol A (BPA) with cord blood adiponectin, leptin, fetal growth; adiposity and neoantal complications in a newborn cohort.

Objective: To evaluate the relation between cord blood bisphenol A (BPA), leptin, adiponectin, birth weight, height, skin thickness, and postnatal results.Method: This study was performed in near East University Medical Faculty, Nicosia, Cyprus with 150 healthy newborns. Cord blood leptin, adiponectin, BPA levels were measured by ELISA and birth weight, heights and back, waist, and arm skin thickness were measured and postnatal problems noted.Results: One hundred eighty-seven newborns were included in the study. Mean ± SD of BPA, adiponectin, leptin levels were 48.3 ± 2.22 ng/mL, 65.60 ± 15.29 µg/mL and 3.08 ± 2.08 ng/mL. Mean birth weight, height, head circumferences were 3156.76 ± 493.45 g, 48.28 ± 2.04 cm, 34.14 ± 1.74 cm. The association anthropometric measurements, BPA, leptin, and adiponectin levels were not statistically significant (p>.05). The relation between cord blood leptin, adiponectin, and BPA levels and small for gestation, large for gestation and average for gestation groups were not significant (p>.05). Moreover, relation between back, waist and arm skin thickness and BPA, leptin, and adiponectin were not statistically significant (p>.05). However, newborns who were hospitalized and had newborn jaundice had higher BPA levels (p<.05).Conclusion: In previous studies, higher BPA levels were associated with small for gestational age (SGA) birth, however, this relation was not noted in our study. Furthermore, there is no relation between skin thickness, BPA, leptin, and adiponectin. This difference may be as a result of higher cord BPA levels compared with previous studies.

Use of T cell-based diagnosis of tuberculosis infection to optimize interpretation of tuberculin skin testing for child tuberculosis contacts.

BACKGROUND: Treatment of recent tuberculosis infection in children aged <2 years is essential, because of high risk of progression to disease, but diagnosis is hindered by the inaccuracy of the tuberculin skin test (TST). More-accurate T cell-based tests of infection could enhance diagnosis by optimizing interpretation of the TST results. METHODS: A total of 979 child tuberculosis contacts in Istanbul underwent the TST and enzyme-linked immunospot assay. Using enzyme-linked immunospot test results as a reference standard, we assessed the effect of age and bacille Calmette-Guérin (BCG) vaccination on the sensitivity and specificity of the TST, and we computed the optimal TST cutoff points, using receiver operating characteristic curves. RESULTS: With a TST cutoff point of >or=10 mm, the sensitivity of the TST was 66% for children aged <2 years, which was lower than that for older children (P= .006). Specificity was 75% for BCG-vaccinated children, compared with 92% for unvaccinated children (P= .001). Optimal cutoff points improved TST specificity for children with 1 BCG scar, with little loss of sensitivity. Despite the use of optimal cutoff points, TST sensitivity remained <70% for children aged <2 years, specificity remained <87% for BCG-vaccinated children aged >or=2 years, and overall accuracy was low for children with >1 BCG scar. CONCLUSIONS: Negative results of the TST cannot exclude tuberculosis infection for child tuberculosis contacts aged <2 years, which supports the use of preventive therapy regardless of the TST results for this age group. In children aged >or=2 years, the accuracy of the TST can be improved by adjustment of cutoff points for BCG-vaccinated children but remains poor for children with >1 BCG scar. This methodology can define optimal TST cutoff points for diagnosis of tuberculosis infection tailored to target populations.