Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome.

PURPOSE: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. METHODS: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. RESULTS: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. CONCLUSION: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

Can allergy patch tests with food additives help to diagnose the cause in childhood chronic spontaneous urticaria?

INTRODUCTION: Chronic spontaneous urticaria (CSU) is characterized by the onset of symptoms which are not induced by specific triggers, but are rather spontaneous. A considerable number of patients report that foods or food additives might be responsible for their chronic urticaria. AIM: To determine the prevalence of sensitization to food additives in children with CSU using atopy patch tests (ATP). MATERIAL AND METHODS: Atopy patch tests for 23 different food additives were applied to 120 children with CSU and 61 healthy controls. RESULTS: Seventeen (14.1%) children with CSU were sensitized with food additives. None of the control group had positive APT. Azorubine and Cochineal red were the food additives detected with the highest sensitization rates (5.8% (n = 7) and 6.7% (n = 8), respectively). CONCLUSIONS: There can be an association between food additives and CSU. APT tests may be a helpful tool in the assessment and management of CSU so that easier to follow diets and effective treatments can be offered to families.

Evaluation of periostin level for predicting severity and chronicity of childhood atopic dermatitis.

INTRODUCTION: Periostin has some effects on the pathogenesis of atopic dermatitis (AD) via release of pro-inflammatory cytokines and chemokines from activated keratinocytes and it is related to chronicity of skin lesions. AIM: To evaluate the relationship between plasma periostin levels and severity and chronicity of AD in children. MATERIAL AND METHODS: The study population consisted of 29 children with atopic dermatitis without concomitant allergic disease such as asthma or allergic rhinitis and 31 healthy controls. Data of demographic features, serum eosinophil, total IgE and skin prick test results were collected through the patient's medical records. The severity of the disease was assessed by the SCORAD index. Serum periostin levels were measured with a human periostin ELISA kit. RESULTS: The mean ages of the AD patients and the control group participants were 80.7 ±52.8 and 90.3 ±41.6 months, respectively. Mean plasma periostin levels were 63.0 ±19.0 ng/ml in AD patients, and 23.6 ±7.3 in healthy controls, and there was a statistically significant difference between the two groups (p = 0.001). Plasma periostin level did not vary according to total IgE or serum eosinophil count (p > 0.05). Age of onset and duration of symptoms also were not correlated with plasma periostin levels. Although there was a positive relationship between plasma periostin level and the SCORAD index of patients, it was not statistically significant (r = 0.19, p > 0.05). CONCLUSIONS: This study showed that plasma periostin levels were increased in children with atopic dermatitis. Periostin may have a partial role in the pathogenesis of atopic dermatitis, but it is not associated with severity or chronicity in children with atopic dermatitis.

Plasma lipoxin A4 levels in childhood chronic spontaneous urticaria.

Dilek F, Özçeker D, Güler EM, Özkaya E, Yazici M, Tamay Z, Koçyigit A, Güler N. Plasma lipoxin A4 levels in childhood chronic spontaneous urticaria. Turk J Pediatr 2018; 60: 527-534. Chronic spontaneous urticaria (CSU) is an idiopathic inflammatory disorder. Despite great research progress, the pathogenesis of the disease is still not fully understood. Lipoxins (LXs) are autacoid lipid metabolites that are the first discovered members of a new genus named called `specialized proresolving mediators`. In this study, we aimed to investigate the possible role of LXA4 in the pathogenesis of CSU. Forty-two children with CSU and 25 healthy children were enrolled in the study. The demographic and clinical features of patients were evaluated, autologous serum skin tests (ASSTs), and routine laboratory assessments were performed. Disease activity was determined using the urticaria activity score. An enzyme-linked immunosorbent assay was used to evaluate LXA4 plasma levels. The median value of plasma LXA4 was found to be 60.8 ng/ml (interquartile range, 48.1-71.8) in CSU patients and 137.4 ng/ml (121.4-150.8) in the control group. The difference between the groups was statistically significant (p < 0.001). Additionally, the median plasma LXA4 levels in the ASST-positive patients were significantly reduced compared to the ASST-negative ones (45.8 [36.7-67.6] versus 63.8 [58.3-78.9] ng/ml, respectively, p < 0.05). Our results showed that diminished LXA4 biosynthesis may be a critical part of CSU pathogenesis in children, especially in patients with an autoimmune component.

Evaluation of nasal fluid ß-defensin 2 levels in children with allergic rhinitis.

AIM: Knowledge about the role of the innate immune system in the pathogenesis of allergic diseases has been expanding in recent years. Defensins are antimicrobial peptides that are components of the innate immune system. Defensins have strong efficacy against bacterial, viral, and fungal infections. Moreover, they have regulatory functions in many physiologic processes such as antitumoral immunity, chemotaxis, inflammation, and wound healing. In this study, we aimed to investigate ß-defensin 2 levels in the nasal fluids of children with allergic rhinitis. MATERIAL AND METHODS: Study and control groups consisted of 28 patients with newly diagnosed allergic rhinitis who were not taking any medication, and 23 healthy children. Skin prick tests were performed on patients with allergic rhinitis and disease severity was assessed using the total symptom score. Nasal fluid samples were obtained using a modified polyurethane sponge absorption method from patients and control subjects. Nasal fluid ß-defensin 2 levels were determined using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The median value of nasal fluid ß-defensin 2 levels were 173.8 pg/mL (interquartile range; 54.8-205.9 pg/mL) in allergic rhinitis group and 241.6 pg/mL (163.5-315.2 pg/mL) in the control group. There was a statistically significant difference between the two groups (p=0.01). Moreover, nasal fluid ß-defensin 2 levels showed a significant negative correlation with total symptom scores (rho= -0.78, p<0.001). CONCLUSIONS: Children with allergic rhinitis have reduced nasal fluid ß-defensin 2 levels compared with controls, and ß-defensin 2 levels were negatively correlated with disease severity. A more definite understanding of the roles of defensins and other antimicrobial peptides in allergic inflammation can open up new horizons in the management and treatment of these common diseases.

Elevated Nitrosative Stress in Children with Chronic Spontaneous Urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is an idiopathic condition that seriously affects quality of life. It is well known that oxidative stress and nitrosative stress (NS) are generally involved in many chronic inflammatory diseases. This study aimed to evaluate the possible role of NS in the pathogenesis of CSU. METHODS: Thirty-two children with CSU and 22 healthy control subjects were enrolled in the study. Demographic and clinical features were defined, and disease activity was quantified using the urticaria activity score (UAS). Serum NS was assessed by the plasma levels of total nitric oxide (NOx) metabolites and nitrite and nitrate measurements using a Griess method-based commercial kit. RESULTS: Plasma NOx levels were 82.5 ± 11.3 µmol/L in the CSU group and 50.9 ± 9.4 µmol/L in the control group. The difference was statistically significant (p < 0.001). CSU patients also had higher plasma nitrite levels than controls (53.3 ± 13.8 vs. 30.2 ± 10.1 µmol/L, respectively, p < 0.001). The median values of plasma nitrate were 27.5 µmol/L (IQR 19.1-35.5) in CSU patients and 20.9 µmol/L (IQR 17.9-23.2) in the control group, and the difference was statistically significant (p = 0.009). In addition, plasma NOx and nitrite levels were positively correlated with the UAS (rho = 0.512, p = 0.03 and rho = 0.452, p = 0.011, respectively). CONCLUSION: Plasma NS is elevated and positively correlated with disease activity in children with CSU.

Plasma Levels of Matrix Metalloproteinase-9 in Children With Chronic Spontaneous Urticaria.

PURPOSE: Chronic spontaneous urticaria (CSU) is a disease that is primarily seen in adults and is comparatively rare in children. Consequently, only a few studies have focused on the pathogenesis of the disease in children. This study investigated the possible role of metalloproteinase-9 (MMP-9) in the pathogenesis of CSU in children. METHODS: The study group was composed of 54 children with CSU; 34 healthy children comprised the control group. The demographic and clinical features of the study group were extensively evaluated, and laboratory assessments were also performed. An enzyme-linked immunosorbent assay was used to evaluate levels of plasma MMP-9. Disease activity was quantified using the urticaria activity score (UAS). RESULTS: The median value of plasma MMP-9 was 108.9 ng/mL (interquartile range, 93.3-124.1) in the CSU group and 87.8 ng/mL (69.4-103.0) in the control group. The difference between the 2 groups was statistically significant (P<0.001). Also, MMP-9 levels showed a significant positive correlation with UAS (rho=0.57, P<0.001). Twenty-six percent of patients had positive autologous serum skin test (ASST) results. Neither UAS nor plasma MMP-9 levels were significantly different between ASST-positive and -negative patients (P>0.05). CONCLUSIONS: Plasma MMP-9 levels were elevated in children with CSU and were positively correlated with disease activity. MMP-9 may be both a good biomarker of disease activity and a potential therapeutic target in CSU.

Oxidative Stress in Children with Chronic Spontaneous Urticaria.

The pathogenesis of chronic spontaneous urticaria (CSU) has not been fully understood; nevertheless, significant progress has been achieved in recent years. The aim of this study was to investigate the possible role of reactive oxygen species (ROS) in the pathogenesis of CSU. Sixty-two children with CSU and 41 healthy control subjects were enrolled in the study. An extensive evaluation of demographic and clinical features was done, and serum oxidative stress was evaluated by plasma total oxidant status (TOS) and total antioxidant status (TAS) measurements. The median value of plasma TOS was found to be 10.49 µmol H2O2 equiv./L (interquartile range, 7.29-17.65) in CSU patients and 7.68 µmol H2O2 equiv./L (5.95-10.39) in the control group. The difference between the groups was statistically significant (p = 0.003). Likewise, the median plasma TAS level in the CSU group was decreased significantly compared to that of the control group (2.64 [2.30-2.74] versus 2.76 [2.65-2.86] mmol Trolox equiv./L, resp., p = 0,001). Our results indicated that plasma oxidative stress is increased in children with CSU when compared to healthy subjects, and plasma oxidative stress markers are positively correlated with disease activity.

Nasal fluid secretory immunoglobulin A levels in children with allergic rhinitis.

OBJECTIVES: There is growing knowledge about the immunoregulatory and possibly preventative roles of immunoglobulin A (IgA) in allergic diseases. This study aimed to investigate secretory immunoglobulin A (SIgA) levels in the nasal fluid of children who were either being treated for their allergic rhinitis (AR) with intranasal mometasone furoate or were not receiving treatment. METHODS: The study population contained 55 children with persistent AR. Group I included 27 newly diagnosed AR patients not taking any medication and group II included 28 patients treated with intranasal steroids for at least 6 months. 27 healthy control subjects were also enrolled in the study. Total symptom scores (TSS) were calculated for each patient. Nasal secretions were obtained using a new modified polyurethane sponge absorption method, and samples were analysed by ELISA. RESULTS: The median value for nasal fluid SIgA level in each group was 127.2µg/ml (interquartile range; 67.3-149.6) in group I, 133.9µg/ml (102.1-177.8) in group II and 299.8µg/ml (144.5-414.0) in the control group. Groups I and II both had statistically significant reductions in nasal fluid SIgA levels compared to the control group (p<0.001). However, there was no statistically significant difference between groups I and II (p=0.35). A statistically significant and negative correlation also existed between TSS and nasal fluid SIgA levels in both groups I and II (p=0.006, rho=-0.512 and p=0.01, rho=-0.481, respectively). CONCLUSIONS: SIgA levels in the nasal fluid are significantly reduced in children with AR independent of treatment and are negatively correlated with the TSS.

Rapid Desensitization for Immediate Hypersensitivity to Galsulfase Therapy in Patients with MPS VI.

Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic, and multisystem lysosomal storage disease. Enzyme replacement therapy (ERT) with the recombinant human arylsulfatase B enzyme (galsulfase [Naglazyme]) is recommended as first-line therapy. It is generally reported as safe and well tolerated. Frequently observed mild to moderate infusion-related reactions which can be easily handled by reducing or interrupting the infusion and/or administering additional antihistamines, antipyretics, and corticosteroids are mostly mediated by non-IgE mechanisms. Here we report two children with MPS VI who experienced IgE-mediated reactions with galsulfase at the second year of the therapy. One child had anaphylaxis and the other had urticarial eruptions. They could receive ERT after successful rapid desensitization. To our knowledge, this is the second report on galsulfase allergy with IgE-mediated reaction. It is important to recognize IgE-mediated reactions since they can be life-threatening and do not respond to the standard therapies. We recommend allergy skin tests in the evaluation of infusion-related reactions unresponsive to standard therapies, so that continuation of ERT will be feasible after successful desensitization.

Plasma total thiol pool in children with asthma: Modulation during montelukast monotherapy.

BACKGROUND: Inflammation, which is a hallmark of asthma, is one of the main sources of oxidative stress in the human body. Thiols are powerful antioxidants that protect cells against the consequences of oxidative stress. We aimed to investigate whether asthma and montelukast monotherapy affect the total plasma thiol pool in children. METHODS: A total of 60 children with asthma and 35 healthy controls participated in the study. Group I consisted of newly diagnosed asthmatics who did not have regular anti-asthmatic therapy previously. Group II consisted of patients who had been undertaking montelukast monotherapy regularly for at least 4 months. Plasma total antioxidant status (TAS) and plasma total thiol (PTT) were measured using spectrophotometric methods. RESULTS: Bronchial asthma patients in both groups I and II had decreased median TAS levels compared with the control group (1.59 [interquartile range, 1.04-1.70] and 1.67 [1.50-1.75] vs. 2.98 [2.76-3.16] Trolox equiv./L, respectively; P<0.001). Group I had decreased PTT concentrations compared with the control group (0.18 [0.16-0.20] vs. 0.21 [0.19-0.22] mmol/L; P<0.001), and group II had similar PTT levels to the control group (0.20 [0.17-0.22] mmol/L; P>0.05). In addition, the median TAS and PTT levels for groups I and II were not statistically different (P>0.05). There was a positive correlation between TAS and PTT levels (rho=0.38, P<0.05) in group I. CONCLUSION: In order to balance the oxidative stress, both TAS and PTT which are markers of the antioxidant system are reduced in children with asthma. Montelukast monotherapy can limit oxidative stress and thus restore PTT levels but not TAS levels in asthmatic children.

Effect of montelukast monotherapy on oxidative stress parameters and DNA damage in children with asthma.

BACKGROUND: There is ample knowledge reported in the literature about the role of oxidative stress in asthma pathogenesis. It is also known that the interaction of reactive oxygen species with DNA may result in DNA strand breaks. The aim of this study was to investigate if montelukast monotherapy affects oxidative stress and DNA damage parameters in a population of pediatric asthma patients. METHODS: Group I consisted of 31 newly diagnosed asthmatic patients not taking any medication, and group II consisted of 32 patients who had been treated with montelukast for at least 6 months. Forty healthy control subjects were also enrolled in the study. Plasma total oxidant status (TOS) and total antioxidant status (TAS) were measured to assess oxidative stress. DNA damage was assessed by means of alkaline comet assay. RESULTS: The patients in both group I and group II had statistically significant higher plasma TOS (13.1 ± 4 and 11.1 ± 4.1 µmol H2O2 equivalent/liter, respectively) and low TAS levels (1.4 ± 0.5 and 1.5 ± 0.5 mmol Trolox equivalent/liter, respectively) compared with the control group (TOS: 6.3 ± 3.5 µmol H2O2 equivalent/liter and TAS: 2.7 ± 0.6 mmol Trolox equivalent/liter; p < 0.05). DNA damage was 18.2 ± 1.0 arbitrary units (a.u.) in group I, 16.7 ± 8.2 a.u. in group II and 13.7 ± 3.4 a.u. in the control group. There were statistically significant differences only between group I and the control group (p < 0.05). CONCLUSIONS: According to the findings, montelukast therapy makes only minimal but not statistically significant improvement in all TOS, TAS and DNA damage parameters.