Laura Tenero

Colostrum-derived B and T cells as an extra-lymphoid compartment of effector cell populations in humans

Colostrum contains cellular components that convey immunological protection to offspring. In the present study the main subsets of lymphocytes present in colostrum and in peripheral blood of healthy screened mothers were compared through the evaluation of >15 different flow cytometry markers. Colostrum and peripheral blood samples were collected within 3 days after full-term delivery. Flow cytometry assays and laboratory tests were performed soon after collection. Among B cells, percentages of CD19+CD5+ cells, pertaining to natural immunity system, were significantly higher in colostrum than in peripheral blood (33 vs. 5%, p = 0.047). CD4+ T cells, effector cells (CD45RA+/CD27–) and effector memory cells (CD45RA–/CD27–) were significantly higher in colostrum (p < 0.001) than in peripheral blood, as well as activated CD4+ T cells (HLA–DR+) (36% vs. 6% p = 0.0022) and CD4+ terminally differentiated effector T cells (CD57+) (p < 0.001). With regards to CD8+ T cells, a comparable significant increase in effector (p < 0.02) and effector memory cells (p < 0.001) was also observed. Moreover, an increased surface expression of HLA-DR and CD57 (p < 0.001) on CD8+ T cells in colostrum was detected. Colostrum contains a different distribution of lymphocyte subsets with respect to peripheral blood from mothers, confirming the observation that lymphocytes probably migrate in milk in a selective way. Colostrum T and B lymphocytes appear to be enriched with subsets possessing effector functions or belonging to the innate immune system, what could transfer a prompt line of defence to offspring.

Chronic Urticaria and Celiac Disease: A Case Report

Abstract:   We describe a case of a 9‐year‐old girl who presented chronic urticaria associated with celiac disease. The prevalence of the manifestation of chronic urticaria in celiac disease is unknown but increase in atopic immunologic disorders has been reported in the setting of gluten enteropathy. Relationship between the clinical manifestations is not clear. The present case of subclinical celiac disease diagnosis in an otherwise asymptomatic child with chronic urticaria further reinforces the evidence that differential for celiac disease warrants to be always considered in children with refractory urticaria.

Antioxidant supplementation and exhaled nitric oxide in children with asthma.

BACKGROUND The effect of allergen avoidance on airway inflammation is similar to that observed with treatment with inhaled steroids, whereas inhaled steroids have no effect on oxidative stress-induced inflammation. OBJECTIVE The aim of this study was to retrospectively evaluate the potential effect of an antioxidant dietary supplement on exhaled nitric oxide over a month in pediatric patients on stable antiasthma treatment. METHODS Forty-seven children with moderate-to-severe asthma were retrospectively evaluated. All the patients were sensitive to Dermatophagoides pteronyssinus and Dermatophagoides farinae, and they were receiving the minimum inhaled corticosteroid dosage required to maintain adequate control. Within a few weeks of admission at Misurina Hospital in the Alps, the regular treatment was gradually reduced, then some children who were receiving a daily dose of inhaled corticosteroids, ≤200 mcg of fluticasone propionate, were prescribed a nutraceutical dietary supplement for at least 4 weeks. Lung function and fractional exhaled nitric oxide (FeNO) measurements were recorded at the beginning and after 1 month of the dietary supplementation. RESULTS Baseline lung function and FeNO values did not differ between the two groups of patients. After 4 weeks of nutraceutical supplementation, FeNO values decreased, from 19.00 ppb (interquartile range, 14-31 ppb) to 11.00 ppb (interquartile range, 6-23 ppb) (p = 0.03). No significant reduction was observed in the group that did not receive the supplementation, and no significant difference between groups was observed, both at baseline and after 4 weeks of nutraceutical supplementation. CONCLUSION Supplementation with a nutraceutical of antioxidants and anti-inflammatory compounds, such as curcumin, resveratrol, soy phospholipids, zinc, selenium, and vitamin D, may be associated with reduced airway inflammation, as documented by a fall in FeNO.

Wheezing in preschool children

Abstract Wheezing is a common condition in pediatric practice, it can be defined as a musical sound, high-pitched and continuous, emitting from the chest during breath exhalation. Although almost 50% of children experiences wheeze in the first 6years of life, only 40% of them will report continued wheezing symptoms after childhood. The classification of wheeze in preschool children is more difficult compared to school aged children. It is based on the onset and duration of symptoms and divided children in three categories: transient early wheezing, non-atopic wheezing and atopic wheezing/asthma. History and physical examination, skin prick test, exhaled nitric oxide, lung function test are the parameter to evaluate children with wheezing. The aim of management of wheezing is to finalize the control of symptoms, reduce exacerbations and improve the quality of life. All guidelines underline the complexity in making a diagnosis of asthma under five years and the need to identify phenotypes that may help paediatricians in the therapeutic choices.

Bioimpedance monitoring of airway inflammation in asthmatic allergic children

BACKGROUND Asthma in childhood is characterized by chronic inflammation. Measurement of bioimpedance (BI) is a non-invasive way of detecting airway inflammation. The aim was to compare BI with exhaled nitric oxide (eNO) and lung function evaluations in asthmatic allergic children while not exposed to offending allergens. METHODS 22 asthmatic children allergic to house dust mites have been enrolled while residents at high altitude in an environment free of house dust mites. They were evaluated at T0 after allergen exposure at home, at T1 and at T2 after 1 and 4 months of allergen avoidance, respectively. RESULTS eNO decreased from 32.21 +/- 5.70 ppb at T0 to 21.92 +/- 4.36 ppb at T1, after one month at high altitude (p = 0.038), without a further decrease at T2. Data in electrical activity showed a significant decrease in conductivity of lower airways between T0 (48.53 +/- 3.53 microA) and T1 (42.08 +/- 3.47 microA) (p = 0.023). deltaB parameter (difference between conductivity of lower respiratory tract and average yield) showed significant decrease from T0 (20.75 +/- 2.64 microA), and T1 (12.84 +/- 2.52 microA) (p < 0.01), but no further decrease at T2. No difference in lung function parameters was observed. CONCLUSION Allergen avoidance regimen modifies inflammatory parameters in allergic asthmatics. Evaluation of extracellular bioelectrical conductivity seems to represent a promising non-invasive method to assess airway inflammation.

Sensitivity and Specificity of Soluble Triggering Receptor Expressed on Myeloid Cells-1, Midregional Proatrial Natriuretic Peptide and Midregional Proadrenomedullin for Distinguishing Etiology and to Assess Severity in Community-Acquired Pneumonia.

Study Design This study aimed to evaluate the diagnostic accuracy of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), midregional proatrial natriuretic peptide (MR-proANP) and midregional proadrenomedullin (MR-proADM) to distinguish bacterial from viral community-acquired pneumonia (CAP) and to identify severe cases in children hospitalized for radiologically confirmed CAP. Index test results were compared with those derived from routine diagnostic tests, i.e., white blood cell (WBC) counts, neutrophil percentages, and serum C-reactive protein (CRP) and procalcitonin (PCT) levels. Methods This prospective, multicenter study was carried out in the most important children’s hospitals (n = 11) in Italy and 433 otherwise healthy children hospitalized for radiologically confirmed CAP were enrolled. Among cases for whom etiology could be determined, CAP was ascribed to bacteria in 235 (54.3%) children and to one or more viruses in 111 (25.6%) children. A total of 312 (72.2%) children had severe disease. Results CRP and PCT had the best performances for both bacterial and viral CAP identification. The cut-off values with the highest combined sensitivity and specificity for the identification of bacterial and viral infections using CRP were ≥7.98 mg/L and ≤7.5 mg/L, respectively. When PCT was considered, the cut-off values with the highest combined sensitivity and specificity were ≥0.188 ng/mL for bacterial CAP and ≤0.07 ng/mL for viral CAP. For the identification of severe cases, the best results were obtained with evaluations of PCT and MR-proANP. However, in both cases, the biomarker cut-off with the highest combined sensitivity and specificity (≥0.093 ng/mL for PCT and ≥33.8 pmol/L for proANP) had a relatively good sensitivity (higher than 70%) but a limited specificity (of approximately 55%). Conclusions This study indicates that in children with CAP, sTREM-1, MR-proANP, and MR-proADM blood levels have poor abilities to differentiate bacterial from viral diseases or to identify severe cases, highlighting that PCT maintains the main role at this regard.

Recurrent wheezing in children

Recurrent wheezing have a significant morbidity and its estimated that about one third of school-age children manifest the symptom during the first 5 years of life. Proper identification of children at risk of developing asthma at school age may predict long-term outcomes and improve treatment and preventive approach, but the possibility to identify these children at preschool age remains limited. For many years authors focused their studies to identify early children with recurrent wheezing at risk to develop asthma at school age. Different phenotypes have been proposed for a more precise characterization and a personalized plan of treatment. The main criticism concerns the inability to define stable phenotypes with the risk of overestimating or underestimating the characteristics of symptoms in these children. The aim of this review is to report the recent developments on the diagnosis and treatment of recurrent paediatric wheezing.

Effect of montelukast on markers of airway remodeling in children with asthma.

BACKGROUND Asthma is a pathology characterized by chronic inflammation and remodeling of the airways. OBJECTIVES To evaluate the effect of montelukast treatment on markers of airway inflammation and remodeling in children with mild asthma and to evaluate if the administration of montelukast to children with mild asthma could inhibit the release of matrix metallopeptidase 9, matrix metallopeptidase 12, tissue inhibitor of metalloproteinase 1, transforming growth factor beta 1, C-peptide terminal procollagen type (PICP), and eosinophils count, which are markers of inflammation and remodeling in induced sputum. METHODS Thirty children with mild asthma were recruited. They were randomized into two groups: group A received montelukast and as needed beta-2-agonist for 8 weeks (T0-T1), whereas group B received placebo and as needed beta-2-agonist for 8 weeks. After 2 weeks of washout (T1-T2), they were reallocated for treatment according a crossover design (T2-T3). Tests for lung function, oral exhaled nitric oxide, and hypertonic saline solution-induced sputum level were performed at T0-T1-T2-T3. RESULTS In the placebo group, the PICP mean (standard deviation [SD]) value at baseline was 2279.42 ± 2530.77 pg/mL and 1916.00 ± 2178.75 pg/mL after treatment. Patients treated with montelukast, in contrast, showed a baseline mean (SD) value of 2439.29 ± 2834.51 pg/mL and 1406.72 ± 1508.65 pg/mL after treatment. The difference between the mean pre- and posttreatment decrease of PICP in the two groups was statistically significant (delta -690.21 pg/mL [95% confidence interval, -1220.83 to -159.5844 pg/mL]; p = 0.011). The mean (SD) percentage of the eosinophil count in the placebo group was 3.11 ± 4.03% at baseline and 4.86 ± 5.83% after treatment. Patients treated with montelukast, in contrast, showed a percentage mean (SD) value at baseline of 4.51 ± 5.48% and, after treatment, of 3.06 ± 3.29%. The difference between the mean pre- and posttreatment decrease of the percentage eosinophil count in the two groups was statistically significant (delta -2.76% [95% confidence interval, -4.65 to -0.87%]; p = 0.004). CONCLUSION This study investigated in vivo effects of montelukast on remodeling markers. The reduction of PICP levels and eosinophil count supported the hypothesis that montelukast can modulate collagen deposition in airways and reduce eosinophilic airway inflammation. Clinical Trials database clinicaltrials.gov (NCT00875082).

Measuring Airway Inflammation in Asthmatic Children

Asthma is the most common chronic respiratory disease in children characterized by airways inflammation, bronchial hyperresponsiveness, recurrent reversible airways obstruction, and respiratory symptoms. The diagnosis of the disease is based on clinical history, airways obstruction at spirometry, and bronchial reversibility. Asthma treatment is aimed to disease control, through the use of controller treatment and monitoring lung function. However, lung function and symptoms not always reflect the underlying airways inflammation and response to the therapy. Objective parameters of asthma inflammation could be important for the clinician in the management of patients with asthma. In the last years, some studies were focused on biomarkers to identify phenotype, inflammation, and pathobiological pathways to help the clinician in the diagnosis and in personalizing the management. Accordingly, clinically feasible tests are represented by the collection of exhaled breath condensate (EBC) and measurement of exhaled nitric oxide (FeNO). Other—methods such as the evaluation of volatile organic compound (VOCs), that reflect airways inflammation and treatment efficacy, are currently used for research purposes For some of these methods, The lack of standardization in pre-collection, collection, post-collection of samples, and interpretation of the results may a problem in clinical practice. Improved these limitations, several biomarkers will be useful to distinguish patients with a different disease condition to personalize the treatment.

Vitamin D supplementation in children with asthma

Worldwide, asthma is a chronic inflammatory respiratory disease affecting over 300 million people, and some of these patients remain inadequately controlled by usual therapies and experience exacerbations. In cross-sectional studies in asthmatic children, vitamin D deficiency has been linked to increased severity and exacerbations of symptoms (1, 2) and reduced asthma control (3, 4). However, it is difficult to find a temporal causal relationship in cross-sectional observations. Biologically, as an adjunct therapy, vitamin D should improve disease control in severe asthma as it enhances glucocorticoid responsiveness; skews immune cells toward a regulatory phenotype; reduces the incidence of infections; mitigates airway smooth muscle hyperplasia, eosinophilia, and airway remodeling; and may lower the levels of IgE (5, 6). At demonstration of the critical biologic role that vitamin D plays in human immunity and physiology, a systematic review and meta-analysis of five clinical trials, reporting asthmarelated respiratory outcomes following vitamin D administration at a dose ranging from 500 to 2000 IU/day, found a 59% reduction in the risk of asthma exacerbation (RR 0.41) with supplementation (7). Asthma exacerbations are mainly associated with viral respiratory tract infections, and there is evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more susceptible to severe viral respiratory infections of the lower airway and thus to increased risk of exacerbation (8). At this regard, observational studies have documented an association between low vitamin D status and increased risk of acute viral respiratory infections in agreement with the immunomodulatory effect of vitamin D (9). However, results from recent trials, assessing the effect of vitamin D supplementation on the prevention of childhood acute respiratory infections, have been inconsistent, and a recent systematic review of seven randomized controlled trials on vitamin D supplementation, for the prevention of childhood acute respiratory infections in children, found no significant effect on the reduction of childhood acute respiratory infections (RR 0.79) but, in subjects previously diagnosed with asthma, vitamin D supplementation resulted in a 74% reduction in the risk of asthma exacerbation (RR 0.26) (10). At the same time, a systematic review and meta-analysis of eight randomized controlled trials provided some low-quality evidence to support vitamin D supplementation for the reduction of asthma exacerbations (11), a result which is strikingly different from the conclusion of other groups who analyzed in part the same studies. So what is going wrong with vitamin D supplementation in asthma if we have conflicting results even from systematic reviews and meta-analysis? In this issue of the Journal, Kerley et al. (12) evaluated the effect of vitamin D supplementation in children with not controlled asthma and found no effect of supplementation on subjective asthma control and lung function, but a significant decrease in school days missed due to asthma which seems clearly a contradicting and difficult to explain finding. If we observe conflicting results within the same study, we should not be surprised to see discordant results in studies performed with different designs with different patients and with different outcomes’ evaluation. Some cautions are needed interpreting this study results. In the Kerley et al. study, only 39 patients completed the trial and they were divided into four groups (VD deficient + supplementation, VD sufficient + supplementation, VD deficient + placebo, and VD sufficient + placebo) resulting in a small number of subjects in each group. The authors found that vitamin D supplementation was associated with decrease in school days missed and alkaline phosphatase, but no beneficial effects are founded regarding asthma control (c-ACT, mPAQLQ), IgE, ECP, and hsCRP. However, ninety percent of the patients were allergic and total IgE level was lower in the vitamin D-supplemented group than in the placebo (not significant only because the limited number of patients), and thus, there was more room for increasing if exposed to relevant allergens (no information is available on allergen avoidance strategies eventually adopted). Also, baseline eosinophils and EP levels were half in the supplemented group compared to the placebo. If the negative outcome of vitamin D on several parameters is attributable to a biologic effect of vitamin D itself, this