Katarzyna Smejda

Comparison of the long-term efficacy of 3- and 5-year house dust mite allergen immunotherapy

BACKGROUND The recommended duration of specific immunotherapy (SIT) treatment relies on empiric data and is not well documented. OBJECTIVE To detect possible differences in the long-term effectiveness between 3 and 5 years of house dust mite (HDM) SIT in asthmatic children. METHODS We performed a 3-year natural history study of 90 asthmatic children who were sensitive only to HDM. Three groups were recruited: 30 who had completed 3 years of HDM SIT (SIT3), 30 who had completed 5 years of HDM SIT (SIT5), and 30 who had an indication for HDM SIT but whose parents refused HDM SIT. Patients attended an enrollment visit in 2007, after SIT discontinuation, and 3 annual follow-up visits at the clinic. The long-term effectiveness of HDM SIT was primarily assessed via analysis of the reduction in required inhaled corticosteroid dose, forced expiratory volume in 1 second, and asthma remission. RESULTS A total of 84 children completed the study. Both SIT durations produced excellent results; asthma remission in both SIT3 (50%) and SIT5 (54%) groups was significantly higher when compared with control (3.3%). The minimal controlling inhaled corticosteroid dose reduction in SIT5 group (median, 75%) was significantly higher compared with the SIT3 group (median, 50%) after immunotherapy discontinuation; after 3 years without SIT, no differences were found between the SIT5 and SIT3 groups (median, 100% and 94%, respectively). We observed a slightly higher increase in forced expiratory volume in 1 second in the SIT5 group compared with the SIT3 group. CONCLUSION Three years of SIT is an adequate duration for the treatment of childhood asthma associated with HDM allergy because 2 further years of SIT added no clinical benefit.

Risk factors for the development of atopic dermatitis and early wheeze.

A global assessment of allergic diseases and prenatal and postnatal exposure to various environmental risk factors is needed to enable early prevention of allergic diseases. This study was designed to evaluate an inner-city urban birth cohort to identify early environmental factors associated with atopic dermatitis and food allergy, as well as the incidence of wheezing during the 1st year of life. We evaluated 501 children from the Polish Mother and Child Cohort Study (2007-2011). The childrens health, socioeconomic status, and housing conditions were assessed using a questionnaire. Exposure to tobacco was assessed based on questionnaire data and cotinine measurements. Multiple regression analysis showed that parental atopy, higher paternal education, and more frequent house cleaning significantly predicted atopic dermatitis in the 1st year of life; odds ratio (OR) for the variables was 2.7 (95% CI, 1.3-1.57), 2.8 (95% CI, 1.5-5.0), and 1.8 (95% CI, 1.1-2.9), respectively. Keeping a pet at home during pregnancy increased the risk of food allergy (OR, 1.48; 95% CI, 1.02-2.16). Longer breast-feeding decreased the risk of both food allergy (OR, 0.88; 95% CI, 0.82-0.95) and atopic dermatitis (OR, 0.9; 95% CI, 0.8-0.95) in the 1st year of life. Positive association between maternal exposure to increased concentrations of particulate matter 10 and atopic dermatitis in univariate analyses was found. Atopic dermatitis/food allergy and wheezing/inhaled corticosteroid use had distinct risk factors. The risk factor profile of atopic dermatitis/food allergy in early childhood that is defined in this study support the following recommendations: (i) longer breast-feeding, (ii) avoid pets during gestation, (iii) avoid too frequent house cleaning, and (iv) living in an area with decreased traffic density. This study was a part of the clinical trial NCT01861548 registered in www.clinicaltrials.gov.

Decreased markers of atopy in children with presumed early exposure to allergens, unhygienic conditions, and infections.

BACKGROUND Several risk factors for the development of asthma and atopic disease in children have been described. Furthermore, there is consistent evidence that the prevalence of atopy increases with higher socioeconomic status. The knowledge about risk factors and preventive factors for atopy needs to be improved. OBJECTIVE To compare 2 child populations (foster care and reference children) with different risk and protective factors for the development of atopy. METHODS The study group consisted of 415 children, living in all 10 community foster homes in Lodz, a large industrial city in Poland. The study was performed from April 2, 2004, to April 30, 2006. The reference group consisted of 500 children, living with their parents at home, recruited from primary care centers. The primary outcome measures were skin prick test results and specific IgE in serum. Secondary outcomes included symptoms of allergic diseases and family history, including life conditions in early childhood. RESULTS The full analysis set included 408 study children and 402 reference children. Significant differences were observed in the prevalence of atopy between the study and reference groups (11.3% vs 25.9%). We observed more positive skin prick test results in children from the reference group than in study children. To explain this phenomenon, we selected 16 variables that differ in both groups in early life and relate these to atopy. We found that the more cumulative features characteristic of the foster home population (poor living conditions), the lower the risk of atopy. CONCLUSION Extremely unfavorable environmental circumstances, which are characteristic of the foster home population during early childhood, might prevent from atopy.

Correlation of vitamin D with Foxp3 induction and steroid-sparing effect of immunotherapy in asthmatic children

BACKGROUND Vitamin D promotes different toleragenic processes of the immune system; however, its role in allergen specific immunotherapy (SIT) is still undefined. OBJECTIVE To determine whether the immunologic and clinical effectiveness of allergen SIT depends on the serum level of 25-hydroxyvitamin D (25[OH]D) and its changes during SIT in asthmatic children. METHODS This is a retrospective secondary analysis of pooled data obtained from our 2 recently published prospective, randomized, placebo-controlled trials on asthmatic children undergoing allergen immunotherapy. Both trials, which assessed the effect of different pharmacologic modulation of SIT effectiveness, were conducted according to the same study protocol. Children from the placebo arms in these trials were treated with immunotherapy only and were included in the present analysis. The study population consisted of 36 children. Data concerning clinical (asthma symptoms score and percent change in minimal daily inhaled corticosteroid dose) and immunologic parameters (including serum level of 25[OH]D) were analyzed in all patients. RESULTS Patients with a higher serum level of 25(OH)D experienced more significant reduction in asthma symptoms score and steroid-sparing effect of SIT and had higher transforming growth factor â production and higher Foxp3 induction during SIT. Steroid-sparing effect correlated with 25(OH)D serum level at baseline, after 3 months of SIT, and with the changes in serum level of 25(OH)D during the build-up phase of SIT. Better response to SIT was observed among children with an 25(OH)D serum level higher than 30 ng/mL. CONCLUSION The efficacy of allergen SIT correlates with 25(OH)D serum concentration. It seems that a serum level of 25(OH)D higher than 30 ng/mL facilitates the optimal effect of allergen immunotherapy.

School environmental factors are predictive for exercise-induced symptoms in children.

BACKGROUND Environmental factors in schools have a significant effect on the exercise-induced bronchoconstriction and symptoms in a general paediatric population. OBJECTIVES To determine the environmental factors such as atmospheric conditions and the presence of allergens in gymnasiums, that could be predictive of the presence of exercise-induced symptoms/bronchospasm in children during physical education (PE). METHODS 1370 schoolchildren were enrolled. Children attended 45 min PE lesson with similar exercise intensity. Pulmonary function tests were performed before and after PE lesson. Air temperature, humidity and pressure, samples of dust for allergen exposure in the gymnasiums were taken. Children who reported symptoms induced during PE lesson were invited to the clinic for ETC (exercise treadmill challenge) and atopy measurement. RESULTS 1033 participants were included into the analysis. Sixty seven(6.5%) children reported dyspnea/cough, and in 94(9.4%) children bronchoconstriction induced during PE lesson was documented. There is a correlation between the results of the ETC and bronchoconstriction after PE (OR: 2.55; 95%CI: 1.07-6.05; p = 0.034). Exposure to higher air pressure and higher humidity independently increase the risk of clinical symptoms reported during or after PE lesson. Exposure to cats allergens increase the risk of bronchoconstriction (independently from atopy status). We showed significant interaction between presence of asthma and current ICS therapy as a risk of physical inactivity at school (OR: 4; 95%CI: 1.3-12; p < 0.001). CONCLUSION This study showed an effect of cat allergen and environmental factors (humidity, air pressure) on the appearance of exercise related cough/bronchoconstriction during activity class in a natural environment at school in a large urban population of schoolchildren.

Exhaled nitric oxide correlates with IL-2, MCP-1, PDGF-BB and TIMP-2 in exhaled breath condensate of children with refractory asthma

Introduction There is evidence that parameters obtained from exhaled breath condensate (EBC) reflect changes in the level of the airway lining fluid. The telation between exhaled nitric oxide (NO) and EBC inflammatory markers has not been analyzed in the context of the inflammatory profile in the airways in asthmatic children. Aim To show the cytokine profile in EBC of children with severe/refractory asthma as well as correlations between the fractional exhaled NO (FeNO) level and cytokine concentrations. Material and methods The study population consisted of eight children aged 8 to 17 years with IgE-dependent, severe/refractory asthma with a duration of at least 2 years. This was an observational study, the first consecutive eight patients with asthma symptoms on the day of the study visit, when EBC samples were obtained. Results The inter-subject variability of study cytokines ranged from 8.6 to 54.6. Cytokines with coefficient of variation < 20% were: interferon-γ, interleukins IL-2, IL-7, IL-15, IL-16, monokine induced by interferon γ (MIG) and tumor necrosis factor α. We showed a significant positive correlation between the FeNO level and crucial mediators in asthma development and progression (IL-2, MCP-1), and potent markers of airway remodeling (PDGFBB, TIMP-2). All correlations between two different variables were controlled for the effects of age, forced expiratory volume in 1 s and number of asthma exacerbations during last 12 months. Conclusions The profiling of cytokine expression in EBC can be reproducibly performed in children with severe/refractory asthma. When treating asthma in children, the FeNO level should be monitored as a prevention strategy of the progression of the remodeling leading to refractory/severe asthma. Exhaled breath condensate may be a useful tool to phenotype asthma via a non-invasive approach.

Predictive value of fractional nitric oxide in asthma diagnosis-subgroup analyses

BACKGROUND There are no studies investigating the benefit of using FeNO measurements in correlation with sensitization to perennial and seasonal allergens in children with asthma. OBJECTIVE To define the group of children with respiratory symptoms in whose FeNO measurement has predictive value for asthma. We assessed the effect of age, allergy profile, atopy, lung function and the presence of allergic rhinitis on interpretation of FeNO levels for clinical applications. METHODS It was a retrospective, cross-sectional study. We evaluated data from medical documentation of 1767 children with symptoms of allergic diseases such as asthma and/or allergic rhinitis. We included in the analyses subjects who had the following tests done during diagnostic procedures (single measurement): FeNO, spirometry, specific IgE results. All subjects had undergone a minimum 3-years prospective clinical observation after the first FeNO measurement until the later assignment (or not) of an asthma/allergic rhinitis diagnosis. RESULTS We included 1767 children into the analysis; asthma diagnosis was confirm in 1054 (59.6%) children. We showed that only atopy (OR: 1.9; 95%CI: 1.5-2.4) and presence of allergic rhinitis (OR: 1.6; 95%CI: 1.4-1.9) were independently associated with increased FeNO level. Only among patients with atopy and allergic rhinitis FeNO level (above 23 ppb) was associated with asthma diagnosis. Sensitivity, specificity, positive predictive value and negative predictive value of FeNO >23 ppb for asthma diagnosis were as follows: 0.9(95%CI: 0.68-0.98), 0.52(95%CI: 0.42-0.61), 0.25(95%CI: 0.16-0.37), 0.97(95%CI: 0.88-0.99). CONCLUSION We showed that in children with atopy and with allergic rhinitis a negative predictive value for asthma diagnosis was very high with the optimal cut-off point of FeNO 23 ppb. Therefore we showed the utility of FeNO measurements to exclude asthma in the subgroup of patients with atopy and allergic rhinitis.

Transforming growth factor-beta1 and IL-13 response to allergen predict steroid needs in asthmatic children.

BACKGROUND The remission of asthma, which is induced during specific immunotherapy (SIT) or appears spontaneously in children is not completely understood and predictors of this phenomenon are still undefined. OBJECTIVE To assess CD4(+)CD25(+)Foxp3(+) Treg cells and cytokine/proliferation response to allergen-specific stimulation of PBMC as predictors of steroid sparing effect of SIT and steroid dosage needs without SIT during 5 years of follow-up in asthmatic children. METHODS This is a 5-year long study of 32 asthmatic children, sensitive only to house dust mite (HDM). Eighteen children who had completed 5 years of HDM SIT - SIT group, and 14 children without SIT as a control group were studied. All patients had baseline clinical/immunological assessment; before and after observation the minimum effective ICS dose was defined and lung function was measured. RESULTS In children from SIT group minimum effective ICS dose was reduced more than in children from control group (median reduction 65% vs. 0%; p<0.001). Among patients in control group asthma severity was reduced after 5 years of observation in those who had at baseline higher TGF-beta1 and lower IL-13 answer to allergen stimulation of PBMC. Better response to 5 years immunotherapy was observed in those who had at baseline higher TGF-beta1 and lower proliferation answer to allergen stimulation of PBMC. CONCLUSION Similar processes may decide on both, SIT-induced and spontaneously appearing, reduction in asthma severity. Immunotherapy was much more effective than pharmacotherapy in our study. IL-13 overproduction may impede reduction of disease severity in asthmatic children independently from TGF-beta pathway.

Predictors of deterioration of lung function in Polish children with cystic fibrosis

Introduction Severity of lung disease varies in patients with the same CFTR genotype. It suggests that other factors affect the severity of cystic fibrosis (CF). The aim of the study was to identify risk factors that determine lung function decline in Polish cystic fibrosis children. Material and methods The follow-up time was no less than 5 years of respiratory status observation based on the forced expiratory volume in 1 s value (FEV1). The socio-economic data, perinatal interview, presence of meconium ileus (MI), time of CF diagnosis, initiation of tobramycin inhalation solution (TIS), pancreatic function, sensitization to Aspergillus fumigatus, presence of impaired glucose tolerance (IGT) or diabetes mellitus, chronic bacterial colonization and number of exacerbations and hospitalizations were assessed. Results The mean age of 61 included children was 13.3 ±7.6 years. Delta F508 homozygosity was detected in 45.9%, 44.3% were delta F508 heterozygous, and 9.8% had other genotypes. FEV1 decline was observed among 20% of patients; the rest of the patients presented stable values of FEV1 during at least 5 years of observation. The most significant predictors related to the decline of FEV1 were presentation of MI (p = 0.0344), IGT (p = 0.0227), number of exacerbations (p = 0.0288), and early Pseudomonas aeruginosa (PA) chronic colonization (p = 0.0165) followed by late TIS initiation after the first detection of PA (p=0.0071). Neither time of diagnosis nor type of CFTR mutation was statistically significant as a predictor of lung deterioration. Conclusions The presence of MI, IGT, chronic PA colonization, and number of exacerbations are risk factors for lung function deterioration.

Children with severe asthma can start allergen immunotherapy after controlling asthma with omalizumab: a case series from Poland.

Anti-IgE treatment reduces exacerbations, symptoms and, in some patients, the dose of inhaled glucocorticoids needed to maintain asthma control [1–3]. Omalizumab, a monoclonal anti-immunoglobulin E antibody, has been successfully used as a supplementary therapy to improve asthma control in children aged ≥ 6 years with severe persistent allergic asthma who experience frequent symptoms and have asthma exacerbation despite the use of high-dose inhaled corticosteroids and long-acting β2-agonists (LABA) [4–6]. Omalizumab might also be a treatment option in patients who fail to achieve the intended maintenance dose of specific immunotherapy (SIT) [7, 8]. We conducted an observational study of the clinical experience of maintenance treatment with omalizumab (Xolair, Novartis, Switzerland) in 17 Polish children and adolescents with severe asthma who did not tolerate the allergen immunotherapy prior to the initiation of omalizumab. This was a real-life, open, uncontrolled, observational study. We identified 17 patients aged 7–18 years (not randomly selected) with severe uncontrolled allergic asthma who fulfilled the criteria for anti-IgE therapy and were treated with omalizumab. All patients had multiple allergies; the most clinically important allergens were house dust mite (n = 15) and molds (n = 2). Five patients had previously qualified for specific immunotherapy (data from medical history), but the maintenance dose could not be reached because of recurrent asthma exacerbations, and SIT was discontinued. Written consent was obtained from all participants and their parents. Omalizumab was administered according to a dosage table that considers the patient’ s body weight and total IgE levels determined up to 4 weeks before the first injection of omalizumab. At each visit (every 2–4 weeks), the physicians overall assessments of treatment, the number of exacerbations and hospitalizations, the use of inhaled corticosteroids controlling asthma and lung function were evaluated. An asthma exacerbation was defined by the presence of at least one of the following: unscheduled patient visit, need for systemic corticosteroids, hospitalization. The study was approved by the Ethics Committee of the Medical University of Lodz, Poland. To assess changes in study endpoints, repeated measures analysis of variance was used for parametrically (ANOVA) and non-parametrically (Friedman test) distributed variables. Categorical variables were compared with Fishers exact test. To assess the independent effect of SIT on inhaled corticosteroids (ICS) dose reduction or the number of exacerbations, logistic regression analysis was used. All statistical analyses were performed using StatSoft Statistica for Windows, release 8.0 (StatSoft, Inc., Tulsa, USA). Value of p < 0.05 was used as a definition of statistical significance. All 17 patients who received omalizumab for at least 52 weeks were included in the analysis. Patient characteristics are presented in Table I. All patients tolerated omalizumab well. The median number of asthma exacerbations in the 12 months before Xolair initiation was 3 (quartile range: 2–4.5). After 12 months of treatment, the number of asthma exacerbations significantly decreased (Figure 1 A). A similar trend was observed in the number of hospitalizations due to asthma exacerbations (Figure 1 B). After 12 months of therapy, the use of ICS had decreased significantly; only 4 patients were treated with the same dose of ICS after 6 months of omalizumab. Relative change from baseline in forced expiratory volume in 1 s (FEV1) (Figure 1 C) and daily ICS dose (Figure 1 D) are shown in figures. After 12 months of therapy, all patients were treated with lower ICS doses; the median ICS dose reduction was –50% (quartile range: from –50% to –60%), and the lowest reduction was 20%. Additionally, we observed a significant decrease in the percentage of patients treated with add-on LABA and/or leukotriene receptor antagonist (LTRA) therapy (Figure 1 E). In 5 patients, LABA or LTRA therapy was discontinued after 12 months. During the study, SIT was started in 12 (70.6%) patients – in 4 (33%) patients after 3 months, in 5 (42%) patients after 6 months, and in 3 (25%) patients after 9 months of omalizumab treatment – and was successfully continued according to the SIT scheme. In 5 children who had not tolerated immunotherapy before omalizumab treatment, SIT was introduced after 6 months of treatment and has been successfully continued. Logistic regression analysis did not show any independent effect of SIT on the ICS dose reduction or the number of exacerbations; this subgroup analysis did not have sufficient power. Figure 1 Number of asthma exacerbations (A) and hospitalizations due to asthma exacerbations (B) in each participant 12 months before and 12 months after treatment with omalizumab. Relative change from baseline in FEV1 (C) and daily ICS dose (D) after 6 and 12 ... Table I Baseline characteristics of patients before omalizumab introduction At present, this study represents non-randomly selected clinical cases treated with omalizumab in Poland. The treatment with omalizumab was clinically effective in all patients: the frequency of exacerbations and the number of hospitalizations were reduced, and there was a significant decrease in steroid use. This effect of omalizumab allowed the initiation of SIT in children with severe asthma. Only 6 months of therapy led to a significant steroid sparing effect by omalizumab. In most of our patients, omalizumab was combined with immunotherapy; we therefore may suspect that the reduction in ICS use will persist after the discontinuation of anti-IgE therapy. We can compare our results with the landmark study by Kopp et al. [9], in which 16 patients of similar age to those described herein were randomized to receive omalizumab plus placebo or omalizumab plus SIT. The authors reported that omalizumab plus SIT significantly reduced the symptom load in a manner that was clinically relevant when compared with SIT alone. The results of Kopps and our own study may provide new perspectives for the application of SIT in patients with moderate to severe asthma. The clinical implication of the above findings is that children with moderate to severe allergic asthma who are pre-treated with omalizumab might also benefit in the future from SIT as a causal treatment option. Moreover, the administration of omalizumab prior to SIT reduces the risk of SIT-related systemic reactions and enables more patients to achieve the target SIT maintenance dose [1, 9–12]. Our study group primarily included children younger than 12 years old with relatively short-lasting asthma, which may explain the spectacular modifying effect of omalizumab combined with SIT in most of the included patients. This real-life study showed that pretreatment with omalizumab should be specifically considered in children with severe allergic asthma to prevent asthma deterioration/exacerbation. This approach allows for the safe and effective initiation of SIT and changes the natural course of severe allergic asthma in children.