Marek Kulus

Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma.

BACKGROUND Many children with asthma continue to experience symptoms despite available therapies. OBJECTIVE This study evaluated the efficacy and safety of omalizumab, a humanized anti-IgE mAb, in children with moderate-to-severe persistent allergic (IgE-mediated) asthma that was inadequately controlled despite treatment with medium-dose or high-dose inhaled corticosteroids (ICSs) with or without other controller medications. METHODS A randomized, double-blind, placebo-controlled trial enrolled children age 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs. Patients were randomized 2:1 to receive omalizumab (75-375 mg sc, q2 or q4 wk) or placebo over a period of 52 weeks (24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase). RESULTS A total of 627 patients (omalizumab, n = 421; placebo, n = 206) were randomized, with efficacy analyzed in 576 (omalizumab, n = 384; placebo, n = 192). Over the 24-week fixed-steroid phase, omalizumab reduced the rate of clinically significant asthma exacerbations (worsening symptoms requiring doubling of baseline ICS dose and/or systemic steroids) by 31% versus placebo (0.45 vs 0.64; rate ratio, 0.69; P = .007). Over a period of 52 weeks, the exacerbation rate was reduced by 43% versus placebo (P < .001). Omalizumab significantly reduced severe exacerbations. Over a period of 52 weeks, omalizumab had an acceptable safety profile, with no difference in overall incidence of adverse events compared with placebo. CONCLUSION Add-on omalizumab is effective and well tolerated as maintenance therapy in children (6 to <12 years) with moderate-to-severe persistent allergic (IgE-mediated) asthma whose symptoms are inadequately controlled despite medium to high doses of ICSs.

Frequency and Activation of CD4+CD25high FoxP3+ Regulatory T Cells in Peripheral Blood from Children with Atopic Allergy

Background: Atopic allergy is among the immune tolerance-related disorders resulting from a failure of the regulatory network. Regulatory T cells (Tregs) play a leading role in the development of homeostasis in the immune system. The aim of this study was to determine the role of Tregs in the pathogenesis of atopic diseases in children by exploring the relationship between Treg frequency, activation markers and the clinical manifestations of the disease. Methods: Twenty allergic and 50 healthy children were enrolled to the study. Peripheral blood mononuclear cells were stained with monoclonal antibodies (anti-CD25-CD4-CD127-FoxP3-CD69-CD71) and evaluated using flow cytometry. Tregs were identified as CD4+CD25+/highFoxP3+CD127- T cells. Results: The percentage of Tregs in allergic patients (2.3%) was significantly decreased in comparison to healthy controls (4.6%, p = 0.003). The frequency of Tregs in patients with symptoms of atopic dermatitis and/or food allergy (1.7%) was significantly lower than in patients without these symptoms (2.9%, p = 0.04). A significant correlation between the percentage of Tregs and the sIgE serum concentration was observed (p = 0.037). Relative fluorescence intensities of FoxP3 expression in allergic patients were higher than in healthy controls (p = 0.00004). The frequency of CD4+CD25highCD127-CD71+ cells did not differ between the groups. Conclusions: Tregs display substantial deficiencies in atopic children, especially in children with multiorgan involvement, compared to patients with single organ manifestations. Additionally, there is an association between Tregs and the sIgE serum concentration. Better identification and characterization of Tregs in allergy is needed as they limit responses to foreign antigens, thereby minimizing T cell-mediated immunopathology in allergic diseases.

Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma

Abstract Background: Many children with severe persistent allergic (IgE-mediated) asthma remain inadequately controlled despite treatment with high-dose inhaled corticosteroids (ICS) plus a long-acting β2-agonist (LABA). Research and design methods: This pre-specified analysis of a randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of omalizumab in children (6–<12 years) with perennial allergen sensitivity, and history of asthma exacerbations and symptoms despite treatment with ICS (fluticasone ≥500 µg · day−1 or equivalent) plus a LABA. Patients received omalizumab (75–375 mg once or twice a month by subcutaneous injection, as determined from dosing tables) or placebo over 52 weeks (24-week fixed-steroid then 28-week adjustable-steroid phases). Results: Out of 246 randomized patients (omalizumab, n = 166; placebo, n = 80), efficacy was analysed in 235 (omalizumab, n = 159; placebo, n = 76). Over the 24-week fixed-steroid phase, omalizumab reduced the rate of clinically significant asthma exacerbations (worsening symptoms requiring doubling of baseline ICS dose and/or systemic steroids) by 34% versus placebo (0.42 vs 0.63, rate ratio 0.662; P = 0.047). Over 52 weeks, the exacerbation rate was reduced by 50% (P < 0.001). Omalizumab had an acceptable safety profile, with no statistically significant (P < 0.05) differences in adverse events observed between omalizumab and placebo. Conclusion: Add-on omalizumab is well-tolerated and reduces exacerbations in children (6–<12 years) with severe persistent allergic asthma, inadequately controlled despite high-dose ICS plus a LABA. It should be noted that the sample size was not based on providing statistical power in the severe subgroup, and no corrections were made for multiple comparisons; however, outcomes consistently favoured omalizumab. Trial registration: ClinicalTrials.gov identifier: NCT00079937.

Environmental tobacco smoke exposure and risk of allergic sensitisation in children: a systematic review and meta-analysis

Background Environmental tobacco smoke (ETS) exposure in children is linked with the development of allergic asthma. However, its influence on allergic sensitisation in children has not been conclusively determined. Objective To systematically review existing evidence of ETS exposures impact on markers of allergic sensitisation in children. Methods CENTRAL, MEDLINE and EMBASE databases were searched. Included studies assessed following markers of atopic sensitisation: total immunoglobulin E (tIgE) concentrations, at least one specific IgE (sIgE+), and positive skin-prick tests (SPTs+) in ETS-exposed and non-exposed children. Results 8 studies on the influence of ETS on tIgE concentration (2603 patients), 6 studies on ETS and sIgE+ (9230 participants) and 14 papers on ETS and SPT (14 150 patients) met our inclusion criteria. ETS was shown to raise tIgE concentrations by 27.7 IU/mL (95% CI 7.8 to 47.7; I2=58%; results based on 3 studies) and to increase the risk of atopic sensitisation, as assessed by sIgE+ (OR=1.12, 95%CI 1.00 to 1.25; I2=54%; results based on 4 studies) and SPT+ (OR=1.15; 95% CI 1.04 to 1.28; I2=0%; results based on 10 studies). In a subgroup analysis, this effect was most pronounced in children <7 years (preschoolers) by OR=1.20; (95% CI 1.05 to 1.38) and OR=1.30 (95% CI 1.05 to 1.61), (for sIgE+ and SPT+, respectively). Conclusions Current analysis supports an association between ETS exposure in early childhood and the increased risk of allergic sensitisation. Subgroup meta-analyses demonstrate that younger children suffer the most from detrimental immunomodulating effects of ETS exposure. This study underscores ETS as an important but avoidable risk factor for the development of allergic disease in children.

Lung ultrasound in the diagnosis and monitoring of community acquired pneumonia in children.

Lung ultrasound (LUS) is as an easily accessible, radiation-free imaging technique that might be used as a diagnostic tool in community-acquired pneumonia (CAP). The aim of the study was to evaluate the usefulness and accuracy of LUS in the diagnosis and monitoring of childhood CAP. One hundred six consecutive children aged between 1 and 213 (median 52.5) months referred to the hospital with suspicion of CAP were enrolled. All patients underwent LUS on the day of admission, followed by chest radiograph (CXR). Lung ultrasound was also performed in 25 children between 5th-7th and 31 children between 10th-14th day after admission. Radiographic signs of pneumonia were demonstrated in 76 children, while lung ultrasound revealed pulmonary abnormalities consistent with pneumonia in 71 children. LUS gave false negative results in 5 patients with parahilar pulmonary infiltrates demonstrated by CXR. Almost perfect overall agreement between LUS and CXR was found in terms of pneumonia diagnosis (Cohen kappa coefficient of 0.89). The diagnostic performance of LUS in demonstration of lung involvement was as follows: sensitivity of 93.4%, specificity of 100%, positive predictive value of 100%, negative predictive value of 85.7% and accuracy of 95.3%. Our study showed that LUS is a sensitive and highly specific diagnostic method in children with CAP. Therefore, LUS may be considered as the first imaging test in children with suspicion of CAP. A diagnostic algorithm of CAP which includes LUS should be validated in prospective studies. Lung ultrasound can also be used to follow-up resolution of pneumonic lesions.

Local treatment of empyema in children: a systematic review of randomized controlled trials

The aim of the study is to systematically evaluate data from randomized controlled trials (RCTs) on the efficacy of using intrapleural fibrinolytic agents in the treatment of complicated parapneumonic effusions or empyema in children. The Cochrane Library, MEDLINE and EMBASE databases were searched in July 2009. Four RCTs, involving 194 children, were included. In two RCTs, intrapleural fibrinolytic treatment was compared with normal saline. One of these RCTs showed a significantly reduced hospital stay in those treated with urokinase compared with those treated with normal saline. Otherwise, no fibrinolytic agent had an effect on any other outcome. Two RCTs that compared fibrinolytic treatment with video‐assisted thoracoscopic surgery (VATS) revealed no benefit of VATS.

Prolonged Treatment with Inhaled Corticosteroids does not Normalize High Activity of Matrix Metalloproteinase-9 in Exhaled Breath Condensates of Children with Asthma.

The airway remodeling in asthma is associated with increased amount of matrix metalloproteinase (MMP)-9. High levels of MMP-9 were found in mucosal biopsies, sputum and in exhaled breath condensates (EBC) of asthma patients. However, there are no data concerning real in vivo activity. Inhaled corticosteroids are effective in asthma control, but it is unclear, whether they only attenuate inflammation, or also protect against progressive remodeling of respiratory tract. Therefore, the aim of the study was to assess the amount and activity of MMP-9 in context of pro-inflammatory cytokines (IL-6, IL-8 and tumor necrosis factor, TNF), measured in EBC of asthma-suffering children, treated with inhaled steroids. The study involved 27 children with asthma, continuously treated with inhaled fluticasone propionate, and 22 healthy controls. In addition to routine clinical screening, the selected cytokines in EBC were analyzed using Ultrasensitive ELISA, whereas activity of MMP-9 was assessed using a novel immunozymography method. Despite chronic treatment with inhaled steroids mean MMP-9/EBC activity in asthma group was significantly higher than in healthy controls. Moreover, high MMP-9/EBC in asthma-suffering children significantly correlated with IgE serum levels. The IL-6 and IL-8 concentration was below the detection limit in all EBC samples. TNF/EBC levels were similar in both, asthma and healthy children. We hypothesize that MMP-9 hyperactivity in asthma may be closely related to high IgE serum levels. Our results suggest that inhaled steroids may be ineffective to prevent asthma-associated airway remodeling. Finally, we emphasize the necessity of further research focused on MMP-9 inhibition in asthma treatment.

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

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

Necrotizing Pneumonia and Its Complications in Children

Necrotizing pneumonia (NP) is an emerging complication of community acquired pneumonia (CAP) in children. This study aimed at the evaluation of etiology, clinical features, treatment, and prognosis of NP. The institutional database of children with CAP treated between April 2008 and July 2013 was searched to identify children with NP. Then, data on the NP characteristics were retrospectively reviewed and analyzed. We found that NP constituted 32/882 (3.7%) of all CAPs. The median age of children with NP was 4 (range 1-10) years. The causative pathogens were identified in 12/32 children (37.5%) with Streptococcus pneumoniae being the most common (6/32). All but one patient developed complications: parapneumonic effusion (PPE), pleural empyema or bronchopleural fistula (BPF), which required prompt local treatment. The median duration of hospital stay and antibiotic treatment was 26 (IQR 21-30) and 28 (IQR 22.5-32.5) days, respectively. Despite severe course of the disease no deaths occurred. A follow-up visit after 6 months revealed that none of the patients presented with any signs and symptoms which could be related to earlier pneumonia. Chest radiographs showed complete or almost complete resolution of pulmonary and pleural lesions in all patients. We conclude that necrotizing pneumonia is a relatively rare but severe form of CAP that is almost always complicated by PPE/empyema and/or BPF. It can be successfully treated with antibiotics and pleural drainage without major surgical intervention.

The Influence of the Reference Values on the Interpretation of Lung Function in Children: Comparison of Global Lung Initiative 2012 and Polish 1998 Reference Values

Interpretation of spirometry strongly depends on the applied predicted values. New Global Lung Initiative (GLI) reference values have recently been published but their influence on spirometry interpretation in children has not been widely evaluated. The aim of the study was to compare the interpretation of spirometry using GLI-2012 vs. Polish-1998 reference values. Spirometry results of 315 Caucasian children aged 4-18 were analyzed. Airway obstruction was defined as FEV1/FVCLLN. The findings were that FEV1 and FVC expressed as GLI-2012 or Polish-1998 z-scores differed significantly (p<0.05). The mean FEV1 z-score was -0.68±1.25 vs. -0.13±1.70 and the mean FVC was -0.34±1.08 vs. 0.30±1.15 for GLI-2012 and Polish-1998, respectively. There was no difference for FEV1/FVC z-scores. Obstructive and restrictive ventilatory patterns were diagnosed in 20.3% and 7.6% children using GLI-2012 values compared with 17.5% and 3.8% when using Polish-1998 reference values, respectively. In conclusion, the use of GLI-2012 reference values in the population of Polish children increases the number of detected lung function abnormalities compared with Polish-1998 reference values.