Omalizumab (Xolair) in children with seasonal allergic rhinitis: Leukotriene release as a potential in vitro parameter to monitor therapeutic effects

To investigate the effect of omalizumab, a humanized monoclonal antibody, in addition to specific immunotherapy (SIT) on in vitro sulfidoleukotriene release (SLT) (A) before, (B) directly after, and (C) 1 yr after treatment with omalizumab. Children and adolescents (6.3-17.6 yr) with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a Phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomly chosen to receive SIT for either birch or grass pollen and either subcutaneous omalizumab or placebo for 24 wk during the pollen season. Thereafter, omalizumab or placebo treatment ended, but SIT therapy continued. Blood samples were collected from 92 (A, B) and 78 children (C), respectively. Leukocytes were isolated and stimulated with grass and birch pollen allergens. In the supernatants, SLT (LTC4, LTD4, LTE4) were measured using ELISA [cellular allergen stimulation test, DPC-Biermann, Germany]. At the end of treatment the combination of omalizumab + SIT-grass [median SLT-release: 2125 (before) and 416 ng/ml (after omalizumab treatment); p < 0.001] as well as omalizumab + SIT-birch [1404 and 207 ng/ml; p < 0.001] resulted in significantly lower SLT release after stimulation with the corresponding allergen compared to placebo + SIT-grass [2231 and 2490 ng/ml] or placebo + SIT-birch [1324 and 2489 ng/ml]. One year after omalizumab or placebo treatment, there was no significant difference in SLT release between the 4 groups (omalizumab + SIT-grass: 2855; SIT-grass + placebo: 2543; omalizumab + SIT-birch: 2417; SIT-birch + placebo: 2573 ng/ml). These results strongly suggest that the observed effects of decreased SLT release after omalizumab treatment were attributable to the treatment with omalizumab, rather than to SIT therapy.     

Leukotriene C4 in Children with Atopic Asthma II. Plasma Levels in Bronchial Challenge with Specific Allergen

Peptide leukotrienes C₄, D₄ and E₄ are considered to be major mediators of hypersensitivity reactions. In this study, immunoreactive leukotriene C₄ (iLTC₄) in plasma, taken from asthmatic children who had undergone bronchial challenge with a specific allergen, was measured using radioimmunoassay in order to determine whether LTC₄ is released in duo during human allergic reactions. With regard to the bronchial challenge of 10 asthmatic children, plasma iLTC₄ levels at the postchallenge stage (0.131 ± 0.037 pmol/ml) were significantly elevated compared to the prechallenge stage (0.065 ± 0.016 pmol/ml) (p <0.01). The bronchial response was not directly related to the increased plasma iLTC₄ levels, but the strength of the bronchial response did relate to the plasma iLTC₄ levels at the pre-challenge (p<0.05) and postchallenge (p<0.01) states. The prechallenge levels are relevant to bronchial reactivity, and the post-challenge levels are relevant to bronchocon-striction caused by exposure to allergens. The in vivo release of LTC₄ following exposure to a specific allergen suggests that leukotrienes are important in the pathogenesis of asthma.     

Exhaled nitric oxide and exercise-induced bronchoconstriction in young wheezy children – interactions with atopy

The association between exercise-induced bronchoconstriction (EIB) and exhaled nitric oxide (FE_NO) has not been investigated in young children with atopic or non-atopic wheeze, two different phenotypes of asthma in the early childhood. Steroid naïve 3- to 7-yr-old children with recent wheeze (n = 84) and age-matched control subjects without respiratory symptoms (n = 71) underwent exercise challenge test, measurement of FE_NO and skin prick testing (SPT). EIB was assessed by using impulse oscillometry, and FE_NO by standard online technique. Although FE_NO levels were highest in atopic patients with EIB, both atopic and non-atopic wheezy children with EIB showed higher FE_NO than atopic and non-atopic control subjects, respectively. In atopic wheezy children, a significant relationship between FE_NO and the severity of EIB was found ( r  = 0.44, p = 0.0004), and FE_NO was significantly predictive of EIB. No clear association between FE_NO and EIB or predictive value was found in non-atopic wheezy children. Both atopic and non-atopic young wheezy children with EIB show increased FE_NO levels. However, the association between the severity of EIB and FE_NO is present and FE_NO significantly predictive of EIB only in atopic subjects, suggesting different interaction between bronchial responsiveness and airway inflammation in non-atopic wheeze.     

NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children

Exhaled nitric oxide (FE_NO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FE_NO in adults with asthma and cystic fibrosis, was associated with the raised FE_NO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6–18 years) underwent measurements of FE_NO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FE_NO in either the whole sample of healthy children (n = 87) or in the subsample of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FE_NO.     

Associations between cat keeping, allergen exposure, allergic sensitization and atopic diseases: Results from the Children of Lübeck Allergy and Environment Study (KLAUS)

The role of cat keeping on the promotion of allergies is discussed controversially. We investigated the associations between cat keeping, allergen exposure, allergic sensitization and atopic diseases in pre-school children. A total of 606 children (5- to 6-yr old) were studied in the course of the mandatory school entrance examination. Information on doctor diagnosed asthma and allergic rhinitis, pet keeping and confounders was obtained by questionnaire. The prevalence of atopic eczema was determined by dermatological examination, allergic sensitization was assessed by skin prick test, and the allergen exposure to cat allergen Fel d 1 was measured by a commercial wipe test. Cats were present in 16% of the households and results of the exposure categories (0–III) on cat allergen were 47.2%, 25.5%, 24.3% and 3.0% respectively. The prevalence of cat keeping increased significantly with exposure categories from 0.5% to 61.5% (p_trend < 0.001). Children (6.3%) were sensitized to cat allergen and sensitization rates increased also significantly with exposure categories from 3.0% to 15.4% (p_trend < 0.001). Children (9.3%) were diagnosed with atopic eczema and a positive history of asthma/rhinitis was given in 3.6% and 3.9% respectively. Sensitization to cat was associated with atopic eczema (23.3% vs. 7.4%; OR_adj.= 3.8, CI: 1.4–10.8), asthma (12.5% vs. 3.7%; OR_adj.= 4.9, CI: 1.1–21.2), allergic rhinitis (6.9% vs. 2.7%; OR_adj.= 3.1, CI: 0.7–15.2) and any atopic disease (43.5% vs. 16.3%; OR_adj.= 3.8, CI: 1.5–9.5). The data suggest a promoting effect of cat keeping for atopic diseases.     

Leukotriene B4 and C4 generation by human leukocytes after ex vivo stimulation with Ca-ionophore and opsonized zymosan in children with atopic asthma

The ex vivo release of leukotriene B₄ (LTB₄) and leukotriene C₄ (LTC₄) from leukocytes was evaluated after stimulation with both Ca-ionophore (Ca-I) and opsonized zymosan (OZ) in children with atopic asthma. Twenty-seven patients with asthma of varying severity were evaluated and divided into three groups: 1) moderate to severe asthma using inhaled steroids and symptom-free for the last 3 weeks (n = 8), 2) mild asthma with sporadic symptoms, only using inhaled pVagonists < 3 times/week (n = 8), and 3) acute asthmatic attacks admitted to hospital (n = 11). A group of children without atopic disease or any other known disease served as controls (n = 15). Total serum IgE levels were significantly increased in the children with asthma compared with the control group. LTC₄ production was only significantly increased in the group of children with moderate to severe asthma after stimulation with Ca-I, when compared with controls. In the same group, a trend towards increased LTC₄ production after stimulation with OZ was found. LTB₄ was not significantly increased in any patient group compared with the control group. A significant correlation between LTC₄ production after stimulation with Ca-I, but not OZ, and the relative blood eosinophil count was found in all subjects. LTC₄ generation per eosinophilic cell after stimulation with Ca-I or OZ was not statistically different in any patient group compared with the controls. We conclude that the increased leukotriene (LT) levels found after the stimulation of peripheral white blood cells sampled from atopic children with asthma are mainly the result of increased numbers of LT-producing cells, rather than due to increased releasability from these cells.     

Pediatric investigation plans for specific immunotherapy: Questionable contributions to childhood health

Allergen‐specific immunotherapy (SIT) is the only disease‐modifying treatment for children, adolescents, and adults with allergic diseases. The EU has a combined system of national and EU‐wide marketing authorization for all medicines. Germany introduced a new therapy allergen ordinance in 2008. Allergen products manufacturers had to apply for marketing authorization application for the major allergen groups (grass group, birch group, mites group, bee/wasp venom). Due to the EU pediatric regulation, in force since 2007, manufacturers had also to submit a pediatric investigation plan (PIP) for each allergen product. We investigated the allergic rhinoconjunctivitis (ARC) standard PIP, developed jointly by the European Medicines Agency (EMA) and the German Paul Ehrlich Institut (PEI). We analyzed the 118 EMA PIP decisions, looked for SIT trials in children in www.clinicaltrials.gov , and further analyzed EMA/EU justifications. The PIPs request a 1‐year dose‐finding study in adults, a 5‐year placebo‐controlled (PC) efficacy & safety (E&S) study in adults, and a 5‐year PC E&S study in children. Fifty‐eight PIP development programs will have to be performed until 2031. But children benefit even more from SIT for ARC than adults. There is no convincing medical/scientific justification for PC E&S studies in children in the relevant EMA documents. The PIP requirement to withhold effective treatment to thousands of children in the placebo group over a 5‐year period raises profound concerns. The EMA justifications are formalistic and lack scientific foundation. A critical academic review of the ARC PIPs and the entire PIP system is urgently needed.     

Umbilical cord-blood transplantations from unrelated donors in patients with inherited metabolic diseases: Single-institute experience

Abstract:  We evaluated the feasibility of UCBT from unrelated donors and a myeloablative preparative regimen that did not involve anti-thymocyte globulin in five children with lysosomal and peroxisomal diseases. Patients with MPS II (n = 1), adrenoleukodystrophy (n = 1), metachromatic leukodystrophy (n = 2), and Krabbe disease (n = 1) received UCBT between December 2001 and September 2005. All patients received oral Bu (600 mg/m²), CY (200 mg/kg IV), and fludarabine (180 mg/m² IV). Prophylaxis for GVHD consisted of a combination of tacrolimus and a short methotrexate course. Neutrophil engraftment occurred a median of 24 days (range, 21–25) after transplantation. None had graft rejection. One patient developed grade III acute GVHD and the other four patients had grade I acute GVHD; none had extensive chronic GVHD. One patient developed hemorrhagic cystitis. There were no treatment-related deaths. Although one child with MPS II died of PTLD 10 months after the UCBT, four of the five children are alive 14, 20, 31, and 55 months after transplantation with complete donor chimerism. These results suggest the feasibility of the UCBT with Bu, fludarabine, and CY-preparative regimen for patients with inherited metabolic diseases.     

Intrabdominal fat is related to metabolic risk factors in Hispanic Americans, African Americans and in girls

Aim:  This study aimed to test the association of individual adipose depots on cardiometabolic outcomes, whether the association varied by depot and if the associations differed by race/ethnicity or gender in early pubertal children.
Methods:  Three hundred and twenty children (53% male) aged 7–12 years self-identified as African American (AA; n = 114), European American (EA; n = 120) or Hispanic American (HA; n = 86) participated. Insulin dynamics were assessed by intravenous glucose tolerance test; body composition with DXA; fat distribution with CT.
Results:  AA had the least fat in each depot and HA had the most. Fat accumulation negatively impacted cardiometabolic outcomes independent of race/ethnicity or gender. AA and females were reproductively more mature. In AA and HA, each measure of adiposity influenced the insulin sensitivity index (S_I), whereas intra-abdominal adipose tissue (IAAT) did not contribute to S_I in EA. IAAT was positively associated with blood pressure in AA only. In females, adiposity adversely influenced cardiometabolic outcomes such that total fat mass, IAAT and/or SAAT was inversely associated with S_I, and positively associated with blood pressure and fasting insulin.
Conclusion:  IAAT is uniquely related to metabolic risk factors in Hispanic Americans, African Americans and girls, suggesting that either the threshold for adverse effects of IAAT is lower, or the IAAT metabolism differs in these groups.     

The association between ketoacidosis and 25(OH)-vitamin D levels at presentation in children with type 1 diabetes mellitus

Background:  There is considerable evidence supporting the role of vitamin D deficiency in the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D deficiency is also associated with impairment of insulin synthesis and secretion. There have been no formal studies looking at the relationship between 25(OH)-vitamin D₃ and the severity of diabetic ketoacidosis (DKA) in children at presentation with T1DM.
Objective:  To determine the relationship between measured 25(OH)-vitamin D₃ levels and the degree of acidosis in children at diagnosis with T1DM.
Subjects:  Children presenting with new-onset T1DM at a tertiary children's hospital.
Methods:  25(OH)-vitamin D₃ and bicarbonate levels were measured in children at presentation with newly diagnosed T1DM. Those with suboptimal 25(OH)-vitamin D₃ levels (<50 nmol/L) had repeat measurements performed without interim vitamin D supplementation.
Results:  Fourteen of the 64 children had low 25(OH)-vitamin D₃ levels at presentation, and 12 of these had low bicarbonate levels (<18 mmol/L) (p = 0.001). Bicarbonate explained 20% of the variation in vitamin D level at presentation (partial r² = 0.20, p < 0.001) and ethnic background a further 10% (partial r² = 0.10, p = 0.002). The levels of 25(OH)-vitamin D₃ increased in 10 of the 11 children with resolution of the acidosis.
Conclusions:  Acid–base status should be considered when interpreting 25(OH)-vitamin D₃ levels in patients with recently diagnosed T1DM. Acidosis may alter vitamin D metabolism, or alternatively, low vitamin D may contribute to a child's risk of presenting with DKA.     

Expression of chemokine receptor CX3CR1 in infants with respiratory syncytial virus bronchiolitis

Respiratory syncytial virus (RSV) glycoprotein G mimics fractalkine, a CX₃C chemokine, which mediates chemotaxis of leukocytes expressing its receptor, CX₃CR1. The aim of this study was to examine the relationship between RSV infection and expression of perforin and IFN- γ in CX₃CR1-expressing peripheral blood CD8⁺ T cells. Samples were collected from infants with RSV bronchiolitis, both in the acute and convalescence phase (n = 12), and from their age- and sex-matched healthy controls (n = 15). Perforin expression and IFN- γ secretion in CX₃CR1⁺ CD8⁺ T cells were assessed by four-color flow cytometry. The NF- κ B p50 and p65 subunit levels were also determined as markers of RSV-induced inflammation. Study results showed perforin and CX₃CR1 expression to be significantly lower in the convalescent phase of infected infants than in healthy controls. There was no significant difference in IFN- γ secretion and NF- κ B binding activity between two time-points in RSV-infected infants, or when compared with healthy controls. Infants with prolonged wheezing had lower acute-phase CX₃CR1 levels in peripheral blood. These data indicate existence of an event persisting after acute RSV infection that is able to modulate effector functions of cytotoxic T cells, and also link disease severity with CX₃CR1 expression.     

Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy

Mösges R, Graute V, Christ H, Sieber H‐Jochen, Wahn U, Niggemann B. Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy.
Pediatr Allergy Immunol 2010: 21: 1135–1138.
© 2010 John Wiley & Sons A/S The recommendation to use sublingual‐swallow immunotherapy (SLIT) in children and adults with allergic rhinitis has been established over the past decade. Recently, ultra‐rush titration of SLIT has become more and more common, raising concerns about its safety in children with asthma. Fifty‐four children with asthma and adolescents aged 6–14 with documented allergic disease because of tree pollen (birch and possibly alder and/or hazel) from 14 study centers in Germany participated in a randomized, double‐blind, and placebo‐controlled study. Twenty‐seven were randomized to receive SLIT with standardized birch pollen allergen extract and the other 27 to receive placebo. An ultra‐rush high‐dose SLIT titration regimen reaching the maintenance dose of 300 index of reactivity (IR) within 90 min (30–90–150–300 IR) was used. The difference in mean PFR changes during ultra‐rush titration between SLIT and placebo was not significant (p = 0.056). A 95% probability that SLIT does not decrease PFR during ultra‐rush titration was demonstrated. Neither anaphylactic shock nor else serious systemic reactions to the study drug occurred. No serious adverse event assessed by the investigator as related to study drug treatment was reported.     

Exhaled breath condensate eicosanoids and sputum eosinophils in asthmatic children: A pilot study

Cysteinyl leukotrienes (cys-LTs), LTB₄ and 8-isoprostane are increased in the exhaled breath condensate (EBC) from asthmatic patients. The aim of this study was to investigate whether the measurement of cys-LTs, LTB₄ and 8-isoprostane in EBC can reflect the level of airway inflammation assessed by induced sputum in asthmatic children sensitized to house dust mite (HDM) during natural avoidance of HDM allergens. Twelve children were evaluated at the time of admission (T0) and after 3 months of stay (T1) at the Istituto Pio XII (Misurina, Italian Dolomites 1756  m). Sputum eosinophil percentage and measurement of cys-LTs, LTB₄ and 8-isoprostanes in the breath condensate at T0 and T1 were evaluated. Eosinophil percentage in induced sputum was 8.5 ± 1.1% at T0 and 3.5 ± 0.4% at T1 (p = 0.011). Neutrophil percentage in sputum was 1.1 ± 0.5% at T0 and 1.5 ± 1.0% at T1 (ns). Cys-LTs mean level was 14.24 ± 4.53 pg/ml at T0 and 4.65 ± 0.68 pg/ml at T1 (p = 0.0125). LTB₄ level was 2.36 ± 0.19 pg/ml at T0 and 2.41 ± 0.23 pg/ml at T1 (ns). 8-Isoprostane level reduced from 17.47 ± 3.18 pg/ml at T0 to 7.36 ± 3.26 pg/ml at T1 (p = 0.003). This study show that exhaled cys-LTs and 8-isoprostane, as well as eosinophil percentage in induced sputum, are reduced after allergen avoidance in asthmatic children suggesting a potential application of EBC for the non-invasive evaluation of airway inflammation in asthma in allergic asthmatic children.     

Concentrations of LTB4, LTC4, LTD4 and LTE4 in bronchiolitis due to respiratory syncytial virus

Fifty-five infants with bronchiolitis due to respiratory syncytial virus were evaluated for the presence of leukotriene B₄, C₄, D₄ and E₄ in nasopharyngeal secretions. An attempt was made to correlate concentrations of leukotrienes to arterial oxygen tension. Forty participants received conventional therapy consisting primarily of aerosolized albuterol and occasional aminophylline therapy. The other 15 individuals received ribavirin therapy in addition to conventional therapy, and leukotriene concentrations were compared among individuals in these groups. RSV infection was documented by standard methods, and leukotrienes were measured by reverse-phase high pressure liquid chromatography. The leukotriene detected most commonly was LTC₄ (up to 83% of subjects); LTD₄ and LTB₄ were present in approximately 30% of individuals. The mean partial pressure of oxygen was found to be lower in those individuals with detectable LTB₄ than in those without detectable LTB₄ (p < 0.025), and an overall inverse correlation of LTB₄ concentrations with initial pO₂ values was observed (r = 0.318, p < 0.05). The presence and quantity of other leukotrienes did not correlate with the severity of illness. During the first week of illness, the concentration of leukotrienes declined sharply in ribavirin recipients. Individuals receiving conventional therapy during the same time interval exhibited stable or increasing leukotriene concentrations. These observations suggest that LTB₄ may be important in the pathogenesis of bronchiolitis, and that ribavirin therapy may inhibit leukotriene release in the respiratory tract.     

International Study of Asthma and Allergies in Childhood: Validation of the rhinitis symptom questionnaire and prevalence of rhinitis in schoolchildren in São Paulo, Brazil

Written questionnaires (WQ) have been widely used in epidemiologic studies. In order to yield comparable results, they must be validated after translation to another language. The International Study of Asthma and Allergies in Childhood (ISAAC) WQ has been previously validated by a comprehensive study, but its validation in Brazil has not been performed. Our objectives were to validate the rhinitis component of the ISAAC's self-applicable WQ following its translation to Portuguese, and to determine the prevalence of rhinitis and related symptoms among Brazilian children living in the city of São Paulo. A group of 10 pediatricians and 10 pediatric allergists graded the questions from 0 to 2 and established a maximum score for each question. The WQ was answered by parents or guardians of children 6–7 years of age with rhinitis (R) (n = 27) and of control children of the same age without rhinitis (C) (n = 27). The WQ was also completed by adolescents 13–14 years of age with rhinitis (R) (n = 32) and without rhinitis (C) (n = 32). Half of these individuals answered the same WQ after 2–4 weeks, to ensure reproducibility. Cut-off scores of 4 and 3 were identified for the 6–7- and 13–14-year-old groups, respectively, as scores predictive of rhinitis. The prevalence of rhinitis was 28.8% in the group of 3005 children 6–7 years of age and 31.7% in the group of 3008 children 13–14 years of age, respectively. Using the global cut-off score, these prevalences were even higher, in the order of 34.7% and 40.7%, respectively. In conclusion, the rhinitis component of the ISAAC WQ was proven to be reproducible, adequate and able to discriminate children and adolescents with and without rhinitis, and revealed that the prevalence of rhinitis among Brazilian children living in the city of São Paulo was as high as the prevalence of rhinitis in other areas of the world.     

Low‐dose budesonide improves exercise‐induced bronchospasm in schoolchildren

The aim of this study was to compare the clinical efficacy of low‐dose inhaled budesonide (once or twice daily) and placebo, administered via Turbuhaler^®, on exercise‐induced bronchoconstriction (EIB) in children with mild asthma. Fifty‐seven steroid‐naive children (7–16 years old; 41 boys, 16 girls) with EIB participated in this sub‐population study according to the following inclusion criterion: a maximum fall in forced expiratory volume in 1 s ( FEV ₁) ≥ 10% after a standardized treadmill test. Mean baseline FEV ₁ was 100.3% of predicted, and mean maximum fall in FEV ₁ after the standardized exercise test was 22%. The study was a double‐blind, randomized, parallel‐group design. After 2 weeks of run‐in, the children received inhaled budesonide 100 µg or 200 µg once daily in the morning, 100 µg twice daily, or placebo, for 12 weeks. After 12 weeks of treatment, the fall in FEV ₁ after the exercise test was significantly less in all three budesonide groups (7.2–7.8%) vs. placebo (16.7%). Daytime symptom scores were significantly lower in all three budesonide groups compared with placebo (p < 0.02). The three budesonide groups did not differ significantly, and no significant change in lung function was found in any group. Therefore children with mild asthma, but with significant EIB, improved their exercise tolerance and symptom control after 3 months of treatment with a low dose of inhaled budesonide given once or twice daily.     

Cerebrospinal fluid concentrations of leukotriene B4 in bacterial meningitis

We investigated whether leukotriene B₄ (LTB₄), a granulocyte inflammatory mediator, is detectable in cerebrospinal fluid using a high performance liquid chromatographic method. In non-pleocytotic cerebrospinal fluid (n = 5) and in cerebrospinal fluid from children with aseptic meningitis (n = 8). LTB₄ concentrations were below the detection limit (<0.2ngml ¹). In the range 0 20ngml ¹. the recovery rate of LTB₄ that had been added to non-pleocytotic cerebrospinal fluid was >90%. In cerebrospinal fluid with a polymorphonuclear leucocyte (PMN) count higher than 1,000/ml, LTB₄ was detectable in six out of seven specimens with a concentration of 0.35-3.3 ngml⁻¹. LTB₄ concentration was significantly correlated with PMN number. These results, together with observations in animal models, are discussed with regard to a pathophysiological role of LTB₄ in bacterial meningitis.     

Time efficacy of a single dose of montelukast on exercise-induced asthma in children

The aim of this study was to evaluate the timing of onset and the duration of action of a single oral-dose treatment with montelukast in comparison to placebo on exercise-induced asthma (EIA) in asthmatic children. Nineteen children (7–13 years) with stable asthma were evaluated. Patients undertook three consecutive treadmill exercise tests, respectively, 2, 12 and 24 h after a single-dose administration. A double-blind randomized, single-dose, placebo-controlled, crossover design was used. To assess bronchoconstriction after the exercise challenge, the maximal percentage fall in FEV₁ (ΔFEV₁) from the baseline value was considered. Two hours after dosing, ΔFEV₁ was −15.33  ±  2.93 for placebo and −13.33  ±  2.03 for montelukast. At 12 h, ΔFEV₁ was −18.69  ±  2.83 for placebo, −9.78  ±  1.85 for montelukast (p < 0.005). No difference was observed between placebo (ΔFEV₁−10.21  ±  2.07) and montelukast (ΔFEV₁−9.10  ±  2.02) at 24 h. Analysis of the degree of protection showed a significant efficacy of montelukast (p = 0.02) in comparison with placebo only at 12 h. Montelukast showed a significant protective effect 12 h after dosing, but no effect after 2 and 24 h. In mild asthmatics, the timing of administration of single dosage before exercise should be strictly considered in order to obtain the drug protective effects.     

Correlation of nitrites in breath condensates and lung function in asthmatic children

We aimed to evaluate the value of exhaled breath condensates in monitoring airway inflammation in childhood asthma before and after high altitude climate therapy.
Forty-eight asthmatic children on regular anti-asthma treatment with a normal FEV₁ and positive skin prick test for house dust mites were recruited. All children had been referred to an alpine clinic for high altitude climate therapy, because of persistent asthmatic symptoms despite use of daily anti-inflammatory treatment. Subjects were assessed on their arrival and before departure from the alpine clinic. Spirometry, bronchial provocation tests and measurements of nitrites in breath condensates were performed.
Median levels of nitrites were significantly higher before than after high altitude climate therapy (1.27 vs. 0.93 μ m ; p = 0.008). In addition, MEF₅₀ improved significantly (p < 0.0005). There was a significant correlation between nitrites in breath condensates and MEF₅₀ (r = −0.63, p < 0.0001), symptoms (r = 0.47, p = 0.0007) and airway hyper-reactivity (AHR) (r = −0.41, p = 0.004).
In summary, we found a reduction in nitrites in breath condensates after a high altitude climate therapy. Significant correlations were found between nitrites and MEF₅₀, AHR and symptoms. We conclude that the measurement of nitrites may be feasible to objectively assess airway inflammation in asthmatic children in order to detect ongoing inflammation in children with normal FEV₁ but persistent symptoms.     

Evaluation of clinical and immunological effects of inactivated influenza vaccine in children with asthma

Although annual influenza vaccinations are recommended by many authorities, some doctors may be reluctant to vaccinate asthmatic children because of the risk of inducing bronchial reactivity and exacerbating the asthma. In this study, the effect of split influenza vaccine on clinical symptoms, airway responsiveness and its influence on T lymphocytes was evaluated. Twenty-one asthmatic children with stable asthma were recruited and divided into two groups. Eleven patients who received the influenza vaccine formed the vaccination group and 10 patients who received a placebo formed the placebo group. Forced expiratory volume in 1 s ( FEV ₁), airway response (PC₂₀ methacholine, PC₂₀ = provocation concentration causing a 20% fall in FEV ₁) and the T lymphocyte subset ratio (Th1/Th2) were recorded on day 1 pre-vaccination and day 14 post-vaccination. Patients were also asked to record their peak expiratory flow (PEF) every morning and evening and to complete daily symptom scores over the period of 2 weeks. There were no significant changes in PC₂₀, FEV ₁, PEF variability, symptom scores and the Th1/Th2 ratio between the vaccination and placebo groups between day 1 pre-vaccination and day 14 post-vaccination. Similar results of PEF variability and asthma symptom score were obtained when the analysis was restricted to the day 1 pre-vaccination and day 3 post-vaccination. Immunization with split influenza vaccine does not exacerbate asthma in children either with a clinical or immunological effect. These results suggest that children with stable asthma can safely be immunized with a split influenza vaccine.