Urinary leukotriene E4 levels in children with allergic rhinitis treated with specific immunotherapy and anti-IgE (Omalizumab)

Recently, we were able to demonstrate that Omalizumab, a humanized monoclonal anti-IgE antibody, reduces in vitro leukotriene (LT) release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy. The aim of this study was to investigate the effect of anti-IgE in combination with specific immunotherapy (SIT) on urinary leukotriene E₄ (LTE₄) levels. Children and adolescents 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 randomized to receive SIT for either birch or grass pollen and to receive either subcutaneous anti-IgE or placebo for 24 weeks during the pollen season. From a total population of 225 children, we collected three urine samples in a subgroup of 19 children [n = 12 boys (63%); mean age 11.8 years; range 7.2–17.5 years; Group A (n = 10): SIT (grass or birch) + anti-IgE; Group B (n = 9): SIT (grass or birch) + placebo]. Urine samples were collected before, during and at the end of treatment. Endogenous urinary LTE₄ was separated by high-performance liquid chromatography (HPLC) and determined by enzyme immunoassay with a specific antibody. No differences in urinary LTE₄ concentrations were observed between the anti-IgE and the placebo groups before (A: 35.2; B: 36.5 nmol/mol creatinine), during (A: 27.0; B: 29.3) and after treatment (A: 28.9; B: 26.5 nmol/mol creatinine). We conclude that urinary LTE₄ levels are not helpful in monitoring patients treated with anti-IgE and SIT.     

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.     

Maternal pollen allergy may be more important than birch pollen exposure during pregnancy for atopic airway disease in the child

In 1993 extremely high levels of birch pollen were recorded in Stockholm, Sweden. We investigated the effects of this exposure on sensitization and development of atopic airway disease in children. The aim of this study was to assess the influence of maternal birch sensitization and symptoms of pollen allergy, as well as exposure to birch pollen during pregnancy, on sensitization and development of atopic airway disease in children. A total of 387 children with atopic heredity (70% had atopic mothers) and born in Stockholm 1993 or 1994 were investigated at age 4.5-5 yr. The children were examined and skin prick tested with inhalant and food allergens. IgE-antibodies against birch pollen and recombinant birch pollen allergen were analyzed in serum. The same tests were performed on the mothers. Children of mothers with symptoms of pollen allergy more often showed symptoms of rhinoconjunctivitis at age 4.5-5, after both high dose [Odds ratio (OR) 5.3; 95% confidence interval (CI): 2.0-13.7] and low dose (OR 4.0; 95% CI: 1.5-10.9) exposure to birch pollen during pregnancy. Similar tendencies were noted for children of mothers sensitized to birch, where stronger effects were suggested in boys (OR 3.8; 95% CI: 1.3-11.5) than in girls (OR 1.2; 95% CI: 0.2-5.5) in the high-dose exposed group. For asthma symptoms and sensitization to birch in the children the results were less consistent. It may be concluded that, maternal pollen allergy seems to have a stronger influence on the development of rhinoconjunctivitis in children with a family history of atopy than the degree of allergen exposure during pregnancy.     

Placebo-controlled study of the mite allergen-reducing effect of tannic acid plus benzyl benzoate on carpets in homes of children with house dust mite sensitization and asthma

We studied the effect of a spray containing 1% benzyl benzoate, an acaricide, and 1% tannic acid (‘Lowal’; a protein‐denaturing substance), on concentrations of major allergens from house dust mite (HDM) species Dermatophagoides pteronyssinus and D. farinae (Der p 1 and Der f 1, respectively) in carpets. In a double‐blind, placebo‐controlled study with crossover design, 30 homes of children with HDM sensitization and asthma were included. All houses showed ≥ 400 ng/g of Der p 1 + Der f 1 in carpet dust. The first treatment was performed on day 0 (group 1 active treatment, n = 15; group 2 placebo treatment, n = 15). After 2 and 8 weeks, dust samples were collected for quantification of mite allergens. After a 2‐week washout period, the second treatment was performed (group 1 placebo treatment; group 2 active treatment). Again, carpet dust was collected after 2 and 8 weeks. Twenty‐two of 30 families completed the trial: 14/15 in group 1 and eight of 15 in group 2. On day 0, there was no significant difference in mite allergen exposure between group 1 and group 2 (1,498 vs. 2,239 ng/g of Der p 1 + Der f 1, respectively). In group 1, the geometric mean for the difference of mite allergen concentration comparing day 0 and week 6 was 196 ng/g (95% CI: ?7,161 and 8,401) for the first treatment (active) and 15 ng/g (95% CI: ?1,079 and 1,292) for the second treatment (control). In group 2, the difference was 66 ng/g (95% CI: ?398 and 1,515) for the first treatment (control) and 609 ng/g (95% CI: 186 and 9,264) for the second treatment (active). Comparing placebo and active treatment in total, there was a significant decrease following placebo treatment after 14 days (p = 0.026). After 8 weeks, active treatment was superior to placebo treatment (p = 0.049), but the allergen reduction achieved was < 20% (median 1,500 ng/g on day 0 vs. 1,250 ng/g after 8 weeks). We conclude that the slight mite allergen reduction on carpets achieved by the treatment with ‘Lowal’ is unlikely to achieve worthwhile clinical benefit either in the treatment of mite‐sensitive patients or in primary or secondary prophylaxis.     

High dose astemizole in children with allergic rhinoconjunctivitis

In a double blind manner 38 children with hayfever due to birch pollinosis and weighing 25–80 kg (mean 45 kg) were treated with either astemizole 5 mg/d or placebo for 2 wks before the start of the birch pollen season. At the start of the season all children were given astemizole in doses increasing every week, i. e. 5, 10, 20 and 40 mg/d. This part of the study was blind in that patients did not know the actual dose administered and the physiscians did not know the plasma concentrations of the drug. Blood was drawn before the start of the medication and after each week in the single blind phase of the trial. Despite the long half-life of astemizole. prophylactic treatment gave no improvement during the first week of the pollen season. Increasing daily doses from 0. 1 mg/kg body weight gave i'ewer hayfever symptoms up to 0. 25 mg/kg, corresponding to a plasma concentration of 4 ng/ml of astemizole plus hydroxyluted metabolites. Still higher doses up to 40 mg/d, corresponding to 0. 5–1. 6 mg/kg/d. gave littie improvement. Sedation and other side effects did not increase with higher doses. Analyses of various laboratory tests did not reveal any abnormalities that were judged to be a result of the medication. However, liver enzymes increased during the treatment period although all values were within normal limits. Thus, astemizole is safe even in higher doses, but neither prophylactic treatment nor daily doses above 0. 25 mg/kg/d improve treatment results in hayfever. The statistical lime series model used correlating symptoms with pollen exposure allowed a good evaluation of the dose-response of astemizole in hayfever despite the limited number of patients     

Safety of specific sublingual immunotherapy with SQ standardized grass allergen tablets in children

The aim of the study was to confirm the safety of an orodispersible grass allergen tablet 75,000 SQ‐T (Grazax^®, ALK‐Abelló A/S, Hørsholm, Denmark) in children aged 5–12 yr. The study was randomized, double‐blinded and placebo‐controlled. Sixty children aged 5–12 yr suffering from grass pollen‐induced rhinoconjunctivitis (with or without asthma) from five centres in two countries (three in Germany and two in Spain) participated in the study. They were randomized at the ratio of 3:1 as receiving either Grazax or placebo tablet given sublingually once daily for 28 days outside the grass pollen season. A total of 810 treatment‐related adverse events were reported in the Grazax group. The majority of these were local reactions in the mouth or throat and were mostly mild (71%) to moderate (27%) in severity and resolved within days. Thirty‐five (78%) subjects treated with Grazax and five (33%) treated with placebo reported at least one treatment‐related adverse event. Oral pruritus, throat irritation, mouth oedema and ear pruritus appeared as the most frequently reported treatment‐related adverse events. 62% (28 of 45) of the actively treated subjects reported oral pruritus, 36% (16 of 45) throat irritation, 31% (14 of 45) mouth oedema and 22% (10 of 45) ear pruritus. Two actively treated subjects withdrew from the study: one subject due to four adverse events (moderate eye pruritus, moderate pharyngolaryngeal pain, moderate non‐cardiac chest pain and moderate dysphagia) and one subject due to a serious adverse event (asthmatic attack). The subjects recovered completely from the events. In conclusion, in the present study, Grazax was in general tolerated in a paediatric population and considered suitable for further clinical investigations in children.     

Bet v 1-specific IgA increases during the pollen season but not after a single allergen challenge in children with birch pollen-induced intermittent allergic rhinitis

Allergen-specific immunoglobulins of the Immunoglobulin A (IgA) type have been found in the nasal fluid of patients with allergic rhinitis. IgA may play a protective role, but there are also data which show that allergen-specific IgA can induce eosinophil degranulation. The aim of this study was to quantitate Bet v 1-specific IgA in relation to total IgA in the nasal fluid of children with birch pollen-induced intermittent allergic rhinitis and healthy controls, after allergen challenge and during the natural pollen season. Eosinophil cationic protein (ECP), Bet v 1-specific IgA and total IgA were analyzed in nasal fluids from 30 children with birch pollen-induced intermittent allergic rhinitis and 30 healthy controls. Samples were taken before the pollen season, after challenge with birch pollen and during the pollen season, before and after treatment with nasal steroids. During the pollen season, but not after nasal allergen challenge, Bet v 1-specific IgA increased in relation to total IgA in children with allergic rhinitis. No change was found in the healthy controls. The ratio of Bet v 1-specific IgA to total IgA increased from 0.1 x 10(-3) (median) to 0.5 x 10(-3) in the allergic children, p < 0.001. No change was seen after treatment with nasal steroids, although symptoms, ECP and eosinophils were reduced. In conclusion, allergen-specific IgA in relation to total IgA increases in nasal fluids during the pollen season in allergic children but not in healthy controls. These findings are compatible with the hypothesis that allergen-specific IgA plays a role in the allergic inflammation and further studies are needed to clarify the functional role of these allergen-specific antibodies.     

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.     

Five‐grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents

Halken S, Agertoft L, Seidenberg J, Bauer C‐P, Payot F, Martin‐Muñoz MF, Bartkowiak‐Emeryk M, Vereda A, Jean‐Alphonse S, Melac M, Le Gall M, Wahn U. Five‐grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents.
Pediatr Allergy Immunol 2010: 21: 970–976.
© 2010 John Wiley & Sons A/S The efficacy and safety of five‐grass pollen 300IR sublingual immunotherapy (SLIT) tablets (Stallergènes SA, France) have previously been demonstrated in paediatric patients. This report presents additional data concerning efficacy at pollen peak, efficacy and safety according to age, nasal and ocular symptoms, use of rescue medication, satisfaction with treatment and compliance. Children (5–11 yr) and adolescents (12–17 yr) with grass pollen–allergic rhinoconjunctivitis were included in a multinational, randomized, double‐blind, placebo‐controlled study and received either a 300IR five‐grass pollen tablet or placebo daily in a pre‐ (4 months) and co‐seasonal protocol. The severity of six symptoms (sneezing, rhinorrhoea, nasal congestion, nasal and ocular pruritis, and tearing) was scored, and rescue medication use was recorded daily during the pollen season. Patient satisfaction was recorded at the season end. A total of 161 children and 117 adolescents were evaluated (n = 267). 300IR SLIT was effective over the whole season (p = 0.0010) and at the pollen peak (p = 0.0009). The adjusted mean difference between 300IR and placebo groups was significant for both nasal (p = 0.0183) and ocular (p < 0.0001) symptoms. Rescue medication use was statistically lower in the SLIT group during the pollen season and at the pollen peak (both p < 0.05). More patients in the SLIT group were satisfied with their treatment compared to placebo (83.2% vs. 68.1%, p = 0.0030), and compliance was high (SLIT 93.9% of patients were compliant, placebo 94.8% of patients were compliant). SLIT was well tolerated by children and adolescents. 300IR five‐grass pollen tablets are effective and safe during the pollen season and at the pollen peak in children and adolescents with grass pollen rhinoconjunctivitis.     

Comparison between serial skin-prick tests and specific serum immunoglobulin E to mite allergens

Sensitization to dust mite allergens can be determined by means of a skin-prick test (SPT) or by measurement of specific IgE antibodies in serum (sIgE). In our study, concordance of the results of both methods was analyzed on the basis of reproducible SPT results. Three consecutive SPTs were performed on 138 school children (age 6–8 years) at one-year intervals. SIgE was determined at the end of a two-year observation period. Seven common inhalant allergens (Dpt, Df, birch pollens, hazel pollens, grass pollens and cat and dog dander) were analyzed. The majority of subjects with positive SPT reactions to the respective allergen also showed sIgE (Dpt: 82/86; Df: 53/53; cat dander: 31/32; dog dander: 6/9; birch pollens: 29/31; hazel pollens: 22/22; grass pollens: 37/37). A significant correlation between the SPT [weal diameter (P₁) or allergen/histamine ratio (P₂)] and sIgE was found for Dpt (P₁ = 0.004/P₂ = 0.016), birch pollens (P₁ = 0.002/P₂ = 0.0001) and grass pollens (P₁ = 0.0005/P₂ = 0.0001). There was also a significant correlation between sIgE to Dpt and to either Der p 1 (p = 0.0001) or Der p 2 (p = 0.0001), as well as between sIgE of both major allergens (p = 0.0001). In the analysis of co-sensitization of Dpt and Df, most subjects sensitized to Dpt were also sensitized to Df (57/91). Children with sIgE to Dpt (n = 87) usually showed sIgE to Df (n = 83). In this study, SPT and sIgE results are concordant and appear equivalent when using reproducible SPTs. Therefore, in the case of a positive Dpt result, additional testing for sensitization to Df can be regarded as redundant when Dpt and Df are the major contributors to the allergen content of house dust.     

The effects of grass pollen allergoid immunotherapy on clinical and immunological parameters in children with allergic rhinitis

Allergoid immunotherapy is a new form of allergen immunotherapy allowing safe administration of high allergen doses. There is limited information on the effects of allergoid immunotherapy in children with allergic rhinitis. To investigate the immunological and clinical effects of allergoid immunotherapy in children with allergic rhinitis due to grass pollen allergy. Children with allergic rhinitis were assigned to allergoid immunotherapy (n = 27) or control (n = 26, no immunotherapy) groups. Children in the immunotherapy group received seven injections of grass pollen allergoid immunotherapy before grass pollen season and continued to receive maintenance immunotherapy for 27 months. All patients were offered a pharmacotherapy regimen to be used on demand during the pollen seasons. Clinical and laboratory parameters were compared between the immunotherapy and control groups. The rhinoconjunctivitis symptom-medication score and asthma symptom score were lower in the immunotherapy group after 1 yr of maintenance immunotherapy (p < 0.01 for both). Skin test reactivity and nasal reactivity as determined by nasal provocation testing for grass pollen were significantly decreased after 1 yr of immunotherapy (p < 0.001 for both). The seasonal increase in bronchial reactivity and nasal lavage eosinophil cationic protein levels were prevented after the first year of immunotherapy (p < 0.05 for both). The seasonal increase in immunoglobulin (Ig)E decreased (p < 0.05) and grass-specific IgG, IgG(1) and IgG(4) increased significantly already at the end of the seven-injection build-up therapy (p < 0.001, for all). Interleukin (IL)-4 levels in the culture supernatants showed a steady decline from baseline at first and second year of immunotherapy (p < 0.001) but remained unchanged in the control group. Allergoid immunotherapy is an effective method in the treatment of grass pollen-induced allergic rhinitis in children and prevents the seasonal increase in bronchial hyper-reactivity. Changes in specific IgE and IgG levels and decreased IL-4 production in peripheral blood mononuclear cell culture supernatants may account for the observed clinical effects.     

Spezifische Immuntherapie (SIT, Hyposensibilisierung) im Kindesalter

Allergen-specific immunotherapy

Allergen-specific immunotherapy (SIT: specific immunotherapy, hyposensizitation) represents at present the single therapeutic entity for allergic disease, which reduces symptom burden and demonstrates disease-modifying effects.

Indications

In children with allergic rhinitis/rhinoconjunctivitis, allergic asthma, and systemic reactions to hymenoptera stings, SIT has proven efficacy. The use of SIT in children with atopic dermatitis and oral allergy syndrome is under discussion. Prerequisites for the initiation of SIT are the detection of IgE (immunoglobulin E) antibodies or evidence of sensitization with the skin prick test to clinically relevant allergens, the availability of allergen extracts with proven efficacy for the underlying allergic disease, and the impossibility of allergen avoidance.

Contraindications

Contraindications for SIT are partially or fully uncontrolled asthma [FEV₁ <?70?% (FEV₁: forced expiratory volume in 1 s)], severe acute autoimmune disorders, severe immunodeficencies, acute inflammatory syndromes, malignancies, treatment with β-blockers and ACE (angiotensin-converting enzyme) inhibitors and cardiovascular diseases with increased risk of adverse events during administration of epinephrine.     

Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: First results of ETA®

There is a common progression known as the allergic march from atopic dermatitis to allergic asthma. Cetirizine has several antiallergic properties that suggest a potential effect on the development of airway inflammation and asthma in infants with atopic dermatitis. Methods. Over a two year period, 817 infants aged one to two years who suffered from atopic dermatitis and with a history of atopic disease in a parent or sibling were included in the ETAC^® (Early Treatment of the Atopic Child) trial, a multi-country, double-blind, randomised, placebo-controlled trial. The infants were treated for 18 months with either cetirizine (0.25mg/ kg b.i.d.) or placebo. The number of infants who developed asthma was compared between the two groups. Clinical and biological assessments including analysis of total and specific IgE antibodies were performed. Results. In the placebo group, the relative risk (RR) for developing asthma was elevated in patients with a raised level of total IgE (≥ 30 kU/I) or specific IgE (≥ 0.35 kUA/I) for grass pollen, house dust mite or cat dander (RR between 1.4 and 1.7). Compared to placebo, cetirizine significantly reduced the incidence of asthma for patients sensitised to grass pollen (RR = 0.5) or to house dust mite (RR = 0.6). However, in the population that included all infants with normal and elevated total or specific IgE (intention-to-treat - ITT), there was no difference between the numbers of infants developing asthma while receiving cetirizine or placebo. The adverse events profile was similar in the two treatment groups. Discussion. Raised total IgE level and raised specific IgE levels to grass pollen, house dust mite or cat dander were predictive of subsequent asthma. Cetirizine halved the number of patients developing asthma in the subgroups sensitised to grass pollen or house dust mite (i.e. 20% of the study population). In view of the proven safety of the drug, we propose this treatment as a primary pharmacological intervention strategy to prevent the development of asthma in specifically sensitised infants with atopic dermatitis.     

标准化屋尘螨变应原特异性免疫治疗对儿童变应性鼻炎合并哮喘的临床疗效

目的 评估标准化屋尘螨变应原特异性免疫治疗(specific immunotherapy,SIT)对儿童变应性鼻炎合并哮喘的临床疗效.方法 选择我院42例接受标准化屋尘螨SIT的变应性鼻炎合并哮喘儿童为研究对象.所有患儿治疗前、治疗1年后均进行变应原皮肤点刺试验、测定血清屋尘螨和粉尘螨特异性IgE水平、进行肺功能测定和自觉症状评分.结果 治疗1年后屋尘螨和粉尘螨的皮肤指数和自觉症状评分均较治疗前显著降低(P＜0.01,P＜0.05),而治疗前后屋尘螨和粉尘螨特异性IgE水平、肺功能(肺活量、第1秒用力呼气量、最大呼气中段流量)均无明显变化(P＞0.05).结论 变应性鼻炎合并哮喘儿童给予SIT1年后其皮肤敏感性显著改善,临床症状明显好转,但对气道炎症的影响有待于进一步的观察.     

Levocabastine compared with sodium cromoglygate eyedrops in children with both birch and grass pollen allergy

Fifty–five children 6–16 years old with allergic rhinoconjunctivitis due to both birch and grass pollinosis were randomized into 2 parallel groups, treated in double–blind fashion with either levocabastinc (LEV) eye–drops twice daily plus placebo eyedrops twice daily or sodium cromoglycate (SCG) eyedrops 4 times daily for 3 months. Spersallerg® (antazolini chloride + tetryzolini chloride) eyedrops were allowed as rescue medicine. All children received basic treatment with an antihistamine (terfenadine) during the complete trial period, and a local nasal corticosteroid if needed. Eye symptoms were recorded daily by the patients and at 4 visits by the investigator, at start and after 4, 10 and 13 weeks. Pollen counts were performed and a blood sample was collected at start and end of the treatment. The global evaluation of treatment was similar for the 2 groups, and there was no significant difference in any effect parameter except for the symptom, itchy eyes, which had lower score in the SCG group as evaluated by the investigator after 4 weeks. On days with low pollen counts the patients in the SCG group had fewer days with moderate or severe eye symptoms. It is concluded that even though LEV and SCG eyedrops were given in addition to systemic treatment with an antihistamine, no consistently significant differences in clinical effect were found between the 2 treatment groups, but the SCG group experienced slightly less eye symptoms throughout the trial. LEV eye–drops appear safe in long–term treatment in children, and no signs of tachyphylaxis were recorded.     

Do the leukotriene receptor antagonists work in children with grass pollen‐induced allergic rhinitis?

Although cysteinyl-leukotriene receptor antagonists were recently approved for use in allergic rhinitis (AR), there has been no study to date investigating their application in children. The aim was to evaluate whether montelukast provides any benefit in nasal allergen challenge-induced symptoms in children, and whether it could improve the control provided by an antihistamine during pollen season. Two randomized studies, one a double-blind, placebo-controlled, nasal allergen challenge study and one an open-label, cross-over, parallel-group clinical study, were performed in 18 (11.7+/-0.7 years) and 32 children (10.5+/-0.5 years), respectively, with grass pollen allergy. In the first study, the effect of a single dose of montelukast and its combination with loratadine were compared with placebo on nasal responses induced by allergen challenge. In the second study, the additive effect of montelukast to loratadine was tested in an open-label cross-over clinical study. In the challenge study, early-phase and late-phase nasal reactions peaked at 15 min and 4 h after the challenge respectively. During the early phase, combination improved total nasal symptoms (p=0.004) during the first hour and sneezing (p=0.012) at 15 min compared with placebo group. During the late phase, montelukast (p=0.017) and combination (p=0.011) caused less nasal obstruction at 4 h and combination caused less sneezing at 6 h (p=0.015). In the clinical trial, montelukast provided protection on seasonal increase in pulmonary symptoms [0 (0, 14) vs. 6.5 (0, 27.7); p=0.016] and on the decrease in FEF25-75 [-0.09 (-0.34, 0.17) vs. -0.28 (-0.66, 0.02); p=0.002]. However, there was no improvement in nasal symptoms and flows. Although we showed protection against nasal challenge-induced congestion with montelukast, we were not able to show the same in the clinical study possibly because of low pollen counts and mildness of the symptoms of the patients with AR. However, montelukast provided better control of pulmonary symptoms and protection from seasonal decrease in lung function, indicating its potential therapeutic benefit in children with AR.     

Fetal peripheral blood mononuclear cell proliferative responses to mitogenic and allergenic stimuli during gestation

Blood samples were obtained from fetuses and premature babies (n=51) (15-34 weeks gestation) to determine at what stage the fetal immune system was able to produce a positive proliferative response to common allergens. Peripheral blood mononuclear cells (PB MC) were stimulated with the mitogen, phytohaemagglutinin (PHA), and the allergens, house dust mite, cat fur. birch tree pollen, β-lactoglobulin, ovalbumin and bee venom (mellitin). Results were expressed as ratios of stimulated to unstimulated ³H thymidine incorporation, and as percent positive responders. There was an increase in proliferation ratio which correlated with increasing gestational age for PHA (p < 0.0001), cat fur (p=0.042), birch pollen (p=0.022) and β-lactoglobulin (p=0, 006). The point in gestation when cells from some individuals began responding to the allergens with a ratio of 2. 0 was at approximately 22 weeks. PBMC proliferative response ratios were higher from samples from babies > 22 weeks gestation compared to < 22 weeks for the mitogen and all allergens, except mellitin. There was also a greater proportion of positive responders from samples > 22 weeks compared to < 22 weeks for the mitogen and all allergens, except mellitin. Maternal exposure to birch pollen, which has a discrete season, was assessed to determine whether exposure had occurred at 22 weeks gestation or beyond. Results showed a higher prolifera tive response in infant cells stimulated with birch pollen (p=0.005) and higher proportion of positive responders (p=0.01) in the group of babies whose mothers had been exposed to hirch pollen beyond 22 weeks, compared to those whose mothers had not been so exposed. These results suggest that in utero fetal exposure to an allergen from around 22 weeks gestation may result in primary sensitisation to that allergen, leading to positive proliferative responses, at birth.     

New visions in specific immunotherapy in children: an iPAC summary and future trends

Specific immunotherapy is indicated for confirmed immunoglobulin E-mediated airway diseases using standardized allergen products with documented clinical efficacy and safety. For decades the subcutaneous route of administration (SCIT) has been the gold standard. Recently, the sublingual immunotherapy (SLIT) has also been investigated in children. SCIT, especially with grass and birch pollens but also house dust mites, is an effective treatment in children with allergic rhinitis and asthma when a significant part of their symptoms are caused by these allergens. A long-term effect up to 12 yr after discontinuation of SCIT with timothy allergen has been shown. Efficacy and safety of SLIT in pollen allergic rhinoconjunctivitis have been demonstrated in adults. The evidence in children is a little less convincing, and more data is needed. The clinical relevance, long-term results and the size of the effect, as well as the dose, the treatment regimen and duration has not been sufficiently elaborated. It is demonstrated that SCIT has the potential for preventing the development of asthma in children with allergic rhinoconjunctivitis. Also one randomized study indicates a preventive effect of SLIT in children on the development of asthma. At present, there are no studies who clearly demonstrates either a long-term effect or a preventive effect on the development of asthma of SLIT in children. The areas with lack of evidence should be addressed in well performed prospective, randomized long-term studies both with SCIT and SLIT. This review was initiated by iPAC (international Pediatric Allergy and Asthma Consortium) and aims to review current knowledge related to specific immunotherapy in childhood, and to identify needs for future research in this field.     

Results of specific hyposensitization in children with pollinosis

Hyposensitization was carried out in 120 children aged 5 to 15 years with proven sensitivity to various pollen for 3 to 5 years before the start of the season. By reason of the results of intracutaneous tests 90 patients were treated with mixed pollen allergen and 30 patients with grass pollen allergen. A retrospective study was undertaken on the base of a questionnaire. Every year after the season duration and severity of symptoms as well as consumption of medicine were registered. The total success of hyposensitization amounted to 70.8% and this result varied on the one hand in dependence of the duration of disease on the other hand in dependence of the duration of treatment. A more inconvenient result was seen in those children who suffered from asthmatic symptoms exclusively compared to patients with hay fever. Local side effects resulted sporadically in 71.5% and systemic side effects in 15.7% by subcutaneous injection of depot-pollen allergen. Despite of extensive and not indifferent mode of treatment, hyposensitization should be performed in a correct way as soon as possible after exact indication.     

Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis

Increased plasma tumour necrosis factor (TNF) concentration correlates with mortality in sepsis. We suggested that pentoxifylline (PTXF), which is known to inhibit TNF production, may improve survival and attenuate clinical symptoms of sepsis in neonates. Plasma TNF levels were evaluated in 29 newborn infants with sepsis. Patients were randomly assigned into two groups, receiving PTXF in a dose of 5 mg/kg per hour for 6 h or placebo (saline), on 3 successive days. Both groups were subjected to the same conventional therapy. TNF was evaluated before and after PTXF or placebo administration on the 1 st and 3rd days of therapy. There was a statistically significant decrease in plasma TNF level in the PTXF group when the values before the first and after the last PTXF infusion were compared [mean: 671.5 pg/ml; SD: 438; med: 729.6 vs mean: 41.0 pg/ml; SD: 64.1; med: 11.5;P<0.000004]. In the placebo group, decrease was not significant [mean: 633.0 pg/ml SD: 488.6; med: 618.9 vs 246.9 pg/ml; SD: 243.9; med: 191.0]. A significantly higher plasma TNF level, evaluated after the last PTXF infusion, was found in the placebo group [246,9 pg/ml vs 41.0 pg/ml;P<0.001]. Only one of four infants with signs of shock in the placebo group survived, whereas all of five newborns with symptoms of shock in the PTXF group survived [P<0.04]. An increased incidence of metabolic acidosis [P<0.05], necrotizing enterocolitis [P<0.04] and renal insufficiency [P<0.05] was observed in infants in the placebo group.Conclusion PTXF inhibits production of TNF and may have therapeutic value in the treatment of premature infants with sepsis complicatea by shock.