Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children.

BACKGROUND: A 3-year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long-term preventive effect, we performed a follow up--2 years after termination of immunotherapy. METHODS: A total of 183 children, aged 6-14 years with grass and/or birch pollen allergy could be investigated 2 years after discontinuation of SIT or no treatment. Conjunctival provocation tests (CPTs) and methacholine bronchial provocation tests were carried out during the season and winter after 5 years. The development of asthma was assessed by clinical evaluation. RESULTS: The significant improvement in hay fever and CPT results observed after 3 years of SIT persisted at the 5-year follow-up. No difference in bronchial responsiveness to methacholine was found after 5 years because of spontaneous improvement during the follow-up period in the control patients. The immunotherapy-treated children had significantly less asthma after 5 years as evaluated by clinical symptoms [odds ratio 2.68 (1.3-5.7)] in favor of SIT for prevention of development of asthma and significantly less patients reported an increase in asthma scores (P < 0.01). CONCLUSION: Immunotherapy for 3 years with standardized allergen extracts of grass and/or birch shows long-term clinical effect and preventive effect on development of asthma in children with seasonal rhinoconjunctivitis.

Absence of systemic immunologic changes during dose build-up phase and early maintenance period in effective specific sublingual immunotherapy in children.

BACKGROUND: Sublingual immunotherapy (SLIT) has been reported to be a safe treatment for inhalant allergies in children. Yet the immunologic mechanisms resulting in clinical improvement are poorly understood. OBJECTIVE: To identify early systemic immunologic changes during the first 8 weeks of clinically effective SLIT to grass pollen, tree pollen or house dust mite in paediatric patients with allergic rhinoconjunctivitis and/or asthma. METHODS: Peripheral blood mononuclear cells and plasma samples of 13 children with reduced symptoms after 1 year of SLIT were obtained before therapy and at 2 and 8 weeks after the initiation of SLIT. Allergen-specific lymphocyte proliferation assays were performed, and allergen-induced cytokine production (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta(1)) was measured by ELISA and flow cytometry. Allergen-specific IgE, IgG1, IgG4, and IgA levels in plasma samples were determined in ELISA. RESULTS: During the first 8 weeks of successful SLIT, allergen-specific lymphoproliferation (n=13) as well as levels of allergen-specific intracellular (n=8) and secreted cytokines (n=9) did not change significantly. In addition, no alterations in levels of allergen-specific Igs (n=7) were observed. CONCLUSION: We could not find any early systemic immunologic changes during the first 8 weeks of clinically effective SLIT to inhalant allergens in paediatric patients with allergic rhinoconjunctivitis and/or asthma.

Prenatal contact with inhalant allergens.

Pollen contact in early infancy may enhance the risk for subsequent pollen allergy. In this study likelihood of a prenatal antigen contact, as a result of inhalation of pollen allergens by the mother, was investigated. Due to the seasonal occurrence of allergens studied, the date of priming can be estimated, and this can supply data about the maturation of the fetal immune system. Proliferative responses of umbilical cord blood mononuclear cells (UCB MNCs) to the recombinant major allergens of birch (rBet v 1) and timothy grass (rPhl p 1) were analyzed throughout the whole year. A positive proliferative response was regarded as the criterion for a prenatal contact of the immune system with the allergen. Prenatal priming with both allergens was observed. Timothy grass pollen displayed considerably higher antigenicity than did birch pollen. The susceptibility of the fetal immune system to be primed by these allergens varies during the gestation period. The majority of positive responses to rPhl p 1 and rBet v 1 were found in UCB samples in which antigen contact (the respective pollen season) took place in the first 6 mo of pregnancy. Our results offer indirect evidence that, shortly after migration of T cell precursors to the epithelial thymus, T cells are mature enough for priming with antigens. No relationship was found between the susceptibility of the fetal immune system to be primed by these allergens and the clinical history of the family concerning type I allergy.

Early sensitization to airborne allergens.

We report the case of a 7-month-old child with failure to thrive. Celiac disease was suspected because of highly raised antigliadin IgA and IgG antibodies and subtotal villous atrophy. In peripheral blood mononuclear-cells cellular proliferation was found in response to birch pollen, rye pollen and hazelnut extract. Born in June 1992 the infant had not yet experienced a birch pollen season. He had been fed with birch pollen allergy-associated carrot, apple and potato beginning at 6 weeks of life. In the serum, specific IgG, IgM and IgA to birch pollen and profilin, rye pollen and hazelnut antigens were detectable, indicating possible in utero sensitization or T cell cross-reactivity due to early sensitization with related food antigens.

Oral immunotherapy with grass pollen in enterosoluble capsules. A prospective study of the clinical and immunological response.

In a prospective study spanning 2 years, 60 patients with grass pollen allergy were treated with either a low dose oral, a high dose oral or a subcutaneous hyposensitization regime. No significant improvement was seen in the orally treated patients whereas those on the subcutaneous hyposensitization regime demonstrated a decreased specific cutaneous reactivity, a rise in specific IgG antibodies and a reduction in symptoms. This study suggests that oral hyposensitization, even with enterosoluble grass pollen capsules, is ineffective.

The subclass of IgG antibody in allergic disease: II. The IgG subclass of antibodies produced following natural exposure to dust mite and grass pollen in atopic and non-atopic individuals.

In an attempt to understand the role of the different IgG subclasses in allergic disease, we have studied the subclass of IgG antibody to dust mite (HDM) and grass pollen (GP) produced as a result of natural exposure. Studies were carried out on 40 atopic children and 100 atopic adults who had never received immunotherapy. Thirty-two non-atopic adult controls were also studied. The specificity of the assay for IgG antibodies to dust mite was confirmed by inhibition with the homologous extract but not mite culture medium or fetal calf serum. IgG1 antibodies to HDM could be detected in most atopics (94%) and non-atopics (97%), and similar results were obtained for GP (81% and 100%, respectively). IgG4 antibodies to HDM were detected in more atopics (66%) than non-atopics (53%) and the difference was more marked for GP (72% vs. 19%). While the levels of IgG1 antibodies were not significantly different in the two groups, the levels of IgG4 antibodies were much lower in the non-atopics (P less than 0.001, Mann-Whitney U-test). These data show that all subjects were capable of recognizing and mounting an IgG1 antibody response to these inhaled antigens. Atopic individuals differed from normal subjects in the frequency with which they made IgG4 antibodies in response to natural exposure to both dust mites and pollen.

[Allergen immunotherapy with an immunochemically characterized grass pollen extract: change in follow-up sensitization parameters]. / Allergen-Immunotherapie mit einem immunchemisch charakterisierten Gräserpollen-Extrakt: Anderung der Sensibilisierungsparameter im Verlauf.

A perennial hyposensitization treatment over 2 years was performed in 18 pollen-allergic patients (14 children, 4 adults) with a standardized and purified graspollen extract. The selection for therapy was provided by allergen titration in skin prick test, conjunctival test and by the estimation of specific IgE to timothy. The reported decrease of seasonal symptoms was accompanied by reduced sensitivity in skin test and conjunctival provocation test (p less than 0.001, p less than 0.05). No consistent change in specific IgE was observed at the end of the study. Specific IgG antibodies significantly rised and persisted (p less than 0.001). A successful hyposensitization treatment with graspollen could be monitored by in-vivo and in-vitro parameters.

Combination of parenteral and oral immunotherapy in grass pollen-allergic children. A double-blind controlled study of clinical and immunological efficacy.

Twenty patients with a proven sensitization to grass pollens were treated with parenteral "priming" and subsequently with either oral "booster" (n = 10) or placebo (n = 10) extension course. The study was carried out in a double-blind manner. Cumulative preseasonal parenteral dosage was 3,100 NU (Noon Units), patients in the oral group subsequently received 123.9 mg of grass pollen extract during the pollen season. No side effects were noted after intake of the oral preparation. No significant difference (95% confidence interval) were noted comparing results of in vivo (skin prick test and conjunctival provocation test) and in vitro tests (specific serum IgE- and IgG-antibodies) between the two groups. Analysis of symptom and medication scores as well as subjective assessment of patients revealed no superiority of oral "booster" over placebo. Data obtained in this study does not support the concept of combined parenteral and oral treatment. This is in contrast to work reported previously.

The use of monoclonal and polyspecific antibodies in the IgE sandwich ELISA.

The use of antibody to link antigen to microtitre plates in the enzyme-linked immunosorbent assay (ELISA) has been extended to include mouse monoclonal antibodies and polyspecific rabbit antibodies. Small amounts of both reagents could be used. The capacity of the microtitre plate for the antibody was found to be critical and irradiated plates generally gave better results. Both rabbit anti-IgE conjugated to horseradish peroxidase, and monoclonal mouse anti-IgE with alkaline phosphatase-conjugated rabbit anti-mouse IgG could be used as detection reagents. Comparison with the radioallergosorbent (RAST) test showed a good agreement with the sandwich ELISA. The sandwich ELISA using polyspecific rabbit antibody was substantially more sensitive than conventional ELISA and also marginally more sensitive than RAST.

Discontinuation of bee venom immunotherapy in children and adolescents.

Sixty-six patients with a history of systemic allergy reactions to bee stings, positive skin prick test to less than or equal to 100 micrograms/ml bee venom, and positive radioallergosorbent test (RAST) results were given venom immunotherapy. IgE and IgG antibodies to bee venom were measured by RAST and enzyme-linked immunosorbent test (ELISA), respectively. IgE and IgG anti-bee venom levels rose initially, but subsequently fell during immunotherapy. In 31 patients in whom specific IgE fell to low (less than 6% counts bound) or unmeasurable levels, immunotherapy was discontinued, and sting challenge was carried out 1 to 3 years later. All patients tolerated sting challenge well. The specific IgE and IgG antibody levels did not change significantly after treatment was stopped. Our data suggest that hyposensitization treatment can be stopped when specific IgE serum concentrations have fallen to low or unmeasurable levels and specific IgG antibody values are maintained, and that in a considerable number of patients venom immunotherapy has a lasting therapeutic and immunologic effect.

[Efficacy of oral and parenteral hyposensitization with pollen extracts]. / Untersuchungen zur Wirksamkeit oraler und parenteraler Hyposensibilisierung mit Pollen-Extrakten.

Hyposensitization was undertaken in 26 children, aged 4-15 years, with proven sensitivity to grass and wheat pollen, in some orally (ten), in others parenterally (16), for two years before the start of the season. The administered cumulative dose with oral hyposensitization was 1,750,000 PNU (protein nitrogen units), corresponding to 3,500,000 NU (Noon units), and on parenteral sensitization 1,550 PNU, corresponding to 3,100 NU. A symptoms score was registered daily during the pollen season. It showed fewer symptoms in those with parenteral hyposensitization, although subjective assessment of the success of treatment did not indicate any difference between the two groups. Oral hyposensitization produced a higher IgE and a lower IgG immune response. Systemic side-effects were noted in half of those after oral but none after parenteral hyposensitization. Measured by side-effects, the cumulative dose and expense, the effectiveness of oral hyposensitization is inferior to parenteral administration.

[Protective effect of ketotifen and disodium cromoglycate in bronchial challenge tests with allergens (author's transl)]. / Schutzwirkung von Ketotifen und Dinatrium cromoglicicum auf die inhalativ provozierte allergogene Bronchialobstruktion.

The protective effect of ketotifen and disodium cromoglycate (DSCG) was evaluated by a randomised double blind cross-over study in 15 children with allergic bronchial asthma. 13 children were allergic to house dust mite (Dermatophagoides pteronyssinus), two to grass pollen. After a positive bronchial challenge test ketotifen or DSCG was given for 4 days followed by bronchial challenge with increasing allergen concentrations. Seven patients showed better allergen tolerance after ketotifen, 5 after DSCG. Protective action against late reactions was found only in 2 children after ketotifen and one child after DSCG.

[Hyposensitisation treatment with pure bee venom (author's transl)]. / Die Hyposensibilisierungsbehandlung mit reinem Bienengift.

Hyposensitisation with pure bee venom was undertaken in eleven persons with proven allergy to bee stings. Rapid hyposensitisation led to side effects in seven of them during dosage increase. Serial determination of total IgA, IgG, IgM and alpha1-antitrypsin revealed no changes, while allergen-specific IgG and IgE and total IgE increased maximally after 30 days. All persons were exposed to one bee sting during the treatment: all tolerated it well without the allergic reactions which had previously been noted.

[The clinical application of allergen-specific and total IgE determination in pediatric allergology (author's transl)]. / Klinische Anwendung der allergen-spezifischen und Gesamt-IgE-Bestimmung in pädiatrischer Allergologie

Allergen specific IgE determination (Radio-Allergen-Sorbens-Test) were carried out on 150 patients 2 to 14 years old. The agreement with classical skin tests (Prick and intracutaneous tests) was for pollen allergies 87%, for allergies against house-dust and house-dust mites 80% and for allergies against animal denders 69%. There was however no agreement for allergies against molds (only 11%). The total IgE was measured in 51 children by radial immunodiffusion, pathologically high levels were found in 45% of patients. Allergen-specific IgE determinations (RAST) seem to be especially useful for young allergic children.