Oral immunotherapy in birch pollen hay fever

Previous controlled trials with oral administration of allergen have not demonstrated any treatment effect in patients with allergic rhinoconjunctivitis or asthma. In the present double-blind, placebo-controlled trial, we have tested the effect of oral immunotherapy in adult patients with birch pollinosis. Thirty-nine patients completed this 18-month study comprising two birch pollen seasons. The patients received enterosoluble capsules daily, and the actively treated patients reached a cumulated dose of 280 times 10(6) biologic units of birch pollen extract, which is about 200 times higher than the dose used in conventional subcutaneous immunotherapy. We found a significant decrease in eye symptom scores and conjunctival sensitivity to birch pollen, as determined by conjunctival provocation test, as well as a numerical but nonsignificant decrease in nasal symptom scores, nasal sensitivity as determined by nasal provocation test, and antiallergic medication. The treatment was safe, and only a few slight side effects were observed. We thus conclude that our study demonstrates a clinical effect of oral immunotherapy in birch pollinosis.     

The safety and efficacy of subcutaneous birch pollen immunotherapy - a one-year, randomised, double-blind, placebo-controlled study

BACKGROUND: There is only very limited documentation of the efficacy and safety of high-dose subcutaneous birch pollen immunotherapy (IT) in double-blind, placebo-controlled (DBPC) studies. Birch pollen is a major cause of allergic morbidity in northern Europe and in eastern parts of North America. METHODS: Thirty-five patients with severe rhinoconjunctivitis (hay fever) to birch pollen were allocated to double-blinded clustered IT with a depot birch pollen extract (Betula verrucosa) or placebo injections. Seven patients in each group had concomitant self-reported seasonal asthma. Treatment was conducted as a clustered regimen and was performed in a specialist unit. Symptom scores from nose, eyes, and lungs, and use of oral and topical antihistamines, beta-2-agonists, and oral corticosteroids were recorded daily during the season of 2000. Sensitivity to allergen provocation in skin, conjunctiva, and nasal mucosa was measured before and after 10 months of treatment. Post-seasonal assessment of symptom severity was performed using a simple questionnaire. RESULTS: IT reduced the symptom score for both rhinoconjunctivitis and asthma (P-values < 0.05), total medication score (P < 0.02) and use of oral antihistamines (P < 0.01). IT reduced specific conjunctival sensitivity (P < 0.05), skin prick test, and especially cutaneous late-phase response diameters (P < 0.00001), and increased general well-being on post-seasonal evaluation (P < 0.01). IT was safe, with side-effects at the same level as placebo. CONCLUSIONS: High-dose, subcutaneous IT is efficacious and safe in patients with severe birch pollen rhinoconjunctivitis and asthma.     

Clinical pharmacology of H1-antihistamines in the skin

BACKGROUND: Birch pollen is a common allergen in northern, central, and eastern Europe. Earlier studies of specific immunotherapy using birch pollen extract were not placebo-controlled or were only preseasonal. Long-term, placebo-controlled studies with subcutaneously administered standardized birch pollen extract are lacking. OBJECTIVE: The aim of this study was to evaluate the effect of immunotherapy with birch pollen extract on airway symptoms and use of medication in adult birch pollen-allergic patients in a double-blind, placebo-controlled trial. METHODS: Forty-nine patients with histories of birch pollen allergy from the upper and lower airways, positive skin prick test and conjunctival provocation test results, and in vitro specific IgE to birch pollen (Betula verrucosa ) extract were included. Immunotherapy with birch pollen extract was given during 2 consecutive years in a double-blind, randomized, placebo-controlled study. Clinical symptom scores from the upper and lower airways and use of rescue medication were registered throughout the pollen season. RESULTS: Forty-six patients reached the maintenance dose and were maintained on that dose during the 2-year study. The median symptom scores during the 1997 and 1998 seasons were 1.3 and 2.6, respectively, in the specific immunotherapy group and 2.1 and 4.3, respectively, in the placebo group. The differences between the groups were significant (P =.05 in 1997 and P =.005 in 1998). The placebo group used significantly more rescue medication during both seasons than the specific immunotherapy group (P =.004 for 1997 and P =.004 for 1998). CONCLUSION: Specific immunotherapy with birch pollen extract is an effective and safe treatment for reducing clinical allergy symptoms and medication use in birch pollen-allergic patients during the pollen season.     

Cross-reactivity between deciduous trees during immunotherapy. I. In vivo results

Thirty-nine children with rhinoconjunctivitis due to birch pollinosis were given immunotherapy for 3 years with a potent, purified pollen preparation made from either birch alone or from a mixture of birch, alder and hazel. The therapy was evaluated with self-evaluation after each season, daily symptom score during the season, conjunctival provocation test and skin-prick test. All children but one considered that their condition had been improved by the treatment. Symptom scores decreased slightly more in the group treated with the mixture than in the group treated with birch only due to symptoms decreasing faster in the mixture treated group after each pollen peak (P< 0.001). The sensitivity of the conjunctiva and the skin decreased significantly in both groups but without any significant differences between the groups. After 3 years the conjunctival sensitivity correlated strongly to eye symptoms during the season. Immunotherapy with a mixture of birch, alder and hazel appears to be at least as effective as a preparation made from birch only when treating birch pollinosis even in a region where birch is totally dominating among the pollens from deciduous trees.     

Intramuscular betamethasone dipropionate vs. oral prednisolone in hay fever patients

In a double-blind group comparative study, 36 adult, birch pollen-allergic outpatients with seasonal rhinoconjunctivitis, were treated with either oral prednisolone 7.5 mg daily for 3 weeks or an injection with 2 ml suspension of betamethasone dipropionate and betamethasone disodium phosphate (Diprospan) immediately prior to the birch pollen season. Both treatments were able to prevent an increase in symptoms from the nose and the eyes during the 3-week birch pollen season. There was no significant difference in symptom score or nasal peak flow between the two treatments. However, there was a significant suppression of adrenal gland function after oral prednisolone treatment in contrast to Diprospan treatment. Unless there are contraindications for treatment with depot steroid injections (children, pregnant women, patients suffering from peptic ulcer, tuberculosis, eye disease, herpes, hypertension or diabetes) it seems to be a reasonable alternative to oral prednisolone in hay fever patients.     

Nasal challenge testing in grass pollen hay fever.

Nasal sensitivity to rye grass pollen allergens was evaluated by provocation testing in patients with hay fever due to grass pollen using measurements of nasal airways resistance (NAR), a reproducible system for delivery of allergen, and stringent criteria for allergen storage. Reproducibility was assessed in 24 subjects with hay fever by nasal provocation with serial dilutions of Lolium perenne allergens on 3 occasions: during the grass pollen season, immediately after the season, and in early winter. Threshold doses of allergen required to double the saline control NAR or to provoke persistent sneezing and rhinorrhea were slightly higher 1 mo after the pollen season, but there was no significant differences between threshold doses during the pollen season and 8 mo later. When the threshold doses during challenges were exceeded, there were late reactions in 4 of 24 patients. Normal subjects and patients with perennial rhinitis and with negative skin tests to L. perenne extract were unresponsive in nasal challenge tests.     

Challenge tests and specific IgE in hay fever sufferers

The relationship between challenge tests, specific IgE and seasonal effects in hay fever sufferers was studied. There were significant relationships between nasal challenge, conjunctival challenge and skin-prick test threshold doses, although the skin and conjunctiva tended to be less sensitive than the nose. A seasonal effect was apparent on nasal challenge, but not conjunctival challenge or skin-prick testing, with lower threshold doses recorded after the pollen season than in midwinter. There was a significant relationship between specific IgE and nasal challenge, but not conjunctival or skin-prick test threshold doses.     

The seasonal symptoms of hyposensitized and untreated hay fever patients in relation to birch pollen counts: correlations with nasal sensitivity, prick tests and RAST

A 2 year prospective study of thirty-eight birch pollen-sensitive hay fever patients under specific immunotherapy and of nineteen untreated control patients showed a significant correlation between the total seasonal symptom scores of the patients and their clinical sensitivities assessed by the RAST and a graded nasal test. The agreement between a positive nasal test and a positive RAST was 74%. In the early season with low pollen counts the onset of symptoms was significantly associated with high sensitivity of the patients, while many patients showed symptoms in the late season irrespective of their nasal and RAST sensitivity. About 90% of both the treated and the untreated patients reported mild symptoms when the pollen count exceeded 80/m³ in the early season. 80% of them still had symptoms when the count was below 30/m³ in the late pollen season. Although hyposensitization therapy had no effect on the occurrence of the mild symptoms, the treated patients had severe symptoms significantly less often than the untreated ones on days with high pollen counts.     

Treatment of hay fever with loratadine - a new non-sedating antihistamine

The efficacy and safety of loratadine, a new orally active specific H1-receptor blocking antihistamine with poor penetration into the CNS, was evaluated in a double blind comparative study. One hundred and seven hay fever patients, sensitive to birch pollen, were randomized into three parallel groups receiving loratadine 40 mg once daily, clemastine 1 mg twice daily, or placebo during the birch pollen season. Both active treatments showed reduction of symptoms in comparison with placebo, but the results were more pronounced with loratadine treatment, which significantly reduced the overall allergic condition as well as all separate allergic rhino-conjunctivitis symptoms except nasal stuffiness. Compared with placebo the sedation rate was significantly higher with clemastine treatment (P less than 0.05) but not with loratadine. Loratadine was thus concluded to be efficacious in hay fever treatment with a sedation rate not differing from placebo.     

Asymptomatic skin sensitization to birch predicts later development of birch pollen allergy in adults: a 3-year follow-up study

BACKGROUND: The skin prick test is the allergologic test of choice, but asymptomatic skin sensitization to aeroallergens is common. However, no data in the literature describe the clinical phenotype of asymptomatic sensitized adults. OBJECTIVE: The purposes of this investigation were to provide a clinical characterization of skin test-positive subjects without symptoms and to ascertain the predictive values of common allergologic tests. METHODS: Asymptomatic adults with positive skin prick test results for birch (n = 15), nonatopic control subjects (n = 25), and birch pollen-allergic patients (n = 6) were followed through use of daily diary cards during 3 consecutive birch pollen seasons. At inclusion and at the 3-year follow-up visit, conjunctival and nasal challenges, intradermal late-phase reaction evaluation, and measurement of specific IgE were performed. RESULTS: Asymptomatic sensitized subjects defined a clinically significant phenotype between nonatopic and allergic subjects in terms of specific IgE levels and susceptibility to conjunctival provocation testing. Sixty percent (n = 9) of the asymptomatic sensitized subjects developed clinical allergy. This was associated with an initial birch skin prick test weal diameter of > or =4 mm, a positive conjunctival provocation test result, and specific IgE of > or =CAP class 2, as well as with the presence of other allergies. Specific IgE of > or =CAP class 2 was 87.5% predictive for allergy development, whereas a negative conjunctival provocation test result was 100% negatively predictive. Nasal provocation testing possessed no additional prognostic information. No changes in clinical phenotype were seen in nonatopic or birch-allergic subjects. CONCLUSION: Asymptomatic skin sensitization is a risk factor for later allergy development. At risk is any subject with target organ sensitivity, an elevated specific IgE level, and/or a skin prick test weal diameter of >4 mm.     

A comparison of the clinical and immunological effects of an alum-precipitated five-grass extract with a conjugated two-grass extract in the desensitization of hay fever

Thirty-nine patients with pollen hay fever were randomly allocated to receive either an alum-precipitated five-grass extract (Allpyral®) or a two-grass conjugated extract (Conjuvac®) prior to the 1982 pollen season. Efficacy was assessed by means of symptom scores, drug usage and specific IgE and IgG antibody response. Both nasal and eye symptom scores were significantly higher during the pollen season in those patients receiving Allpyral. Specific IgE and IgG measured after the pollen season showed similar rises in each group. Seven patients showed a marked elevation in specific IgE and nine a marked elevation in specific IgG, but no patient showed both. Those with a high specific IgE level tended to be younger. Symptom scores bore no relation to either specific IgE or IgG antibodies. Side-effects were mainly local and were equal in both groups.     

Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis

BACKGROUND: Specific immunotherapy (SIT) and treatment with monoclonal anti-IgE antibody have complementary modes of action. OBJECTIVE: The purpose of this study was to determine whether combined therapy could provide better efficacy than either treatment alone. METHODS: We conducted a randomized, double-blinded trial to assess the efficacy and safety of subcutaneously administered anti-IgE (omalizumab) or placebo in children and adolescents with seasonal allergic rhinitis in both a birch pollen season and a grass pollen season (sequential seasons together lasting an average of 84 days). There were 4 treatment arms. Each subject was started on SIT-birch or SIT-grass, and anti-IgE or placebo was started before and maintained during the anticipated pollen seasons (a total of 24 weeks). The primary efficacy variable was symptom load, the sum of daily symptom severity score plus rescue medication use. RESULTS: A total of 221 subjects (intent-to-treat population) aged 6 to 17 years were analyzed for efficacy. Combination therapy reduced symptom load over the 2 pollen seasons by 48% (P <.001) over SIT alone. When analyzed separately by season, the 2 groups receiving unrelated SIT were considered placebo controls. In the grass season, symptom loads were as follows: unrelated (birch) SIT + placebo, 0.89 (reference value); unrelated (birch) SIT + anti-IgE, 0.49 (-45%); SIT-grass + placebo, 0.61 (-32%); SIT-grass + anti-IgE, 0.26 (-71%). CONCLUSION: Anti-IgE therapy conferred a protective effect independent of the type of allergen. Additional clinical benefit was demonstrated in both pollen seasons, whether there was coverage by SIT or not. This combination might prove useful for the treatment of allergic rhinitis, particularly for polysensitized patients.     

High dose grass pollen tablets used for hyposensitization in hay fever patients

Previous, placebo-controlled clinical trials with oral hyposensitization in grass pollinosis have been disappointing. Since the results possibly could be explained by too low doses of ingested allergens, the present study was initiated to evaluate the effect of high doses of allergens. Forty-two adults with symptoms in the grass pollen season and with grass pollen sensitivity demonstrated by skin prick test and conjunctival provocation test were included. Enterosoluble tablets were administered daily for 1 year. Twenty-two patients, who completed the study, received placebo and 17 mixed grass pollen allergens from rye grass, timothy grass, cultivated rye and velvet grass. Evaluated either by self-assessment or by symptom and medicine score before and after treatment, the group receiving pollens did not improve clinically compared the controls. During the study, conjunctival sensitivity decreased equally in the two groups, and changes in specific IgE, allergen-induced histamine release from blood cells and skin prick test were insignificant and with no difference between groups. Five patients, who received pollen allergens, had episodes of urticaria or angioedema, and a further three patients on the same treatment had slight gastrointestinal side effects. In conclusion, enterosoluble grass pollen allergens in contrast to birch pollens did not have any therapeutic effect, even in doses more than 4,000 times higher than those used for subcutaneous hypersensitization. The reason may be degradation of allergens before the immune system is reached.     

Clinical and Immunological Effects of Oral Immunotherapy with a Standardized Birch Pollen Extract

Oral immunotherapy (IT) was evaluated in a pilot study in two centres in children aged 8-15 years with allergic rhinoconjunctivitis. High doses (up to 20 X 10(6) BU monthly) of a defined freeze-dried birch pollen extract administered in enteric-coated gelatine capsules were given either daily for seven consecutive days every month or once weekly. Symptom scores, as assessed by sneezing, dripping and blockage of the nose, and redness, itching and swelling of the eyes, were significantly lower in treated patients compared to untreated, or placebo treated controls after 3 to 5 months of therapy. In all the 16 treated, but only in three of eight untreated patients, the scores were lower during the pollen season 1982 than during the pollen season preceding the treatment period, despite comparable pollen counts during the two seasons. One year after beginning treatment the reactivity in conjunctival provocation tests was decreased about 10-fold (P less than 0.001) in the patients receiving more than 2 X 10(5) BU monthly compared to about two-fold in patients receiving lower doses, or placebo. Increased levels of IgE antibodies directed against birch pollen were recorded in the serum and saliva of most patients after 3-4 months of active IT. In contrast, IgG antibody responses were poor in most of the patients. Side effects, particularly from the gastrointestinal tract, appeared in all treated children. In one of them a systemic reaction occurred during IT. The study indicates that properly performed oral IT with a potent birch allergen extract in enteric-coated capsules may be effective.     

Efficacy of an oral antihistamine, astemizole, as compared to a nasal steroid spray in hay fever

The efficacy and side effects of the oral H1-antihistamine, astemizole, were compared with those of nasal beclomethasone in 158 adult birch-pollen allergic hay fever patients. 148 patients completed the 5-week, controlled trial which took place in Stockholm, May 1986, during the birch pollen season. Daily pollen counts were found to be at a rather low level throughout the study period. The effect and tolerability of both drugs were found to be excellent, although beclomethasone reduced nasal symptoms (sneezing, rhinorrhoea, blocked nose) significantly more effectively than astemizole. Eye symptoms were mild and equal in both groups. The results indicate that oral astemizole is an effective non-sedating antihistamine, though less so than nasal beclomethasone, in the treatment of nasal hay fever symptoms.     

Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study)

BACKGROUND: Children with allergic rhinitis are likely to develop asthma. OBJECTIVE: The purpose of this investigation was to determine whether specific immunotherapy can prevent the development of asthma and reduce bronchial hyperresponsiveness in children with seasonal allergic rhinoconjunctivitis. METHODS: From 6 pediatric allergy centers, 205 children aged 6 to 14 years (mean age, 10.7 years) with grass and/or birch pollen allergy but without any other clinically important allergy were randomized either to receive specific immunotherapy for 3 years or to an open control group. All subjects had moderate to severe hay fever symptoms, but at inclusion none reported asthma with need of daily treatment. Symptomatic treatment was limited to loratadine, levocabastine, sodium cromoglycate, and nasal budesonide. Asthma was evaluated clinically and by peak flow. Methacholine bronchial provocation tests were carried out during the season(s) and during the winter. RESULTS: Before the start of immunotherapy, 20% of the children had mild asthma symptoms during the pollen season(s). Among those without asthma, the actively treated children had significantly fewer asthma symptoms after 3 years as evaluated by clinical diagnosis (odds ratio, 2.52; P <.05). Methacholine bronchial provocation test results improved significant in the active group (P <.05). CONCLUSION: Immunotherapy can reduce the development of asthma in children with seasonal rhinoconjunctivitis.     

Effect of vitamin E supplementation on the regular treatment of seasonal allergic rhinitis.

BACKGROUND: Vitamin E supplementation is widely used in clinical practice for the prevention and treatment of different medical conditions. Evidence from basic science studies suggests that vitamin E may reduce immune allergic responses. However, only a few clinical studies of the effect of vitamin E on allergic conditions have been performed in patients with atopic dermatitis and asthma, and none have been performed in patients with allergic rhinitis. OBJECTIVE: To determine the effect of high-dose vitamin E supplementation in combination with the usual ("real-life") treatment on the symptoms of seasonal allergic rhinitis during the pollen season. METHODS: In a double-blind, placebo-controlled, randomized study, 112 patients with documented hay fever received either vitamin E (800 mg/d) or placebo in addition to their regular antiallergic treatment during the pollen season. Patients recorded their daily nasal and eye symptoms and their daily need for other medications to control allergic symptoms. RESULTS: Although no effect was observed on ocular symptoms, nasal symptom scores were lower in patients who received vitamin E supplementation during the hay fever season. However, there was no reduction in the percentage of days with serious symptoms or in the percentage of days that medications were used to control allergic symptoms during the pollen season. CONCLUSIONS: Vitamin E supplementation may be a valuable addition to the treatment of patients with seasonal allergic rhinitis. However, further clinical and basic science studies are needed to determine its real value.     

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.     

Blood Lymphocyte Proliferation Response to Pollen Extract as a Monitor of Immunotherapy

In a study of immunotherapy 41 children with seasonal rhinoconjunctivitis due to deciduous tree pollen allergy were monitored by means of symptom scoring, patient self-evaluation, conjunctival provocation tests and lymphocyte proliferation in vitro to the allergen. The lymphocyte responsiveness to birch pollen decreased significantly during the first year of immunotherapy. However, neither the lymphocyte responsiveness before treatment nor changes in lymphocyte reactivity during the immunotherapy correlated with the clinical efficacy of the therapy as evaluated by changes in symptom scores, self-evaluation or conjunctival provocation test changes in the individual patients. The results indicate the lymphocyte responsiveness to an allergen cannot be used to select patients for immunotherapy, i.e. to predict whether a patient would benefit from immunotherapy or not, or to evaluate the effects of immunotherapy after beginning the treatment. However, lymphocyte proliferation response to an allergen indicates clinical sensitivity.     

The effect of cromolyn sodium powder as a treatment for ragweed pollinosis

The effect of treating ragweed pollinosis with intranasal cromolyn sodium powder was evaluated in 26 patients in a double-blind clinical study. Thirteen matched patient pairs were treated by either nasal insufflation of cromolyn sodium powder, 20 mg three times daily, or by a placebo powder. Patients were monitored for severity of symptoms by means of daily symptom diaries collected weekly throughout the pollen season. Serum samples were obtained in July prior to the ragweed season and following the ragweed season during the first and fourth weeks of October for the determination of ragweed-specific IgE antibody levels by the radioallergosorbent test. A significant reduction in symptom severity was observed in the treated patients with high preseasonal levels of IgE antibody to ragweed. Initially the levels of IgE antibody to ragweed did not differ between the two groups. IgE antibody levels increased in both groups after pollen exposure, but the treated group showed a significantly greater rise in IgE antibody levels. The results suggest that treatment with cromolyn sodium enhanced IgE antibody response to pollen exposure and significantly reduced the severity of hay fever symptoms in patients with high preseasonal levels of IgE antibody to ragweed.