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.     

Intestinal Permeability as Assessed with Polyethyleneglycols in Birch Pollen Allergic Children Undergoing Oral Immunotherapy

Twenty-four children with rhinoconjunctivitis due to birch pollinosis were treated in a double-blind manner with enteric-coated capsules containing either a high dose of a birch pollen preparation (n = 11) or placebo (n = 13). The permeability of the small intestine was analysed at three different occasions with a mixture of differently sized polyethyleneglycols (PEG 400 and PEG 1000), before the start of oral immunotherapy (OIT), at the moment of maximum allergen dose, and after 3 months of therapy which was at the beginning of the pollen season. The actively treated children did not significantly change their permeability characteristics as determined from PEG recovery in the urine. By contrast, in the control group of patients the recovery of larger PEG molecules was decreased after 3 months of therapy, possibly due to the commencing pollen season. In addition, small bowel biopsies were taken at the time of maximum allergen dose from two children openly treated with OIT. Both specimens were normal.     

Allergy to Apple, Carrot and Potato in Children with Birch Pollen Allergy

Skin sensitivity to apple, carrot and potato, clinically related to birch pollinosis was investigated. Different skin test techniques using fresh fruit were compared. A simple prick test (SPI) technique with a lancet piercing the apple peel just before pricking the skin was shown to be the most practical and to give reproducible results. The allergenic activity in apple was found to be heat labile and deteriorated during storage at room temperature, Apple, carrot, potato, hazelnut and birch reactivity was transferable in Prausnitz-Küstner test like IgE antibodies. SPT reactivity to fresh material from apple, carrot and potato was investigated in 174 children of whom 128 suffered from pollen allergy. Positive SPT results were obtained almost exclusively in children who were SPT positive to a birch pollen extract. Children who noticed clinical symptoms when eating apple, raw carrot or potato were found to have a significantly larger SPT reaction than children with a negative history.     

Immunotherapy with partially purified and standardized tree pollen extracts

Patients allergic to tree pollen entered a 3-year course of immunotherapy (1980-83) with either birch pollen extracts alone (n = 26) or patient-tailored extracts of birch, alder and hazel pollen (n = 27). The clinical and immunological results of this study are published elsewhere. This paper contains an evaluation of skin prick test and nasal provocation test results. There were no significant differences between the two treatment groups concerning these two parameters. In both groups the allergen-specific sensitivity in the skin showed seasonal variations but a significant decrease. During the years of treatment there was also a significant decrease in the specific sensitivity of the nasal mucosa. With the present demands for purification and standardization of allergen extracts it is of practical and economic interest to know that tree pollen-allergic patients showing positive reactions to birch, alder and hazel extracts can be effectively treated using birch pollen extract alone.     

Immunotherapy with a calcium phosphate-adsorbed five-grass-pollen extract in seasonal rhinoconjunctivitis: a double-blind, placebo-controlled study

BACKGROUND: Calcium phosphate-adsorbed allergen extracts are used for subcutaneous immunotherapy to avoid the use of aluminium adjuvants. OBJECTIVES: A double-blind, placebo-controlled study was performed in order to confirm the safety and assess the efficacy of a standardized five-grass-pollen extract adsorbed onto calcium phosphate for specific immunotherapy (IT). METHODS: Twenty-nine patients with seasonal rhinoconjunctivitis were randomized to receive either the active preparation (16 patients) or placebo (13 patients), in a 1-year study. During the increasing dose phase, an extract ranging from 0.1 IR per ml to 50 IR per ml was administered at a rate of one subcutaneous injection per week until a maintenance dose was reached. The patients were assessed by symptom diary and rescue medications during seasonal exposure and specific nasal and skin reactivity before and after IT. Immunological parameters (specific IgE and IgG4 antibodies) were assessed before, during and after IT. RESULTS: The overall symptoms score (mean AUC) was not significantly different between the IT group and the placebo group during grass-pollen exposure (49.6 vs. 56, respectively). The total medication score (mean AUC) was significantly lower in the IT group than in the placebo group (11 vs. 41, P < 0.01, Mann-Whitney U-test). The cumulative symptom/medication score was significantly lower in the IT group than in the placebo group (64.5 vs. 102.3, P < 0.05, U-test). A significant increase in nasal reactivity threshold was observed after IT in the IT group (21. 4 IR/mL before IT vs. 63.4 IR/mL after IT, P < 0.01, Wilcoxon), whereas no significant changes were observed in the placebo group (31.0 IR/mL before IT vs. 37.7 IR/mL after IT). IT induced a significant reduction in grass pollen cutaneous reactivity in the actively treated group (P < 0.001). A significant increase in serum-specific IgG4 antibody response was observed in the IT group (3.1% before IT vs. 10.1% after IT, P < 0.001). Nine patients in the IT group developed moderate immediate systemic reactions vs. two patients in the placebo group. CONCLUSION: Specific immunotherapy with calcium phosphate-adsorbed standardized grass pollen extract was safe and effective for the treatment of patients with seasonal allergic rhinoconjunctivitis.     

Birch Pollen Allergy in Children Role of Milk Feeding during the First Birch Season of Life

The effect of exclusive breast-feeding throughout the first birch pollen season of life was examined in 59 children compared to 67 children on cow milk formula and to 27 children weaned to cow milk-based formula duting theit first birch season. The infants were about 3 months of age in their first birch season, and allergy to birch pollen was evaluated at 5 years of age by history and prick and provocation tests. Breast-feeding throughout the first birch season did not prevent birch pollen alletgy; a similar birch alletgy prevalence of about 10% was found in children initially fed on human or cow milk. Instead. weaning to cow milk-based formula during the first birch season seemed to protect from subseauent development of birch pollen allergy. Analogous results were obtained regarding allergy to grass pollen. This unexpected finding may be related to the immunological stress on the young infant provided by introduction of cow milk proteins at an early age.     

Nasal and Skin Sensitivity during Immunotherapy with Two Major Allergens 19, 25 and Partially Purified Extract of Timothy Grass Pollen

In a double blind 3-year prospective study 40 grass pollen allergic patients were allocated to specific immunotherapy (hyposensitization) with two timothy major allergens, 19, 25, or partially purified timothy extract. The extracts were biologically standardized and coupled to aluminium hydroxide for treatment.
Efficacy of hyposensitization was evaluated by titrated nasal provocations and skin prick tests with the two treatment extracts and a five-grass mixture. The threshold dose for skin prick test (skin (threholds) produced reactions identical to histamine chloride 5.43 mmol/l, and the threshold dose for nasal provocations (nasal thresholds) produced two of the three reactions: at least 0.5 ml of nasal secretion, at least five sneezes, and/or at least a 20 % fall in nasal peak flow.
Nasal thresholds showed highest efficacy from partially purified timothy extract but equal protection against timothy and I he five -grass mixture. Nasal thresholds of 14 untreated patients corresponded to treatment with the two major allergens.
Changes in skin and nasal thresholds after 12 and after 64 weeks of treatment predicted the severity of hay fever. Increase in nasal thresholds coincided with a marked effect on asthma. Nasal thresholds below 1 HEP before treatment predicted major systemic side effects.     

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.     

Immunotherapy with Hymenoptera venoms

Immunotherapy with Hymenoptera venoms is widely used throughout the world and is accepted as an effective treatment for most patients with Hymenoptera venom allergy. There are, however, still some unresolved problems with this form of treatment. At present there is no definite test which makes it possible to identify patients at risk - and thus candidates for immunotherapy - unequivocally. On the basis of prospective studies on the natural history of Hymenoptera allergy, venom immunotherapy is indicated in adults with severe systemic anaphylaxis. It is usually not necessary in patients with large local reactions only. Children with mild systemic reactions, e.g. urticaria, will need immunotherapy only in case of repeated reactions and/or a high risk of re-exposure. The selection of venoms for immunotherapy may lead to some confusion owing to common antigenic determinants shared by venoms of various Hymenoptera species. Many different regimens for immunotherapy have been proposed. At present, the three main are: rush, stepwise or clustered and classical. The maintenance dose of 100 micrograms usually protects from life-threatening reactions. However, in some patients 200 micrograms are necessary for complete protection. The usual interval between maintenance injections is 4 to 6 weeks. In many patients a strong increase of venom specific serum IgG-antibodies usually parallels clinical protection induced by venom immunotherapy, although many exceptions have been reported. Allergic side effects of venom immunotherapy are not rare, especially with honey bee venom and during the initial phase of dose increase. The question of the duration of venom immunotherapy is handled differently: although some authors recommend treatment for life, most suggest treating patients until skin tests and RAST become negative.     

Birch pollinosis and atopy caused by apple, peach, and hazelnut; comparison of three extraction procedures with two apple strains

This study aimed, first, to study the prevalence in The Netherlands of atopy caused by apple, peach, and hazelnut in patients with tree pollinosis, and, second, to compare three extraction procedures for skin prick testing with two different apple strains. Skin prick tests and RAST were performed on 79 consecutive patients with tree pollinosis, visiting the department of allergology during spring 1995. In skin prick tests, we used three different extracts (juice, freeze-dried extract, and low-temperature acetone powder extract) of two apple strains, Golden Delicious and Granny Smith. Case histories for apple, peach, and hazelnut were positive in 35 (44.3%), 23 (29%), and 35 (44.3%) patients, respectively. More than two-thirds of the patients had symptoms characteristic of oral allergy syndrome. Skin prick tests for apple, peach, and hazelnut were positive in 51 (64.6%), 61 (77.2%), and 71 (89.9%) patients, respectively. Granny Smith showed more positive skin reactions and a better agreement with clinical history than Golden Delicious, and juice was superior to the two other extraction procedures for both apple strains. RAST for apple, peach, and hazelnut was positive in 53 (68.8%), 13 (16.9%), and 31 (40.3%) patients, respectively. Concordance between skin prick test and case history was found in 77%, 52%, and 54%, for apple, peach, and hazelnut, respectively. We found a high percentage of concurrence of clinical allergy to birch pollen and apple, peach, and hazelnut, confirmed by both skin prick testing and RAST. Approximately half of these patients had symptoms (especially oral allergy syndrome) after eating these products. We also found an easy extraction procedure (juice extract) suitable for apple skin prick testing, superior even to freeze-dried extraction or the low-temperature acetone powder technique.     

Rationale for Specific Immunotherapy of Grass Pollen Allergy with Extracts of Rye Pollen

In immunotherapy of grass pollen allergy, an extract of rye ( Secale cerebale ) is often included. The aim of this study was to investigate by skin prick test (SPT) and immunochemical methods whether rye pollen contains specific allergens justifying the use of this extract separately. Twenty grass pollen allergic patients were skin prick tested with a dialysed freeze-dried raw extract of rye pollen (Sc), timothy extract (Soluprick® SQ, 1 HEP) and two other rye extracts (Soluprick®). Sera from the patients were RAST-tested using Sc and timothy (Pp). CRIE was performed using Sc and rabbit-anti grass (aNG) antibodies. The antigenic relations between rye and common grasses were investigated by CLIE using Sc and aNG as references, and by RAST inhibition. The ability of aNG to absorb the allergen activity of Sc was also tested. Significant correlations were found between timothy and rye when compared by means of SPT and RAST. The immunochemical analyses did not reveal any rye antigens containing rye epitopes only. However, the possibility of rye antigens with several epitopes, of which at least one is specific for rye, could not be excluded. Clinical symptoms supposedly elicited by rye alone can be explained quantitatively by the strongly time-limited and concentrated natural exposition. Diagnosis and treatment can, however, be performed with extracts of common grasses.     

Allergy to Birch Pollen and Apple, and Gross-Reactivity of the Allergens Studied with the RAST

Apple-pulp allergens arc unstable, but fresh material can be used for skin testing. In this study stable allergens, probably of a protein nature, were extracted from apple seed and used in radioallergosorbent tests (RAST). Apple-seed allergens were shown by RAST inhibition to cross-react with birch pollen allergen(s). Cross-reactivity may explain the frequent co-occurrence of birch pollen and apple allergy. Approximately 50% of patients in a group with immediate hypersensitivity to birch pollen were also sensitive to apple as judged by a history of symptoms, skin tests with apple-pulp and apple-seed preparations, and apple-seed RAST.     

A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen

BACKGROUND: Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available. METHODS: In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38). RESULTS: The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026). CONCLUSION: Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo.     

Allergy to Pollen from Different Deciduous Trees in Sweden

92 adult patients with springtime allergy were investigated with skin tests, provocation tests and the RAST. Allergen extracts from 12 different deciduous trees were used.
Positive reactions, often of high intensity, were most often found with birch, alder, bog-myrtle, beech and hazel allergens whereas oak, aspen, linden, elm, sallow, maple and poplar allergens more often gave negative or only weak positive test results. Cross sensitizations were found between botanically related as well as between less related species of the trees. Almost all patients with a clinically relevant tree pollen allergy had positive provocation tests with birch pollen. No patient had positive reactions to all the 12 allergens included in the study. 68% had positive provocation tests with the combination birch, alder and hazel.
It is concluded that for diagnostic screening purposes it is sufficient to use birch pollen allergen. If the majority of relevant tree pollens are to be included in a diagnostic or therapeutic programme in Western Sweden it should contain birch, alder, hazel, beech and bog-myrtle allergens.     

Humoral and Cell-Mediated Immune Responses to Fractions of Birch Pollen Extract

IgE and IgG antibodies (ab) and lymphocyte transformation (LT) were studied in untreated and hyposensitized birch pollen allergic subjects and in non-atopic controls using whole extract and fractions obtained by gel filtration of birch pollen extract. All the allergic subjects had positive IgE ab, IgG ab and LT responses to the whole extract. Both the untreated and the hyposensitized subjects had peak IgE ab and LT responses against the allergenic fractions of the extract, while negative responses were obtained in the non-atopic controls. Only hyposensitized subjects had developed high IgG ab responses to the allergenic fractions. Most of the treated and untreated subjects showed IgG ab and LT responses to the high molecular weight fractions with low allergenic activity. Significantly higher IgE ab responses to these fractions were observed in the treated subjects than in the untreated ones, indicating potentiation of IgE ab responses against some antigens during immunotherapy. Some of the allergic subjects also responded to the fractions of low molecular size (mol.wt. 2000-5000) with low allergenic activity. Both IgE ab, IgG ab and LT responses to these fractions were observed.     

The significance of hypersensitivity to nuts in patients with birch pollen allergy

This study was performed in patients with allergic rhinitis/conjunctivitis to birch pollen to determine whether patients with additional hypersensitivity to nuts and apples differed from patients without such hypersensitivity; the determination was in terms of results of skin prick test (SPT), specific IgE antibodies (RAST), and symptoms during the pollen season. Forty-seven patients with birch pollen allergy were investigated by RAST against birch and hazel pollen and by SPT. They were treated in a randomized, double-blind, placebo-controlled study with fluticasone propionate aqueous nasal spray or placebo. The area of the SPTs was larger and the specific IgE values higher in patients with hypersensitivity to nuts and apples. These patients also had more symptoms during the pollen season. We conclude that hypersensitivity to nuts is an indication of a more severe allergy in patients with birch pollen allergic rhinitis.     

Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut

BACKGROUND: The efficacy of specific immunotherapy (SIT) in pollen allergy is well established. However, its effect on pollen associated food allergy particularly the oral allergy syndrome (OAS) is not definitely ascertained. OBJECTIVE: The purpose of this controlled prospective study was to investigate whether SIT with tree pollen, mainly birch, has an effect on OAS induced by apple or hazelnut in birch pollen-allergic individuals. METHODS: Twenty-seven birch pollen-allergic subjects with OAS induced by apple or hazelnut underwent open oral provocation tests (OPT) with increasing doses (1 to 128 g) of fresh apple or ground hazelnut 1 year apart. Fifteen of 27 subjects were treated with SIT and 12 were not. Skin-prick test with birch pollen, apple and hazelnut, and specific serum IgE, IgG and IgG4 to rBet v 1, apple and hazelnut were determined. RESULTS: Thirteen of 15 (87%) SIT-treated subjects could eat significantly (P <0.001) more of apple or hazelnut without any symptoms/signs. The average tolerated quantity increased from 12.6 to 32.6 g apple after 1 year in this group. In contrast, only one of 12 (8%) individuals without SIT was able to consume a higher amount without symptoms. On evaluating laboratory parameters, only IgG4 antibodies to rBet v 1 were found to be significantly (P <0.01) increased in the SIT-treated group after 1 year. CONCLUSIONS: The study shows that SIT with extracts containing birch pollen has a positive impact on OAS to apple or hazelnut in birch pollen-allergic individuals. In spite of this outcome, the amount of apple/hazelnut tolerated is still small. Thus, the effect of SIT on the patients' management of OAS remains limited.     

Clinical History, Skin Prick Test and RAST in the Diagnosis of Birch and Timothy Pollinosis

The diagnostic efficacy of clinical history (CH), skin prick test (SPT) and RAST was estimated in relation to nasal and conjunctival provocation tests (NPT, CPT) in 69 patients with seasonal rhinoconjunctivitis. The extracts used were freeze-dried, and biologically standardized birch and timothy allergen preparations matched to the extracts on Phadebas RAST discs. Based on single determinations the sensitivity, specificity and predictive values were calculated. There were highly significant (P less than 0.001) correlations between all parameters: NPT, CPT, CH, SPT and RAST. For birch the combination of SPT and RAST made the PTs superfluous as both sensitivity and specificity then reached 100%. With timothy the sensitivity was 97% and with the addition of CH 100%. However, the specificity was only 79% through combining CH, SPT and RAST. The present study using the same standardized allergen preparation in all tests showed a good correlation between indirect test results and provocation tests.     

Diagnosis and Immunotherapy of Mould Allergy

Thirty-three adult asthmatic patients suspected of mould allergy were investigated by in vivo and in vitro tests in order to establish a specific diagnosis of asthma caused by the mould species Cladosporium. The patients were evaluated by daily symptom scores in the peak Cladosporium season, bronchial provocation test (BPT), skin prick test (SPT), RAST, histamine release from basophil granulocytes (HIST), and crossed radioimmunoelectrophoresis (CRIE), and the results were scored as negative (score 0), equivocal (score 1) or positive (score 2). Based on daily symptom scores and the result of BPT the patients were classified as being manifest allergic (asthma) to Cladosporium (positive allergy), inconclusive or negative. Positive allergy was defined as asthma symptoms oscillating with the spore concentration and a BPT score 2 (positive at allergen concentration less than 10,000 BU). Negative allergy was defined as no asthma symptoms and a negative BPT (score 0) and inconclusive in the case of symptoms and BPT sum of score 1-3. According to the classification a final diagnosis (positive or negative) could be established in 85% of the patients. "False positive" tests were found: for BPT in 27%, SPT 18%, RAST 0%, HIST 18%, and CRIE 0%. The corresponding figures for "false negative" were: BPT 0%, SPT 0%, RAST 27%, HIST 18%, and CRIE 23%. The relative risk of being allergic in spite of a negative test result was 0% for BPT and SPT, and 25-30% with RAST, HIST, and CRIE. In the case of positive test the risk was 90-100%. Excluding BPT, SPT was found to be the optimal single test to predict/rule out clinical allergy. A stepwise combination of positive SPT and positive RAST was found exclusively in patients clinically evaluated as positive, and does not call for an additional BPT. Using a potent allergenic extract a negative SPT excluded clinically important allergy. The primary conclusion of the study, however, is that the final diagnosis of Cladosporium asthma could not be based on a positive BPT alone (due to "false positive"), but only on a combination of clinical symptoms during the spore season and a positive BPT.