Preseasonal IgE ragweed antibody level as a predictor of response to therapy of ragweed hay fever with intranasal cromolyn sodium solution.

Intranasal administration of a 4% solution of cromolyn sodium for the treatment of ragweed hay fever was tested in an 8-week double-blind matched-pair study involving 66 patients. Patients on active drug received 5.2 mg into each nostril 6 times daily; control patients received a placebo spray. The treated group showed a significant reduction in mouth breathing (p less than 0.001), stuffy nose (p less than 0.002), runny nose (p less than 0.003), and postnasal drip (p less than 0.035). Patients receiving the active drug also reported fewer sneezing episodes (p less than 0.003) and nose blowing episodes (p less than 0.015). One patient using cromolyn solution developed nasal ulceration, tongue swelling, coughing, and wheezing. Other side effects were minimal and occurred with equal frequency in both groups. In the treated group relief of symptoms was most marked in patients with high preseasonal levels of IgE ragweed antibody. Intranasal 4% cromolyn solution appears to be an effective drug for the treatment of ragweed hay fever; measurement of the preseasonal level of IgE ragweed antibody is a useful screening test to identify patients most likely to achieve a maximal beneficial response to treatment.     

Effect of corticosteroids on seasonal increases in IgE antibody

We analyzed seasonal changes in IgE antibodies to ragweed antigens in 28 patients with ragweed hay fever during the 1972 pollination season. Thirteen patients were treated with an injection of 60 mg. of triamcinolone acetonide suspension and 16 mg. of methylprednisolone orally on 3 successive days shortly after the onset of their symptoms in late August. Fifteen patients were untreated and served as controls. Serum samples were obtained in July (control group) or just prior to steroid treatment in August, and from both groups in mid-September and finally in mid-October. Initially, IgE antibody levels did not differ between the groups. IgE antibody increased after pollen exposure in both groups, but there was no significant difference in the increases. In contrast, symptom scores were significantly less in patients treated with steroids (P < 0.01). The results indicate that corticosteroid treatment does not prevent the seasonal increase in IgE antibody after pollen exposure but does significantly reduce the severity of hay fever symptoms.     

Topical ocular administration of cromolyn sodium for treatment in seasonal ragweed conjunctivitis.

We studied topical ocular administration of a 4% solution of cromolyn sodium (CS)for treatment of 112 patients with ragweed conjunctivitis in two 8-wk, double-blind, matched-pair studies. During the 1977 and 1978 ragweed seasons, patients instilled a daily total of 12.8 or 19.2 mg CS into each eye, control patients received placebo drops. Treatment efficacy was assessed by daily symptom score diaries, ophthalmic examinations, and a subjective report by the patient at the end of the trials. In the 1977 trial, CS pair members whose preseasonal immunoglobulin E antibody level was <99 ng/ml showed a significant reduction in eye itching (p < 0.01), eye irritation (p < 0.02), visual blurring (p < 0.025), and nasal congestion (p < 0.025) and required less supplemental medication (p < 0.02) during the peak pollen period. In the 1978 trial all patients had IgE antibody levels >100 ng/ml. CS pair members showed a significant reduction in rhinorrhea (p < 0.004) and nasal congestion (p < 0.007) only; no significant reduction in eye symptoms was noted. Transient eye burning was noted by a total of 38 CS and 39 placebo patients from both studies; ophthalmic examinations were unremarkable; and no other side effects were noted. The 4% CS ophthalmic solution provided significant relief of nasal symptoms in both the 1977 and 1978 trials, but significant relief of ocular symptoms was noted only in the 1977 trial and only in those patients with lower preseasonal IgE ragweed antibody levels.     

The clinical and immunologic specificity of immunotherapy

In order to study the specificity of immunotherapy for respiratory allergy, a group of patients sensitive to both ragweed and grass pollens were selected. From 87 volunteers with a history of both spring and fall hay fever, 42 patients with evidence of strong sensitivity by basophil histamine release to both ragweed pollen and mixed grass pollen extracts were selected for study. On the basis of the histamine release data, the patients were divided into two groups matched for sensitivity to both grass and ragweed pollens. In 1970, May and June symptom diaries showed the two groups to suffer quite similar severity of symptoms during the grass pollination season. One group of patients was started on a preseasonal course of immunotherapy with alum-precipitated aqueous extract of ragweed pollen while the other group received placebos containing histamine. By fall there had been a considerable rise in IgG-blocking antibodies to ragweed in the treated group. Symptom diaries in August and September showed that the treated group showed significantly less severe symptoms than the placebo group. Both groups received booster injections at 2-wk intervals from the fall of 1970 to the fall of 1971. Doses in the treated group were raised to attempt to administer the largest possible dose. Again there was no difference in the symptoms reported by the two groups during the grass pollination season, but an even greater difference emerged between the two groups during the ragweed season. The following year 1972 the same results were obtained. These data demonstrate that treatment with ragweed pollen extracts has little or no effect on grass pollen symptoms and confirm that immunotherapy is clinically as well as immunologically specific. Antibody responses to the second year of high-dosage booster injections was not greater than responses to a comparatively short preseasonal course given the first year.     

Allergen injection therapy with glutaraldehyde-modified--ragweed pollen-tyrosine adsorbate. A double-blind trial.

The effect of a preseasonal course of four injections of glutaraldehyde-modified—ragweed pollen-tyrosine adsorbate (MRTA), in a total dose of 7,000 Noon pollen units, was compared with a tyrosine base placebo in a double-blind trial in 43 matched patients with ragweed pollen-induced allergic rhinitis. During the pollen season, troublesome symptoms were treated with a standardized therapeutic regimen. The minimum medication requirement that adequately controlled symptoms was used as the main indicator of severity of the allergic rhinitis. Consequently, the symptom scores were similar in both treatment groups; however, the MRTA-treated group required approximately 50% less medication than the placebo group (p < 0.05). Subjective improvement was reported by 67% of the MRTA group and 38% of the placebo group (0.05 < p < 0.1). Serum concentrations of IgE and IgG antibodies to ragweed increased in response to MRTA (p < 0.02) but not in response to placebo. Side effects of MRTA included generalized urticaria in 2, mild asthma in 1, and large late swellings at the injection site which necessitated stopping the injections in 6 patients. MRTA was superior to placebo in reducing the severity of ragweed pollen-induced allergic rhinitis and was associated with a modest incidence of side effects.     

Cromolyn sodium nasal solution in the prophylactic treatment of pollen-induced seasonal allergic rhinitis.

A large-scale multicenter investigation was undertaken in 3 cities with comparable pollen seasons and atmospheric pollen concentrations in order to obtain more definite information about the safety and efficacy of cromolyn sodium in the treatment of pollen-induced seasonal rhinitis. The 9-wk double-blind study was conducted in 104 patiets in Pittsburgh, Pa., Cleveland, Ohio, and Louisville, Ky., during the 1975 ragweed season. It indicated that a nebulized 4% aqueous solution of cromolyn sodium is effective in reducing sneezing, rhinorrhea, nasal congestion, and ocular irritation in ragweed hay fever patients. The efficacy of the drug was notable despite the fact that patients used an average of 52 mg instead of the recommended 62.4 mg daily. Cromolyn sodium did not appear to have a significant effect on transseasonal antiragweed IgE (IgEAR) levels. Patients acceptance of the cromolyn nasal solution was good, and there were no significant adverse reactions. The side effects, which were distributed equally between the drug and placebo groups, were mild and of limited duration.     

Ragweed hay fever: treatment by local passive administration of IgG antibody

To determine whether the local administration of IgG antibodies might reduce the symptoms of ragweed hay fever, we tested the effect of this treatment in fourteen patients in a double-blind pilot trial. The patients were randomly divided into two groups, treatment and placebo, and their symptoms and medication usage were determined during the ragweed pollination season. One group used a nasal spray consisting of phosphate-buffered saline (PBS) containing human serum albumin, whereas the other used PBS containing purified IgG from a subject with a high titre of IgG antibody to partially purified ragweed antigen E. Treated and control groups used comparable quantities of nasal spray, and neither noted any ill effects. Comparison of individual symptoms of hay fever, medication usage, and total symptom scores showed no significant differences between the groups except a lessening of eye symptoms (P<0.05) in the treated group. The results suggest that nasal administration of IgG antibody up to five times daily does not alter the severity of symptoms in ragweed hay fever. Furthermore, total serum IgE protein and specific IgE levels increased comparably in both groups, suggesting that passive administration of IgG antibody does not suppress the production of IgE antibody during the pollination season.     

Maximal rise in IgE antibody following ragweed pollination season.

Patients allergic to ragweed pollen who did not receive immunotherapy had an increase in ragweed-specific IgE antibodies associated with seasonal exposure. Of 17 such patients, 15 reached peak levels between mid-September and mid-October. Two had peak values after mid-October; the levels were only slightly higher than earlier values. Our study shows that serum obtained in mid-October reflects approximately the maximal IgE antibody level attained 0y ragweed-sensitive patients in our area and that this value can be used as a baseline in monitoring the subsequent decline in antibodies. In addition, our data support an earlier observation that the magnitude of seasonal rise in IgE antibody is related to the preseasonal value. The significantly positive correlation of the results of carefully performed skin tests (end point titration) with radioallergosorbent test (RAST) values suggests the possibility that the RAST can be employed as a reliable diagnostic aid, perhaps even replacing the skin test.     

Local intranasal immunotherapy with high-dose polymerized ragweed extract

Thirty-one ragweed-allergic patients received preseasonal local intranasal immunotherapy (LNIT) with high doses of gluteraldehyde-polymerized ragweed extract (average total dose 544 micrograms antigen E). Minimal side effects were reported during treatment and did not interfere with the dosing schedule. During the ragweed pollen season, LNIT-treated patients had lower symptom scores for sneezing, rhinorrhea and nasal congestion than a comparable group of untreated ragweed-allergic patients. There was no difference in ragweed-induced eye symptoms between the two groups. Secretory ragweed-specific IgA and IgG rose following LNIT treatment. Absolute antibody titers and changes in titers did not correlate with clinical improvement. LNIT with the polymerized ragweed did not block the seasonal rise in serum ragweed-specific IgE. These results suggest that LNIT with high-dose polymerized ragweed extract is a safe, simple and effective form of immunotherapy.     

Local nasal immunotherapy: efficacy of low-dose aqueous ragweed extract

In previous studies preseasonal local nasal immunotherapy (LNIT) with moderate doses of aqueous ragweed extract (mean total dose 59 micrograms of AgE and 139 micrograms of AgE) was an effective treatment for ragweed hay fever; however, local adverse reactions during therapy were common. This study evaluated the clinical and immunologic responses to LNIT by use of lower doses of aqueous ragweed extract in order to minimize these adverse reactions. Patients were administered preseasonal LNIT for 7 wk and received a mean total dose of 4.7 micrograms of AgE. During the ragweed season, symptom/medication scores (SMS) of the treated patients were equivalent to SMS of untreated patients. Serum ragweed-specific IgE and nasal secretory ragweed-specific IgA rose slightly in the treated patients but not to the extent observed in previous studies. After the ragweed season treated and untreated patients had a substantial increase in serum ragweed IgE antibody titers. No correlation could be found between antibody responses and SMS. This study indicates that LNIT with lower doses of aqueous ragweed extract is clinically ineffective.     

Diagnostic tests in ragweed hay fever. A comparison of direct skin tests, IgE antibody measurements, and basophil histamine release

In 87 patients with both spring and fall hay fever symptoms the radioallergosorbent test (RAST) technique for specific IgE antibodies to ragweed was compared with basophil histamine release and direct intradermal skin testing by the threshold dilution technique. The three techniques gave good agreement except with the leastsensitive patients, some of whom had a positive skin test but undetectable histamine release or IgE antibodies. Twenty-one patients who were highly sensitive to ragweed as measured by all three techniques were followed without specific immunotherapy. There was significant agreement between the level of positivity of all three tests and the symptom index obtained during the ragweed season. In 14 of the 21 patients there was a significant correlation between daily ragweed pollen counts and daily symptom indexes during the season. On the other hand, among the 16 least-sensitive patients (as judged by histamine release) the correlation between daily ragweed pollen counts and symptom indexes was significant in only 3 patients. Other significant allergens could not be identified in the latter group, and the cause of their symptoms is not clearly identified but appears not to be ragweed. The RAST is a quantitative technique that gives diagnostically useful information in ragweed hay fever, although not significantly different from basophil histamine release or carefully performed skin testing. The convenience to the patient may, however, offer a noticeable advantage.     

Preseasonal intranasal immunotherapy with nebulized short ragweed extract

We determined the effect of preseasonal intranasal short ragweed (SRW) immunotherapy in a double-blind, nonpaired, 20-wk study involving 33 SRW-sensitive patients. Patients were selected on the basis of an elevated IgE serum antibody level, a positive intradermal skin test, and a positive intranasal challenge to SRW antigen. SRW-treated patients sprayed SRW solutions intranasally six times a day for 12 wk preseasonally. Placebo-treated patients used nebulized solutions containing buffer or histamine that were interchanged randomly throughout this period. The SRW-treated group reported more preseasonal symptoms than the placebo-treated group (p < 0.003); however, during the SRW pollination season, the SRW-treated group reported significantly less sneezing, nasal congestion, rhinorrhea, red/itchy eyes, itchy nose/throat, and cough/wheeze. Supplemental antihistamine usage was similar in both groups. The treatment did not affect serum IgE antibody levels to crude SRW, AgE, Ra3, or Ra5 in either group at any time during the study. No significant production of IgG antibody to SRW was seen in either group. One SRW-treated patient developed acute sinusitis after 2 wk of treatment; otherwise no side effects other than symptoms of hay fever were noted. Although intranasal SRW immunotherapy may offer an effective and less costly alternative to parenteral immunotherapy, reduction in hay fever symptoms during the pollination season was achieved at the expense of provoking these symptoms during the preceding weeks.     

Measurement of the absolute levels of IgE antibodies in patients with ragweed hay fever: Effect of immunotherapy on seasonal changes and relationship to IgG antibodies

The effect of immunotherapy with aqueous ragweed pollen extract on changes in IgE antibody was analyzed in 40 untreated patients with ragweed hay fever and compared to changes in 63 treated patients. Treated patients received cumulative doses prior to and during treatment ranging from 1.4 × 10⁵ to 4.8 × 10⁶ protein nitrogen units (PNU). IgG antibody to ragweed antigen E (AgE) was measured by radioimmunoprecipitation, while IgE antibody to allergens in crude ragweed extract was measured by the radioallergosorbent test (RAST). The RAST procedure was calibrated using a serum whose content of IgE antibody in nanograms per milliliter had been determined by immunoabsorption, and with this method the absolute quantities of IgE antibodies to ragweed allergens could be measured. Control experiments indicated that the IgG antibodies in the sera of the treated patients did not interfere with the measurements of IgE antibodies. The levels of IgE antibody in serum varied from less than 5 ng/ml to approximately 3,000 ng/ml. IgE antibodies decreased from October, 1973, to July, 1974, and rose sharply from July to October, 1974, following the pollination season. In both untreated and treated patient groups the magnitudes of the decreases were related (p < 0.001) to the levels of IgE antibody in October, and the magnitudes of the rises were related to the levels of IgE antibody in July. In the treated patients with IgE antibody less than 71 ng/ml in October, the rate of decrease (October to July) was less than in the untreated patients. Comparison of the rises in IgE antibody from July to October revealed that these were partially suppressed in the treated group (p < 0.001), and this effect was most marked in patients with July levels less than 36 ng/ml. Levels of IgG antibody to AgE in the treated patients were approximately 70-fold greater than in untreated patients and showed little change over the study period. The levels of IgG and IgE antibody in the treated patients were positively correlated (p < 0.001) at all time periods, and patients with high levels of IgG antibody also had greater declines and rises in IgE antibodies. The results indicate that immunotherapy is associated with (1) a reduction in the seasonal decrease in IgE antibody from October to July in patients with the low levels of IgE antibody, (2) a partial suppression of the rises in IgE antibody from July to October, and (3) that both these effects are related to the level of IgE antibody before the change. In many treated patients both IgE and IgG antibodies were low in spite of parenteral administration of ragweed extract. This result is consistent with the view that overall humoral immunologic reactivity to ragweed antigens is reduced in these patients.     

Immunotherapy in Hay Fever with Two Major Allergens 19, 25 and Partially Purified Extract of Timothy Grass Pollen

Grass pollen hay fever patients were hyposensitized in a prospective 3-year double blind study with two timothy extracts. Group WPA (20 patients) was treated with partially purified extract = whole pollen allergens (WPA) (Alutard®SQ) and group PPA (20 patients) was treated with a purified pollen allergen (PPA) = two isolated major allergens, Ag19 and Ag25. Both aluminiumhydroxide adsorbed extracts were biologically standardized. Clinical results from the first season have been recently published and WPA showed significantly fewer symptoms (P= 0.001) than PPA. Corresponding preseasonal and seasonal in vitro results are presented here. Serum total IgE, specific IgE versus total and individual allergens of timothy pollen and allergen-specific IgG showed a rapid increase in both groups until the season but showed no further increase or decrease during the season. Specific IgE was shown to correlate to specific IgG during hyposensitization. Group WPA, with fewer symptoms in grass pollen season than group PPA showed a significantly higher increase of specific IgG and IgE than group PPA, but individual symptom scores were not correlated to specific IgG or IgE, or their ratio. Specific IgE and IgG increases were not correlated to dosage. Surprisingly, almost all females were low-responders to specific IgG and IgE though they had equal symptom scores, dosage, and side effects as males, while the characteristics of high-responders to antibody were: youngest individuals and shortest duration of symptoms prior to treatment. Crossed radioimmunoelectrophoresis (CRIE) showed specific reaction to stimuli but no development of allergy against new timothy antigens. High response of IgE to Ag 19 in CRIE during initial hyposensitization seems suitable as marker for prospective evaluation of clinical effect in grass pollen hyposensitization. Nasal secretion was collected after methacholine provocation, and total IgE and specific IgE detected. There was no response to treatment, only a slight increase during the season. No decrease in nasal reactivity to methacholine was noted during one preseasonal hyposensitization.     

Controlled trials with four per cent cromolyn spray in seasonal allergic rhinitis*

Thirty-two patients with seasonal allergic rhinitis due to weed pollen were treated beginning prior to the weed pollen season of 1974 with either 4% cromolyn sodium or placebo nasal spray. The patients were followed on treatment with symptom diary cards and bi-weekly physician examinations for a period of 10 weeks. Radioallergosorbent (RAST) titres for the major weeds in the Denver area (ragweed, Russian thistle, and sage) were determined before the weed pollen season, and one and three months after the weed pollen season. There was no significant difference in symptom scores between the 4% cromolyn sodium- and placebo-treated groups, nor objective evidence on bi-weekly examinations by a physician to suggest differences in the two groups. Significant differences in favor of the 4% cromolyn-treated group were noted in the amount of antihistamines taken for symptomatic relief during the weed pollenating season, suggesting some protective effect of the drug. The clinical significance of this finding is not clear. Selecting patients with high baseline RAST titres for one or more of the major weeds did not alter the results of the study. In a second double-blind study twenty-two patients reporting to the allergy clinic with symptomatic seasonal allergic rhinitis due to weeds were randomly assigned to receive 4% cromolyn sodium or placebo nasal spray and followed through the weed pollen season. There was no difference between the two groups in either symptom scores or use of antihistamines for asymptomatic relief.     

A controlled study of the effectiveness of the Rinkel method of immunotherapy for ragweed pollen hay fever

In a double-blind study, we compared the effects of the Rinkel method of immunotherapy with ragweed pollen extract and placebo on symptoms of ragweed hay fever and immunologic parameters in 24 ragweed-sensitive patients. Each had a skin-test end point by Rinkel serial dilution titration to ragweed pollen extract at 1:312,500 w/v or greater dilution, a 2+ skin test to ragweed AgE at 0.1 μg/ml or greater dilution, and in vitro leukocyte histamine release by ragweed pollen extract. None had had immunotherapy for at least 7 yr. Patients matched on the basis of leukocyte histamine release by ragweed were assigned to two treatment groups (12 patients in each group). One group received ragweed pollen extract, and the other, placebo, both administered by the Rinkel method between June and October, 1978. Treatment doses were derived from skin-test end points. The median maintenance (“optimal dose”) for patients receiving ragweed pollen extract was 0.53 ml of 1:312,500 w/v and the mean cumulative dose of ragweed pollen extract given during the study contained 0.094 μg of ragweed AgE. Symptom-medication scores of all patients rose and fell with ragweed pollen counts. No significant differences were observed in mean daily symptom-medication scores, antiragweed IgG or IgE levels, leukocyte histamine release by ragweed, total IgE levels, or skin-test end-point dilutions with ragweed pollen extract between the group receiving ragweed pollen extract and the group receiving placebo. Despite the absence of specific effect on symptom-medication scores and measured immunologic variates, 10 of the 12 ragweed-treated patients and 10 of the 12 placebo-treated patients were of the opinion that their hay fever symptoms during the ragweed pollen season were less severe in 1978 than in 1977 and that they had been helped by Rinkel method immunotherapy. Under the conditions of the study, Rinkel method immunotherapy with ragweed pollen extract was no more effective than placebo given in an imitation of the Rinkel method.     

Clinical and immunologic evaluation of glutaraldehyde-modified, tyrosine-adsorbed short ragweed extract: a double-blind, placebo-controlled trial

Glutaraldehyde-modified, tyrosine-adsorbed ragweed extract (GTR) is a modification of allergen extract to reduce allergenicity but retain immunogenicity. We evaluated the clinical efficacy and immunologic changes associated with the administration of GTR (16,350 protein nitrogen units) or placebo to a group of 100 atopic subjects with ragweed hay fever. The study was carried out in a double-blind, placebo-controlled fashion. Clinical response was measured by daily symptom diaries. physician evaluations, and patient responses. Changes in ragweed-specific IgE and IgG antibody were evaluated with an amplified enzyme-linked immunosorbent assay (alpha-ELISA) and were compared with measurements by RAST and a protein A-binding assay for IgG antibody. Treatment with GTR resulted in a sixfold increase in blocking IgG antibody and a small increase in IgE-specific antibody. No changes occurred in the placebo treated group. Mild immediate local reactions occurred after 74% of injections, and late-onset local reactions occurred after 62% of injections in the treated group. The placebo-treated group experienced immediate or late local reaction after only 12% of injections. There were two mild late-onset urticarial reactions of a generalized nature in the treatment group. The treatment group experienced significantly fewer symptoms than the placebo group throughout the season (p less than 0.02), although the difference was not dramatic. The results showed that GTR could be safely given in five preseasonal injections, with retained immunogenicity but less potential for generalized reactions. GTR is an improved method of allergy immunotherapy with the potential for clinical benefit when used in a brief preseasonal treatment regimen.     

Rinkel injection therapy: a multicenter controlled study

The American Academy of Allergy sponsored a 2-yr “double blind” multicenter study of the effect of Rinkel injection therapy (RIT) compared with a histamine placebo in subjects with atopic rhinitis. Accumulated data included the symptom, medication, and physical examination scores and specific IgE antibody levels measured by the radioallergosorbent test (RAST). A total of 155 subjects (81 treated, 74 placebo) entered the project from six centers during their respective ragweed, grass, and mountain cedar pollen (from one center) seasons for a total of 11 pollen seasons. The total mean cumulative dose of extract was 18.6 PNU, which is much lower than recommended for standard immunotherapy. With one exception, none of the centers reported a consistent significant difference between the pollen extract-treated and placebo-treated groups in any of the weekly mean scores or the RAST before, during, and after the pollen seasons. For 4 wk after the height of the mountain cedar season the group treated with pollen extract showed a significant decrease in weekly mean symptom and medication scores as compared with the placebo group. The overall comparison of the mean seasonal scores for the entire study, however, showed no significant difference between the treated and placebo groups. We conclude the RIT is no more effective than a histamine placebo in influencing the weekly mean symptom, medication, and physical examination scores or IgE antibody levels.     

Controlled studies of intranasal immunotherapy for ragweed pollenosis

During 1978 a double blind study compared the efficacy of preseasonal short ragweed (RW) extract intranasal immunotherapy with a histamine placebo; in 1979 more prolonged treatment with a larger dose of polymerized ragweed (PRW) was evaluated. In neither year did the placebo-treated patients show significantly more severe disease as assessed by daily symptom diaries, examination in season, comparison of overall symptom severity with previous years or changes in nasal challenge tests. Following treatment in 1979 there was a significantly greater amount of secretory IgA and IgG ragweed antibodies secreted by the nose of the PRW-treated group, but these titers did not correlate with clinical results.     

Prolonged preseasonal treatment phase with Grazax sublingual immunotherapy increases clinical efficacy

BACKGROUND: Sublingual immunotherapy treatment with grass allergen tablets (Grazax) is initiated preseasonally without up-dosing and treatment is continued throughout the entire grass pollen season. Aims of the study: The influence of the duration of preseasonal treatment on clinical efficacy obtained within the grass pollen season was investigated. METHODS: Data from three randomized, double-blind, placebo-controlled, multi-centre trials with varying preseasonal treatment periods were analysed. In the grass pollen season, symptom and medication score reductions relative to placebo were calculated and correlated with the duration of the preseasonal treatment period. RESULTS: The analysis was based on data from 934 patients. A significant reduction in seasonal daily rhinoconjunctivitis symptom and medication scores (17%, CI: 1-33% and 23%, CI: 1-47%, P < 0.05) was observed for patients treated with Grazax compared with placebo after approximately 8 weeks of pretreatment. The magnitude of the reductions in rhinoconjunctivitis symptom and medication scores increased with longer duration of preseasonal treatment (P < 0.0001). CONCLUSIONS: Sublingual immunotherapy with Grazax) must be initiated at least 8 weeks prior to the grass pollen season to provide a significant clinical efficacy. A longer preseasonal treatment period (>8 weeks) improves the clinical efficacy (relative to placebo) during the grass pollen season.