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Keywords:

  • allergen-specific immunotherapy;
  • clinical efficacy;
  • controlled study;
  • randomized;
  • rhinitis;
  • side-effects;
  • subcutaneous;
  • sublingual

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Background:  Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed.

Objective:  To investigate the clinical efficacy of SLIT vs SCIT and secondary to compare SLIT and SCIT with placebo and to evaluate the relative clinical efficacy in relation to systemic side-effects.

Methods:  A 3-year randomized, placebo-controlled, double-blind, double-dummy study including 71 adult birch pollen hay fever patients treated for two consecutive years after a baseline year. Allocation to treatment groups was based on disease severity in the baseline season, gender and age.

Results:  Clinical efficacy was estimated in 58 patients completing the first treatment year by subtracting baseline data and by calculating the ratio first treatment season vs baseline. SLIT diminished the median disease severity to one-half and SCIT to one-third of placebo treatment. No statistical significant difference between the two groups was observed. Both for symptoms and medication scores actively treated patients showed statistically significant and clinical relevant efficacy compared with placebo. SLIT treatment only resulted in local mild side-effects, while SCIT resulted in few serious systemic side-effects.

Conclusion:  Based on the limited number of patients the clinical efficacy of SLIT was not statistically different from SCIT, and both treatments are clinically effective compared with placebo in the treatment of birch pollen rhinoconjunctivitis. The lack of significant difference between the two treatments does not indicate equivalent efficacy, but to detect minor differences necessitates investigation of larger groups. Due to the advantageous safety profile SLIT may be favored.

Allergen-specific immunotherapy is, along with allergen avoidance, the only specific treatment of allergic disorders (1, 2). Furthermore, subcutaneous immunotherapy (SCIT) is the only treatment with documented long-term efficacy after termination (3–6), it may prevent new sensitization (7), reduce the development of asthma in patients with allergic rhinitis (4, 8), and is recommended by WHO as an integrated part of the allergy management strategy (2).

While the clinical efficacy of conventional SCIT in allergic rhinoconjunctivitis is well documented (9, 10), the clinical application is to some extent limited by the risk of inducing systemic side-effects (2, 9, 11). Consequently other routes of administration have been investigated (12).

Multiple controlled sublingual immunotherapy (SLIT) studies have been performed (13–34), and most prove SLIT an effective, safe and convenient allergen-specific treatment. The number of controlled immunotherapy studies for rhinoconjunctivitis using birch pollen allergen extract is limited. Clinical efficacy has been documented for orally (35–37), intranasal (38, 39), subcutaneous (4, 40–44) and sublingual (21) administration.

The primary aim of this study was to compare SLIT and SCIT in relation to efficacy and the frequency and severity of side-effects in adult birch pollen rhinoconjunctivitis patients and secondary to determine the magnitude of clinical efficacy of SLIT and SCIT vs placebo. The design was a randomized, double-blind, placebo-controlled, double-dummy study over a 2-year treatment period. Birch pollen rhinoconjunctivitis was chosen due to the well-defined season which makes it a valuable clinical model for other allergen systems.

Patients

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Based on the estimate that two-thirds of actively treated patients would improve compared with 10% of placebo treated, 25 patients in each group were required to give a 5% risk of type 1 error and 10% of type 2 error (45). Eighty-nine patients (mean age 30 years, range 20–58 years) with at least 2 years of seasonal birch pollen rhinoconjunctivitis uncontrolled by conventional pharmacotherapy (1) were enrolled. Birch pollen allergy was verified by a positive skin prick test and a positive conjunctival provocation test using a standardized extract (ALK-Abello, Hørsholm, Denmark), and the presence of specific IgE [∃radioallergosorbent test (RAST) class 2] using the CAP System (Pharmacia Diagnostics, Uppsala, Sweden). Patients with mild seasonal birch pollen induced asthma were accepted for inclusion. Exclusion criteria were: perennial allergy, chronic, nonallergic rhinitis or sinusitis, previous immunotherapy with birch pollen within the last 5 years or ongoing immunotherapy with other allergens, treatment with β-blockers or patients on continuous corticosteroids, pregnancy or planned pregnancy, participation in another clinical trial, and the standard contraindications for immunotherapy (1).

Informed consent was obtained from all patients. The study was conducted according to guidelines for Good Clinical Practice and approved by the local Ethics Committee.

Study design

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

A randomized, placebo-controlled, double-blind, double-dummy study. Allocation to the three study groups was done by minimization (46), a simple randomization algorithm that ensures an equal distribution of patients to study groups based on disease severity during the baseline season, gender and age. All study personal and participants were blinded to treatment assignment for the 2-year duration of treatment in the study.

Based on the baseline registration 71 patients were allocated into three groups: SLIT-group: receiving sublingual immunotherapy (drops) and placebo injections; SCIT-group: receiving subcutaneous immunotherapy (injections) and placebo sublingual drops; Placebo-group: receiving placebo sublingual drops and placebo subcutaneous injections.

Treatment was continued from September 1997 to September 1999. During the birch pollen seasons patients completed diary cards recording allergic symptoms, medication consumption, and adverse events. A quality of life questionnaire was completed immediately after each of the three pollen seasons. The study outline is shown in Fig. 1.

image

Figure 1. Flow-chart describing study including the number of patients at different time-points and withdrawals.

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Allergen extracts and treatment

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Active treatment involved a birch pollen extract standardized in terms of the major allergen Bet v 1 administered as glycero-saline solution (SLIT, Staloral®; Stallergènes SA, Antony, France) or adsorbed on calcium phosphate (SCIT, Phostal®; Stallergènes SA). The placebo preparations included caramelized sugar for sublingual and histamine dihydrochloride 0.01, 0.1 and 0.5 mg/ml for injections to ensure an identical visual appearance and taste for SLIT preparations and the induction of local reactions for SCIT. The success of blinding was evaluated by a questionnaire after termination of the study.

The sublingual treatment was self-administered at home. Drops were held under the tongue for 2 min before swallowing. A 30-day sublingual induction phase was followed by a maintenance phase of 21–23 months. The initial dose was 0.0164 μg and the top dose 49.2 μg Bet v 1 administered every second day. The treatment schedule was adjusted according to the individual patient's tolerance.

Subcutaneous injections were administered in the clinic and included a 12-week (weekly injections) induction phase starting with a dose of 0.0164 μg and a monthly maintenance phase of 3.28 μg Bet v 1. The scheduled dose was adjusted according to the individual patient's tolerance. During pollen seasons the dose was reduced 20–40% in symptomatic patients. The patients were observed for 30 min after each injection (1).

Symptom-medication scores and rescue medication

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

During the birch pollen season patients recorded daily symptoms of rhinoconjunctivitis (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Patients were provided with acrivastine (8 mg; Warner-Lambert, Ballerup, Denmark), levocabastine 0.5 mg/ml eye drops (Jansen-Cilag, Birkerød, Denmark) and levocabastine 50 μg/dose nasal spray (Jansen-Cilag) for self-medication. If rhinoconjunctivitis symptoms were uncontrolled by acrivastine 24 mg, levocabastine six eye drops and nasal spray levocabastine six puffs, 5 mg prednisolone tablets (Nycomed, Roskilde, Denmark) were allowed. Nasal corticosteroids, long-acting antihistamines and other antiallergic drugs were not allowed. Rescue medication was scored as follows: 8 mg acrivastine (four points); two eye drops of levocabastine (one point); two puffs of levocabastine nasal spray (one point); one tablet (5 mg) prednisolone (six points).

Estimation of clinical efficacy

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Clinical efficacy was evaluated separately for clinical symptoms (symptom scores) and for use of rescue drugs (medication scores). To take advantage of the pretreatment monitoring and to compensate for the varying pollen load the clinical efficacy of immunotherapy was calculated by comparing treatment seasons with the pretreatment season (within-group comparisons). To avoid overlooking a late onset of clinical efficacy in SLIT the treatment period was extended to 2 years.

Adverse events

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Recording of adverse events included time of onset and resolution, previous doses of study medication, severity, any action taken, estimation of possible relationship to study drugs and outcome. Systemic side-effects were classified and graded according to the recommendation of the European Academy of Allergy and Clinical Immunology (1). All randomized patients were included in the side-effects analysis.

Statistics

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

To avoid problems with data not being normally distributed, nonparametric statistics were used. Demographic data between the groups were analyzed by chi-square test or Fisher's exact test (two-tailed). Between-group comparison of symptom and medication scores in the pretreatment season was done by Kruskal–Wallis’H-test. Within-group comparison Wilcoxon tests were applied for the primary outcome parameter, i.e. clinical efficacy and Mann–Whitney for side-effects. P-values <0.05 were considered significant.

Patients

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Out of 71 randomized patients only 58 were evaluable for efficacy during the first pollen season (SCIT 21, SLIT 18, and 19 placebo patients). Forty-eight patients were evaluable for the second pollen season (SCIT 19, SLIT 14, and 15 placebo patients). The number of patients completing the study and withdrawals are shown in Fig. 1. The demographic characteristics are shown in Table 1. No significant differences were seen among the three groups with respect to gender, incidences of sensitization to grass- and house-dust mites, or frequency of asthma. The number of withdrawals was not statistically different in the three groups. With respect to symptom scores the three groups were perfectly matched in the pretreatment season (Fig. 2A). As for medication scores the random withdrawal of patients resulted in a (nonsignificant) higher drug scores in the SLIT group (Fig. 2B).

Table 1.  Demographic characteristics of patients completing the first treatment season
 SLITSCITPlaceboStatistics
  1. Values are given as n (%).

Gender
 Female7 (39)10 (48)7 (37)P = 0.762
 Male11 (61)11 (52)12 (63) 
Grass pollen symptoms, June and July
 No8 (44)13 (62)11 (58)P = 0.527
 Yes10 (56)8 (38)8 (42) 
Sensitized to Der p or Der f
 No16 (89)18 (86)17 (89)P > 0.99
 Yes2 (11)3 (14)2 (11) 
Asthma symptoms
 No11 (61)15 (71)12 (63)P = 0.769
 Yes7 (39)6 (29)7 (37) 
image

Figure 2. Mean weekly rhinoconjunctivitis symptom scores (A) and medication scores (B) of the three treatment groups in the baseline pretreatment season, the first treatment season (C, D) and the second treatment season (E, F). The hatched area indicate the daily birch pollen count. The rectangle indicate the defined pollen season (95% of total pollen exposure).

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Pollen exposure

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

The 1997 birch pollen seasons (baseline) corresponded to an average season, in 1998 (first treatment year) pollen counts were high and in 1999 (second treatment year) low. For statistical calculations, the pollen season was defined as the 3–4 weeks comprising 95% of the total pollen load in order to avoid interference by primary grass pollen. The mean weekly pollen counts in this period were 133, 305, and 78 pollen grains/m3 in 1997, 1998, and 1999, respectively.

Treatment

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

The cumulative dose of allergen after the first treatment season was 4717 μg Bet v 1 in the SLIT group and 27 μg Bet v 1 in the SCIT group, implying that SLIT-treated patients in the first treatment year on average received 175 times more allergen than the SCIT group. The accumulated mean dose over the 2-year treatment period was 11 182 μg Bet v 1 for SLIT-treated, and 51 μg Bet v 1 for SCIT-treated patients. Based on a questionnaire the patients were not (statistically) able to identify which treatment they received.

Symptom and medication score

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Calculation of clinical efficacy was based on weekly symptom/medication scores to compensate for missing data (1.4% missing registrations of symptoms and 0.6% for medication). Only patients completing the first treatment season are included in the statistical calculations. Due to paucity of pollen in the second treatment season all patients experienced few symptoms and used limited medications. Consequently the second season is not included in the evaluation of efficacy.

The relation between pollen counts and the mean weekly rhinoconjunctivitis and medication score during April and May 1997, 1998 and 1999 are shown in Fig. 2. In contrast to the usual close parallellity of symptoms and drug consumption with grass pollen counts (51) a considerable carry-over effect of symptoms and drug intake at a high level for 2–3 weeks was observed after the intense, but short birch pollen peak. Both for symptoms (Fig. 2A) and for medication (Fig. 2B) the groups were perfectly matched in the pretreatment season (no statistical difference between the three groups). Figure 2C,D shows mean weekly symptom and medication scores during the first and second treatment seasons.

The immunotherapy-induced treatment effect in the defined pollen season was calculated by two different methods. The first included subtracting the pretreatment values for individual patients from data obtained in the succeeding treatment season. In the first treatment season the median rhinoconjunctivitis symptom score was improved by 0.36 score points (on a 0–3 scale) in SLIT treated (95% CI 0.18–0.86), by 0.75 score points in the SCIT group (0.02–1.31) and deteriorated by 0.2 score points in the placebo group (−1.05–0.22). Median medication scores increased by 0.29 score points in the SLIT group (−2.57–0.82), were unchanged in the SCIT group (−1.52–2.65), and increased by 1.35 score points in the placebo patients (−4.04–0.12). These data imply a statistical significant difference of changes in rhinoconjunctivitis scores (P < 0.002) and medication scores (P < 0.02) comparing SLIT and placebo as well as SCIT and placebo (P < 0.002 and P < 0.002, respectively) (Fig. 3A). No statistical difference between the SLIT and the SCIT group was observed.

image

Figure 3. Estimation of clinical efficacy by the ‘subtraction’ (A) and the ‘ratio’ method (B) in the first treatment birch pollen season (for further details see text). The graphs indicate medians and 95% confidence intervals.

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The second method evaluated the first treatment season relative to the pretreatment season. The 1998 first treatment season pollen exposure was 2.29 times higher compared with the pretreatment season, and consequently placebo-treated patients deteriorated in symptom scores by a factor 1.45 (0.87–2.09) and increased in medication score by 2.01 (1.02–3.56). The SLIT-group improved, i.e., changed symptoms by a factor 0.78 (0.6–1.06) and drugs by a factor 1.03 (0.77–1.75) (P < 0.01 and P < 0.05) resulting in a disease severity being only half of the placebo group (Fig. 3B). For the SCIT-group symptoms improved, i.e., changed by a factor 0.48 (0.28–1.02) and reduced drugs by 0.78 (0.3–2.0) indicating a disease severity of only one-third of the placebo group (P < 0.001 and P < 0.02, respectively). No significant differences were found between the SLIT and the SCIT group.

Adverse events

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

Systemic side-effects grade 2 (mostly rhinoconjunctivitis) occurred in all three treatment groups: SLIT, 15 patients; SCIT, 14 patients; and placebo, 11 patients (NS). Five cases of systemic reaction grade 3 and one grade 4 were observed in the SCIT group (all but one occurred within 30 min after injection) and one grade 3 in the placebo group. All grade 3 and 4 were successfully treated, two with adrenaline. No grade 3 or 4 reactions occurred in the SLIT group. There were no withdrawals due to grade 3 or 4 reactions. Local reactions related to injections were considered normal and not registered as a side-effect.

In the SLIT group there was an over-representation of itching or mild edema in the mouth and/or throat associated with drop intakes (13 patients vs two and four in the SCIT and placebo group, respectively). Most local side-effects appeared during the induction phase and disappeared when the dose was temporary reduced. Gastrointestinal complaints were rarely reported and occurred in one patient in each of the three groups.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References

To our knowledge, this is the first randomized, placebo-controlled, double-blind, double-dummy study comparing sublingual and subcutaneous immunotherapy in allergic rhinitis. The study was designed to fulfill the standard for conclusive studies (52) including daily registration of symptom/medication scores during a baseline pollen season to ensure optimal randomization of the treatment groups (balancing patients with respect to disease severity) and to reduce the intra-personal variability (by using the individual patient as his own control).

We are aware that including a baseline year may cause problems due to high variability in pollen counts between years, but the succession of a moderate baseline pollen year by a high pollen year does not cause any logistic problems. In the first (1998) treatment season the almost 2.3 times higher pollen loads compared with baseline resulted in deterioration of rhinoconjunctivitis symptoms and medication scores during the birch pollen season in the majority of patients in the placebo group in contrast to improvements in most active treated patients.

Looking at changes in disease severity from pretreatment, two methods were applied: 1) the difference in mean daily symptom and medication scores obtained by subtracting pretreatment data from values obtained in the first treatment season, and 2) the ratio of first treatment season to pretreatment. Both of these strategies imply methodological reservations. Subtraction favors patients with severe disease (more room for improvement) while ratios favor patients with mild disease. Using the subtraction method both SLIT and SCIT treated showed a significantly better outcome compared with placebo treated. Results obtained by the ratio method indicate that the SCIT group had a disease severity reduced to one-third and the SLIT group to half the severity observed in placebo treated. Neither the ‘subtraction’ nor the ‘ratio’ method showed statistically difference between the SLIT and the SCIT group (which does not imply that the two treatments are equally effective). The risk of type 2 statistical error is notable due to the limited number of patients included and completing the study.

The paucity of pollen in the 1999 birch pollen season resulted in few clinical symptoms in all three groups without any significant difference between the groups. When the study was designed, we anticipated a slower onset of action in SLIT and consequently extended the period of active treatment to 2 years (in order not to overlook efficacy that would only show up during the second treatment season). The unequivocal and significant clinical efficacy achieved during the first treatment season indicates that SLIT is in fact clinically effective after only 1 year of treatment.

Beside the primary outcome of clinical efficacy based on daily symptom/medication scores during the birch pollen season, patients were asked to rate possible changes in quality-of-life. In contrast to another asthma immunotherapy study (53) we were not able to show any changes by intergroup or intragroup comparisons in hay fever patients.

According to the protocol, investigating the efficacy of immunotherapy in asthma was not a primary outcome in the study. Asthma symptoms were recorded, but objective measurements of asthma were not done systematically to justify a scientific evaluation. Furthermore, asthmatic patients only constituted one-third of the study population making statistical calculations problematic. Asthma symptoms were taken into account, when safety was evaluated, but we cannot make any conclusions on the efficacy of SCIT and SLIT in birch pollen seasonal asthma.

The number of sublingual immunotherapy studies is increasing rapidly. Some reservations regarding the routine use have been raised by international position papers (1, 2), but the latest (10) conclude that the treatment is convincingly documented. Clinical efficacy implies a reduction in disease severity, i.e. reduction in clinical symptoms and/or intakes of drugs that from a clinical point of view significantly improves the well-being of the patients (9). Looking at the published studies, a convincing clinical efficacy has been documented in some studies (15–17, 25, 28–31, 33). Other studies are difficult to interpret due to methodological flaws (13, 14, 19, 20, 21, 23, 27, 32), and some studies do not find any statistical significant efficacy (18, 22, 24, 26, 30, 34). Although most studies indicate efficacy, a crucial question (beside the documentation of a statistical significant difference from placebo) is the magnitude of efficacy compared with the subcutaneous standard care immunotherapy (9). A symptom/medication score amelioration of <30% has arbitrarily been considered not to justify a treatment involving a risk of side-effects, and probably not to be appreciated worthwhile by the patients (9). A slightly diminished clinical efficacy is acceptable if the safety profile clearly favors sublingual immunotherapy.

Sublingual immunotherapy with birch pollen extracts has been investigated in two studies only (21, 34). The former study did not evaluate clinical efficacy by symptom-medication scores, but by challenge chamber test, and the latter used a mixture of alder, birch and hazel. So the factual effect on clinical symptoms by natural exposure to birch pollens is limited. Comparative studies of sublingual and subcutaneous treatment are hampered by a lack of placebo (17) and blinding (25). In the Quirino study (17) symptom and medication scores were reduced by approximately 50% in both groups (NS) comparing disease severity in two comparable grass pollens seasons. The crucial question not answered in that study is whether this change is different from placebo. The study by Mungan et al. (25) includes a placebo group, but treatment was not administered in a double-blind fashion using the double-dummy technique, i.e. only the sublingual treatment was placebo-controlled and double-blinded. Consequently, concluding about the magnitude of clinical efficacy of the two treatment options is difficult.

Like most SLIT studies (14–19, 21–26, 28–34), we observed no severe allergic side-effects. Most systemic reactions in SLIT treated were rhinitis symptoms statistically not different from the placebo and SCIT group. Basically, local side-effects were itching in the mouth/throat dominating in SLIT treated. Most local side-effects disappeared during maintenance treatment. Five cases of severe side-effects occurred in the SCIT group (grade 3 and 4). All responded adequately to rescue treatment.

The rationale of using immunotherapy as a supplement to pharmacotherapy in the treatment of allergic rhinitis includes: 1) high clinical efficacy, 2) long-lasting efficacy, and 3) disease modifying effects, e.g. preventing the development of asthma in rhinitis patients (1, 2, 10). While several studies have shown a statistical significant clinical effect of SLIT (54), the magnitude of the efficacy in relation to the standard care of specific treatment, i.e. SCIT, and to placebo (which is more relevant to the patients) have so far not been investigated. No studies have dealt with long-term efficacy of SLIT, and it is unknown if SLIT has any preventive capacity. Studies examining these issues are needed (55).

In summary, our findings demonstrate that birch pollen sublingual immunotherapy has a statistical significant and clinical relevant capability to reduce birch pollen-induced hay fever symptoms and the need for rescue drugs compared with placebo, and furthermore that the magnitude of efficacy in this study including a limited number of patients is not statistically different from subcutaneous injection immunotherapy. Sublingual immunotherapy is well tolerated presenting only harmless local side-effects. The long-term efficacy and preventive capacity as well as cost-effectiveness should be evaluated in large-scale clinical studies before a general introduction as a disease modifying treatment.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Patients
  5. Study design
  6. Allergen extracts and treatment
  7. Symptom-medication scores and rescue medication
  8. Quality of life questionnaire
  9. Pollen counts
  10. Estimation of clinical efficacy
  11. Adverse events
  12. Statistics
  13. Results
  14. Patients
  15. Pollen exposure
  16. Treatment
  17. Clinical efficacy
  18. Symptom and medication score
  19. Quality of life
  20. Adverse events
  21. Discussion
  22. Acknowledgments
  23. References
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