- Top of page
- Material and methods
Background: In a previous controlled study we demonstrated that preseasonal grass pollen immunotherapy for three years was effective in children. In the current study we examined the same group of patients to see if there is still a benefit six years after discontinuation of treatment.
Methods: Thirteen of 14 patients with previous specific immunotherapy (SIT) and 10 out of 14 patients of the control group were prospectively followed during the grass pollen season. Outcome measures were seasonal symptom scores for eyes, nose and chest, the use of symptomatic medication and visual analog scale. Objective measures included skin prick test reactivity to seasonal and perennial allergens and conjunctival provocation testing.
Results: During the 13 week observation time scores for overall hayfever symptoms (P < 0.004) and individual symptoms for eyes (P < 0.02), nose (P < 0.04) and chest (P < 0.01) as well as combined symptom and medication scores (P < 0.002) remained lower in the group with previous SIT. Only 23% of patients with previous pollen-asthma who had received SIT experienced pollen-associated lower respiratory tract symptoms compared to 70% in the control group (P < 0.05). There was no significant difference in the use of pharmacological treatment during the pollen season except for asthma medication. The average visual analog scale was lower in the post-SIT group (P < 0.05). Six years after cessation of SIT the immediate skin response to grass pollen remained decreased compared to the reaction of the controls (P < 0.01). There was also a tendency for higher allergen concentration to provoke a conjunctival response in the post-SIT group but without reaching statistical significance. Eight years after commencement of SIT, 61% of the initially pollen-monosensitized children had developed new sensitization to perennial allergens compared to 100% in the control group (P < 0.05).
Conclusions: There is still a significant clinical benefit six years after discontinuation of preseasonal grass pollen immunotherapy in childhood. SIT in children with pollen-allergy reduces onset of new sensitization and therefore has the potential to modify the natural course of allergic disease.
Many controlled studies have demonstrated that specific immunotherapy (SIT) with standardized pollen extracts is an effective treatment of seasonal allergic disease (1–8). However only limited knowledge exists about the optimal duration, age of commencement, route of administration and duration of the therapeutic response. There are only a few follow-up studies after discontinuation of pollen immunotherapy (9–14). All of them were performed in adults. Little is known also about the course of the seasonal allergic rhinoconjunctivitis and asthma after early intervention with SIT in children. Since hayfever most commonly begins in childhood and adolescence,early intervention with SIT is an important issue in this age group.
In a previous study we enrolled 28 children with IgE-mediated seasonal allergic rhinoconjunctivitis with or without seasonal asthma. All patients were sensitized to seasonal pollen-allergens only and had no history of allergic disease outside the pollen season. The children were either treated with subcutaneous grass pollen immunotherapy (n = 14) in the years 1989, 1990 and 1991 or with standardized pharmacological treatment only (n = 14) during the three grass pollen seasons. The study demonstrated a significant clinical benefit and decrease of skin test reactivity after discontinuation of SIT when compared with the control group (5).
In order to assess the duration of efficacy of this treatment we decided to follow-up prospectively the two study populations six years after cessation of SIT. All patients had to record their symptoms and their need for medications during the pollen season 1997. Objective measures included immediate sensitivity of conjunctiva as well as of the skin by performing prick tests with a panel of common inhalant and food allergens. This study was designed to determine whether:
1) SIT with grass pollen allergoids in childhood is still effective six years after discontinuation
2) the natural course of the disease can be modified by early intervention with SIT, especially with regard to disease progression and onset of new sensitizations.
- Top of page
- Material and methods
This prospective controlled follow-up study has shown that there is still a significant clinical benefit six years after discontinuation of subcutaneous grass pollen immunotherapy in childhood. Scores for all hayfever symptoms, for symptoms plus medication, and for VAS were reduced during the pollen season compared to the control group. As an objective parameter immediate skin response to grass pollen remained decreased when compared to the reaction of the controls. Thirty percent of patients who received SIT no longer required pharmacological treatment during the pollen season. It shows that in most of the hayfever patients SIT does not cure the allergic disease, but it decreases disease severity and hence has the potential to improve quality of life. This is especially important in children who participate in a lot of outdoor activities in spring and early summer.
A striking finding of this study was the reduced onset of new sensitization to perennial allergens in the SIT group and the better evolution of pollen asthma after three years of preseasonal allergen vaccination. These results suggest that SIT has also the potential to modify the long-term course of the allergic disease with regard to the development of multiple allergies and disease progression.
The selection of patients for SIT is important. We think that the good long-term results in our SIT-group are due to restrictive inclusion criteria of patients with sensitivities to seasonal allergens only, without a history of perennial allergic disease. SIT in children with multiple allergies and sensitization to perennial allergens has been shown to be less effective (15).
Though many studies have confirmed the efficacy of SIT in patients with hayfever, only a few studies exist about its long-term effect (9–14). To our knowledge this is the first controlled follow-up study of previous SIT with a standardized grass pollen extract in children. Two of the studies performed in adults also observed clinical improvement and reduced skin test reactivity six years after discontinuation of three-year SIT with grass pollen (9) and birch pollen, respectively (13). However both studies were not controlled and Mosbach and Osterballe's results may have been biased by an adjustment of the symptom and medication score for the increase in pollen exposure during the follow-up period, assuming that there is a linear relationship between pollen exposure and symptoms. Another controlled study using allergoid (ragweed) in adults showed a maintenance in clinical improvement two years after discontinuation of a five-year duration of SIT (12).
Durham et al. recruited 32 adult patients with severe hayfever symptoms unresponsive to pharmacological treatment. In a double-blind placebo-controlled trial the authors have demonstrated that three to four years of grass pollen SIT remained effective for three years after cessation (14). There was no significant difference when compared to a group of patients who continued SIT. However the population in this elegant study is different from our enrolled subjects in terms of age and disease severity. We chose SIT as an early intervention in children to prevent disease progression.
Our patients with previous SIT maintained decreased immediate skin reactivity to grass pollen compared to the control subjects. There was also a tendency for decreased reactivity to rye pollen (Fig. 3) whereas wheal sizes in response to tree pollen were the same in both groups. Since the applied allergoid extract contained 80% grass and 20% rye pollen only, we speculate that the relatively small amount of sc administered rye pollen was not sufficient to sustain decreased specific skin test reactivity after cessation of SIT.
The immunologic mechanism by which SIT exerts its effect has not been fully determined. Earlier work (16, 17) focused on changes in circulating antibodies (specific IgE and IgG) and effector cells (mast cells and eosinophils). Recent studies suggest that these changes may be secondary to the influence of SIT on allergen-specific T-cell responses. Successful SIT may be associated with a down-regulation of Th2 response (decreased IL-4 and IL-5 production) or increased Th1 response (increased IFN-γ) (19, 20). However neither changes in antibody levels, in effector cells, nor changing patterns of cytokines have been demonstrated to correlate with the clinical response to SIT.
Recent studies have discovered that T-cell immunity is directed by transcription factors (i.e. GATA-3) which have been shown to regulate the production of key cytokines (20). Further studies have to demonstrate if measurement of allergen-specific T-cell transcription factors is an effective way to monitor effectiveness of SIT.
An important finding of the present study is the result of the assessment of the natural course of the allergic disease. Thirty-nine percent of the pollen-sensitized children had not developed any new sensitization eight years after commencement of SIT compared to 0% in the control group. The most prevalent new sensitizations were to cat and house dust mites. The recent study of Des Roches et al. (21) was the first to evaluate the evolution of sensitivities during SIT in children monosensitized to house dust mites. Forty-five percent of their children who received SIT with a standardized D. pteronyssinus extract did not develop new sensitization, compared to 0% of previously monosensitized children without SIT in a three-years follow-up survey. Our data correspond very well with their findings and demonstrate that SIT has the potential to modify the long-term course of allergy also in another group of children with early onset of pollen allergy without perennial allergic disease.
Most of our study patients in both groups presented with seasonal asthma at enrolment. The long-term outcome of asthma was significantly better in the group with SIT. This is in accordance with other studies, which showed that more children with allergic asthma have become asymptomatic after SIT compared to controls (22, 23). However it remains unanswered whether early commencement of SIT in children with hayfever suffering from allergic rhinoconjunctivitis only has the potential to decrease the incidence of asthma.
Major drawbacks of our follow-up study are the small number of subjects involved and the fact that it was not double-blind placebo-controlled. A study protocol requiring placebo injection in a randomized group of children over a prolonged time is difficult to justify to parents and ethical committees. However more studies in this age group are needed.
In conclusion this prospective follow-up study six years after discontinuation of SIT in children with seasonal allergic disease showed a prolonged clinical benefit of SIT in comparison to pharmacological treatment only. It demonstrates that SIT in children with monovalent pollen allergy prevents development of new sensitization, reduces prevalence of subsequent asthma and therefore has the potential to modify the natural course of the allergic disease.