Long-term preventive effects of allergen specific immunotherapy: a systematic review and meta-analysis Azevedo L; Cardoso P; Coelho J; Gonçalves A; Maranhas M; Oliveira A; Pereira E; Pereira J; Silva V; Teixeira C; [email protected] João Fonseca, MD, PhD; Class 19 BACKGROUND: Allergen specific immunotherapy (SIT) has long been investigated as a treatment for airway diseases such as allergic rhinitis and asthma, decreasing its symptoms and the need for medication. However, its long-term efficacy is less established namely on the prevention of new sensitivities and on the evolution from rhinitis to asthma, although some studies have already encouraged new investigations about this subject. However, there isn’t any synthesis of them, so it is important to summarize the existing data. AIMS: To investigate if SIT has long-term preventive effects after the treatment ceases. We investigated the development of new sensitivities and the evolution from rhinitis to asthma. METHODS: The long-term effects of SIT on rhinitis and asthma were evaluated through a systematic review with meta-analysis. We searched PUBMED database using terms such as immunotherapy, asthma, rhinitis, desensitization or prevention. The articles selected were based on the criteria defined: reporting a controlled study and having data on the effects of SIT in allergic airway diseases after stopping the treatment. The included articles were evaluated by two reviewers. Articles without a clear classification of the initial diagnosis of the participants were excluded. Furthermore, methodological quality assessment of the included studies was elaborated through the Delphi List. RESULTS: Seven studies were included. Three of them demonstrated that SIT reduces the probability of progression from rhinitis to asthma, even long after the treatment ended. Two studies concluded that SIT is efficient on the prevention of new sensitizations, after the treatment ceased. Only one study was considered of high quality. Regarding the development of asthma symptoms we obtained an odds ratio of 0.36 [0.21, 0.62] (p=0.0002) and regarding the appearance of new sensitivities the valour was 0.15 [0.07, 0.32] (p<0.00001). CONCLUSIONS: Despite the limited number of studies, this systematic review with meta-analysis showed that SIT seems to prevent the development of asthma symptoms and the onset of new sensitizations in patients with allergic rhinitis, even long after the treatment ended. KEYWORDS: immunotherapy [Mesh]; asthma [Mesh]; rhinitis [Mesh]; desensitization, immunologic [Mesh]; prevention [Mesh] INTRODUCTION During the last decades the number of people suffering from allergic diseases and asthma has increased considerably.1 Today these diseases are very frequent; 2.7 million children in the United States suffer from asthma and over a hundred million people suffer from asthma, allergy and chronic obstructive pulmonary disease in Europe.2 An allergy, which may also be designated as hypersensitivity, is a disorder of the immune system which appears in response to a substance (pollen, dust mites, mold spores, etc), usually proteic, that isn’t harmful for the non sensitized people. People who suffer from allergies have a high amount of a substance, Immunglobin E, in their blood. Sensitivity is a term which designates a body reaction to a substance without the intervention of Immunglobin E. When a person suffers from a sensitivity only parts of the immune system intervene. Rhinitis is frequently an allergic disease which consists of an inflammation of the mucous membrane of the nose due to allergens, bacteria or irritant viruses. The consequence of this inflammation is the formation of an excessive quantity of mucous, causing runny nose, nasal congestion and post-nasal drip, which means, it causes the obstruction of the airways. Asthma is often an allergic disease, too. It is characterized by airway obstruction and variable inflammation. Clinically, asthma frequently causes breathing difficulties. Allergen specific immunotherapy (SIT) is a desensitization method used to treat allergic diseases. It reduces or even eliminates an organism’s negative reaction caused by a substance that, in this case, is an allergen. Desensitization “teaches” the immune system to tolerate allergic triggers. To find a solution for airway diseases like asthma and rhinitis, SIT has been developed. This kind of treatment consists in the repeated administration of a specific allergen reducing the response of the immune system and protecting against the allergic symptoms and inflammatory reactions which are associated to natural exposure to the allergen in sensitive people. 3 Through the introduction of small but increasing amounts of allergen at regular intervals, the way the immune system of people who are being treated with SIT reacts will be altered. This means that SIT increases the organism’s tolerance to a specific allergen. There are two kinds of allergic SIT: sublingual (SLIT) and subcutaneous (SCIT). SCIT consists of a subcutaneous injection of an extract of the allergen in solution. 4,5 On the other hand, SLIT is a more recent form of administration and consists in the use of an allergen solution under the tongue. A systematic review concluded that SIT is efficient in the treatment of allergic rhinitis and asthma.6 During the treatment, the observed results are the improvement in symptom control and a reduction of the medication needs, which means that patients who have been treated with SIT are less likely to require medication in comparison with patients who hadn’t taken SIT. 3,6,7,8 Nowadays, many authors support the idea that allergen SIT may be the only treatment for diseases like asthma and rhinitis with long term efficacy.6 Some studies have suggested that SIT may also prevent the development of new sensitivities and the reduction of the risk of developing asthma in patients with allergic rhinitis.8 The long term efficacy has been tested in few studies whose results show that adult patients who suffered from rhinitis and received SIT during three years didn't develop asthma in the next six years.9 However, there is no control group to compare with. In a recent published article the SIT’s efficacy in the prevention of asthma is justified with a reference to just one study which concluded that in two different populations of children suffering from rhinitis – the one that received SIT and the placebo–treated children – there were significant differences. While in the children that received SIT only 28% developed asthma, in the children that weren’t treated with SIT 78% developed this airway disease.10 Another study concluded that in a population of twenty two children who received SIT, 45% (10 out of 22) didn’t develop new sensitivities while in the control group all of them developed new sensitivities. 11 In figure 1 the current knowledge about the effects of SIT is summarized. SIT group Patients with airways allergic diseases Progression from rhinitis to asthma ?? Control group Follow-up period New allergic sensitivities ?? During the study End of the intervention - End of Follow-up Decrease symptoms; Decrease medication. Figure 1 – Graphic contextualising the problem of this systematic review and meta-analysis. In spite of these promising results, there are no studies summarizing the long-term effects of SIT after the treatment ceases. It is well re-established that SIT decreases symptoms and medication needs compared to placebo. However the long-term effects, namely the prevention of new allergic sensitivities and the decrease in the risk of developing asthma, have been less studied and there is a need to. Data suggests that SIT may prevent the evolution from rhinitis to asthma and the appearance of new sensitivities. Therefore we will do a systematic review to investigate this hypothesis, in order to answer the question "Does allergen specific immunotherapy (SIT) have long-term preventive effects in patients with allergic diseases?”. - Aims: To investigate if SIT has long-term preventive effects after the treatment ceases. We investigated the development of new sensitivities and the evolution from rhinitis to asthma. PARTICIPANTS AND METHODS The studies of interest were those reporting controlled trials on SIT treatment of allergen rhinitis or asthma that provide information about the follow-up period. Criteria selection The inclusion criteria are: - Articles which refer to patients with allergic rhinitis or asthma treated with SIT; - Studies with, at least, one year of follow-up after the treatment ceases; - Articles reporting original data on the effects of immunotherapy on the: - • progression from rhinitis to asthma ; • appearance of new allergic sensitivities; Controlled studies. The exclusion criteria are: - Studies that combine SIT with other types of treatment or medication; - Studies without a rigorous definition about the existence or not of asthma in the patients, at the beginning of the treatment; - Articles in other language than the English. Search Strategy To make our systematic review we searched PUBMED database using the search terms ("Immunotherapy"[MeSH Terms] OR "Immunotherapy"[All Fields] OR ("desensitization, immunologic"[MeSH Terms] OR "desensitization"[All Fields]) AND (("asthma"[MeSH Terms] OR "asthm*"[All Fields]) OR ("rhinitis"[MeSH Terms] AND "rhinitis"[All Fields]) OR ("airway diseases"[All Fields])) AND sensitive clinical query from PUBMED. Furthermore, we searched for the references of the included studies and consulted the review articles that have already been published about topics related to SIT. 6,12,13 Data Collection Methods The articles found with the defined search terms were submitted to an evaluation by two reviewers. When there wasn’t an agreement between them a third reviewer intervened, debating with the other two in order to get an agreement between them. During this phase only titles and abstracts were analysed (Figure 3). This analysis followed the selection criteria previously defined. When there wasn’t sufficient information on the title or on the abstract, the article proceeded to the next phase. The articles which didn’t accomplish the criteria were excluded and the reasons for that exclusion were registered. After this screening phase we proceeded with the inclusion phase. Here, the full text of the potential included articles were searched and reviewed again by, at least, two reviewers following, again, the selection criteria. The excluded articles at this point of the work also had a registry of the reasons for that exclusion. Finally, we searched for the references of included articles and review articles on this subject. At the end of this phase we had a list of the included articles. Items extracted from each article were: Study identification: author, year, country Type of study; Study’s objective; Participants: number, age (children or adults), sex, health condition Interventions: use of SLIT or SCIT, type of allergen administrated Variables analysed: progression from rhinitis to asthma in patients treated with SIT and in group control, severity of the symptoms (if developed), development of new sensitivities in both patient groups, type of sensitivity developed (if developed), behaviour’s differences in both groups; Type of treatment; Treatment duration; Follow-up duration; Control or placebo group; Time: seasonal, not-seasonal, co-seasonal; Results: development or not of asthma’s symptoms in patients with rhinitis that didn’t have asthma at the beginning of the study; appearance or not of new allergic sensitivities; development of other kinds of symptoms. The methods used for data collection were similar to the recommendations for this type of studies.15, 16, 17 The instrument for data collection that was used consists of a form that has been filled with information extracted from the included articles. Software Review Manager 4.2 Version and SPSS Software were used to process the data. Variables description The dependent variables studied were the non evolution from rhinitis to asthma and the prevention of new sensitivities. We analysed if the patients, one year at least after the treatment with SIT ceases, developed or not asthma symptoms or new sensitivities. The proportion of these variables is expressed in odds ratio and intervals of confidence (95%). The independent variables studied are the sex, age group and health condition of the participants, the type of treatment administrated, the duration of treatment and follow-up, the existence of a control or placebo group and the time of the administration (not-seasonal, co-seasonal or seasonal). Methodological quality assessment Two reviewers independently assessed the methodological quality using the Delphi list (Table 1).18 Each item (D1-D11) was scored as yes (=1), no (=0) or unclear (=0). The overall methodological quality of a trial was computed by counting the number of positive scores, with equal weights applied on all items. The trials with a score >/= 6 (range 0-11) were considered of high quality. Number of the item D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 Description of the item Was a method of randomization performed? Was the treatment allocation concealed? Were the groups similar at baseline regarding the most important prognostic indicators? Were both inclusion and exclusion criteria specified? Was the outcome assessor blinded? Was the care provider blinded? Was the patient blinded? Were point estimates and measures of variability presented for the primary outcome measures? Did the analysis include an intention-to-treat analysis? Was the withdrawal/drop-out rate <20% of the total study population? Was the withdrawal/drop-out rate unlikely to cause bias? Table 1 – Items of the Delphi-list for the assessment of the methodological quality of the articles. Statistical Analysis The proportion of patients who developed new sensitivities and symptoms of asthma in the intervention and in control groups were expressed through the calculation of odds ratio (OR), in order to analyse the relation between the exposure and the outcome. Intervals of confidence were also calculated. Moreover, tests of heterogeneity (Chi-Squared) were applied in order to evaluate the validity of generalizations. Forest plot graphics were elaborated in order to summarize the data and to explore the heterogeneity. The software used for this statistical analysis was Review Manager 4.2 Version. We also used SPSS for the descriptive statistics proportion (Bar Graphics). RESULTS Identification and selection of the literature The search strategy resulted in 531 titles and abstracts. 125 were immediately considered unsuitable for inclusion because they were review articles. So, 406 titles and abstracts were analysed. After this analysis, 392 papers were excluded mainly because they didn’t have a follow-up period or weren’t controlled studies. 14 full texts were obtained and analysed according to the criteria selection. 10 of these 14 papers were excluded because they didn’t meet the minimum period of follow-up that we defined (n= 9) and they didn’t refer to patients suffering from asthma and/or rhinitis treated with SIT (n=1). Three trials were included after consulting the review papers on this subject. Finally, 527 articles were excluded and 7 studies were included on the systematic review and meta-analysis. 531 references identified electronically 125 excluded - review articles 392 excluded based on title/abstract 14 electronically screened for detailed evaluation - 10 reports excluded 9 without one year, at least, of follow-up 1 not relative to patients suffering from asthma and/or rhinitis 3 articles included after consulting the review papers on this subject 4 reports included 7 studies included on the systematic review Figure 2 - Flow diagram for the process for inclusion in the systematic review. Description of the included articles The included articles were analyzed according to the items already defined. In Annex I tables summarizing the information obtained are presented. The participants were children in four studies and adults in three. While in two of them 19, 20 the participants only had rhinoconjunctivitis, in other four the participants had rhinitis and/or asthma. In relation to the type of treatment administrated, two of the studies 19, 20 used SCIT with the same allergen extracts (Phleum pratense and Betula verrucosa), another22 used SLIT while three of them didn’t specify the type of SIT administrated. Three studies administrated grass pollen allergen extracts while in the others the type of allergen wasn’t reported. Six studies had in common the period of treatment duration – 3 years, while in another 22 the treatment lasted 4 to 5 years. In relation to the follow – up period, it was 3, 5, 8, 10 to 12 years. In two studies 19, 20 SIT was administrated out of the season. In another study the treatment was co-seasonal and in another it was seasonal. In two articles this information wasn’t referred. Two included articles23, 24 are relative to the same study but with different follow-up periods. Methodological quality assessment The total Delphi’s values were similar, ranging from 4 to 6 out of 11. However one trial21 presented high quality, while the other six were considered of low quality (Table 2). The description of “treatment allocation” (D2) and the “blinding of the care provider/patient” (D6/D7) was insufficient in most trials, resulting in a low score of these items. Article D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 Total Delphi* L. Jacobsen, et al.2007 1 0 1 0 1 0 0 1 1 0 0 5 B. Niggemann, et al.2006 1 0 1 0 1 0 0 1 1 0 0 5 Pajno GB, et al.2001 0 0 1 1 0 0 0 1 1 1 1 6 Di Rienzo V, et al.2003 0 0 1 0 0 0 0 1 1 1 1 5 Eng, PA, et al. 2006 0 0 1 0 0 0 0 1 1 1 1 5 Eng, PA, et al. 2002 0 0 1 0 0 0 0 1 1 1 1 5 Durham SR., et al.1999 0 0 1 1 0 0 0 1 1 0 0 4 * Total Delphi (range 0-11): total score >/= 6 = high quality; <6 = low quality Table 2 – Results of the methodological quality assessment. Data extraction and analysis The studies that analysed the progression from rhinitis to asthma concluded that during the follow – up period, the number of patients who developed asthma symptoms were less in the SIT group than in the control group (Table 3). Development of new sensitivities Development of asthma symptoms Study Pajno GB, et al. 2002 Eng PA, et al. 2002 Eng PA, et al. 2006 Di Rienzo V, et al. 2003 L. Jacobsen, et al. 2007 B. Niggemann, et al. 2006 SIT Group 25% 61% 0% 9% 25% 20% Control Group 67% 100% 0% 96% 45% 43% Table 3 – Results obtained by the included studies. One study 19 obtained as a secondary outcome the development of new sensitizations. 57% of the children who developed asthma also developed a new sensitization, while in the group of children who didn’t develop asthma the percentage of children with new sensitizations was 50%. In this study, 16 out of 64 (25%) patients in SIT group developed asthma symptons, in comparison with 24 out of 53 (45%) in control group (OR=0.40 [0.18, 0.88]). Niggemann, B, et al. 2006 20 concluded that 20% (15 out of 75) of the patients in SIT group evolved from rhinitis to asthma while in the control group this percentage was 43% (29 out of 67). The odds ratio of this study was 0.33 [0.16, 0.69]. The Di Rienzo V, et al. 2003 study 22 concluded that 9% of the patients of SLIT group developed asthma, in comparison with 96% of the control group (OR=0.00 [0.00, 0.04]). It also verified an increase of the number of patients with multiple sensitizations in SLIT group, in comparison with the control group. One study21 that analysed the development of new sensitizations concluded that 25% of the children in SIT group show, at least, a new sensitization, while in the control group the percentage of children who developed new sensitizations was 67% (OR=0.16 [0.07, 0.36]). The Eng PA, et al. 2002 study 24 also analysed the appearance of new sensitizations. In this trial, 61% (8 out of 13) of the SIT patients developed a new sensitivity, while in the control group this percentage was 100% (10 out of 10). In this study the odds ratio was 0.07 [0.00, 1.53]. The Eng PA, et al. 2006 study 23 analysed both the development of new sensitivities and the prevalence of asthma. It observed that the prevalence of sensitizations was 90% in the control group, in comparison with 67% in the SIT group. They concluded, in comparison to a previous observation that had been made six years before, that no patients (control or SIT group) developed new sensitizations in that period. Stephen R. Durham, et al. 1999 25 verified a decrease in the late skin response to allergen challenge, after the discontinuation of SIT. This paper wasn’t referring any numbers or percentages. Development of new sensitivities Progression from rhinitis to asthma 2 studies: SIT is preventive 3 studies: SIT is preventive Figure 3 – Diagram summarizing the results obtained in the systematic review. Figure 3 - Meta-analysis of development of asthma symptoms: odds ratio (OR) with 95% confidence interval (CI) for each study and all studies combined (include test for heterogeneity). In this meta-analysis we didn’t include Di Rienzo V, et al. 2003 study 22, once it is impossible to calculate the odds ratio valor through the results this study presents. The odds ratio in favour of the treatment was 0.36 with 95% CI ranging from 0.21 to 0.62 (p=0.0002). There was a non significant homogeneity (Chi2 = 0.14, p = 0.71, I2 = 0%) among these studies. Figure 4 - Meta-analysis of development of new sensitivities: odds ratio (OR) with 95% confidence interval (CI) for each study and all studies combined (include test for heterogeneity). In this meta-analysis we didn’t include the Eng, PA, et al. 2006 continuation of the Eng, PA. 2002 24 23 study once it is a study. The odds ratio in favour of the treatment was 0.15 with 95% CI ranging from 0.07 to 0.32 (p<0.00001). There was a non significant homogeneity (Chi2 = 0.25, p = 0.61, I2 = 0%) among these studies. DISCUSSION The results that we obtained suggest that this kind of treatment is efficient not only during its administration but also after the treatment ceases. The majority of the included studies as well as the results of the meta-analysis indicate that patients suffering from asthma and/or rhinitis that have been submitted to SIT are less exposed to the appearance of new sensitivities after its end in comparison with patients who didn’t take it. Besides, our analysis also proposes that people suffering from rhinitis who have already been treated with SIT have less probability of developing asthma symptoms, in comparison with people with the same disease but not submitted to this treatment. One of the limitations of this systematic review with meta-analysis was the use of only one database to search the articles. Although PUBMED is a wide database, some important studies that could have been published only in other databases were missed out. However, the search of references from studies and reviews improved the search. Another limitation of our work is the publication bias, once the studies with negative results tend to be less published. So, there could be studies contradicting the information that we obtained, however, they aren’t accepted to be published once they are considered, by the editors, less significant in comparison with studies which obtain the opposite results. Moreover, the number of studies is very limited. Despite these limitations, the relevance of our work should be emphasized once there are few systematic reviews and meta-analysis on this subject, that is, the number of articles which, nowadays, focus on the long-term effects of SIT after the treatment ceases is small. On the other hand, the number of studies reporting data on the effects of this type of treatment during its administration is higher. Future research is needed in order to obtain more information about the details of the influence of SIT when the treatment stops and all the implications it could have in a long-term period. Despite the limited number of studies, this systematic review with meta-analysis showed that SIT seems to prevent the development of asthma symptoms and the onset of new sensitizations in patients with allergic rhinitis, even long after the treatment ended. ACKNOWLEDGEMENTS Grateful thanks are extended to Altamiro Costa Pereira, MD, PhD for the constructive critics and to João Fonseca, MD, PhD, for having supervised our work. REFERENCES 1. TePas EC, Umetsu DT. Immunotherapy of asthma and allergic diseases. Curr Opin Pediatr. 2000 Dec; 12(6):574-8. 2. Chin ES. Pediatrics, Reactive Airway Disease. eMedicine [Internet]. 2006 Nov [updated 2006 Nov 8; cited 2007Nov]. http://www.emedicine.com/emerg/TOPIC363.HTM 3. James T. Li, MD, PhD; Richard F. Lockey, MD; I. Leonard Bernstein, MD; Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol. 2003 Jan; 90(1):13-4. 4. O'Hehir RE, Sandrini A, Anderson GP, Rolland JM. Sublingual allergen immunotherapy: immunological mechanisms and prospects for refined vaccine preparation. Curr Med Chem. 2007;14(21):2235-44. 5. Greenberger PA, Ballow M, Casale TB, Platts-Mills TA, Sampson HA. Sublingual immunotherapy and subcutaneous immunotherapy: Issues in the United States. 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A six-year followup study. Clin Exp Allergy. 2001 Sep;31(9):1392-7. 22. Di Rienzo V, Marcucci F, Puccinelli P, et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy. 2003 Feb;33(2):206-10. 23. Eng PA, Borer-Reinhold M, Heijnen IA, et al. Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy. 2006 Feb;61(2):198201. 24. Eng PA, Reinhold M, Gnehm HP. Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy. 2002 Apr;57(4):306-12. 25. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999 Aug 12;341(7):468-75. ANNEX I Study identification: Author L. Jacobsen et al. B. Niggmenn, et al. Year 2007 2006 Country Participants: Type of study Study’s objective To investigate if the preventive effect of Denmark Prospective developing study asthma persisted 7 years after termination of SIT (at 10 year follow-up) To investigate the potential long-term preventive effects on the Prospective development Germany study of asthma in children with seasonal allergic rhinoconjuncti vitis 2 years after termination of SIT(at 5 year follow-up) Number Sex 147 Not reporte d 183 121males; 62female s Age (children or adults) Variables analysed Health condition rhinoconjunctivitis 16-25 years 11-20 years Progression from rhinitis to asthma in patients treated with SIT and in group control rhinoconjunctivitis Progression from rhinitis to asthma in patients treated with SIT and in group control Eng, PA, et al. Di Rienzo V, et al. Pajno GB, et al. 2006 2003 2001 Switzerla nd Italy Italy Prospectiv e study Clinical Trial Clinical Trial To investigate whether there is a prolonged benefit 12 years after SIT is stopped To evaluate whether a long-lasting effect of SLIT occurs, in a prospective parallel group controlled study. To increase the knowledge of the ability of SIT to prevent the onset of new sensitizations in monosensitize d subjects, so far poorly documented. 22 16 males; 6 female s Male: 31 60 Femal e: 29 Male: 58 138 Femal e: 80 20 -31 years Rhinoconjunctiviti s with or without asthma; sensitivity to grass pollen Skin prick test (SPT) reactivity to grass pollen; development of new sensitizations; prevalence of seasonal asthma due to grass pollen allergy Children Mean age: 8.5 years Children 5-8 years Allergic asthma/ rhinitis due to mites Intermittent asthma with or without rhinitis, with single sensitization to mite allergen - The presence and frequency of asthma Grading severity of asthma The rate of asthma/ asthma+ rhinitis at the beginning of the trial and the occurrence of new sensitizations in SIT-treated and untreated children. Eng, PA, et al. Durham SR, et al. 2002 1999 Switzerla nd England Prospectiv e study Clinical Trial Determine if SIT with grass pollen allergoids in childhood is still effective six years after discontinuation and if 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. To examine the effects of the discontinuation of immunotherap y for three years in the 28 Not report ed Male: 29 47 Femal e: 18 Children 5-16 years Adults: 33-42 Severe hayfever and IgEmediated sensitivity to seasonal allergens only (grass pollen with or without tree pollen). IgEmediated seasonal allergic rhinoconjunctivitis with or without seasonal asthma Seasonal allergic rhinitis Hayfever symptom score, individual eye nose and chest symptoms score, the appearance of new sensitivities, seasonal rhinoconjunctivitis (and pollen asthma in addition to this). Scores for seasonal symptoms and the use of rescue medication. The conjunctival response and the immediate and late skin responses to same group of patients Table 4 – Characteristics of the included studies. allergen challenge. Study L. Jacobsen et al. Type of treatment* SCIT : - allergen extracts of grass pollen (Phleum pratense) and/or birch pollen (Betula verrucosa) SCIT: B. - allergen Niggmenn, et extracts of al. grass pollen (Phleum pratense) and/or birch pollen (Betula verrucosa) Treatment duration* Followup duration Time Control (seasonal, or not placebo seasonal, group* coseasonal)* 3 years 10 years Control group Not seasonal 3 years 5 years Control Group Not seasonal Results Before the beginning of SIT there were 117 patients without asthma. After the 10 year period, the number of patients who developed asthma among controls was 24 of a total of 53 and in the actively treated group 16 of a total of 64. The odds ratio was 2,5 (1,1 – 5,9). It has already been verified that 30% (18 of 61) of the children who developed asthma during the 10year follow-up also developed a positive skin prick test to house dust mites compared with 17% (15 of 86) of the children who did not develop asthma. Furthermore, in the group of children who developed asthma during the 10 year period there were 35 out of 61 (57%) who also developed a positive skin prick test to one or more of the following allergens – house dust mite, cat or dog allergen – in comparison with 50% (43 of 86) of the children who did not develop asthma. Of the 183 patients, 142 had no asthma at inclusion. In SIT group it was verified that 20% (15 out of 75) of the patients developed asthma (it was considered non significant) while in control group the percentage of people with asthma symptoms was 39% (29 out of 67) (P < 0.01), after 5 years. The odds ratio in favour of the hypothesis that SIT can prevent the long-term development of asthma was 2.68 (1.3 – 5.7, P < 0.05). Eng, PA, et al. 3 years 12 years Control group Coseason al SIT Di Rienzo V, et al. Pajno GB, et al. SLIT 4 to 5 years 10 years Control group SIT 3 years 3 years Control group 3 years Eng, PA, et al. SCIT : -grass pollen allergen extracts 8 years Control group Not reported Not reported Seasonal There was a reduction in development of new sensitizations after SIT in the 12-year follow-up study (P < 0.05). The prevalence of sensitization to tree pollen was 90% in the controls and 67% in the post-SIT group. There was a tendency for lower asthma prevalence in the post-SIT group, but without reaching statistical significance (P ¼ 0.08). In the SLIT group there was a significant difference vs. baseline for the presence of asthma (P </= 0.01), whereas no difference was observed in the control group. The mean peak expiratory flow result was significantly higher in the active group than in the control group after 10 years. No change was seen as far as new sensitizations were concerned. Specific IgE showed a near-significant increase (baseline vs. 10 years, P = 0.06) only in the control group. 123 children completed the follow-up study. At the end of the study, 52 out of 69 children (75.4%) in the SIT Group showed no new sensitization, compared to 18 out of 54 children (33.3%) in the Control Group (P < 0.0002). Parietaria, Gramineae and Olea were the most common allergens responsible for the new sensitization(s). During the 13 week observation time scores for overall hayfever symptoms and individual symptoms for eyes, nose and chest remained lower in the group with previous SIT. Only 23% of patients with previous pollen-asthma who had received SIT experienced pollenassociated lower respiratory tract symptoms compared to 70% in the control group. 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. 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 pollenmonosensitized children had developed new sensitization to perennial allergens compared to 100% in the control group. Durham SR, et al. SIT 3-4 years 3 years Control AND Placebo group Not reported Scores for total hay fever symptoms, rescue medication, and the visual analogue scale for both the maintenance group and the discontinuation group had no significant differences in any of these scores between these two groups throughout the three-year period. Symptom and rescue-medication scores in both groups were markedly lower than those in patients in the control group. * Relative to the clinical trial that is associated Table 5 – Characteristics of the included articles.