Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Double-blind, placebo-controlled clinical trial of preseasonal treatment with allergenic extracts of Olea europaea pollen administered sublingually. Safety and efficacy of Juniperus ashei sublingual-swallow ultra-rush pollen immunotherapy in cypress rhinoconjunctivitis. A double-blind, placebo-controlled study. A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen. Specific immunotherapy with high dose SO standardized grass allergen tablets was safe and well tolerated. Allergic rhinitis due to house dust mites: evaluation of the efficacy of specific sublingual immunotherapy. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. Randomized double-blind controlled study with sublingual carbamylated allergoid immunotherapy in mild rhinitis due to mites. House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a double-blind, placebo-controlled study. Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. A double-blind placebo-controlled evaluation of sublingual immunotherapy with a standardized ragweed extract in patients with seasonal rhinitis. Evidence for a dose-response relationship. Efficacy of sublingual immunotherapy in children with asthma and rhinitis: a double-blind, placebo-controlled study. Safety of specific sublingual immunotherapy with SQ standardized grass allergen tablets in children. [Clinical evaluation for sublingual immunotherapy of allergic asthma and atopic rhinitis with Dermatophagoides Farinae Drops]. Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralingually. Safety and efficacy of sublingual rush immunotherapy with grass allergen extracts. A double blind study. Clinical efficacy and safety of preseasonal sublingual immunotherapy with grass pollen carbamylated allergoid in rhinitic patients. A double-blind, placebo-controlled study. Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization. A double-blind, placebo-controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardized five-grass-pollen extract in rhinitis. Double-blind placebo-controlled study of sublingual immunotherapy with house dust mite extract (D.pt.) in children. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. Sublingual immunotherapy with a standardised grass pollen extract; a double-blind placebo-controlled study. Clinical and immunologic effects of a rush sublingual immunotherapy to Parietaria species: A double-blind, placebo-controlled trial. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Sublingual immunotherapy in tree pollen allergy. Double-blind, placebo-controlled study with a biologically standardised extract of three pollens (alder, birch and hazel) administered by a rush schedule. Safety and immunological changes during sublingual immunotherapy with standardized quality grass allergen tablets. Sublingual immunotherapy: a double-blind, placebo-controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma, or both. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. A double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized cat extract. Sublingual immunotherapy in Parietaria pollen-induced rhinitis: a double-blind study. Immunomodulation during sublingual therapy in allergic children. Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. [Sublingual immunotherapy with cat epithelial extract. Personal experience]. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study. Double-blind placebo-controlled evaluation of sublingual-swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double-blind study. Clinical efficacy and safety of sublingual immunotherapy with tree pollen extract in children. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. Efficacy of sublingual specific immunotherapy in Cupressaceae allergy using an extract of Cupressus arizonica. A double blind study. Sublingual-swallow immunotherapy (SLIT) with a standardized five-grass-pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. Safety of various dosage regimens during induction of sublingual immunotherapy. A preliminary study. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. Efficacy and safety of specific immunotherapy with a high-dose sublingual grass pollen preparation: a double-blind, placebo-controlled trial. Three-year follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing sub-lingual immunotherapy. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled fluticasone propionate.
Sublingual immunotherapy (SLIT) is considered safer and more convenient than subcutaneous therapy and therefore has been proposed as especially suitable for children and in primary care. Most efficacy studies in children lack power to be conclusive, and all have been performed in referral centers.
                To investigate the efficacy of SLIT with grass pollen allergen in children and adolescents with rhinoconjunctivitis in a primary care setting.
                Youngsters aged 6-18 years with hay fever were enrolled from general practices and randomly assigned to receive placebo or grass pollen mix for 2 years. The primary outcome was the mean daily total symptom score (scale 0-15) comprising sneezing, itching nose, watery running nose, nasal blockage, and itching eyes during the months May-August of the second treatment year.
                Out of 204 youngsters randomized, 168 entered the intention-to-treat analysis (91 verum, 77 placebo). The mean daily total symptom score did not differ between participants allocated to verum and those allocated to placebo (difference for verum minus placebo: -0.08, 95%CI, -0.66-0.50; P = .78). No differences were found for rescue medication-free days, disease-specific quality of life, and overall evaluation of the treatment effect. Local side effects were more frequent in the verum group (39% vs 17% of participants; P = .001).
                Sublingual immunotherapy with grass pollen in a primary care setting is not effective in children and adolescents.
                Currently, SLIT cannot be recommended for general practitioners as a therapeutic modality in youngsters with grass pollen allergy. Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed.
                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.
                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.
                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.
                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. In a double-blind, placebo-controlled, pilot clinical trial we evaluated the clinical efficacy and safety of immunotherapy (IT) with an extract of the pollen of the tree Olea europaea administered sublingually. The parameters tested were symptom score, dose-response bioassay of skin prick test and specific IgE and IgG, and the absolute value at a single serum dilution of each IgG subclass. Fifteen patients allergic to this pollen with symptomatology of rhinitis and/or rhinoconjunctivitis were randomly allocated to the placebo group (6 patients) or to the extract group (9 patients). Immunotherapy was administered in a short preseasonal period of time, practically no side effects being recorded. The group of patients treated with extract presented a slightly lower incidence (0.05 < p < 0.1) of nasal symptoms of sneezing and obstruction, and, more importantly, developed less dyspnea (p < 0.05) than the group treated with placebo, suggesting that IT can act as prophylaxis for the development of bronchial symptoms. No differences were observed in the immunological determinations. Differences in skin tests between the two groups displayed a slight significance (0.05 < p < 0.1) at the end of the trial; hence, a higher concentration of the allergen was needed in the group treated with extract to induce the same wheal as in the placebo group. In both groups the size of the wheal showed a time-dependent variation, which was dependent on the time of the year and independent of the type of treatment received, indicating a significant modification in the in vivo skin response to allergen challenge, demonstrated by a shift in the kinetics of allergen-ligand binding (slope) and in the magnitude of the measured response (intercept). The safety and efficacy of high-dose sublingual-swallow immunotherapy (SLIT) has been established in pollen rhinoconjunctivitis. This treatment has now been evaluated using an ultra-rush incremental dose regimen with a Juniperus ashei allergen extract in patients allergic to Cupressus sempervirens and Cupressus arizonica.
                Patients received either placebo or SLIT. Evaluation of safety was based on the frequency of adverse events during the incremental dose period (half a day) and during maintenance therapy (4 months). Evaluation of efficacy was based on symptom and medication scores at the pollen peak.
                Seventy of the 76 patients included completed the study. There were no drop-outs during the rush procedure. One patient in the active group dropped out during the maintenance therapy due to adverse events: gastric pain and vomiting. There was also 1 drop-out in the placebo group due to pregnancy. Adverse events were infrequent, local and mild. Symptom scores for rhinitis and conjunctivitis were not statistically different between groups, but there was a marked and significant (p < 0.03) decrease of the medication score (about 50%) and nasal steroid consumption (about 75%) in the active treatment group. An increase from baseline of serum IgE and IgG4 J. ashei-specific antibodies was only observed in actively treated patients (p < 0.04 and p < 0.01, respectively).
                The tolerability and safety of high-dose ultra-rush SLIT were comparable to those reported in previous SLIT studies. SLIT with J. ashei extract, due to its high Jun a 1 content, significantly reduced nasal steroid consumption in patients allergic to European cypress. Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available.
                In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38).
                The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026).
                Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo. Sublingual immunotherapy with grass allergen tablets may be the future treatment for grass pollen allergy because it reduces symptoms and medication use, improves quality of life and is easy to use. Rhinoconjunctivitis and asthma co-exist and we aimed to find a safe dose range of a self-administered grass allergen tablet (ALK Abello A/S) in patients suffering from rhinoconjunctivitis and asthma.
                Four doses were investigated in a randomised, double-blind, placebo-controlled, dose escalation trial. Outside the pollen season 4 groups of 12 patients commenced treatment in a staggered manner, at intervals of 1 week. For 28 days doses of 75000 (approximately 15microg Phleum pratense protein 5), 150,000, 300,000, 500,000 standardised quality tablet (SQ-T) units or placebo were given once daily as sublingual tablets.
                Fourty three patients were randomised to receive either active treatment or placebo (3:1). Each dose group consisted of 12 patients except the 500000 SQ-T group (5 active, 2 placebo). No asthma exacerbations were seen and no serious or severe adverse events were reported. The majority of adverse events were local reactions. The number of adverse events was dose related. No patients withdrew from the study.
                Treatment with grass allergen tablets in doses up to 500000 SQ-T in patients with asthma and rhinoconjunctivitis was safe and well tolerated. The efficacy and safety of sublingual immunotherapy (SLIT) in patients with chronic rhinitis related to sensitization to house dust mites are still controversial.
                After application of an anti-mite mattress cover, patients were only included in the study when the cumulative symptom score over a fortnight was greater than 70 out of a possible total of 168. Thirty-two of the 120 patients selected were randomized to receive SLIT for 2 years: 17 received placebo and 15 received the Dermatophagoides pteronyssinus and D. farinae 50/50 allergen extract.
                Significant between-group differences were observed after 1 year and persisted at the end of the second year for the rhinitis total score (P < 0.02), blocked nose score (P < 0.01) and nasal itching score (P < 0.01). Skin reactivity to house dust mites was significantly reduced in the group receiving house dust mite extract (P < 0.03). No statistical difference was observed between the two groups for medication scores, but a low medication consumption was observed in all patients. No serious and no systemic adverse reactions were reported.
                This study indicates the superiority of active treatment vs. placebo, evaluated on efficacy criteria (rhinitis score) or objective criteria (skin reactivity). The availability of a solid form (tablet) could represent a progress in terms of patient acceptability. To date, there have been no randomized, double-blind studies showing the effectiveness of sublingual immunotherapy with multiple allergens.
                The purpose of this study was to examine whether the efficacy of sublingual immunotherapy (SLIT) with standardized timothy extract was reduced by combination with other allergen extracts.
                A single-center, randomized, double-blind, placebo-controlled trial with SLIT was conducted. After an observational grass season, SLIT was administered for 10 months to 54 patients randomized to 1 of 3 treatment arms: placebo, timothy extract (19 microg Phl p 5 daily) as monotherapy, or the same dose of timothy extract plus 9 additional pollen extracts. Symptom and medication scores were collected and titrated nasal challenges, titrated skin prick tests, specific IgE, IgG4 and cytokines release by timothy-stimulated lymphocyte proliferation were performed.
                Perhaps because of a very low grass pollen season in 2008, there were no significant differences in medication or symptom scores in either treatment group compared with placebo. Compared with placebo, in the timothy monotherapy group, thresholds for titrated nasal challenge and skin prick tests (P = .03 and P = .001, respectively), and serum-specific IgG4 levels (P = .005) significantly increased, and IFN- gamma levels decreased (P = .02), whereas in the multiallergen group, there was significant improvement only in the titrated skin prick tests (P = .04) which was less than in the monotherapy group. There were no significant differences between the 2 active groups in any outcome measure, and both active groups experienced more adverse events than placebo. There were no systemic reactions.
                Improvement in multiple relevant outcomes strongly suggests that SLIT with timothy extract alone was effective; however, the results for symptom and medication scores were not significant. The differences between multiple allergen SLIT and placebo only in skin sensitivity to timothy suggest a reduction in SLIT efficacy in this group. However, further studies are required to confirm these observations. The clinical efficacy of sublingual immunotherapy (SLIT) in mite allergy and in mild disease is still a matter of debate, thus we performed a long-term clinical trial.
                The study was randomized, double-blind and placebo-controlled. After a 1-year assessment, 68 patients with mild rhinitis with/without asthma due to mites were randomized to drugs + placebo or drugs + SLIT for 2 years. Sublingual immunotherapy was given as soluble tablets of monomeric carbamylated allergoid. Clinical scores for asthma and rhinitis (0, absent to 3, severe) and drug consumption were assessed by diary card in the period November-February. Quality of life was assessed before and after each observation period and pharmaco-economy data were evaluated as well.
                Fifty-six patients completed the study. The rate of dropouts was similar in the two groups. No relevant side effect was reported. There was a significant reduction of total clinical scores (P < 0.05) in the active group vs placebo at the first year, but not at the second whereas nasal obstruction significantly improved in both years (P < 0.05). The reduction of drug intake score was significant only at the first year. No change was observed concerning most of the Short Form-36 items, because at baseline all patients displayed a normal profile. A significant change in SLIT group was seen for the item 'change in health status'. The need for extra visits was significantly lower in the active group (25%vs 43%).
                Sublingual immunotherapy was clinically effective and safe in mite-induced mild disease. The safety and efficacy of sublingual-swallow immunotherapy (SLIT) in rhinitis caused by house-dust mite were evaluated in a double-blind, placebo-controlled study including 75 patients for 24 months.
                Patients received either placebo or SLIT with a standardized Dermatophagoides pteronyssinus (D.pt.) - D. farinae (D.f) 50/50 extract. The mean cumulative dose was 90,000 IR, equivalent to 2.2 mg of Der p 1 and 1.7 mg of Der f I. Symptom and medication scores were assessed throughout the study. Exposure to house-dust mite, skin sensitivity, and serum specific IgE and IgG4 were assessed before starting treatment and after 12 and 24 months.
                Seventy-two patients (36 active-36 placebo) were eligible for intent-to-treat analysis. Thirty-six patients dropped out of the study. The number of patients who dropped out due to lack of efficacy was eight out of 37 (21.6%) in the active treatment group compared to 15 out of 38 (39.5%) in the placebo group (chi-square=2.81, P=0.09). Total symptom and medication scores decreased significantly after 12 and 24 months (P<0.05) of treatment in both groups, but no significant difference was observed between the active and placebo groups. After 24 months, the number of patients with high levels of indoor allergenic load decreased significantly in both groups compared to baseline data (P=0.01). Specific IgE (D.pt. and D.f.) increased significantly in the active treatment group after 12 and 24 months, while no change was observed in the placebo group. Specific IgG4 levels were not significantly modified in either group. Two patients in each group reported mild adverse effects. No severe adverse effects were reported.
                We conclude that SLIT in rhinitis caused by house-dust mite was safe, but there was a lack of consistent clinical benefit compared to placebo, probably due to the impact of the allergen avoidance measures that lowered the allergen burden. We assessed the efficacy of preseasonal local allergoid immunotherapy in a group of children with asthma and/or rhinitis and/or rhinoconjunctivitis due to grass pollen.
                We randomly assigned 24 children allergic to grass pollen to receive local allergoid immunotherapy for 3 months before the pollen season and 24 such patients to receive identically appearing placebo. The immunotherapy consisted of tablets of monomeric allergoid grass pollen allergens held in the mouth until they dissolved and then swallowed. The study was double-blind. Symptoms and medications were scored on diary cards during the pollen season. Nasal eosinophil cationic protein levels were measured by the monoclonal antibodies EG1 and EG2 outside the pollen season and at low and at high pollen concentration during the pollen season.
                The active-treatment group had a statistically significant reduction of total symptoms (P<0.05), especially bronchial symptoms (P<0.05), in comparison with the placebo group. Immunotherapy was well tolerated and compliance was good. Nasal levels of EG2 and EG1 increased significantly during the pollen season, but there was no difference between groups. EG2/EG1 increased significantly only in the placebo group during natural allergen exposure (P<0.01).
                Our results suggest that this immunotherapy is effective for the treatment of asthma due to grass pollen in children. There is a growing consensus on the benefits of sublingual-swallow immunotherapy in the treatment of allergic diseases.
                This randomized, double-blind placebo-controlled study was undertaken to assess the efficacy and safety of sublingual immunotherapy with standardized ragweed pollen extract tablets, in patients with an allergic rhinitis. A total of 110 outpatients were randomized (immunotherapy [I]: 55; placebo [P]: 55), of whom 99 were analyzable for efficacy (I: 48; P: 51) and 106 analyzable for safety (I: 53; P: 53). After a 28-day progression phase, the patients received a maintenance treatment during 6.5 months. Efficacy variables included a global assessment of efficacy (patient/ investigator), symptoms and medication scores as well as the frequency of asthma attacks.
                In the active treatment group, 43 patients completed the study, versus 49 on placebo. During the whole period of pollination, the difference favoring immunotherapy was highly significant for the global assessment by the patient (p = 0.004) and by the investigator (p = 0.005). Adverse reactions were reported more often in the active treatment but mild or moderate, and they abated after dose adjustment. A subgroup analysis of those patients receiving the highest dose of immunotherapy (3 tablets 3 times a week) showed a highly significant response for rhinitis and conjunctivitis total scores by comparison to lower dosages.
                This study confirms the efficacy and safety of sublingual immunotherapy and strongly suggests a dose-response relationship.
                Copyright 2003 S. Karger AG, Basel To evaluate the efficacy of specific sublingual immunotherapy (SLIT), we enrolled 15 children with asthma and rhinitis (7 girls, 8 boys, mean +/- SD age of 11.7 +/- 3.3) allergic to house dust mite (HDM) into a double-blind, placebo-controlled study. After a run-in period, patients were randomized to receive either placebo (n = 7) or SLIT (n = 8) with a standardized Dermatophagoides pteronyssinus (D. pteronyssinus) + Dermatophagoides farinea (D. farinea) 50/50 extract. They received increasing doses up to 100 index units of reactivity (IR) every day for 4 weeks, then 100 IR/day for another 4 weeks, followed by maintenance therapy consisting of 20 drops 2 times a week for 4 months. Efficacy was assessed at the end of 6 months of therapy according to symptom and medication scores, serum total IgE levels, results of lung function tests, methacholine provocation tests, and skin prick tests. Daily means for the asthma score and use of inhaled beta-2-mimetics decreased significantly in the SLIT group (P = 0.05, P = 0.028, respectively), whereas no such difference was observed in the placebo group. At the end of follow-up, mean daily doses of intranasal steroids needed for control of rhinitis symptoms decreased significantly in the SLIT group (P = 0.04). Baseline skin sensitivity to D. pteronyssinus and D. farinea was not significantly different between in the two groups, whereas end-point wheal diameter obtained with D. pteronyssinus extract was significantly less in the SLIT vs. the placebo group (P = 0.026). At the end of 6 months, peak expiratory flow (PEF) values in the placebo group was significantly lower than in the SLIT group (P = 0.049). Throughout the treatment period, the SLIT group was found to have less asthma exacerbations than the placebo group (P = 0.007). The provocation concentration causing a 20% drop in forced expired volume in 1 sec did not change throughout the treatment period in either groups. None of the patients reported local or systemic side effects from SLIT. Results of this study suggests that SLIT may be a useful alternative or additional therapy in the treatment of children with asthma/rhinitis due to HDM.
                Copyright 2001 Wiley-Liss, Inc. The aim of the study was to confirm the safety of an orodispersible grass allergen tablet 75,000 SQ-T (Grazax, ALK-Abelló A/S, Hørsholm, Denmark) in children aged 5-12 yr. The study was randomized, double-blinded and placebo-controlled. Sixty children aged 5-12 yr suffering from grass pollen-induced rhinoconjunctivitis (with or without asthma) from five centres in two countries (three in Germany and two in Spain) participated in the study. They were randomized at the ratio of 3:1 as receiving either Grazax or placebo tablet given sublingually once daily for 28 days outside the grass pollen season. A total of 810 treatment-related adverse events were reported in the Grazax group. The majority of these were local reactions in the mouth or throat and were mostly mild (71%) to moderate (27%) in severity and resolved within days. Thirty-five (78%) subjects treated with Grazax and five (33%) treated with placebo reported at least one treatment-related adverse event. Oral pruritus, throat irritation, mouth oedema and ear pruritus appeared as the most frequently reported treatment-related adverse events. 62% (28 of 45) of the actively treated subjects reported oral pruritus, 36% (16 of 45) throat irritation, 31% (14 of 45) mouth oedema and 22% (10 of 45) ear pruritus. Two actively treated subjects withdrew from the study: one subject due to four adverse events (moderate eye pruritus, moderate pharyngolaryngeal pain, moderate non-cardiac chest pain and moderate dysphagia) and one subject due to a serious adverse event (asthmatic attack). The subjects recovered completely from the events. In conclusion, in the present study, Grazax was in general tolerated in a paediatric population and considered suitable for further clinical investigations in children. To evaluate the safety and efficacy of sublingual immunotherapy with 'Dermatophagoides Farinae Drops' in D. farinae allergic asthma and/or rhinitis patients.
                A 25-week double-blind, placebo-controlled, multi-centered trail was conducted in 278 children (aged 4 - 18 yr) with mite-induced asthma and/or rhinitis. Patients were randomly assigned to receive sublingual immunotherapy (SLIT) with 'Dermatophagoides Farinae Drops' (n = 139) or placebo (n = 139) for 25 weeks and the dosage and administration strictly followed the manufacturer's instructions. At the beginning of the 2nd, 3rd, 4th, 6th, 10th, 14th, 18th, 22nd week of the treatment, the patients were asked to accept follow-up visit, during the clinical trial all patients and parents were asked to keep a daily record of their asthma symptom scores, rescue medicine use, rhinitis symptom scores, morning and evening peak expiratory flow. Asthma symptom scores, reduction in use of rescue medicine, rhinitis symptom scores, lung function tests, skin sensitivity to mite, mite-specific immunoglobulin (Ig) E and IgG4, and quality of life and adverse effect were assessed during the study.
                (1) Of the 278 children, 27 dropped out before the study completion. (2) After 25 weeks of treatment, the median variability of PEFR was -1.38 for SLIT group and -0.90 for the placebo (P < 0.05). (3) Besides, the mean variability of medicine score of asthma was -0.08 for SLIT group and 0.52 for the plcebo (P < 0.05). (4) The median variability of rhinitis symptom score was -1.96 for SLIT group and -1.03 for the placebo (P < 0.01). (5) The rescue medicine usage of SLIT reduced but did not show significant differences between SLIT and placebo. (6) After 25 weeks treatment, the increase of D. farinae specific IgE antibody of two groups were similar, while specific IgG4 increased significantly in SLIT compared to the patients in control one (P < 0.01); (7) No severe adverse events happened in the trial and the most-likely adverse events were mild asthma and local rash.
                Dermatophagoides Farinae Drops is safe and effective in treating allergic asthma and atopic rhinitis. Forty-one patients suffering from grass pollen allergy underwent specific immunotherapy with standardized allergen extract consisting of six grass pollens (H-Al per os) administered either sublingually or supralingually for one year. In order to investigate clinical and immunological changes induced by the administration of allergens via the oral mucosa, the double-blind, placebo-controlled, randomized design of the trial with 30 other patients enrolled in placebo groups was applied. Specific immunotherapy with oral drops administered sublingually or supralingually was performed in the same way, keeping the drops under or on the tongue, respectively, for 1-2 min before swallowing them; at the end of the trial the cumulative dose of the allergen was almost 20 times higher than that of the subcutaneous therapy with corresponding allergen preparation. Data about symptoms scores and drugs intake during grass pollen season, as well as skin reactivity, levels of specific IgG and IgE antibodies, before the study and after the study's completion, were obtained. It was found that both routes of administration are effective according to subjective clinical parameters and drug consumption, with a highly significant reduction of symptoms and drug intake favoring sublingual administration where a reduction of more than 60% was achieved. Only sublingual active group showed a significant increase in Dactylis glomerata-specific IgG serum levels. Adverse effects were limited to a small number of generally mild local and/or systemic reactions. The results suggest that the administration of allergens via the oral mucosa is safe and clinically effective, favoring the sublingual rather than supralingual route. Thirty-four patients suffering from rhinoconjunctivitis with or without asthma due to grass pollen, were submitted to sublingual immunotherapy according to a double blind placebo controlled experimental plan; eighteen patients received the active therapy, sixteen the placebo. A rush preseasonal treatment schedule was followed in order to reach the maintenance dose in 15 days with two administrations per day; the top dose reached was then administered three times a week until the end of the pollen season. The symptoms and drugs related to rhinoconjunctivitis and asthma were recorded by means of diary cards and grass pollen counts were performed during the season. The actively treated group showed a reduction of symptoms of rhinoconjunctivitis and asthma and a lower intake of drugs for the same symptoms; all these differences resulted to be statistically significant. No patient showed local or systemic side effects of any relevance. According to these results of our study, sublingual rush immunotherapy is clinically effective and because of the ease of handling, the shortness of the treatment, the absence of relevant side effects and the high compliance of the patient can be considered as an alternative to classic injective immunotherapy in grass pollen allergic patients. The aim of this study was to confirm the clinical efficacy and safety of a preseasonal sublingual immunotherapy (SLIT) in a group of allergic patients with seasonal rhinoconjunctivitis with or without mild intermittent or mild persistent asthma. The immunotherapy was administered through the oral mucosa with a monomeric carbamylated allergoid (allergoid SLIT) for grass pollens. A secondary endpoint was to evaluate the effect of the allergoid SLIT on nasal reactivity.
                A single-center, randomized, double-blind, placebo-controlled study was performed. Patients were selected and randomly allocated to two groups: one group received active treatment (allergoid SLIT) for 2 years and the other received placebo. Both groups received the necessary drug treatment throughout the trial. Thirty-three outpatients (20 men and 13 women, mean age: 30 years; range: 19-43) attending our center were enrolled in the study. Symptoms and medications were scored on diary cards during the pollen season. An allergen nasal challenge was performed at baseline and after 2 years of SLIT to evaluate nasal reactivity. Because the clinical scores were non-normally distributed, the Mann-Whitney and the Chi-square tests for intergroup comparisons and the Wilcoxon test for intragroup comparisons were used. The results were evaluated after 1 and 2 years of treatment. Between the first and second years of treatment, no changes in the scores for the placebo group were found, while for the active vaccine group significant decreases were found in rhinorrhea (p < 0.03), sneezing (p < 0.03), and conjunctivitis (p < 0.02). Symptom scores after nasal challenge decreased (p < 0.03) after 2 years' treatment. Nasal steroid use significantly decreased in the active treatment group during May and June in both the years of treatment (p < 0.02). Only two mild local adverse events were reported in the active group and none was reported in the placebo group.
                The results of this study show that the allergoid SLIT is safe and effective in decreasing symptom scores and drug use in rhinitic patients allergic to grass pollen. Sublingual treatment of grass pollen induced rhinoconjunctivitis might provide easier access to specific immunotherapy (SIT) and minimize the risk of serious adverse events (AEs) compared to subcutaneous SIT.
                To identify a safe dose range for once-daily administration of a grass allergen tablet in participants with grass pollen induced seasonal rhinoconjunctivitis.
                A randomized, double blind, placebo-controlled Phase I trial was conducted outside the grass pollen season. Seven dosage groups [25,000, 75,000, 150,000, 300,000, 500,000, 750,000, or 1,000,000 standardized quality tablet (SQ-T)], consisting of 12 participants randomized either to active treatment or placebo (3 : 1) daily for 28 days, commenced treatment in a staggered manner at intervals of approximately 1 week to allow for intermittent safety reviews.
                The grass allergen tablet did not cause any serious, systemic or significant (leading to withdrawal) AEs. The overall incidence of AEs was 74% (1,013 events); all of mild or moderate intensity and most considered treatment-related. The most frequently reported treatment-related AEs, including irritation of the throat, and itching sensations in the mouth and ears, increased with dose. These were primarily mild in intensity, started shortly after medication intake and lasted for minutes to a few hours maximum. Objective oral findings were also dose-dependent. No clinically significant observations were found in safety laboratory, vital signs and 12-lead ECG.
                A sublingual grass allergen tablet in doses up to 1,000,000 SQ-T daily caused no serious or systemic AEs displaying a safety profile that allows further investigation as once-daily self-medication. For evaluation of the efficacy and the safety of specific sublingual immunotherapy with high allergen dose, 66 children with seasonal asthma, rhinitis, and conjunctivitis due to sensitization to olive pollen were enrolled in a double-blind, randomized, placebo-controlled study between October 1994 and October 1996 in Greece. Thirty-four patients were randomly allocated to the active group, and 32 received placebo. Immunotherapy consisted of olive-allergen extracts (Stallergènes SA) administered sublingually pre- and coseasonally from January to July for 2 consecutive years. Serial concentrations from 1 to 300 IR. were used up to the maintenance dose of 20 drops of 300 IR daily. The cumulative dose for each patient was 300 times higher than in parenteral immunotherapy, and the cumulative dose of the major allergen Ole e 1 was 8.1 mg/2 years. The patients were assessed by clinical parameters (symptom and medication scores from patients' daily diaries) and immunologic measurements (specific IgE, IgG4, eosinophil cationic protein [ECP]) were performed. The actively treated patients had a significantly lower score for dyspnea (P<0.04 during the first season; P<0.03 during the second season). At the pollinic peak during the second year, a lower score of conjunctivitis was recorded (P<0.05) in the actively treated patients. The analysis of intragroup evolution showed that the total score of rhinitis increased significantly during the pollinic peak in the group under placebo, whereas there was no symptomatic peak for the same period in the group under active treatment. However, the difference between the groups was not significant. The medication score did not differ significantly between the groups. Oral steroids were the only variables with a P value near the significance level (P=0.06) in favor of the actively treated group. A significant decrease in skin reactivity was recorded in the active group after 2 years of treatment. No significant variation in specific IgE and IgG4 was detected. A significantly lower level of serum ECP was observed at the pollinic peak in the actively treated patients during the first pollen season (P=0.01), but this was not confirmed the second year when the ECP levels doubled in both groups without correlation to the clinical findings. Tolerance was excellent with only a few minor side-effects reported. In conclusion, high-dose specific sublingual immunotherapy appears to be safe and effective in improving mild seasonal asthma and conjunctivitis linked to olive-pollen sensitization. Fifty-eight patients with well-documented history of seasonal rhinoconjunctivitis caused by grass pollens were allocated randomly on a double-blind basis to receive either sublingual therapy with a solution of purified, standardized allergen preparation (Stallergènes) or a matched placebo for 17 weeks. The assessment of the effect of oral immunotherapy, done with drops of five-grass allergen extract, was on the clinical symptoms and on the medication score of the authorized rescue treatments. The actively treated patients had significantly (P < 0.05 to P < 0.01) fewer symptoms of rhinitis (sneezing and rhinorrhea) and of conjunctivitis (redness and tears) during the pollen season than the placebo group. Consumption of nasal solution of sodium cromoglycate and of betamethasone and dexchlorpheniramine was significantly less in the desensitized group (P < 0.01). Side-effects were negligible. This study concludes that perlingual immunotherapy with grass pollen extract in grass-pollen-sensitive seasonal hay fever and conjunctivitis patients is effective, easy to perform, inexpensive, and safe. Sublingual-swallow immunotherapy (SLIT) using high doses of standardized allergen extracts has been found to be effective in reducing allergic symptoms and medication needs. A double-blind, placebo-controlled study was carried out in a large number of patients to determine whether medication needs can be reduced by SLIT. Some 136 patients with grass-pollen rhinitis with or without mild asthma were studied. Patients received either placebo or SLIT with a standardized grass-pollen extract administered daily with increasing doses up to 300 IR (index of reactivity) from January to the end of July 1994. During the grass-pollen season, patients were instructed to use medications as required and to visit their doctors in case of asthma. Symptom-medications scores were assessed during the pollen season, and serum-specific IgG4 was measured before and at the end of SLIT. In the SLIT group, drug consumption dropped significantly throughout the pollen season (P < 0.02). Moreover, at the peak of the pollen season, betamethasone consumption was significantly reduced in the SLIT group (P < 0.02). Only one patient in the SLIT group had an asthma attack compared to eight patients in the placebo group (P < 0.02). IgG4 levels increased significantly in the SLIT group (P < 0.001) but without correlation with symptoms. Side-effects were comparable in both groups. This study indicates that SLIT in grass-pollen rhinitis is well tolerated, improves overall clinical symptoms, and reduces drug consumption and the need for oral corticosteroids. Safety and efficacy of sublingual (sublingual-swallow) immunotherapy (IT) with house dust mite extract were evaluated in 30 children (6-15 2/3 years of age) over the first 12 months of an ongoing study. The cumulative dose was 570 micrograms Der p I (five times that administered with subcutaneous therapy). Safety: One patient on active treatment dropped out after 8 weeks because of a subjective feeling of severe weakness, questionably induced by the therapy. Five patients on active therapy and one patient on placebo reported minor local side effects. Efficacy: Pulmonary symptoms were reduced after 12 months in actively treated asthmatics, but this was not consistent with the lack of improvement in bronchial reactivity, skin sensitivity and specific IgG and IgG4 against D.pt. in this group. In patients with rhinitis nasal sensitivity was reduced in the placebo group without concomitant improvement in the nasal symptom score. Specific IgE (D.pt. and D.f.) increased significantly more in the active treatment group after 3 and 12 months. We conclude that sublingual IT over 12 months with the fivefold Der p 1 dose of subcutaneous IT was well tolerated, but there was no consistent clinical or immunological benefit compared to placebo. Sublingual immunotherapy is well tolerated and data suggest its effectiveness for the treatment of allergic rhinitis in adults, but it lacks optimum dose definition.
                To assess the efficacy, safety, and optimal dose of grass pollen tablets for immunotherapy of patients with allergic rhinoconjunctivitis.
                In this multinational, randomized, double-blind, placebo-controlled study, 628 adults with grass pollen rhinoconjunctivitis (confirmed by positive skin prick test and serum-specific IgE) received 1 of 3 doses of a standardized 5-grass pollen extract, or placebo, administered sublingually using a once-daily tablet formulation. The treatment was initiated 4 months before the estimated pollen season and continued throughout the season. The primary outcome was Rhinoconjunctivitis Total Symptom Score; secondary outcomes included 6 individual symptom scores, rescue medication use, quality of life, and safety assessments.
                Both the 300-index of reactivity (IR) and 500-IR doses significantly reduced mean Rhinoconjunctivitis Total Symptom Score (3.58 +/- 3.0, P = .0001; and 3.74 +/- 3.1, P = .0006, respectively) compared with placebo (4.93 +/- 3.2) in the intent-to-treat and per-protocol analyses. The 100-IR group (4.70 +/- 3.1) score was not significantly different from placebo. Analysis of all secondary efficacy variables (sneezing, runny nose, itchy nose, nasal congestion, watery eyes, itchy eyes, rescue medication usage, and quality of life) confirmed the efficacy of the 300-IR and 500-IR doses. No serious side effects were reported.
                In the first pollen season, the efficacy and safety of sublingual immunotherapy with grass tablets was confirmed. The 300-IR and 500-IR doses both demonstrated significant efficacy compared with placebo.
                The risk-benefit ratio favors the use of 300-IR tablets for clinical practice. To assess the efficacy and safety of sublingual immunotherapy in patients with allergic rhinitis/conjunctivitis, a double blind placebo controlled study was performed.
                Fifty-seven (57) patients with a well-documented history of seasonal grass pollen allergy were evaluated in a DBPC trial over a period of 10 months (January to November 1995) with a view to investigating the efficacy and safety of sublingual immunotherapy with a grass pollen extract, 9,500 BU/ml. The course of treatment consisted of an incremental phase of approximately 3 weeks followed by a twice weekly maintenance dosage of 9,500 BU. Compared with the placebo group (30 patients), the group treated with grass pollen extract (27 patients) showed a significant (p < 0.03) lower mean severity of allergic complaints, i.e. sneezing, and itchy nose, a watery runny nose and itching of the eyes during the maximum pollen counts of the season. The use of anti-allergic medication was similar in the two groups. Both groups showed a significant increase in grass-pollen-specific IgG serum levels. However, the increase shown in the patients treated with grass pollen extract occurred earlier in the season and was significantly (p < 0.002) higher than the increase detected in the placebo group. Side effects were limited to a small number of generally mild local reactions.
                The treatment with sublingually applied grass pollen extract in patients suffering from allergic rhinoconjunctivitis caused by grass pollen was well tolerated and served to reduce the severity of allergic complaints, without reducing the consumption of anti-allergic medication. The local (noninjection) routes of immunotherapy are presently regarded as viable therapeutic options for respiratory allergy, and their mechanisms of action are currently undergoing investigation.
                We evaluated the clinical efficacy of a preseasonal rush sublingual-swallow immunotherapy and its effects on allergic inflammation in patients with seasonal rhinoconjunctivitis caused by Parietaria species.
                Thirty patients with Parietaria species-induced rhinoconjunctivitis (13 with mild intermittent asthma) were randomly assigned sublingual-swallow immunotherapy or placebo in a rush preseasonal course. We assessed the seasonal symptom-drug intake score by diary card and the inflammatory infiltration and the intercellular adhesion molecule 1 expression on nasal epithelium after specific allergenic challenge before and after treatment.
                The investigated immunotherapy was well tolerated, and no side effects were recorded. A significant reduction of the symptom score (P =.016) and drug intake score (P =. 008) after immunotherapy was observed only in the active group. A decrease of the cumulative score was observed also in the placebo group (P =.046), but the significance was clearly higher (P =.006) in the active group. In the active group a reduction of neutrophils (P =.001), eosinophils (P =.01), and intercellular adhesion molecule 1 expression (P =.04) after specific nasal challenge was also detected.
                The present results suggest that this sublingual-swallow immunotherapy administered through a rush schedule is clinically effective and safe and that it decreases the immune-mediated inflammatory responses to the allergen. Non-injective routes of immunotherapy are thought to be valuable therapeutic options for respiratory allergy. We investigated the clinical efficacy and the effects of sublingual/oral immunotherapy on conjunctival allergic inflammation in patients with mite-induced respiratory allergy.
                We used a double-blind placebo-controlled design. 20 patients with mite-induced rhinoconjunctivitis (six of whom also had mild asthma) were randomly assigned sublingual/oral immunotherapy (n=10) or placebo (n=10) for 2 years. We assessed symptom score by diary cards and inflammatory-cell infiltrate, and expression of intercellular adhesion molecule 1 (ICAM-1) in the conjunctiva after specific allergen challenge at enrollment and after 12 and 24 months of treatment.
                We found significantly lower symptom scores in the immunotherapy group than in the placebo group in most of the winter months (p=0.05). Compared with the placebo group, inflammatory-cell infiltration after conjunctival challenge, and ICAM-1 expression on conjunctival epithelium decreased significantly in the first year of treatment in the immunotherapy group (p=0.04 and p=0.02, respectively). These effects were also seen for the minimum persistent inflammation, in symptom-free patients exposed constantly to allergens (p=0.02). Serum concentrations of eosinophil cationic protein decreased significantly (p=0.04). Immunotherapy was well tolerated and compliance was good.
                Our results suggest that this immunotherapy is clinically effective in rhinoconjunctivitis and that it decreases the immune-mediated inflammatory responses to the allergen. sublingual immunotherapy has been recognised as safe and effective but it is still poorly documented in tree pollen allergy. Allergy to alder, birch and hazel is important in Northern European countries but its clinical relevance is increasing in Southern Europe.
                thirty patients, selected and observed for one pollen season, were randomised to receive placebo (15 patients) or active treatment (15 patients). Twenty-seven patients completed the first year and 24 of them were treated with active therapy during the second year of the study in comparison to a parallel group of ten patients treated only with drugs. Symptom and drug scores during each pollen season, birch-specific IgE, changes in skin test reactivity, changes in specific Nasal Provocation Test and the daily average pollen count for the relevant trees were considered for the assessment of the efficacy of the treatment.
                both active and placebo group showed a statistically significant improvement in scores in comparison to the previous year, under a lower allergenic pressure. The improvement was higher in the active group (76.04 % reduction of drugs) but not significantly different from that registered in the placebo group (37.05 % reduction). In the open phase of the study, treated patients showed significantly better scores in comparison to the control group. No significant changes in skin reactivity, specific IgE and Nasal Provocation Test were registered. SLIT tolerance was very good.
                our data show a better but not statistically significant clinical outcome for patients actively treated with SLIT, but the placebo effect and the year-by-year variability of the environmental allergenic load in our small-size pilot study do not allow for a conclusive statement about the efficacy of this form of therapy. Immunotherapy is the only treatment for allergy that has the potential to alter the natural course of the disease. Sublingual immunotherapy for grass pollen-induced rhinoconjunctivitis has been developed to make immunotherapy available to a broader group of allergic patients. Here, a safe dose range and the safety during daily sublingual administration were investigated for a new tablet-based sublingual immunotherapy for grass pollen allergy. Simultaneously, immunological changes were monitored. A randomized, double-blind, placebo-controlled phase I trial was undertaken, with stepwise dose-escalation during the dose-finding period, and afterwards with daily dosing 8 weeks prior to and 15 weeks during the grass pollen season (2500, 25000, or 75000 standardized quality tablet [SQ-T] units, or placebo). Fifty-two participants with grass pollen-induced rhinoconjunctivitis and a positive skin prick test and specific IgE to Phleum pratense entered the trial. During the daily-dose treatment periods, 67% of the participants reported adverse events. The most frequent were itching in the mouth, eyes, or throat, and rhinitis, and most were mild and resolved within 1 day. Two participants withdrew due to adverse events (sting and blisters in the mouth and itching in the mouth). Time- and dose-dependent increases of P pratense-specific IgG, IgA, IgE, and IgE-competing components were found in serum during the first 8 weeks of daily dosing, indicating that the treatment had a significant allergen-specific effect on the immune system. In conclusion, the grass allergen tablet, administered in a dose of 75000 SQ-T once daily, was well tolerated and displayed systemic immunogenicity. New routes of administering immunotherapy in respiratory allergy are being studied as an alternative to conventional injective immunotherapy. We carried out a study to evaluate the clinical efficacy and effects of sublingual immunotherapy in patients with Parietaria judaica-induced respiratory allergy.
                A double-blind, placebo-controlled design was followed. Thirty patients with P. judaica rhinoconjunctivitis, mild asthma, or both were randomly chosen for sublingual immunotherapy (14 patients) or placebo treatment (16 patients). The patients underwent preseasonal rush induction treatment followed by coseasonal maintenance treatment during the Parietaria pollen season. Symptom and drug scores, as well as specific IgE and specific IgG4, were recorded.
                Significantly lower symptom and drug scores were found (P=0.04), especially during the Parietaria pollination period, in the immunotherapy group. No significant difference in specific IgE and specific IgG4 was detected between the active and placebo groups; a statistically significant increase of specific IgE was detected in both groups (P=0.05). No patient undergoing active sublingual immunotherapy reported local or systemic side-effects.
                Our data suggest that sublingual immunotherapy is both clinically effective and safe in treating patients with Parietaria-induced rhinoconjunctivitis and mild asthma. The best way to prevent allergy symptoms is to treat the allergic condition. Specific immunotherapy with grass allergen tablets 75,000 SQ-T (Grazax, Phleum pratense, ALK-Abelló) is safe and efficacious in rhinoconjunctivitis patients. As rhinoconjunctivitis often co-exists with asthma, we aimed to confirm safety and efficacy in grass allergic subjects with asthma and rhinoconjunctivitis.
                A randomized, double-blind, placebo-controlled, multicentre trial was performed 10-14 weeks prior to and during the grass pollen season 2004. About 114 subjects were randomized 2 : 1 to grass allergen tablets or placebo. The primary end points were average asthma medication and symptom scores during the grass pollen season, and secondary variables were average rhinoconjunctivitis symptom and medication scores during the grass pollen season. Additionally, number of well days was defined post hoc.
                Differences in asthma medication and symptom scores between the treatment groups were negligible. The mean difference in asthma medication score was below 0.1 and 0.3 for asthma symptom score [a single inhalation of salbutamol (200 microg) was scored 2]. No serious adverse events were reported. A reduction in rhinoconjunctivitis symptom score of 37% (P = 0.004) and a 41% (P = 0.036) reduction in medication score was found in the grass pollen season for subjects treated with the grass allergen tablet compared with placebo. Well days increased by 54% (P = 0.002).
                Self-administration of the grass allergen tablet was safe. The treatment did not impair asthma control and confirmed considerable symptom prevention and reduced medication use. It addresses the allergic condition and represents a baseline treatment for grass pollen allergy. Specific immunotherapy is the only treatment modality that has the potential to alter the natural course of allergic diseases. Sublingual immunotherapy has been developed to facilitate access to this form of treatment and to minimize serious adverse events.
                To investigate the efficacy and safety of sublingual grass allergen tablets in seasonal allergic rhinoconjunctivitis.
                A multinational, multicenter, randomized, placebo-controlled trial conducted during 2002 and 2003. Fifty-five centers in 8 countries included 855 participants age 18 to 65 years who gave a history of grass pollen-induced allergic rhinoconjunctivitis and had a positive skin prick test and elevated serum allergen-specific IgE to Phleum pratense. Participants were randomized to 2500, 25,000, or 75,000 SQ-T grass allergen tablets (GRAZAX; ALK-Abelló, Hørsholm, Denmark) or placebo for sublingual administration once daily. Mean duration of treatment was 18 weeks.
                Average rhinoconjunctivitis scores during the season showed moderate reductions of symptoms (16%) and medication use (28%) for the grass allergen tablet 75,000 SQ-T (P = .0710; P = .0470) compared with placebo. Significantly better rhinoconjunctivitis quality of life scores (P = .006) and an increased number of well days (P = .041) were also observed. Efficacy was increased in the subgroup of patients who completed the recommended preseasonal treatment of at least 8 weeks before the grass pollen season (symptoms, 21%, P = .0020; and medication use, 29%, P = .0120). No safety concerns were observed.
                This study confirms dose-dependent efficacy of the grass allergen tablet. Although further studies are required, the greater tolerability of the tablet may permit immunotherapy to be available to a much broader group of patients with impaired quality of life caused by grass pollen allergy.
                For patients with grass pollen allergy, sublingual immunotherapy is well tolerated and can reduce symptoms and improve quality of life. In light of the controversial status of sublingual immunotherapy in patients with allergic rhinitis, we undertook a double-blind study of this form of treatment.
                Forty-one subjects with cat allergy presenting as rhinoconjunctivitis underwent 105 days of sublingual immunotherapy, with 20 subjects receiving a standardized cat extract (total dose approximately 4,500,000 allergy units) and 21 a matching placebo. Effectiveness of treatment was assessed by changes in symptoms and nasal-blockage index during 90 minutes of exposure in an apartment containing cat dander, which was performed before and after the course of treatment. Changes in cat-specific IgG and IgE levels and skin-test reactions were also monitored.
                Although there were fewer symptoms and less nasal obstruction on cat dander exposure at the end of the study the changes were not significantly different in those receiving active or placebo treatment. Specific IgG and IgE levels and prick skin test results did not change significantly during the course of the study.
                We conclude that sublingual immunotherapy with high-dose standardized cat extract was no more effective than placebo in reducing symptoms or affecting immunologic measures of cat sensitivity. A double-blind, placebo-controlled study of immunotherapy was conducted in 31 patients with allergic rhinitis due to Parietaria pollen to evaluate the efficacy and safety of high doses of allergen via the sublingual route. The patients were assessed before and after a 10-month period of treatment by clinical (symptom-medication scores and specific nasal reactivity) and immunological (total IgE, specific IgE, IgG and IgG4 antibodies) parameters. High doses of Parietaria extract corresponding to a cumulative dose of 105 BU for each patient were administered with negligible side effects. The actively treated patients had significantly lower medication scores than those on placebo (p < 0.05) when the maximum pollen count was recorded, and at the end of the trial they showed a significant decrease in nasal reactivity (p < 0.02) and a significant increase in serum specific IgG4 (p = 0.02). No differences were detected in any of these parameters in the placebo group. Possible explanations for the mechanisms of sublingual immunotherapy are proposed. The clinical efficacy of sublingual immunotherapy (SLIT) has been demonstrated, but its mechanism of action is still controversial. The most recent experimental observations suggest that a critical role in the modulation of immune response is sustained by Th2 cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, by co-stimulatory molecules, such as CD40 on B cells, and by hormones and neuropeptides. To better understand whether SLIT affects immune responses we used a double-blind placebo-controlled design. Eighty-six children with mild asthma due to allergy to Dermatophagoides pteronyssinus (33 of whom also had rhinoconjunctivitis) were randomly assigned SLIT (n = 47) or placebo (n = 39). We assessed symptom scores using diary cards of each patient and determined the expression of CD40 on B cells and the serum concentration of ECP, IL-13, prolactin (PRL) and ACTH at enrolment and after 6 months of therapy. We observed a significant reduction in asthma and rhinitis scores in the immunotherapy group compared with the placebo group, no variation in CD40 and ACTH, but a significant decrease in ECP, IL-13 and PRL after 6 months of therapy (p <0.01). Our results confirm the efficacy and safety of SLIT, and lead us to believe that it could modulate the synthesis of Th2 cytokines, as revealed from the decrease of IL-13. In addition, the reduction of PRL might be a signal of reduced activation of T lymphocytes. Data supporting a carry-over effect with sublingual immunotherapy (SLIT) are scarce. This randomized, double-blind, placebo-controlled study evaluated the efficacy, carry-over effect and safety of grass pollen SLIT using co-seasonal treatment.
                Patients (7.9-64.7 years) with grass pollen allergy received ultra-rush titration with increasing doses (30, 90, 150 and 300 IR) of a 5-grass pollen mixture every 20 min at the start of the pollen seasons, followed by 300 IR daily until the end of the pollen seasons. A baseline season (no SLIT) was followed by three consecutive treatment seasons and one follow-up season. Symptoms, medication and adverse events were documented and specific immunoglobulin (Ig)E and IgG(4) measured.
                Data were analysed for 183 of the 213 randomized patients. Mean treatment duration varied between seasons (81.8-92.7 days). Combined scores (symptoms and medication) improved progressively across treatment seasons (up to 44.7% improvement for SLIT compared with baseline) and fluctuated between -11.3% and -14.8% for placebo (P < 0.05). Similar changes were observed for symptom scores, with a successive decrease of 39.7% (SLIT) and fluctuations between +13.6% and -1.51% for placebo (P < 0.05). Combined score (P = 0.0508) and symptom score improvements (P = 0.0144) with SLIT continued during follow up. Increases in specific IgG(4) observed in the first season were sustained for SLIT vs placebo throughout treatment (P = 0.0001). Titration and daily SLIT were well tolerated. No serious systemic or anaphylactic reactions were reported.
                Seasonal SLIT with ultra-rush titration is well tolerated and effective from the first treatment season onwards. These data indicate a carry-over effect of seasonal SLIT. Because cats are a common pet in many houses and tourist complexes in the Canary Islands, sensitization to cat epithelium is a frequent problem. A total of 19.2% of patients with intrinsic asthma are sensitized to cat epithelium. In the Canary Islands, the percentage of sensitization among patients with a household cat is 18.1%, which higher is higher than in the rest of Spain (11.9). Many patients with extrinsic asthma sensitized to house dust mites undergo conventional subcutaneous immunotherapy but evolution is unsatisfactory due to sensitization to cat epithelium (whether a cat is present or not). The aim of this study was to evaluate the clinical effectiveness of sublingual immunotherapy with extract of cat epithelium in monosensitized patients with perennial allergic rhinitis and/or bronchial asthma. Forty patients monosensitized to cat epithelium were selected. Of these, 20 were administered sublingual immunotherapy and another 20 received placebo. The following evaluation was carried out in both groups: in vivo and in vitro: symptom score, skin tests, nasal challenge with cat epithelium, specific IgE determination, specific IgG4 and eosinophilic cationic protein. After 1 year of treatment the cumulative dose was 3.6 micrograms of Fe ld I, equivalent to 10 ng/drop. Duration of treatment was 365 days. Our conclusions, based on our patients in the Canary Islands, were the following: 1. Sublingual Fel d I therapy is effective after 1 year of treatment. 2. There were no modifications in IgE, eosinophilic cationic protein or skin tests. 3. An increase in IgG4 occurred which was related to clinical improvement. 4. In general, tolerance was good, except in one patient who presented urticaria and sublingual pruritus. 5. In polysensitized patients, sublingual immunotherapy to cat epithelium is complementary to immunotherapy to dermatophagoides. The efficacy and safety of the 300-index of reactivity (IR) dose of 5-grass-pollen sublingual immunotherapy (SLIT) tablets (Stallergènes, Antony, France) have been demonstrated for the treatment of hay fever in adults.
                We sought to assess the efficacy and safety of this tablet in children and adolescents with grass pollen-related allergic rhinitis.
                In this multinational, randomized, double-blind, placebo-controlled study, 278 children (5-17 years of age) with grass pollen-related rhinoconjunctivitis (confirmed by means of a positive grass pollen skin prick test response and serum-specific IgE measurement) received once-daily SLIT tablets or placebo. Treatment was initiated 4 months before the estimated pollen season and continued throughout the season. The primary outcome was the rhinoconjunctivitis total symptom score (RTSS), a sum of 6 individual symptom scores: sneezing, runny nose, itchy nose, nasal congestion, watery eyes, and itchy eyes. Secondary end points included rescue medication intake, individual scores, and safety.
                The intent-to-treat population included 266 children (mean age, 10.9 +/- 3.22 years). The RTSS for the 300-IR group was highly significantly different from that of the placebo group (P = .001). The 300-IR group showed a mean improvement for the RTSS of 28.0% over that seen with placebo and a median improvement of 39.3%. Significant differences between the 300-IR and placebo groups were also observed regarding rescue medication score and proportion of days using rescue medication during the pollen season (P = .0064 and P = .0146, respectively). Adverse events were generally mild or moderate in intensity and expected. No serious side effects were reported.
                Five-grass-pollen SLIT tablets (300 IR) reduce both symptom scores and rescue medication use in children and adolescents with grass pollen-related rhinoconjunctivitis. Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double-blind placebo-controlled study in children with grass pollen allergy using high dose allergen extracts.
                A total of 161 children with seasonal rhinoconjunctivitis of which, 68 had also asthma symptoms were enrolled in a multicenter double-blind placebo-controlled study for 1 year and treated on a daily basis with sublingually applied allergen drops. After 1 year all children were given treatment for another 2 years in an open-controlled setting. Symptom scores and medication were assessed during the pollen seasons with structured interviews. Applied allergen dosage, compliance, and side effects were documented by daily diary cards. Primary endpoint was a clinical index (CI) combining symptom scores with medication index. Titrated skin prick tests (SPT) and specific antibody measurements were performed each year.
                Combining symptom with medication scores to CI was highly reliable (reliability coefficient = 0.89, standard error = 9.6%). Allergen-specific IgE- and IgG-subclass antibodies increased significantly in patients treated with SLIT indicating an activation of the immune response induced by the locally applied grass pollen extract. SPT reactivity did not change during therapy. After 1 year of SLIT in the original design we observed no significant difference in the CI between treatment and placebo analyzing all patients included in the study per intention to treat and per protocol. However, subgroup analysis in a repeated measures model revealed that patients with SLIT and severe symptoms before the beginning of treatment (CI > mean/ > 1.51) showed a significant improvement of clinical symptoms after 3 years.
                In this study SLIT was accompanied by a significant placebo effect. Efficacy of treatment could only be seen in children with severe clinical symptoms and this became clinically marked after 3 years of therapy. Sublingual-swallow immunotherapy was recently recognized in the World Health Organization Position Paper (Allergen immunotherapy: therapeutic vaccines for allergic diseases) "as a viable alternative to parenteral injection therapy to treat allergic diseases" in adults. More controlled studies were required to assess the efficacy and safety of this treatment in children.
                This study was carried out to assess the clinical efficacy and safety profile of sublingual-swallow immunotherapy with high-dose allergen in children with allergies.
                We used a double-blind placebo-controlled design. Forty-one children with Parietaria -induced rhinoconjunctivitis were randomized to receive sublingual standardized Parietaria judaica extract (n = 20) or placebo (n = 21) for 2 years. The cumulative dose of allergen was 375 times higher than that used in parenteral immunotherapy and the cumulative dose of Par j 1 major allergen was 52.5 mg over 2 years. The main efficacy assessment criteria were symptoms and rescue medication scores recorded on the patients' diary cards. Secondary criteria were changes in skin and conjunctival specific reactivity as well as blood parameters, analyzed after 1 and 2 years of immunotherapy. The safety of the treatment was assessed by evaluating the frequency and severity of adverse effects.
                A significant reduction in rhinitis symptoms was observed in the active treatment group during the second season (P =.02), with no difference in medication scores. A significant decrease in skin reactivity (P =.002 after 2 years of treatment) and an increase in the threshold dose for conjunctival allergen provocation test (P =.02) were observed in the active treatment group compared with the group receiving placebo. A significant increase in specific IgG(4 ) levels (P =.02) was also observed in the active group. Immunotherapy was well tolerated.
                Sublingual-swallow immunotherapy in Parietaria -allergic children provided a clinical benefit and a decreased specific reactivity to the allergen. The safety profile of this treatment, which constitutes an important issue, indicated good tolerance and compliance. Fifty eight patients under 12 years of age, positive to mites (Dermatophagoides pteronyssinus and D. farinae) according to prick, "in vitro" specific IgE and challenge tests, suffering from asthma and rhinitis, were randomly assigned on a double blind basis to receive per os either a biologically standardized extract of mites (active therapy TA = 30 patients) or a saline buffered solution (placebo = 28 patients). Patients took sublingually increasing doses of the solution, followed by maintenance therapy consisting of 15 drops 3 times a week. The results of the trial were assessed after 12 an 18 months, according to the following parameters: symptom scores recorded in diary cards, total and specific IgE levels, total IgG level, IgG1 and IgG4 levels, lymphocytes underpopulations, nasal challenge test, side effects. During the first 18 months, the patients on active therapy had significantly lower scores (p less than 0.001) and clear variations of rhinomanometric parameters (p less than 0.01); IgG also significantly increased. After 12 months, bronchial specific and specific challenge tests showed significantly higher threshold values in comparison to initial values (p less than 0.05). No statistically significative variation was registered in the placebo group. Subcutaneous immunotherapy has been the principal approach of immunotherapy in the treatment of allergic diseases. Several clinical studies with birch, alder or hazel pollen extract conducted as subcutaneous immunotherapy have been published suggesting a well-tolerated and clinically effective treatment. Only a few clinical studies of sublingual immunotherapy (SLIT) with these allergens have been published. This study investigated the clinical efficacy, safety and dose-response relationship of SLIT in children suffering from rhinoconjunctivitis with/without asthma.
                Eighty-eight children (5-15 years) with a history of tree pollen-induced allergic rhinoconjunctivitis with/without seasonal asthma for >or=2 years were included. Allergy to tree pollen was confirmed by positive skin-prick test, positive specific IgE and positive conjunctival provocation test. The extract used was a glycerinated mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa 100,000 SQ-U/ml. Children were randomized into three groups receiving SLIT 5 days a week for up to 18 months; dose group 1: accumulated weekly dose of 24,000 SQ-U; dose group 2: accumulated weekly dose of 200,000 SQ-U; and placebo.
                In the birch pollen season, dose group 2 showed a significant reduction of symptom (P = 0.01) and medication scores (P = 0.04) compared with placebo. Dose group 1 showed a significant reduction of symptom scores (P = 0.03). There were no statistical differences between dose groups 1 and 2. All children tolerated the treatment well.
                SLIT with tree pollen extract provided dose-dependent benefits in tree pollen-allergic children in terms of significantly reduced symptoms and medication use. The treatment was well tolerated. Immunotherapy with the SQ-standardized grass tablet Grazax is efficacious and well-tolerated in adult patients with rhinoconjunctivitis. Allergic asthma and rhinoconjunctivitis are closely linked, and a strategy combining treatment of the upper and lower airways is recommended.
                To investigate the efficacy of treatment with the grass tablet on grass pollen-induced rhinoconjunctivitis and asthma as well as the immunologic response and the safety profile in children.
                A total of 253 children age 5 to 16 years, with grass pollen-induced rhinoconjunctivitis with/without asthma, were randomized 1:1 to active treatment or placebo. Treatment was initiated 8 to 23 weeks before the start of the grass pollen season 2007 and continued throughout the entire season. Symptomatic medication was provided as relief medication to both groups in a stepwise fashion. Primary endpoints were rhinoconjunctivitis symptom and medication scores.
                The rhinoconjunctivitis symptom and medication scores and the asthma symptom score were all statistically significantly different between the 2 treatment groups. The differences in medians relative to placebo were 24%, 34%, and 64% in favor of active treatment. The immunologic response was similar to that observed in adults. The most common adverse reaction was oral pruritus, reported by 40 subjects (32%) in the active and 3 (2%) in the placebo group. Six subjects withdrew because of adverse events. No serious adverse events were assessed as treatment-related.
                Immunotherapy with the grass tablet reduced grass pollen-induced rhinoconjunctivitis and asthma symptoms in a pediatric population and introduced an immunomodulatory response, consistent with treatment of the underlying allergic disease. The treatment was well tolerated. non-injective routes of immunotherapy in respiratory allergy have being proposed as an alternative to conventional immunotherapy. We carried out a study to evaluate the clinical efficacy and effects sublingual immunotherapy (SLIT) in patient with Cupressaceae pollen respiratory allergy.
                twenty patients with Cupressaceae pollen (C. sempervirens) rhinoconjunctivitis, mild asthma or both were randomly chosen for sublingual immunotherapy (10 patients) or placebo treatment (10 patients) using a double blind placebo controlled technique. We have used an extract of Cupressus arizonica because of its better stability in solution and its crossreactivity with Cupressus sempervirens. The patients underwent treatment for 12 months (from april 1999 to april 2000). Symptoms and drug scores as well as nasal provocation tests were recorded. The pollen counts were carried out, during all the same period.
                we found significantly lower symptom scores (p < 0.05) and drug consumption scores (p < 0.05) in the immunotherapy group than in the placebo group, during the pollen season, after the first year of therapy. Besides threshold of allergen reactivity in nasal provocation tests was increased in the active group (p < 0.01). No untoward reactions have been observed.
                SLIT with Cupressus arizonica (pollen extracts) produced, after one year treatment, a significant improvement of allergic symptoms and a decrease of drug consumption scores and allergen-specific nasal reactivity. SLIT with Cupressus arizonica appeared to be effective and safe in the treatment of Cupressaceae pollen respiratory allergy. Recent studies have demonstrated the efficacy of sublingual-swallow immunotherapy (SLIT) in seasonal and perennial rhinitis. Sublingual administration of solutions is not convenient for all patients. The aim of the study was to evaluate the efficacy and safety of immunotherapy administered sublingually, initially as drops, and then as tablets during maintenance therapy.
                A total of 126 patients with grass-pollen seasonal rhinitis were included in this double-blind, randomized, placebo-controlled trial. During the progression of doses phase, the five-grass extract was given as sublingual drops from 1 to 100 IR/ml. Once the 100 IR dose was reached, the drops were replaced by a single 100-IR sublingual tablet per day.
                Throughout the grass-pollen season, patients in the active treatment group had significantly lower (P < 0.05) total conjunctivitis and ocular redness scores. Rhinitis symptoms were not significantly different between the two groups. Patients given the active treatment were significantly (P < O.02) less likely to have asthma symptoms. The global medication score showed no significant difference between the two groups. A highly significant difference in favor of the active treatment group was seen in inhaled salbutamol use (P < 0.01).
                Clinical benefits achieved during the present study included significant improvements in conjunctivitis symptoms and prevention of asthma symptoms. The overall safety profile of the active treatment (drops or tablets) was good. Allergen immunotherapy (desensitization) by injection is effective for seasonal allergic rhinitis and has been shown to induce long-term disease remission. The sublingual route also has potential, although definitive evidence from large randomized controlled trials has been lacking.
                The aim was to confirm the efficacy of a rapidly dissolving grass allergen tablet (GRAZAX, ALK-Abelló, Hørsholm, Denmark) compared with placebo in patients with seasonal rhinoconjunctivitis.
                A longitudinal, double-blind, placebo-controlled, parallel-group study that included 51 centers from 8 countries. Subjects were randomized (1:1) to receive a grass allergen tablet or placebo once daily. A total of 634 subjects with a history of grass pollen-induced rhinoconjunctivitis for at least 2 years and confirmation of IgE sensitivity (positive skin prick test and serum-specific IgE) were included in the study. Subjects commenced treatment at least 16 weeks before the grass pollen season, and treatment was continued throughout the entire season.
                The primary efficacy analysis showed a reduction of 30% in rhinoconjunctivitis symptom score (P < .0001) and a reduction of 38% in rhinoconjunctivitis medication score (P < .0001) compared with placebo. Side effects mainly comprised mild itching and swelling in the mouth that was in general well tolerated and led to treatment withdrawal in less than 4% of participants. There were no serious local side effects and no severe systemic adverse events.
                Sublingual immunotherapy with grass allergen tablets was effective in grass pollen-induced rhinoconjunctivitis. The tablet was well tolerated with minor local side effects.
                The grass allergen tablet represents a safe alternative to injection immunotherapy suitable for home use. Sublingual immunotherapy (SLIT) has been demonstrated to be a viable alternative to injection immunotherapy. Administration of high doses of allergens to ensure efficacy has been shown to be well tolerated. The aim of the present study was the first step to address the issue of fast-induction regimens using various induction SLIT regimens in paediatric and adult patients.
                Sixty-four patients (age range 5-46 years) with grass pollen rhinoconjunctivitis were enrolled in an 8-month double-blind, placebo-controlled trial of SLIT. Sixty-three patients were randomized to four groups and evaluated at the end of the study. One group received placebo (n = 16) and the other three groups (n = 47) received five grass pollen extracts according to three different induction regimens: regimen 1 starting with 3 IR tablets (n = 15), regimen 2 starting with 10 IR (n = 16) and regimen 3 starting with 30 IR (n = 16). The maintenance phase was made with sublingual-swallow drops at the same concentration of 300 IR/ml for all the patients. Adverse events were recorded on diary cards.
                During induction phase, 25/47 patients in the SLIT groups had adverse reactions in comparison to 2/16 patients in the placebo group (p < 0.05). The rate of adverse reactions was 33.3% (11.8-61.6) (95% CI) for regimen 1, 31.3% (11.0-58.7) for regimen 2, 43.8% (19.8-70.1) for regimen 3 and 12.5% (1.6-38.3) for placebo. Fifty-seven reactions were local reactions involving the oral region (54 SLIT, 3 placebo) and 13 were systemic reactions (all in the SLIT groups). 11/13 reactions were mild (gastrointestinal disorders, rhinoconjunctivitis), 1/13 consisted of moderate asthma and 1/13 consisted of severe abdominal pain. No urticaria, angioedema or life-threatening events were observed.
                These preliminary data showed that various induction regimens for SLIT are generally well tolerated and could allow a fast build-up phase of SLIT.
                Copyright 2002 S. Karger AG, Basel Seasonal allergic rhinitis is common and troublesome. Sublingual immunotherapy (SLIT) has been proposed as an alternative to injection immunotherapy and might offer some advantages if it were effective and practical in a community setting.
                To assess the efficacy and side-effect profile of SLIT in patients with summer hay fever uncontrolled on current standard medication. To assess the feasibility of delivering SLIT in a United Kingdom general practice setting.
                Double-blind, placebo-controlled study in 186 patients with severe summer hay fever identified from 16 United Kingdom general practices. After a baseline year to ensure balanced groups, subjects were randomized, and SLIT was given for 1 or 2 years and compared with placebo. The principal outcome measure was symptoms as recorded on diary cards. Secondary criteria were skin and conjunctival reactivity, allergen-specific IgE and IgG 4 , and the frequency and severity of adverse effects.
                One hundred thirty-six subjects completed the study. After 1 year, no significant differences were found between actively treated subjects and the placebo group. After the second year of therapy, subjects who had received 2 years treatment were 6.8 times more likely to show a reduction in nose running (P <.001) and 2.4 times more likely to have reduced sneezing (P <.05) compared with subjects in the placebo group. Benefits for nasal blockage were found at the peak pollen season and were similar in both actively treated groups.
                Sublingual immunotherapy can be given successfully and safely in the community. High-dose SLIT has beneficial effects on nasal symptoms during the peak pollen season in patients with severe seasonal allergic rhinitis. At least 2 years of treatment with SLIT is required to show a benefit. Sublingual immunotherapy (SLIT) is increasingly being used for the treatment of allergic rhinitis, but there are conflicting study results demonstrating clinically relevant efficacy.
                To show clinical efficacy and safety of a new high-dose grass pollen preparation for SLIT.
                In a 2-year, double-blind, placebo-controlled trial, 185 subjects with rhinitis or rhinoconjunctivitis, with or without asthma, were treated with a recently developed, high-dose, 6-grass pollen mixture for SLIT once daily.
                The primary end point, a combined symptom-medication score, showed almost no change in the placebo group during a 42-day evaluation period in the grass pollen season from 2003 to 2005, whereas active treatment was associated with a significant and clinically relevant improvement (full analysis set, P = .01; main data set, P = .002). The effect was irrespective of asthma diagnosis. Allergen-specific IgE showed no difference in both groups, and specific IgG4 and IgG1 increased with active treatment in the first and second study years compared with placebo, clearly indicating the immunogenic effect of the active treatment. The SLIT was well tolerated. No serious adverse drug reactions occurred.
                High-dose, sublingual, specific immunotherapy with an extract of a 6-grass pollen mixture showed a significant and clinically relevant improvement in subjects with grass pollen-associated rhinitis or rhinoconjunctivitis, with or without asthma. The treatment with the sublingual solution was well tolerated. Parallel follow-up of clinical and inflammatory markers during sub-lingual immunotherapy (SLIT) is highly beneficial. Twenty-four children (age 4-16) monosensitized to house dust mite were randomized to receive either active or placebo SLIT for 1 yr in a double-blind placebo controlled design (Marcucci et al., Allergy 2003: 58: 657-62). Thereafter, for 2 yr they all received active treatment. Symptom scores for rhinitis, asthma, and drug usage were daily recorded. Eosinophil cationic protein (ECP) and tryptase in sputum and nasal secretions, serum and nasal mite-specific immunoglobulin E (IgE) were recorded before treatment and at 10-12 months intervals. Nasal ECP and nasal tryptase after specific nasal provocation tests were significantly reduced as compared to baseline values (p = 0.0043 and 0.0195, respectively) in the third year of active treatment. None of the other inflammatory parameters was increased. In placebo treated patients all these parameters tended to decrease only after switching to active treatment. Clinical scores did not improve in treated vs. placebo patients in the double-blind placebo-controlled phase of the study. In both cohorts a clinical benefit was observed as intra-group score reduction as compared to baseline. A significant difference was reached in patients treated for 2 yr for rhinitis and asthma (p = 0.0009 and 0.0019, respectively) but not for drug usage and in patients treated for 3 yr for rhinitis, asthma, and drug usage (p = 0.0105, 0.0048, and 0.02, respectively). SLIT in children monosensitized to mites reverted the spontaneous increase in nasal IgE and in local parameters of allergic inflammation. These outcomes were followed by a consolidated clinical improvement in the second and third year of treatment. Immunotherapy is a recognized treatment for allergic respiratory diseases.
                To study the usefulness of immunotherapy in combination with optimal pharmacological therapy.
                Thirty-eight children (8-14 years) suffering from seasonal asthma+/-rhinoconjunctivitis due to Parietaria poorly controlled by anti-allergic drugs treatment were selected. After randomization according to a double-blind placebo-controlled design they received active sublingual immunotherapy (15 children) or placebo (15 children) for 13 months combined with inhaled fluticasone twice a day during the pollen season. Eight children were taken as control, whereas all patients were instructed to take symptomatic drugs on need. Early and late skin response to the allergen were assessed in all patients before and after treatment. Drug and symptom scores, as well as visual analogue scores (VASs) and Parietaria pollen counts were assessed during the pollen season.
                Groups were well balanced for age, gender, early and late skin response before treatment. Four children dropped out, in one case in relationship with active sublingual immunotherapy (SLIT) administration. Chest and nose symptoms, as well as drug scores and VASs were significantly better in both the active or placebo SLIT+fluticasone (S+F) as compared to the control group (P between <0.001 and 0.043). Eye symptoms were significantly better in the active S+F group as compared to control (P=0.025). The VASs were significantly better in the active S+F group as compared to the placebo S+F group (P=0.037). The early skin response decreased significantly in the active S+F group (P<0.001), whereas the late skin response changed significantly in all groups, with an increase in the placebo+fluticasone group (P=0.019) and in the control group (P=0.037) and a decrease (P<0.0001) in the active S+F group.
                The clinical efficacy of S+F is equal to that of fluticasone alone, but the addition of SLIT has effects also on non-bronchial symptoms.
This updated review reinforces the conclusion of the original 2003 Cochrane Review that sublingual immunotherapy is effective for allergic rhinitis and has been proven to be a safe route of administration.