Silvia Pecora

Post‐marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years

Background The age below 5 years is considered a prudential limit for immunotherapy in view of the possible severity of side‐effects. Sublingual immunotherapy (SLIT) seems to be safe, but no study in very young children is available. We performed a safety post‐marketing surveillance study in children below 5 years.

Quantitative assessment of the compliance with once‐daily sublingual immunotherapy in children (EASY Project: Evaluation of A novel SLIT formulation during a Year)

Compliance is a major determinant for allergy treatment, especially in children. Sublingual immunotherapy (SLIT) is self‐managed at home, and no quantitative data on pediatric adherence are available. We studied the compliance in a large real‐life setting. A simplified schedule of SLIT was used, consisting of a 10‐day updosing phase followed by maintenance treatment in monodose containers to be taken daily (SLITOne®). Italian specialists throughout Italy assessed the compliance in children who were newly prescribed SLIT according to guidelines. Parents were contacted with unscheduled telephone interviews at the third and sixth month of therapy and asked to count at that moment the remaining vials. Data from 71 children (38 boys, age range 2–13 yr) were enclosed in the database. Thirty had rhinoconjunctivitis, four asthma and 37 rhinoconjunctivitis + asthma. SLIT was prescribed for: mites in 57 (81%) subjects, grasses in 11 (15%) and 3 (4%) grass + olive mixture. Compliance data were available for all children at 3 months, and for 56 at 6 months. At 3 months, 85% of subjects had a compliance rate >75% (69% of them adhered >90%). At 6 months, 84% had a compliance rate >75% (66% of them adhered >90%). In four cases SLIT was discontinued for economical reasons, and in one case (1.4%) for side effects probably related to therapy. These data obtained in a quite large sample of children and in real‐life confirm that the compliance with SLITOne® is good, despite the therapy managed at home.

Three-year follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing sub-lingual immunotherapy

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 proten (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.

Sublingual immunotherapy efficacy in patients with atopic dermatitis and house dust mites sensitivity: a prospective pilot study.

ABSTRACT Background: Specific subcutaneous immunotherapy (SCIT) with house dust mite (HDM) preparation has recently been shown to improve eczema in patients with atopic dermatitis (AD). So far, there is less data regarding efficacy and safety of specific sublingual immunotherapy (SLIT) in patients with AD. Study aim: To evaluate in an open non-controlled, non-randomized pilot trial the effect of SLIT with HDM allergen extracts preparation (SLITone, ALK Abellò Italy) on SCORAD in adult patients with mild–moderate AD. Patients and methods: 86 Subjects (53 females and 33 males) between 3 and 60 years of age with AD and IgE-proved (Class > 2) HDM sensitization were enrolled after their informed consent in the trial. Exclusion criteria were severe asthma and treatment with systemic or high potent topical corticosteroids or immunosuppressant agents. Patients were treated with SLIT (Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts: SLITone, ALK-Abellò) for at least 12 months. SCORAD was evaluated at baseline and after 12 months of treatment. Results: Baseline SCORAD value, mean ± SD, was 43.3 ± 13.7 (range 15–84). After 1 year of SLIT, mean ± SD, SCORAD value was reduced to 23.7 ± 13.3 (range: 0–65) (p = 0.0001; unpaired t-test vs. baseline). This was a 46% reduction in SCORAD in comparison with baseline value. A significant improvement, defined as a SCORAD reduction of > 30%, was observed in 51 out of 86 patients (59%). In 5 patients (5.8%) SCORAD values did not change at the end of the observation period. In 30 patients (35%) the SCORAD reduction after SIT was ≤ 30% in comparison with baseline. Total and specific IgE serum levels were significantly (p = 0.001) reduced after SLIT. No severe adverse events were observed during the trial. Conclusion: In this open non-controlled trial SLIT with HDM extracts in patients with mild to moderate AD was effective in reducing the SCORAD after 1 year of SLIT treatment. In addition the treatment was very well tolerated. Treatment with SLIT, furthermore, has allowed a gradual and relevant reduction of concomitant therapies with topical corticosteroids or immunosuppressants. Present results require further controlled trials in order to confirm the potential clinical benefit of SLIT in this clinical setting.

A pre-seasonal birch/hazel sublingual immunotherapy can improve the outcome of grass pollen injective treatment in bisensitized individuals. A case-referent, two-year controlled study

BACKGROUND The study tests the hypothesis of a reduction of priming due to tree allergy in patients sensitised to both birch/hazel and grass pollen undergoing an associated preseasonal Sublingual/Injective immunotherapy. METHODS 36 out of 49 bisensitized candidates were pair-matched into 18 case-referent couples. During two years all patients were administered preseasonal grass-SIT and one patient in each couple received also birch/hazel-SLIT. Diary cards were fulfilled for three consecutive grass pollen seasons. Specific Nasal Provocation Test (NPT) for grass and aspecific bronchial challenge were done; sera were analyzed for specific IgE and IgG. RESULTS During the peak of the grass pollen season both groups showed a significant improvement in total symptom-score. Conjunctivitis and cough improved significantly more in patients with associated therapies. While antihistamine score decreased significantly in both groups, antiasthmatics did only in the SLIT-SIT group. The follow-up documented a significant increase in grass- and birch-specific IgG and a decrease in grass-specific IgE. Grass-NPT threshold was clearly higher in SLIT-SIT-group (p = 0.01) and only in this group PD20 methacholine improved significantly (p < 0.05). CONCLUSIONS Combined birch/hazel-SLIT and grass-SIT are safe and improve clinical outcomes of SIT alone in young bisensitized patients. Priming reduction is supported by specific NPT and bronchial hyperresponsiveness.

Randomized open comparison of the safety of SLIT in a no-updosing and traditional updosing schedule in patients with Parietaria allergy

BACKGROUND Due to optimal safety of sublingual immunotherapy (SLIT), it was suggested that a slow up-dosing phase maybe not necessary, and therefore the treatment will be more patient-friendly, avoiding dosing mistakes. PATIENTS Twenty adult patients suffering allergic rhinitis due to Parietaria, were enrolled. Half of them received the traditional schedule and the other half immediately started with 200 STU. RESULTS No difference was observed between the traditional up-dosing treatment schedule and no-up-dosing treatment schedule in terms of side effects, even mild local side effects, even mild local side effects was greater with traditional regimen.

Observational study of sublingual specific immunotherapy in persistent and intermittent allergic rhinitis: the EFESO trial

ABSTRACT Background: Sublingual specific immunotherapy (SLIT) is a valid treatment for allergies. However, there are few data on a large sample size regarding its clinical role in ‘real life’. Study aim: We performed a multicentre, case-control study to evaluate the effectiveness of SLIT in patients with allergic rhinitis (AR). Methods: A total of 305 patients with AR were enrolled. Cases (n = 154) were defined as patients with intermittent (64%) or persistent (36%) AR who were treated daily for at least two consecutive years with specific SLIT. Controls (n = 151) were defined as age-, sex- and type of allergen-matched AR subjects who were never treated with specific immunotherapy. The main outcomes of the study were the rhinoconjunctivitis symptom score (SS) and the symptomatic medication score (MS). SS and MS were evaluated at the end of the observational period in relation to the peak of relevant pollen season or during the period of maximum allergen exposure in case of non-seasonal allergens. Results: SS mean (SD) value was 5.1 (3.0) in cases and 9.3 (3.3) in controls (−43%) ( p = 0.0001). MS mean (SD) value was 2.6 (1.8) and 4.4 (2.6) in the case and control groups, respectively (−41%) ( p = 0.0001). At the end of the observation period, asthma-related symptoms were present in 8.5% of cases and in 20% in the control group ( p = 0.01). Conclusion: The EFficacia nella rinitE allergica di SlitOne (EFESO) trial shows that SLIT treatment in AR is associated with lower SS and MS in comparison with controls. SLIT is also associated with a lower incidence of asthma and new sensitizations. As this was an observational study, our results need to be confirmed in randomized, double-blind, controlled trials.

A Multicenter, Randomized, Parallel-Group Trial Assessing Compliance, Tolerability, Safety, and Efficacy to Treatment with Grass Allergy Tablets in 261 Patients with Grass Pollen Rhinoconjunctivitis

Background. Allergen-specific sublingual immunotherapy (SLIT) is considered a causal treatment of respiratory allergies. Compliance to the SLIT is an important aspect for a positive clinical outcome. Study Aim. To evaluate if compliance with grass Allergy Immunotherapy Tablet (AIT) can be increased by providing an electronic compliance device (CED) (Memozax; a tablet-container with a programmable daily acoustic alarm). Patients and Methods. 261 patients with grass allergy were enrolled and randomized (1 : 1) to 1-year treatment with AIT (Grazax) using a CED (group A; n = 122) or without (Group B, n = 139). Compliance was measured through tablet count at each visit. Results. The 12-month compliance, mean (SD), in group A was 83% (21) and 83% (24) in group B. A total of 81% of patients reported a significant clinical improvement of symptoms after treatment in comparison with the previous year. No severe adverse reactions were observed in the study. Conclusion. Compliance to the treatment with AIT administered for 12 consecutive months is in general good. The use of CED is not associated with a greater compliance. AIT treatment was associated with a significant clinical improvement in >80% of patients with a good tolerability and safety profile.

A method for the analysis of milk and egg allergens for the atopy patch test.

Abstract:  The patch test with food antigens (atopy patch test, APT) has been reported as a more specific method than prick or RAST for the early detection of cow’s milk and/or egg sensitizations in children. Standardization of APT extracts is a major issue on the road towards full clinical exploitation of this assay. Here, we used sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS‐PAGE) to characterize sensitivity and specificity of commercial preparations of APT for milk and egg allergies, which are expected to improve the reliability of this test, when compared with fresh food allergen sources. We found that: (i) SDS‐PAGE is an appropriate technique for quality control of APT and (ii) commercial milk and egg APT are equivalent to fresh food preparations in terms of allergen content. Clinical trials aimed at characterizing sensitivity and specificity of APT in the diagnosis of food allergy in children will benefit from this technique.

Author's reply to de Bot et al.

Editors, We thank you for the opportunity to answer to the interesting observations of our colleagues Cindy de Bot, Heleen Moed and Johannes C van der Wouden about the recent paper of ours published in your Journal. We found their comments very pertinent and useful to clarify a few issues, which a critical reading of our paper could actually raise. 1 A relatively large difference was indeed present between mite-specific immunoglobulin E (IgE) levels in active when compared with placebo children. Nasal IgE values in actively treated patients [median 0.50 KU/l, interquartile range (IQR) 0.35–2.56] ranged from 0.36 to 10.50 KU/l at baseline, due to three single high-score patients who had 3.39, 4.90. and 10.50 KU/l, respectively. In contrast, no values above 1.2 KU/l were found among placebo patients (median value 0.50, IQR 0.36–0.62, min–max 0.36–1.20 KU/l). Thus, large individual variability within the active, but not within the placebo group accounted for the reported difference at baseline in the case of mite-specific nasal IgE. This difference was remarkably reduced in the following years of follow-up, due to the reduction in the highest values. Serum mite-specific IgE values at baseline had a median value of 32.60 KU/l (IQR 11.30–49.10, min–max 0.36–100 KU/l) in actively treated patients, and of 9.86 KU/l (IQR 3.95–17.50, min–max: 0.37–100 KU/l) in patients originally assigned to the placebo group. Thus, in this case, besides high inter-individual variability, several patients with higher levels of mite-specific serum IgE were actually present in the actively treated group at baseline when compared with placebo, and this hold true at subsequent time points. We do not have any justification for this observation, except that this happened by chance and could visibly influence the distribution of IgE values due to the relatively little sample size of the two experimental groups. This explanation is particularly convincing in the case of mitespecific nasal IgE, where a few outliers accounted for the observed variability. However, we believe that overall this discrepancy was not dependent on problems in the assignment of patient to the respective group in the randomization phase of the study. Moreover, we would like to stress the fact that in absolute terms the observed differences were rather limited. The trend towards a reduction in nasal, rather than of serum mitespecific IgE observed in the course of sublingual immunotherapy (SLIT) deserves more extended studies. 2 We also agree about the fact that after deblinding clinical observations are relatively uncontrolled. A 3-yr double-blind follow-up would be necessary to establish at a higher level of reliability the consistency of data on the longterm efficacy of SLIT. However, the possibility of convincing parents to keep their children in a double-blind trial for such a long time is, quite understandably, extremely difficult. Another difficulty is posed by Italian ethics committees, which do not approve that this kind of pressure is put on children for so long times. Finally, in Italy patients undergoing clinical trials cannot receive any payment. Having said that, we would like to point out that the major end points of our study were the biologic parameters we evaluated, which were reasonably not as much influenced by subjective factors, as may happen for the symptoms used to generate clinical scores. 3 Mattresses and pillows were enclosed as a preventive measure in both placebo and actively treated patients. Thus, this could not have alerted patients about the treatment they were receiving. However, it may explain why the placebo group experienced an apparently more rapid reduction in inflammation parameters and clinical scores when compared with patients originally assigned to the active group. In fact, the first study year was the same calendar year for all children, and at that time all patients of both experimental groups were advised, for ethical reasons, to adopt measures aimed to reduce exposure to house dust. Thus, whereas in actively treated patients these environmental precautions were Pediatr Allergy Immunol 2006: 17: 316–317