BackgroundAllergen-specific immunotherapy is the only causal form of therapy for IgE-mediated allergic diseases. Subcutaneous immunotherapy (SCIT) is considered safe and well tolerated in adults, yet there is less evidence of safety in the pediatric population. MethodsA non-interventional prospective observing longitudinal study was carried out to determine the incidence of local and systemic side effects by SCIT, routinely performed in pediatric patients. A total of 581 pediatric patients were observed in 18 study centers between March 2012 and October 2014, recording 8640 treatments and 10015 injections. ResultsA total of 54.6% of the patients experienced immediate local side effects at least once; delayed local side effects were seen in 56.1%. Immediate systemic adverse reactions occurred in 2.2% of patients; 7.4% experienced delayed systemic side effects. However, severe systemic side effects (grade III in the classification of Ring and Messmer) were seen in 0.03% of all treatments, all appearing within 30minutes after the injections. No grade IV reactions were observed. In addition, many potential risk factors were investigated, yet only a few were found to be associated with the occurrence of side effects. ConclusionsSubcutaneous immunotherapy is a safe form of therapy in pediatric patients, with similar rates of local side effects compared to adult patients and low rates of severe systemic side effects. However, local and systemic reactions occurring later than 30minutes after injection were observed more often than expected, which makes it essential to be attentive on behalf of pediatricians, patients, and parents.

Background. Nonperception of efficacy ranks among the most commonly cited causes for nonadherence to sublingual immunotherapy (SLIT). Quality of life (QoL) in patients is a determining factor influencing adherence. We investigated QoL and adherence separately in SLIT patients at one pediatric practice in Germany. Methods. We conducted a noninterventional, cross-sectional, retrospective, quality-of-life survey among pediatric patients treated with SLIT. QoL was assessed using the generic SF-12 health survey in German. The items contained in the SF-12 health survey are weighted, added up, and converted to obtain a physical component score (PCS) and a mental component score (MCS). Each component score ranges from 0 to 100; the higher the score, the better the QoL perceived. Results. 201 surveyed patients who had undergone SLIT showed PCS-12 of 49.3 (± 7.0) and MCS-12 of 52.6 (± 7.2). These figures correlate strongly with those reported for the German general population (n = 2453): PCS-12 of 49.6 (± 8.7) and MCS-12 of 52.3 (± 8.0). 70.2% (73) of 104 patients were adherent at this practice. Conclusions. QoL in the SLIT patients surveyed here appears as good as that of the general population. Adherence to SLIT at this practice was remarkably better than that reported elsewhere.

Safety data on ‘real‐life’ allergen immunotherapy (AIT) in children and adolescents is usually extrapolated from studies in adults.

BackgroundThe safety and efficacy of pre- and coseasonal sublingual allergen immunotherapy (SLIT) with a 5-grass pollen sublingual tablet have been demonstrated in a randomized clinical trial (RCT) in children and adolescents. Observational, real-life' studies can usefully complement the results of RCTs.MethodsA prospective, open-label, observational, multicentre post-marketing study of children and adolescents (aged 5-17, with grass pollen-induced allergic rhinitis) treated with the 5-grass pollen sublingual tablet was performed between June 2009 and January 2011 in Germany. Adverse events (AEs) were recorded during consultations with the investigating physicians; AEs judged to have at least a possible causal link to the tablet were classified as adverse drug reactions (ADRs).ResultsEight hundred and forty-nine patients were enrolled (by 207 investigating physicians), 829 (means.d. age: 10.9 +/- 3.3yr) completed the study without major protocol deviations, and 796 were fully documented with respect to AEs. Ninety-four of the 796 patients (11.8%) experienced at least one ADR on the first day of SLIT and 218 (27.4%) experienced at least one ADR during the study. Four hundred and sixty-six of the 596 ADRs (78.2%) were mild or moderate. The most common ADRs were throat irritation (19.1% of the reactions), oral paresthesia (8.2%), oral pruritus (6.5%) and oedema mouth (6.2%). Serious ADRs occurred in five patients. No epinephrine use was reported. Seventy-six of the 829 patients (9.2%) discontinued SLIT due to AEs. Tolerability was judged to be good or very good by patients (84.7%), parents (87.0%) and investigators (89.7%).ConclusionsIn clinical practice, pre- and coseasonal treatment with a 5-grass pollen sublingual tablet is safe and well tolerated in children and adolescents.

Background: Sublingual allergen-specific immunotherapy is a viable alternative to subcutaneous immunotherapy particularly attractive for use in children.Objective: This study investigated efficacy and safety of high-dose sublingual immunotherapy (SLIT) in children allergic to grass pollen in a randomized, double-blind, placebo-controlled trial.Methods: After a baseline seasonal observation, 207 children aged 4 to 12 years with grass pollen-allergic rhinitis/rhinoconjunctivitis with/without bronchial asthma (Global Initiative for Asthma I/II) received either high-dose grass pollen SLIT or placebo daily for 1 pre-/co-seasonal period. The primary end point was the change of the area under the curve of the symptom-medication score (SMS) from the baseline season to the first season after start of treatment. Secondary outcomes were well days, responders, immunologic changes, and safety.Results: Mean changes in the area under the curve of the SMS from the baseline to the first grass pollen season after the start of treatment were -212.5 for the active group and -97.8 for the placebo group (P = .0040). Rhinoconjunctivitis SMS (P = .0020) and separated symptom and medication scores were also statistically different between the 2 groups (P = .0121 and P = .0226, respectively). The number of well days and the percentage of responders were greater in the active group. Changes in allergen-specific IgE and IgG levels indicated a significant immunologic effect. The treatment was well tolerated, and no serious treatment-related events were reported.Conclusions: This study confirmed that this SLIT preparation significantly reduced symptoms and medication use in children with grass pollen-allergic rhinoconjunctivitis. The preparation showed significant effects on allergen-specific antibodies, was well tolerated, and appeared to be a valid therapeutic option in children allergic to grass pollen. This trial was registered at www.clinicaltrials.gov as NCT00841256. (J Allergy Clin Immunol 2012; 130:886-93.)

Background: 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.Objective: 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.Methods: 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.Results: 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.Conclusion: 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. (J Allergy Clin Immunol 2009;123:167-73.)

Current reconstructive techniques to repair torn tendons consist of autografts, allografts or synthetic prosthesis. Unfortunately, none of these surgical alternatives provide a long-term adequate solution. In this study, we defined a novel mechanism that mediates the differentiation of MSCs into tendon based on the SMAD8 signaling molecule, which could be used as a regenerative platform. A variant of SMAD8, deficient of the MH1 domain, was transfected to MSCs that express bone morphogenetic protein 2 (BMP2). The in vitro phenotype of the engineered MSCs was evaluated using RT-PCR, Histochemistry and morphology. In addition, the cells were injected into subcutaneous tissue and into the kidney capsule of female C3H/HeN mice in order to assess the tissue formation in vivo. Engineered MSCs, also expressing Lacz or Luciferase marker genes, were implanted on a Collagen sponge into a 3 mm partial defect of nude rats Achilles tendon. 5 weeks post implantation, the area of the injection or implantation was isolated and analyzed by light and electron microscopy, histochemical staining, RT-PCR and double quantum filtered (DQF) MRI. Cell survival in the implantation site was non-invasively and quantitatively demonstrated in vivo by the detection of Luciferase bioluminescence, using a CCCD system. Our results indicated a tenocytic phenotype of the engineered MSCs, based on microscopy and the expression of the tendon characteristic genes, Six 1and Scleraxis. Formation of tendon tissue in vivo was confirmed by the analysis of injected implants, which revealed the dense connective tissue with parallel-organized fibers and spindle shaped cells (A). Electron microscopic analysis showed tightly packed collagen fibers adjacent to fibroblast-shaped cells with active Endoplasmic Reticulum (B). Moreover, we were also able to repair Achilles tendon defects with the engineered MSCs. CCCD imaging quantitatively monitored cells survival in the operated tendon, and imunohistochmical staining detected the labeled implanted cells in site (C &F). DQF MRI analysis proved that highly ordered Collagen fibers were formed in the site of implantation as opposed to the control group (D, E). Since the expression of BMP2 is known to drive MSCs to osteogenic differentiation, we propose that the expression of SMAD8 in MSCs induces an inhibition of the BMP2 signaling pathway, resulting in the differentiation of MSCs into tendon cells. This is the first study showing that a particular SMAD signaling cascade is involved in tendon formation. Moreover, this is the first time a regenerative effect is shown to be exerted by the combination of a secreted factor and a signaling molecule. These findings may have considerable importance for therapeutic avenue in tendon in which SMAD 8 signaling plays a pivotal role Figure 1.