Recent Advances in Allergen Immunotherapy Treatment of Asthma
In the following paragraphs, we summarize the relevant publications since January 2012, including primary and secondary research, investigating the effect of AIT on asthma endpoints.
Subcutaneous Immunotherapy
Reviewing the literature of the past 18 months shows confirmatory findings on the effectiveness of SCIT in asthma, however without any novel or outstanding scientific advances (Table 1). As the optimal duration for an AIT course is still a matter of debate, the study by Stelmach et al., investigating possible differences in the long-term effectiveness between 3 and 5 years treatment courses in 90 asthmatic children monosensitized to HDMs, yielded interesting data. Both SCIT regimens produced excellent results with significantly higher asthma remissions obtained in both groups (50% after 3 years and 54% after 5 years, respectively) versus untreated controls (3.3%). The minimal controlling ICS dose reduction in the 5-year group (median, 75%) was significantly higher compared with the 3-year group (median, 50%) after immunotherapy discontinuation. After 3 years without SCIT, no differences were seen between the two groups (median, 100 and 94%, respectively), whereas the minimal ICS dose controlling the symptoms did not change in the control group and was significantly higher. The study concluded that 3 years of SCIT is an adequate duration for the treatment of HDM-dependent childhood asthma.
In children, few comparative placebo-controlled studies between SCIT and SLIT are available. In a study comparing both AIT regimes (HDM) in 32 asthmatic patients during 1 year in a double-dummy placebo-controlled randomized design, all disease-related parameters were equally improved, although the study was not powered to show differences between both active groups, so no conclusion can be drawn in this respect. SCIT significantly diminished symptom and medication scores for both asthma and allergic rhinitis. Similarly, SLIT reduced these outcomes, except asthma medications, but this reduction was not significantly different from placebo. Although both treatment options were found immunologically active, bronchial provocative doses and sputum eosinophil increments after bronchial challenge were reduced only with SCIT.
In a recent retrospective evaluation in asthmatic children, 5–16 years of age, some factors predicting the response to AIT were identified, that is: the age of onset of wheezing and BHR. In addition, bronchial allergen provocation was found to be a useful and objective tool to assess the effectiveness of SCIT. This parameter exhibited significant improvements after 1 year of SCIT against HDM in 60.7% of the patients and was also able to identify the nonresponders to treatment.
Sublingual Immunotherapy
Concerning paediatric studies of the past 18 months, most data on effectiveness of pollen SLIT on asthma outcomes came from studies in which seasonal allergic rhinitis was the leading disease, thus they were not adequately designed or powered to detect changes in asthma symptoms or medication (Table 1). The largest double-blind randomized placebo-controlled study involved 207 children aged 4–12 years with grass pollen rhinitis with or without intermittent or mild-persistent asthma according to GINA severity criteria. As compared to placebo, grass pollen SLIT drops given for 8 months in a precoseasonal regimen produced a significant reduction in the mean area under the curve of the overall allergy symptoms and medication scores from the baseline of the previous run-in season. The number of well days (defined as the number of days with symptoms score ≤ 4 and medication score = 0) and the percentage of responders were greater in the active group, with changes in allergen-specific IgE and IgG levels indicating a significant immunologic effect, but unfortunately no explicit information on asthma outcomes were reported.
The comparative effect of precoseasonal and continuous grass pollen SLIT in children has been investigated by Stelmach et al., who included 20 asthmatic patients among 60 monosensitized patients aged 6–18 years with allergic rhinitis in a 2-year prospective, randomized, double-blind, placebo-controlled trial. Both precoseasonal and continuous regimens were similarly associated with a substantial reduction in the combined symptoms/medication score, including the asthma score, when compared with placebo. However, no significant changes were observed between treatments throughout the study in the morning peak inspiratory flow (PEF), forced expiratory volume in 1 s and nonspecific BHR. As compared with placebo, a similar significant decrease in exhaled nitric oxide (FeNO) level was found in both active groups.
In recent years, the primary goal of asthma treatment has been aimed at reaching disease 'control', a composite outcome including all the primary clinical and functional aspects, while different strategies have been developed to avoid the long-term downsides of ICSs. A number of studies have compared different asthma medication modalities, nevertheless studies directly comparing therapeutic approaches including AIT reached controversial conclusions. A recent study investigated whether SLIT (birch pollen) can provide any advantage in disease control in a real-life setting in patients with mild-persistent asthma related to birch pollen compared with increasing doses of ICS or low dose ICS and antileukotrienes. After 3 years of treatment, it was found that adult patients inadequately responding to a fixed low-dose of inhaled budesonide may be better and safely controlled by adding SLIT for 12 weeks from February to April using a hypoallergenic allergoid. This finding suggests a potential steroid-sparing effect of SLIT, of particular relevance in patients with allergic rhinitis and coexisting asthma frequently forced to administer both nasal and bronchial corticosteroids.
SLIT with HDM drops appeared an effective and highly safe option for the cough variant asthma of 106 children included in a randomized study, wherein SLIT was superior and faster compared with conventional treatment in decreasing symptom scores and serum eosinophils level and improving PEF.
The results of a large, retrospective, observational study confirmed the efficacy and tolerability of HDM SLIT in routine French practice in a real-world setting. In this study, Trebuchon et al. randomly selected 139 allergy specialists to include and monitor for at least 2 years 1289 patients (57% under the age of 18) with a respiratory allergy and proven sensitization to HDM treated with SLIT. Among them 50% also suffered from asthma, and their symptoms improved in 63% of the patients, with a concomitant reduction in symptomatic medication intake.
A 3-year case–control study evaluated 140 children (6–14 years) with allergic asthma and allergic rhinitis, treated with multiallergen SLIT or symptomatic drugs. SLIT exhibited a significant improvement from baseline in asthma symptoms scores, and the benefit was independent of age and monosensitization or polysensitization status.
Finally, confirmatory findings on the effectiveness of AIT on outcome measures of asthma come from three very recent systematic reviews that graded the evidences of effect of SCIT and SLIT (off-label use of subcutaneous aqueous allergens for sublingual desensitization) by adapting an evidence grading scheme recommended by the Grading of Recommendations Assessment, Development and Evaluation Working Group. The most updated review, through to December 2012, concluded that strong evidence supports that SLIT improves asthma symptoms, with eight of 13 studies reporting greater than 40% improvement versus the comparator (placebo, pharmacotherapy or other SLIT regimens). Overall, moderate evidence came from 16 out of 41 studies that SLIT could reduce asthma medication use by more than 40%. The second systematic review, including only paediatric studies through May 2012, analysed 13 trials with 920 children receiving SCIT or standard care, and 18 studies with 1583 children receiving SLIT or usual care. The authors concluded that the strength of evidence was moderate and low that SCIT improves asthma symptoms and medication scores, respectively, while high evidence was provided that SLIT can improve asthma symptoms. Overall, there was low evidence supporting SCIT over SLIT for improving asthma or rhinitis symptoms or medication usage. Similar conclusions were reached by the third comprehensive review, updated to May 2012, including 74 references on SCIT, 60 on SLIT and eight comparative (SCIT versus SLIT) studies. Despite some variation across outcomes and studies, overall, moderate-to-high (somewhat weaker in children) evidence was found for the efficacy and safety of both SCIT and SLIT for the treatment of allergic rhinitis and asthma, with unknown superiority of either route over the other.