Sublingual immunotherapy (SLIT) is a treatment modality that is only just awakening interest in many parts of the world, after its first publication in 1986 [1•] and its subsequent expansion from Italian investigational centers to some parts of Europe at the beginning of this millennium. Its apparently higher safety and its more friendly route of application make SLIT especially appealing for use in the pediatric age group. However, this year some negative systematic reviews on SLIT for allergic rhinitis in children have been published, based on articles presented until June 2006 [2•,3•].
The reviewer feels that these systematic reviews have their shortcomings and offers an in-depth analysis of these SLIT articles, as well as an analysis of trials published on the pediatric age group up until July 2008. This updated review shows a more optimistic picture.
Publications on sublingual immunotherapy for respiratory allergy in children
Reviewing the many articles published on SLIT since more than two decades ago, it becomes clear that there is great heterogeneity in many aspects of the treatment given. Moreover, the patient populations enrolled vary, as well as the study designs and primary efficacy variables [4,5].
In 2006, an effort was made, with support of the World Allergy Organization, to publish recommendations for clinical trials on immunotherapy [6••]. Additionally, as more is being learnt about the probably effective quantity and frequency of the application of SLIT, very recently conducted studies have become more homogeneous. This does make a January-2009-updated discussion and comparison of their results meaningful. This has not been the case for review articles and meta-analysis on SLIT in children written so far, as no publications from 2007 onward had been included [2•,7,8•,9].
When making comments on the efficacy of SLIT in children, both positive and negative SLIT studies will have to be analyzed to draw balanced conclusions and to point out in which areas the to-date knowledge still falls short. An in-depth analysis of these negative studies is generally not presented in the review articles written on SLIT.
In consideration of above-mentioned fact, we decided to analyze on one hand the meta-analyses and systematic reviews on SLIT for allergic respiratory disease in children published the past 3 years, reviewing one by one the included articles and paying special attention to the studies with negative outcome. Possible explanations for their lack of meeting statistically significant improvement of the primary efficacy variable will be speculated on.
On the other hand, we did a review of articles published since and up until January 2009, using three different search strategies. A PubMed search was conducted using the keywords immunotherapy next sublingual, allergen, hyposensiti*, child*, pediatr* to identify clinical trials published the past 3 years. Second, the most up-to-date information was added, searching the abstracts from the 2008 annual meeting of the American Academy of Allergy, Asthma and Immunology and from the 2008 annual meeting of the European Academy of Allergy and Clinical Immunology. Finally, some article and abstract authors were asked for more in-depth information, especially on the exact dosing used in the studies.
Types of patients in reviewed articles
In this review, we include original articles of trials for which exclusively allergic patients 18 years of age or younger were recruited.
Meta-analysis of sublingual immunotherapy for children with allergic respiratory disease
According to guidelines, the highest level of evidence for certain treatment modalities is given by the results of meta-analyses . However, the quality of the meta-analyses depends in a high degree on the quality of the studies included and their homogeneity. On SLIT, various meta-analyses have been published, first on SLIT in patients of any age group with rhinoconjunctivitis under the strict regime of the Cochrane Collaboration method [11,12••]. On patients with asthma, Calamita et al.  published a meta-analysis with some methodological restrictions [14•]. Lately, there have been specific papers on SLIT in children with rhinitis , with asthma [8•] or with both .
The meta-analyses all show a significant reduction in allergy symptoms with standard mean differences (SMDs) ranging from −0.42 to −1.14 and a reduction in medication score with a SMD between −0.41 and −1.63. However, in some of these meta-analyses, the high heterogeneity reduces the power of the conclusions. According to Higgins et al. , the heterogeneity of a meta-analysis can be classified as low, moderate or high according to the I 2 values of 25, 50 and 75%, respectively. The meta-analyses published on SLIT in children have an I 2 for the symptom and medication reduction in allergic rhinitis  of 81 and 85.5%, respectively and for asthma [8•] of 94.4 and 95.4%, respectively.
In the light of these two variable results for meta-analysis of SLIT in children, it seems important to also look at individual studies or systematic reviews, without pooling all data together.
Systematic reviews of sublingual immunotherapy for children with allergic respiratory disease
In 2004, the first systematic review on SLIT in children was published . This review included articles up until June 2003 and concluded there were too few well designed studies to draw any definite conclusions about the efficacy of SLIT in children. In that paper, the authors conclude that SLIT has low-to-moderate clinical efficacy only for mild-to-moderate asthma in children monosensitized to house dust mite (HDM).
In 2008, two more systematic reviews have been published. The first one on immunotherapy in children and adolescents with allergic rhinoconjunctivitis [2•] includes all administration routes for immunotherapy and only focuses on the improvement in nasal symptoms. The second one [3•] is exclusively on SLIT, but reviews studies in which SLIT is given for both allergic rhinoconjunctivitis and asthma.
The systematic review done by Roder et al. [2•] is well structured and the quality of the studies was assessed with acceptable tools (Delphi list), as well as interreviewers' variability (Cohen's κ). The authors conclude that analysis of the SLIT subgroup does not show evidence of effect.
The second systematic review [3•] finally selected 13 double-blind placebo-controlled (DBPC) trials of SLIT in the pediatric age group, five with HDM extracts and eight with pollen extracts. Positive results reported by the authors of the included studies in this systematic review came principally from statistically significant improvement within the intervention group before and after treatment and not from statistically significant difference between the active and placebo group. Thus, once again, the main conclusion of Hoeks et al. [3•] is that there exists insufficient evidence for the efficacy of SLIT in children. In the conclusion of the article, the authors state that the efficacy of SLIT in children with allergic rhinoconjunctivitis or asthma cannot be demonstrated because of insufficient quality of the studies.
Authors of both systematic reviews mention that the heterogeneity of the trials makes the execution of a meta-analysis impossible and that dosing differences might be part of the explanation for the differences in efficacy found. Therefore, the analysis of characteristics of each study individually might give some further clues on why the studies might have come out negative and how efficacy of SLIT in children could be improved. This was done by the reviewer in a letter to the editor  and more in detail here below. Afterward, the latest SLIT trials on pediatric allergic disease in which these concepts have been applied and that did show clear benefit will be discussed.
Individual analysis of studies included in the pediatric meta-analyses and systematic reviews
All studies included in the meta-analyses and the systematic reviews discussed above have been scrutinized and some details in each study that could influence efficacy are tabulated in Table 1 [18–32]. We do include the publication from Wuthrich et al. , excluded by some reviewers, because the author confirmed randomization was applied. On the contrary, the study from Caffarelli et al. , erroneously included in both meta-analyses on SLIT in the pediatric age group, will not be discussed, because immunotherapy was oral and not sublingual (confirmed by personal communication). The studies have been ordered according to study quality – in keeping with the Delphi criteria – and from highest to lowest relative monthly dose (RMD; see below).
The author of this article is convinced that the dosing in SLIT is one of the crucial issues for its efficacy, as has been shown in the past for subcutaneous immunotherapy (SCIT). The probable effective dose per month for SCIT falls in the range of 5–20 μg of major allergen [33,34,35••]. In SLIT studies, the amount of allergen given per dose and the dosing frequency vary. Therefore, for dosing comparison in Table 1, the RMD is calculated: the monthly dose used in the reviewed SLIT trials in children has been expressed as relative to monthly SCIT-recommended dose for each allergen.
Factors influencing sublingual immunotherapy efficacy
In two recent publications from the reviewer [17,36•], some details were analyzed that might have contributed to the negative outcome of some pediatric SLIT trials (see Table 1).
Dosing and timing of treatment: The quantity of allergen extract that is given to the patient at each dose and the dosing schedule are important variables that might influence efficacy. There has been great variation in these parameters in different studies as mentioned below:
- Dose: recent SLIT studies on adults [37,38••] and children with tree-pollen allergic rhinitis and asthma have shown a clear dose–effect relationship , with RMDs of 14–30 times the SCIT monthly dose being most effective. However, low to very low doses were used in many studies included in the reviews.
- Dosing frequency: although daily dosing is not mandatory, it tends to be more effective than dosing with lower frequency [37,38••,40•]. Only in three of the 15 studies of the reviews, doses were given daily.
- Preseasonal dosing: commencing SLIT at least 4 months before the start of the pollen season augments its efficacy [41••]. This was not the case in four of the nine seasonal studies cited.
- Duration of treatment: four of 15 studies had interrupted treatment. Although a preliminary report of an open trial showed that interrupted SLIT treatment can give good results in some cases [42•], in the latest Cochrane review on SLIT, the best effect was seen in studies with at least 1 year of continuous administration [12••].
Patient selection: Also the selection of the patients for a clinical trial influences the outcome, which has been described as follows:
- Asthma or rhinitis or both: the systematic review of immunotherapy for pediatric allergic rhinitis [2•] included two studies on SLIT for asthma. In these studies, symptoms of rhinitis were secondary (or exploratory) endpoints, with likely insufficient power to detect a difference if one might exist.
- Patient selection, polysensitization: in the study done by Vourdas et al. , polysensitized children were included. In the SLIT group, 30 of 34 were polysensitized and 23 of them showed skin-test sensitivity to grass. The olive pollen season starts in May, showing important overlap with the grass-pollen season that starts just 1 month earlier in Greece. Of the placebo patients, only 15 of 32 were sensitized to grass. Taking a closer look at the figures on symptom scores, it becomes clear that during the first year, the SLIT group showed higher symptoms than the placebo group, whereas during the second year this relationship was reversed with more symptoms in the placebo group. Although statistics did not show difference between groups, with these reservations, a beneficial treatment effect seems likely.
- Number of patients with allergic rhinitis included: almost half the studies were underpowered, with less than 20 allergic rhinitis patients in the actively treated groups.
- Possible confounding by drug effects: in one study, all patients received maintenance inhaled fluticasone during the pollen season, in addition to SLIT/placebo, which may have resulted in marked improvement in both SLIT and placebo groups, thereby reducing intergroup differences for symptoms. (P = 0.059 for nasal symptoms).
- Oral immunotherapy: the study by Caffarelli et al.  has been included in both meta-analyses on SLIT, but this is oral immunotherapy in which the tablets are kept in the mouth until they dissolve (confirmed by personal communication). Moreover, the extract used is an allergoid, not an allergen as in the trials here analyzed.
Pediatric randomized clinical trials 2007–2008 not included in meta-analyses/systematic reviews
Randomized controlled trials (RCTs) and DBPC trials of SLIT in the pediatric population that might give more insight into the efficacy of this treatment modality are those published from 2007 till today. Many of these studies were conducted taking into account the above-mentioned details on dosing and patient selection. These new trials are scrutinized in Table 2 [43••–45••,46•,47•,48,49,50•] and will be discussed briefly below.
The study by Valovirta et al.  is the first trial of pediatric SLIT showing a dose–effect relationship. Children with allergic rhinitis were randomized to receive placebo or SLIT with a birch pollen extract of 1.6 or 13 RMD. Only the high-dose group showed statistically significant improvement in both symptom and medication scores in comparison with the placebo group.
Two large DBPC RCTs have been carried out with grass tablets [43••,45••], giving daily doses and starting at least 4 months preseasonally. Both high-quality studies with each over 100 children in the active groups showed statistically significant improvement in symptom and medication scores for the SLIT groups. Additionally, one of them showed an unexpected 64% median reduction in asthma symptoms in the subgroup of children with seasonal grass-pollen asthma [45••].
The negative trial by Roder et al. [46•] is a study carried out at the primary care level; primary care physicians selected grass-allergic children on the basis of symptoms and specific immunoglobulin E (IgE) measurements, not on the basis of skin-prick tests. Moreover, the allergen was given sublingually only two times a week and 44% of the randomized patients dropped out. This obliged the investigators to just analyze the intention-to-treat population, making up for missing data with the last observation carried forward method. This type of analysis surely has its shortcomings. In a subsequent publication on the same trial, the reasons for discontinuation were investigated: older children with problems to comply with the medication regime and experiencing less effectiveness of the treatment were more prone to abandon SLIT [51•].
The reviewer finds it hard to explain the negative study by Pham-Thi et al. [47•], in which SLIT with a very high dose HDM tablet or placebo was given daily for 18 months to 111 asthmatic children but no effect was found on either symptom or medication scores. However, SLIT did induce statistically significant immunological changes (reduction in skin sensitivity to HDM and rise in HDM-specific IgE and IgG4 antibodies). This might lead to the conclusion that may be allergy was not the prime cause of asthma in these children, although over 80% had concomitant perennial allergic rhinitis. Another explanation – given by the authors of the publication – is that asthma symptoms were too mild and concomitant environmental control biased the outcomes; finally, the active group seemed to have a slightly worse asthma with mean forced expiratory volume in 1 s (FEV1) of 91.9 versus 95.1% in the placebo group.
The RCT by Rodriguez-Santos [50•] showed promising results of HDM SLIT given for 2 years to very young children (2–5 years). The use of healthcare facilities (P < 0.01) and inhaled corticosteroids (P < 0.004) were both lower in the active than in the open control group. Just before this article went to print, similar good results were shown by Stelmach et al. [44••] in a DBPC RCT study in 50 Polish asthmatic children, who were treated for 2 years with high-dose five-grass extract SLIT (Staloral 300IR, Stallergènes, 25 μg group 5 major allergen, RMD 90). Asthma symptoms (41%), asthma medication score (10%) and the forced expiratory volume in 1 s were all statistically significantly reduced after the first year of precoseasonal treatment; after the second year, bronchial hyperreactivity improved, without reaching statistical significance.
Pediatric nonrandomized sublingual immunotherapy trials 2007–2008
There were two studies of HDM SLIT for asthma, both showing a statistically significant reduction in inhaled corticosteroid use with a RMD between 16 and 24. One of them was an open controlled 3-year study [52•], the other one a 3-year retrospective study [53•].
One recent trial on the preventive effect of 3-year SLIT in 216 Italian children showed reduced positivity to bronchial metacholine challenge and reduced number of new sensitizations in the active group . Comments on a reduced percentage of children with persistent asthma in the SLIT group were made in the text, but the exact criteria to diagnose intermittent and persistent asthma were not given, leading to some confusion as some children classified as ‘only rhinitis’ had a positive bronchial metacholine challenge.
Children with respiratory allergic diseases due to Dermatophagoides pteronyssinus, receiving SCIT or SLIT, had a different immunologic response in peripheral blood during treatment. In this study, rises in specific serum IgE and IgG4 were only seen in the SCIT group. The very low dose of SLIT (RMD 1.5) might explain the lack of systemic immunological changes. Interestingly, the clinical improvement was similar with SCIT and SLIT [55•].
The birch study by Valovirta et al. , discussed above, analyzed some immunological parameters in a subgroup of SLIT-treated and placebo-treated allergic rhinitis children . SLIT induced a dose-dependent systemic allergen-specific immunological response, with activation of regulatory cytokine IL-10 and an inhibitory effect on IL-5 increase that was associated with transforming growth factor-β (TGF-β), in the high-dose group. Further analysis [57•] showed – again in the high-dose group only – that IL-18 and signalling lymphocytic activation molecule (SLAM) are upregulated, suggesting that the Th2-type inflammatory response is downregulated during SLIT by increased Th1-type response.
Publications on sublingual immunotherapy for nonrespiratory allergy in children
In a few studies, new indications for SLIT in children have been explored.
Till now one DBPC RCT has studied the usefulness of an 18-month treatment with HDM SLIT in children with atopic dermatitis [58••]. A reduction in the Scoring Atopic Dermatitis (SCORAD) score was noted in the active group in comparison with the placebo group (P = 0.03) from the ninth month on. In a subgroup analysis, the patients with mild–moderate atopic dermatitis were the ones who benefit most (P = 0.01).
SLIT with natural rubber latex was studied in an explorative trial of 10 cases of latex allergy due to multiple surgical procedures, showing improvement in all . In a DBPC study, latex SLIT was effective in children with cutaneous and respiratory symptoms, including oral allergy syndrome to related foods. In comparison with placebo, significant improvements were observed starting at 9 months from study start (P = 0.015) and at 12 months (P = 0.005) .
Six months of milk SLIT induced tolerance in four of eight children with IgE-mediated cow milk allergy . More studies on SLIT with peanut are under way.
Safety of sublingual immunotherapy in children
Safety of SLIT in children certainly deserves an in-depth analysis that goes beyond the scope of this review. Till now, no fatal reactions have been reported with SLIT, either in adults or in children, but some severe adverse systemic reactions have occurred. A good review on this issue can be found in a published evaluation [62•], and Agostinis et al.  published a post-marketing review on the good safety data of SLIT with multiple pollen allergens in children.
New trials on SLIT in adults and children with allergy have been conducted lately, improving on what had been learned from the negative studies in the past: high-dose, daily applications and in the case of pollen SLIT beginning at least 4 months before season's start. Moreover, a more stringent patient selection and evasion of confounding factors have made it possible to show the effect of SLIT more neatly.
With these new studies for the use of SLIT in the treatment of allergic rhinitis caused by pollen allergy in children, there is now quite substantial evidence of effect. More than two high-quality trials show concordant results with a reduction in symptom and medication scores for allergic rhinitis and one trial even demonstrated a dose–effect relationship. For seasonal asthma, results are almost as optimistic, with two high-quality studies supporting evidence of effect.
However, for HDM allergy, data on the efficacy of SLIT in children are not so straightforward, as some well conducted trials show nonconcordant results.
With our increasing understanding of the mechanisms of immunotherapy [64••,65••], new exciting areas are looking for modifications of SLIT extracts to improve their efficacy, adding IL-10 and TGF-β-inducing adjuvants like toll-like receptor agonists  or 1alpha,25-dihydroxyvitamin D3 . Additionally, investigational teams are trying to ameliorate the local absorption, adding mucoadhesive substances or changing the location in the oral cavity to deposit SLIT [68••].
SLIT is starting to become a very attractive alternative to SCIT, especially in the pediatric age group, although its long-term effects and preventive action still need to be documented better. Moreover, the optimal dosing for HDM SLIT is still under discussion. Finally, application of our knowledge on mechanistics of SLIT to further improve its efficacy might be an option for the near future.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
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DBPC RCT of 2-year high-dose precoseasonal SLIT in pediatric asthma
with statistically significant improvement in the treated group for asthma
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tablet for sublingual immunotherapy
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efficacy in children with house dust mite-induced allergic asthma
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50• Rodriguez-Santos O. Sublingual immunotherapy
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in children from two to five years of age with mite allergy. Revista Alergia México 2008; 55:71–75. Randomized trial with HDM SLIT in very young children showing reduction in corticosteroid and healthcare use. No symptom score was recorded.
51• Roder E, Berger MY, de Groot H, Gerth van Wijk R. Sublingual immunotherapy
in youngsters: adherence in a randomized clinical trial. Clin Exp Allergy 2008; 38:1659–1667. Publication of the same trial as
51• [46•] Publication of the same trial as
52• Ozdemir C, Yazi D, Gocmen I, et al
. Efficacy of long-term sublingual immunotherapy
as an adjunct to pharmacotherapy in house dust mite-allergic children with asthma
. Pediatr Allergy Immunol 2007; 18:508–515. Open trial showing efficacy of SLIT in HDM-allergic children, leading to reduction in symptoms and medication for asthma
53• Nuhoglu Y, Ozumut SS, Ozdemir C, et al
. Sublingual immunotherapy
to house dust mite in pediatric
patients with allergic rhinitis
: a retrospective analysis of clinical course over a 3-year follow-up period. J Investig Allergol Clin Immunol 2007; 17:375–378. Retrospective study showing efficacy of SLIT for 3 years.
54 Marogna MT, Tomassetti D, Bernasconi A, et al
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Immunol 2008; 101:206–211.
55• Antunez C, Mayorga C, Corzo JL, et al
. Two year follow-up of immunological response in mite-allergic children treated with sublingual immunotherapy
. Comparison with subcutaneous administration. Pediatr Allergy Immunol 2008; 19:210–218. Mechanistic study showing no changes in IgE or IgG4 with low-dose SLIT treatment.
56 Savolainen J, Jacobsen L, Valovirta E. Sublingual immunotherapy
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57• Savolainen J, Nieminen K, Laaksonen K, et al
-induced in vitro expression of IL-18, SLAM and GATA-3 mRNA in PBMC during sublingual immunotherapy
. Allergy 2007; 62:949–953. Mechanistic study performed in a subgroup of patients from the trial references in
57•  Mechanistic study performed in a subgroup of patients from the trial references in
58•• Pajno GB, Caminiti L, Vita D, et al
. Sublingual immunotherapy
in mite-sensitized children with atopic dermatitis: a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 2007; 120:164–170. First study showing reduction in SCORAD score after 9 months of SLIT.
59 Nucera E, Schiavino D, Pollastrini E, et al
desensitization in children with congenital malformations and latex allergy. Pediatr Allergy Immunol 2006; 17:606–612.
60 Bernardini R, Campodonico P, Burastero S, et al
. Sublingual immunotherapy
with a latex extract in paediatric patients: a double-blind, placebo-controlled study. Curr Med Res Opin 2006; 22:1515–1522.
61 de Boissieu D, Dupont C. Sublingual immunotherapy
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62• Passalacqua GGL, Compalati E, Canonica GW. The safety of allergen
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. Curr Drug Saf 2008; 2:117–123. Review article of SLIT safety.
63 Agostinis F, Foglia C, Landi M, et al
. The safety of sublingual immunotherapy
with one or multiple pollen allergens in children. Allergy 2008; 63:1637–1639.
64•• Francis JN, James LK, Paraskevopoulos G, et al
. Grass pollen immunotherapy
: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol 2008; 121:1120e2–1125e2. Articles showing the relationship between skin test changes and immunological changes during different stages of immunotherapy
65•• Bohle B, Kinaciyan T, Gerstmayr M, et al
. Sublingual immunotherapy
induces IL-10-producing T regulatory cells, allergen
-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol 2007; 120:707–713. Articles showing immunological changes during different time points of SLIT treatment: rise in IL-10 and Foxp3 at 4 weeks, shift toward Th1 after 52 weeks.
66 Van Overtvelt L, Lombardi V, Razafindratsita A, et al
. IL-10-inducing adjuvants enhance sublingual immunotherapy
efficacy in a murine asthma
model. Int Arch Allergy Immunol 2008; 145:152–162.
67 Taher YA, van Esch BC, Hofman GA, et al
. 1alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy
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: role for IL-10 and TGF-beta. J Immunol 2008; 180:5211–5221.
68•• Allam JP, Stojanovski G, Friedrichs N, et al
. Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy
? Allergy 2008; 63:720–727. Vestibular immunotherapy
might be a better option, taking into account the topical distribution of Langerhans cells and mast cells in the oral mucosa.