Our Comparative Effectiveness Review describes the efficacy and safety of specific immunotherapy, subcutaneous and sublingual, in the treatment of allergic rhinitis and asthma. Presently, in the United States, patients with allergies receive immunotherapy via increasing subcutaneous injections of allergen-containing extracts to suppress or eliminate allergic symptomatology. Over the last two decades, interest has grown in using sublingual immunotherapy as an alternate treatment approach. In 1996, a Task Force assembled by the World Allergy Organization on Immunotherapy cited the emerging clinical data on sublingual immunotherapy, recognizing its potential as an alternative to subcutaneous therapy, and encouraged continued clinical investigation to characterize optimal techniques. Sublingual forms of immunotherapy have gained favor in Europe; however, there are no FDA approved sublingual forms of immunotherapy. The aqueous materials developed for subcutaneous immunotherapy can be delivered sublingually, and U.S. physicians are exploring this alternate desensitization approach, off-label, in the treatment of allergic respiratory conditions; however due to differing standardization of potency in the Europe and United States, doses have been extremely hard to translate between countries.

To inform clinicians’ use of these therapies, we reviewed the comparative efficacy and safety of these approaches to immunotherapy in the treatment of allergic rhinitis and asthma. We included studies that enrolled participants with confirmed environmental allergies, and symptoms of allergic rhinitis and/or asthma. The studies were limited to those in which the specific immunotherapy formulations used (or close substitutes) are presently available to clinicians in the United States, even if they were being used off-label. The literature search yielded 5646 citations. After the necessary exclusions, we had 142 English language randomized controlled trials for this review.

Summary of Key Findings

Subcutaneous Immunotherapy

Key Question 1. What is the evidence for the efficacy and effectiveness of subcutaneous immunotherapy in the treatment of allergic rhinoconjunctivitis and/or asthma?

We included 74 randomized controlled studies using subcutaneous immunotherapy. We found high grade evidence to support that subcutaneous immunotherapy improves the following asthma outcomes: symptoms, medication use, and combined asthma plus rhinoconjunctivitis medication use. We found moderate grade evidence to support the use of subcutaneous immunotherapy to improve asthma and rhinitis/rhinoconjunctivitis symptoms and low grade evidence to support the use of subcutaneous immunotherapy to improve combined asthma (with or without rhinitis) symptom-medication scores. The majority of the studies used a single allergen; therefore, our findings primarily reflect the strength of the evidence when a single allergen is used for immunotherapy. In the United States, it is common practice to include multiple allergens in subcutaneous immunotherapy extracts. However, there are much fewer studies investigating subcutaneous immunotherapy using multiple allergens.

We did not grade the evidence for indirect outcomes such as pulmonary function test results and bronchial reactivity. However, we observed that subcutaneous immunotherapy provided consistent improvement in specific bronchial reactivity to allergen challenge. No consistent benefit was observed for pulmonary function test results and nonspecific bronchial reactivity.

When evaluating allergic rhinoconjunctivitis outcomes, we found high grade evidence to support the use of subcutaneous immunotherapy to improve rhinitis/rhinoconjunctivitis symptoms, conjunctivitis symptoms, combined nasal, ocular, and bronchial symptoms, combined asthma plus rhinitis/rhinoconjunctivitis medication use, and disease-specific quality of life. Moderate grade evidence supports the use of subcutaneous immunotherapy to reduce rhinitis/rhinoconjunctivitis medication use. Low grade evidence supports the use of subcutaneous immunotherapy to reduce combined symptom-medication scores. Although we did not grade the evidence for indirect outcomes, we observed that subcutaneous immunotherapy provided consistent improvement in reactivity to nasal provocation testing and conjunctival provocation testing. Similarly to our observation with the asthma studies, majority of the rhinitis/rhinoconjunctivitis studies used a single allergen; therefore our findings primarily reflect the strength of the evidence when a single allergen is used for immunotherapy. We observed that much fewer studies used combined symptom-medication score as an outcome measure. This is probably the reason why the strength of evidence for improving symptom-medication scores is lower than the strength of evidence for improving the individual scores, i.e. symptom scores alone or medication scores alone.

Key Question 2. What is the evidence for safety of subcutaneous immunotherapy in patients with allergic rhinoconjunctivitis and/or asthma?

The lack of a consistent reporting system and grading system for subcutaneous immunotherapy made it impossible to pool safety data across studies. Furthermore, not all studies reported safety data. Fifty-four studies reported safety data. Local reactions are more common than systemic reactions, and anaphylaxis was infrequently reported. The evidence suggests that systemic reactions occurred more commonly in the active immunotherapy arms than in the comparators. No deaths were reported in any of the studies we reviewed.

Key Question 3. Is the safety and effectiveness of subcutaneous immunotherapy different in distinct subpopulations with allergic rhinoconjunctivitis and/or asthma?

We examined the evidence regarding the use of SCIT in subpopulations of interest. Insufficient data exists in the following subpopulations so that strength of evidence regarding efficacy or safety cannot be reported in these subpopulations: the elderly, pregnant women, minorities, inner-city versus rural residents, and severe asthmatics. However, findings from a few studies support that subcutaneous immunotherapy is more beneficial in patients with mild asthma than with severe asthma. There is no apparent difference in efficacy when considering mono-sensitized subjects or poly-sensitized subjects receiving subcutaneous immunotherapy. There were sufficient studies to report on the efficacy and safety in children.

Subcutaneous Immunotherapy in Children

We included 13 randomized controlled pediatric subcutaneous immunotherapy studies with 920 children. We found moderate strength of evidence to support that subcutaneous immunotherapy improves asthma symptoms. As observed in the general population, the majority of the pediatric studies used a single allergen. There is moderate strength of evidence that subcutaneous immunotherapy improves rhinitis/rhinoconjunctivitis symptoms. There is low grade evidence to support the use of subcutaneous immunotherapy to improve asthma medication use, combined asthma plus rhinoconjunctivitis medication use, asthma symptom-medication scores, conjunctivitis symptoms, and rhinitis/rhinoconjunctivitis disease-specific quality of life. When compared with the mixed adult and pediatric population, the strength of the evidence is lower in the pediatric subpopulation; this is likely due to the fact that there are many fewer studies of subcutaneous immunotherapy in children and adolescents.

Inconsistent reporting of adverse events made it impossible to pool safety data across studies. However, local reactions were the most common adverse reactions in children and adolescents receiving subcutaneous immunotherapy. There were no reports of death.

Sublingual Immunotherapy

Key Question 1. What is the evidence for the efficacy and effectiveness of sublingual immunotherapy in the treatment of allergic rhinoconjunctivitis and/or asthma?

Sixty RCTs of sublingual immunotherapy were included. The overall strength of evidence is moderate that sublingual immunotherapy improves allergic rhinitis and asthma outcomes. The evidence is high grade in the following individual clinical outcome: asthma symptoms.,. The evidence is moderate to support that sublingual immunotherapy improves each of the clinical outcomes: rhinitis/rhinoconjunctivitis symptoms, combined asthma plus rhinitis/rhinoconjunctivitis symptoms, combination medication plus symptom scores, quality of life, conjunctivitis symptoms, and medication use.

While the majority of sublingual studies included in this review utilized single allergens, this may not reflect the current off label practice of sublingual immunotherapy in the United States. Practitioners of sublingual immunotherapy in the United States are likely to use multi-allergen specific immunotherapy in treatment. Seven of the included studies utilized mixed or multiple allergens.122,145,147,148,151,153,172 The number of multiple allergen studies combined with the heterogeneity of outcomes reported in these seven studies makes it difficult to comment on the efficacy of single allergen sublingual immunotherapy in comparison to multi-allergen.

Key Question 2. What is the evidence for the safety of sublingual immunotherapy in patients with allergic rhinoconjunctivitis and/or asthma?

The lack of a consistent reporting system and grading system for subcutaneous or sublingual immunotherapy made it impossible to pool safety data across studies. Furthermore, not all studies reported safety data.

Forty-three sublingual immunotherapy studies reported safety data. In these studies, local reactions (reactions at the site of allergen introduction such as oral itching and swelling) were common but mild. Systemic reactions were infrequent and no life-threatening reactions, anaphylaxis, or deaths were reported in these studies.

Key Question 3. Is the safety and effectiveness of sublingual immunotherapy different in distinct subpopulations with allergic rhinoconjunctivitis and/or asthma?

We examined the evidence regarding the use of SLIT in subpopulations of interest. Insufficient data exists in the following subpopulations so that the strength of evidence regarding efficacy or safety cannot be reported in these subpopulations: the elderly, pregnant women, minorities, inner-city versus rural residents, and severe asthmatics.

Sublingual Immunotherapy in Children

We included 18 studies of sublingual immunotherapy in 1579 children in this analysis. We found moderate strength of evidence to support the use of sublingual immunotherapy to reduce rhinitis/rhinoconjunctivitis symptoms, combined asthma plus rhinitis/rhinoconjunctivitis symptoms, conjunctivitis symptoms, and medication use. The strength of evidence is high that sublingual immunotherapy reduces asthma symptoms, conversely, the strength of evidence is low that sublingual immunotherapy reduces combined medication plus symptoms scores. There is insufficient evidence to determine the impact of sublingual immunotherapy on disease specific quality of life.

Inconsistent reporting of adverse events made it impossible to pool safety data across studies. Furthermore, not all studies reported safety data. However, it appears that local reactions are common but are mild. Systemic reactions were described in both sublingual and placebo arms. No life-threatening reactions, anaphylaxis, or deaths were reported

Subcutaneous Versus Sublingual Immunotherapy

Key Question 1. What is the evidence for the efficacy and effectiveness of subcutaneous versus sublingual immunotherapy in the treatment of allergic rhinoconjunctivitis and/or asthma?

Eight RCTs comparing sublingual immunotherapy versus subcutaneous immunotherapy were included. The overall strength of evidence is low grade to support subcutaneous immunotherapy over sublingual for control of asthma symptoms and combined symptom-medication scores, and moderate grade for control of rhinitis and/or conjunctivitis symptoms. However there is insufficient evidence from head to head comparisons to determine the overall superiority of one form of specific immunotherapy over the other.

Key Question 2. What is the evidence for safety of subcutaneous versus sublingual immunotherapy in patients with allergic rhinoconjunctivitis and/or asthma?

Eight RCTs reported on the efficacy and safety of sublingual versus subcutaneous immunotherapy. In comparing the two therapies, there is insufficient evidence from head to head comparisons to conclude that one route of administration is safer than the other.

Key Question 3. Is the safety and effectiveness of subcutaneous versus sublingual immunotherapy different in distinct subpopulations with allergic rhinoconjunctivitis and/or asthma?

We examined the evidence regarding the use of SCIT versus SLIT in subpopulations of interest. Insufficient data exists in the following subpopulations so that strength of evidence regarding efficacy or safety cannot be reported in these subpopulations: the elderly, pregnant women, minorities, inner-city versus rural residents, and severe asthmatics.

Subcutaneous Versus Sublingual Immunotherapy in Children

We included three studies with 135 subjects in this analysis comparing subcutaneous versus sublingual immunotherapy in children. There is low strength of evidence to support subcutaneous over sublingual immunotherapy in children and adolescents across clinical outcomes, including asthma symptoms and rhinitis/rhinoconjunctivitis symptoms. The strength of evidence is low to support comparable improvement of medication use between sublingual immunotherapy and subcutaneous immunotherapy.

There were few local reactions reported for both the subcutaneous immunotherapy and sublingual immunotherapy groups. No systemic reactions were reported in patients receiving sublingual immunotherapy. However, four patients receiving subcutaneous immunotherapy experienced systemic reactions, including one anaphylaxis event and three patients with moderate to severe respiratory symptoms.

Applicability

The results of this systematic review are applicable to patients with allergic rhinoconjunctivitis and/or asthma. We included only studies that confirmed the diagnosis of allergy, either by skin or in-vitro testing. Furthermore, asthma studies were included only if the studies used objective measures to confirm asthma diagnosis. We included only studies in which the specific immunotherapy formulations used (or close substitutes) are available to clinicians in the United States; hence these results should be applicable to practitioners in the United States.

The reviewed outcomes reflect important clinical outcomes for patients with environmental allergies. The majority of outcomes were direct measures of disease symptomatology, which should make the findings of our review meaningful to clinicians and to patients. Some surrogate measures such as pulmonary function testing were also included. While pulmonary function testing is an indirect measure of asthma outcomes, it is used frequently by clinicians in the United States.

However, the following should be considered regarding the applicability of the evidence described in this report. The majority of the included trials used a single allergen for immunotherapy; hence, it is difficult to determine the extent to which this evidence applies to U.S. practitioners using multiple allergen regimens. Based on the findings from a few studies which support that subcutaneous immunotherapy is more beneficial in patients with mild asthma than with severe asthma, the use of subcutaneous immunotherapy to treat asthma is probably most applicable to mild asthmatics. The majority of SLIT studies in this review included subjects with allergic rhinitis/rhinoconjunctivitis and/or mild asthma. Hence, although it may appear from this review that sublingual immunotherapy may be safer than subcutaneous immunotherapy, the safety data from these subgroups of patients must not be extrapolated to the more severely affected patients. There is little evidence supporting the use of immunotherapy in patients with severe asthma.

While a separate sub-analysis of pediatric studies was performed in this review, several studies reported outcomes on a mixed population of adults and children without stratifying the outcomes by age group, so we could not say definitively to which population the results apply. Furthermore, the dosing regimens and durations of treatment reported in these studies varied widely. Therefore, this body of evidence is insufficient to comment specifically on target maintenance dose or the duration of sublingual therapy. This may, however, be interpreted as supporting the effectiveness of immunotherapy across a broad range of doses.

Our findings add to current knowledge on the strength of evidence for the efficacy and safety of allergen immunotherapy for treatment of asthma and allergic rhinoconjunctivitis. These findings are relevant to clinicians who provide care for patients affected by these medical conditions. The findings are also relevant to patients making decisions regarding therapy and can help inform them on the efficacy and safety of allergen immunotherapy. Guideline developers may also find our study useful for making recommendations about the use of allergen immunotherapy in adults and children.

Study Limitations

We included only RCTs in this review; hence, our findings primarily reflect the efficacy, rather than real world effectiveness, of subcutaneous and sublingual immunotherapy. The studies varied substantially in their risk of bias. While all studies used randomization, 90 studies (72%) were double blind, but the majority of studies did not specify explicitly from whom the intervention was concealed. The majority of studies of subcutaneous and sublingual immunotherapy received industry support financially or in the form of supplies. The studies rarely stated clearly the role or extent of involvement of their sponsors. For these reasons, several studies were considered to have a moderate or high risk of bias. The potential risk of bias played an important role in determining the strength of the evidence for each direct outcome.

The body of literature had much heterogeneity. The clinical outcomes reported varied from study to study, and there were no consistent scoring or grading systems for reporting pertinent primary outcomes such as symptoms or medication use. The heterogeneity of the data on symptoms and medication use precluded pooling the data for further analysis. The studies used varying criteria for diagnosing asthma and assessing asthma severity and control. It is possible that some of these asthma criteria may overestimate, while others may underestimate, the degree of asthma control. Some studies that reported combined asthma and rhinoconjunctivitis scores demonstrated significant improvement in individual disease outcomes. It is possible that a preferential effect of immunotherapy on one of these disease processes may have highly influenced the combined scores. Hence, such combined scores may not accurately reflect the degree of control of both disease processes, and yet may be relevant to patients.

Studies with multiple allergens presented a similar dilemma; response to one allergen may have determined the overall clinical score, and the true effect of desensitization with each allergen remains unclear. Another significant limitation of the study is in regards to single and multiple antigen therapy; the majority of studies included in this review were single allergen studies and therefore caution needs to be exercised in applying these conclusions to multiple allergen immunotherapy regimens.

One significant limitation of the current review is the difficulty in comparing European allergens to United States allergens.183 While in the United States the FDA establishes for each standardized allergen an in vitro potency test which all manufacturers must use to compare their extracts, this is not the case in Europe. In Europe, each allergen manufacturer has its own in-house reference standards rather than a European standard. Another difference is that the in vivo potency in the United States is quantified by intradermal testing methods, while in Europe, prick testing is utilized. In order to address this problem, the current review attempted to express where possible sublingual dosing in micrograms of major allergen (Appendix E, Table E14). However, it must be emphasized that due to the above differences in United States versus Europe allergen standardization and potency, caution must be exercised when attempting to translate European dosing to the United States.

Most challenging to this review, there was extreme variability in the dosing and treatment schedules from study to study. The doses were reported in varying units (BU, IR, SQ-U, micrograms, BAU, STU, etc), which made it very hard to compare outcomes across studies. In several studies, major allergen content was not reported. To illustrate, dust mite was the most widely used sublingual allergen (14 studies). When considering the dosing for dust mite in micrograms per month, the highest dose used was over 50 times greater than the lowest dose, yet clinical efficacy was reported at both ends of the spectrum. Treatment schedules varied widely as well; in the sublingual studies, dosing ranged from once a day to once a week, and the duration of treatment used varied from one pollen season to several years. The extreme variability in sublingual doses and treatment schedules makes it impossible to comment on the strength of the evidence regarding dosing and treatment schedule. However, this may also be interpreted as evidence of broad effectiveness of this therapy regardless of dose and schedule.

The same issues of heterogeneity existed with the safety data reported by these studies; the adverse events were reported with different denominators from study to study. The lack of a consistent reporting and grading system made it impossible to pool data. Furthermore, our study reports only the safety data from randomized controlled trials, and is therefore not a comprehensive review of the incidence of adverse events encountered in observational studies or clinical practice. A more inclusive study of randomized, non-randomized, and observational studies would be more applicable to the general population.

There were also deficiencies in the statistical reporting provided in the included studies. We observed that several studies did not report intergroup comparisons. Instead, the studies reported the statistical significance of the pre/post comparisons for each treatment arm. The absence of such comparisons makes it difficult to determine whether the intervention provided a true treatment effect. Relevant statistical information on the outcomes reported as scores was frequently unavailable (such as standard deviation, standard error, or confidence intervals); therefore, precision of the point estimates could not be assessed and these outcomes could not be pooled. As a result, precision was not used for grading the evidence for each outcome; magnitude of effect was used as a proxy for precision. In those few studies that compared subcutaneous and sublingual immunotherapy head-to-head, only three of the eight reported direct statistical comparisons between groups for the clinical outcomes of interest.

Due to the large number of articles identified and limited resources available for language translation, we included only studies published in English. We requested information from the pharmaceutical companies identified, but did not receive any information. We also searched Clinicaltrials.gov seeking for the literature resulted from finalized or ongoing clinical trials. However, all the references we identified from this search were already included in our database. As a result, we could not include any unpublished literature. This raises some concern for publication bias.

Comparison of Results With Prior Systematic Reviews

Most previous systematic reviews evaluating the efficacy, effectiveness, and safety of specific immunotherapy quantitatively pooled the data (meta-analyses). We did not pool data in this review because of the heterogeneity in the interventions across studies including types of allergen extracts, sources of extracts, allergen doses, and treatment duration, as well as heterogeneity in outcome scoring systems. Due to such heterogeneity, a recent review by Calderon et al. advised that results of meta-analyses be examined cautiously.184 In the absence of meta-analyses, our review focused on grading the strength of the evidence for the efficacy and effectiveness of specific immunotherapy.

Subcutaneous Immunotherapy

Traditionally, subcutaneous allergen immunotherapy for allergic rhinitis has been considered a “second line” or slow acting disease modifying treatment. In many cases, subcutaneous immunotherapy is reserved for those who do not respond to conventional therapy or do not wish to remain on medications. In a comparison of four meta-analyses, Matricardi et al. concluded that subcutaneous immunotherapy is at least as potent as pharmacotherapy in controlling symptoms as early as the first season of treatment.185 This study, however, did not conclude that subcutaneous immunotherapy is superior to pharmacotherapy. Another systematic review by Calderon et al., in the Cochrane database, reported that subcutaneous immunotherapy for seasonal allergic rhinitis results in a significant reduction in symptom scores and medication use with a low risk of adverse events.186 Our review parallels these findings in that we found high grade evidence that subcutaneous immunotherapy improves allergic rhinitis/rhinoconjunctivitis symptom scores. Furthermore, we found high grade evidence that subcutaneous immunotherapy improves other relevant allergic rhinitis/rhinoconjunctivitis outcomes, including combined nasal, ocular, and bronchial symptoms, combined asthma plus rhinitis/rhinoconjunctivitis medication use, and disease-specific quality of life.

In a recently updated systematic review of 88 asthma trials by Abramson et al., the investigators concluded that there was a significant reduction in asthma symptoms and asthma medications, as well as improvement in allergen specific bronchial hyper-reactivity following subcutaneous immunotherapy.28 There was also a modest reduction in nonspecific bronchial hyperreactivity, but no consistent effect on lung function.28 Not surprisingly, the investigators also observed significant heterogeneity between studies. 28 Our review was more restrictive in that we only included studies in which the diagnosis of asthma was confirmed using objective measures such as significant response to bronchodilator, positive bronchial provocation testing, or other previously established guidelines for the diagnosing asthma. We found 35 subcutaneous immunotherapy studies that met these criteria. We found similar results in that we found high grade evidence to support that subcutaneous immunotherapy improves asthma symptoms and asthma medication use. We also found consistent improvement in specific bronchial reactivity to allergens following subcutaneous immunotherapy.

Subcutaneous immunotherapy has served as routine treatment in children with allergic rhinitis with or without asthma. Prior systematic reviews evaluating the efficacy of subcutaneous immunotherapy have included pediatric studies, although few have exclusively focused on children. The Cochrane review by Calderon et al. reported significant reduction in seasonal allergic rhinitis symptoms and medication use with subcutaneous immunotherapy, but noted that among their 51 included studies, none were conducted exclusively in children.187 A systematic review, by Roder et al., reviewed immunotherapy for allergic rhinoconjunctivitis in children and adolescents and identified six subcutaneous immunotherapy studies in children which showed conflicting results for clinical efficacy.188 The recent meta-analysis by Abramson, et al, reported improvement in asthma symptoms, medication use, and improved bronchial hyper-reactivity and included multiple studies exclusively evaluating subcutaneous immunotherapy in children, although separate results for this subpopulation were not reported.28

Sublingual Immunotherapy

The first large systematic review of sublingual immunotherapy was reported in 2003189 and was updated in 2011.190 The recent update reported significant reductions in symptoms and medication use with sublingual immunotherapy, which is in agreement with our findings. Radulovic et al. noted the same issues with heterogeneity in scoring systems, safety data reporting, and dosing that we described. Their review also found no serious systemic reactions.

There have been other systematic reviews that focus on the efficacy of sublingual immunotherapy on a particular clinical outcome. A recent systematic review examined the efficacy of sublingual immunotherapy for treating allergic conjunctivitis.187 The authors concluded that sublingual immunotherapy was effective in reducing ocular symptoms of allergy. We found moderate strength grade evidence to support the use of sublingual immunotherapy in allergic conjunctivitis. Another review published in 2008 focused on the effect of sublingual immunotherapy in reducing symptoms of asthma.191 These authors concluded sublingual immunotherapy is beneficial for asthma treatment, but found the magnitude of effect was not large. Our findings are consistent, as we also concluded that sublingual immunotherapy is efficacious in treating asthma symptom. We found high grade evidence to support that sublingual immunotherapy improves asthma symptoms.

Other systematic reviews of sublingual immunotherapy have focused on a particular allergen. In 2009, Compalati performed a meta-analysis of the efficacy of dust mite sublingual immunotherapy,80 and concluded that symptoms were significantly reduced with use. Our systematic review found similar results, with 11 of 14 dust mite studies demonstrating statistically significant improvement in clinical outcomes. Grass allergen sublingual immunotherapy was the focus of a systematic review by Di Bona in 2010.192 These authors found grass allergen sublingual immunotherapy significantly reduced symptoms with a clinically modest benefit. Our review included 14 grass pollen/grass mix studies, with nine of 14 studies finding improvement in clinical outcomes.

Sublingual immunotherapy has been considered to be a favorable alternative to subcutaneous immunotherapy, especially for children, based on convenience and ease of administration without multiple injections.193 Calderon et al. pooled nine studies that included participants aged four to 17 years and showed significant reduction in allergic conjunctivitis symptoms in children treated with sublingual immunotherapy.187 Our study included 3 pediatric studies and concluded that there is low-strength evidence to support that sublingual immunotherapy reduces conjunctivitis symptoms.

Wilson et al. did a subgroup analysis with a small number of pediatric studies using sublingual immunotherapy for allergic rhinitis and did not find a significant treatment effect for symptoms of allergic rhinitis or medication use.189 In contrast, our systematic review included 12 pediatric studies evaluating rhinitis/rhinoconjunctivitis symptoms and we found high strength evidence that sublingual immunotherapy reduces rhinitis/rhinoconjunctivitis symptoms in children.

Sopo et al. evaluated the clinical efficacy of sublingual immunotherapy in children with respiratory allergies and systematically reviewed 8 studies.194 No significant clinical results were found using sublingual immunotherapy in children with respiratory allergies due to seasonal allergens or rhinoconjunctivitis due to house dust mites, although low to moderate clinical effects were found with the use of sublingual immunotherapy in children with mild to moderate persistent asthma due to house dust mites. In our study, high strength of evidence was found that sublingual immunotherapy reduces asthma symptoms and asthma combined with rhinitis/rhinoconjunctivitis symptoms in children and adolescents based upon 11 studies with 808 subjects.

Penagos et al. performed a meta-analysis of nine studies on the efficacy of sublingual immunotherapy in pediatric patients with allergic asthma and found significant reduction in asthma symptoms and medication use 195 Our study similarly found high strength of evidence for sublingual immunotherapy in children for reducing asthma symptoms, and moderate evidence for reduction of medication use. Olaguibel et al. also performed a meta-analysis with 7 studies on the efficacy of sublingual immunotherapy on asthma, rhinitis, and conjunctivitis symptoms in children with allergic rhinitis or asthma. They found statistically significant reductions in asthma and medication scores, but not for rhinitis or conjunctivitis symptoms, although decreasing trends were observed for all symptoms.196 Our study demonstrated moderate strength evidence in improving combination symptoms scores. They too found sublingual immunotherapy to be safe without any reports of severe or systemic reactions, with oral and gastrointestinal complaints as the most common side effects.

Future Research Needs

Additional RCTs are needed to examine the efficacy, effectiveness, and safety of SIT. These should be done with attention to the design elements that reduce bias, such as clear concealment of allocation and masking of the intervention throughout the study, to allow for more definitive conclusions. Future studies will benefit from standardized methods to report symptoms and symptom scoring, adverse events, and dosing quantity, frequency, and formulation. Published guidelines for allergen immunotherapy clinical trials recommend that the combined symptom-medication score be used as the primary outcome measure197; future studies should be encouraged to comply with these guidelines.198200

There is a specific need for studies investigating the efficacy and safety of multiple allergen regimens, as these are commonly used in the United States. There is increasing discussion in the scientific community on the clinical use and efficacy of single allergen versus multiple allergen therapy, and there are an insufficient number of studies which compare these head-to-head. Future studies are needed to directly compare the effectiveness of single allergen versus multiple allergen regimens for desensitization. On the other hand, studies restricting immunotherapy to a single allergen will allow for a greater understanding of a dose effect, dosing strategy effect, and effect of treatment duration on relevant clinical outcomes.

Studies including asthmatic subjects should clearly describe how subjects were diagnosed with asthma. Restricting asthma severity in studies to mild, moderate, or severe asthma would be helpful in assessing whether there is a subgroup of patients with asthma that may benefit from immunotherapy. Adequately powered trials with appropriate subgroups of patients and utilizing correct methodology are needed to address the efficacy and safety of allergen immunotherapy in specific subpopulations (such as pregnant women, monosensitized vs. polysensitized patients, severe asthmatics, urban vs. rural patients).

There is a need to document with future research that immunotherapy has a disease-modifying activity. Especially in the pediatric population, there is a need to determine if immunotherapy can prevent or modify the atopic march in children at high risk for allergic rhinitis and asthma. Additional considerations for pediatric studies include identifying the optimal age for initiation of immunotherapy and evaluating the differential effects of immunotherapy based on the developmental stage of children and adolescents.

Although our studies and others have found sublingual immunotherapy effective for improving symptoms of allergic rhinoconjunctivitis and asthma, there are several unanswered questions. The target maintenance dose, dosing strategies, and the necessary duration of treatment for sublingual immunotherapy with various allergens have not yet been fully determined.

Finally, there is a need for studies that directly compare sublingual to subcutaneous immunotherapy to strengthen this evidence base in children and adults. Future studies comparing subcutaneous to sublingual immunotherapy should use doses previously shown to be effective in earlier, high quality studies, and direct statistical comparisons between the outcomes of the two groups would be useful in regard to ensuring a fair comparison of the two therapies.