Medicine Section - Sublingual Immunotherapy as a Technique of Allergen Specific Therapy

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Allergen specific immunotherapy involves subcutaneously injecting well-characterized allergen extracts whose potencies are measured and compared with a reference standard. An initial induction or build up phase progressively increases the allergen dose; this is followed by multiple years of maintenance injections at the highest dose. Alternate routes of administration have been investigated, including most prominently sublingual immunotherapy (SLIT). SLIT targets absorption to the sublingual and buccal mucosa. Allergen preparations used for SLIT are held under the tongue for one to several minutes and then swallowed or spit out.

Policy/Criteria

Sublingual immunotherapy is considered investigational as a technique of allergy immunotherapy.

Position Summary

This policy is based on a 2003 TEC assessment of sublingual immunotherapy (SLIT) that offered the following observations and conclusions (2):

Studies of sublingual immunotherapy (SLIT) or subcutaneous injection of allergen-specific immunotherapy (ASIT) commonly measure allergic symptoms and use of rescue medications using quantitative scales. Double-blind, placebo-controlled randomized trials have reported attenuated allergic symptoms and reduced medication use after injection ASIT for various allergens. In addition, evidence shows that clinical benefits from multiple years of ASIT persist for several years after injections are discontinued. The TEC Assessment reviewed trials of SLIT if they were placebo-controlled or they directly compared SLIT with ASIT.

Twenty-one placebo-controlled clinical trials met selection criteria. Patient sample size was small in most of them. The predominance of evidence suggested that, when prepared in potencies similar to the available studies and compared with placebo, SLIT decreased one or more symptoms for patients with pollen or dust mite allergies. Systemic side effects occurred in only one study, and these were not life threatening. Evidence on whether SLIT may also reduce use of rescue medications was conflicting and inconclusive.

The established alternative to SLIT has been injection ASIT. Whether SLIT improves health outcomes when compared with injection ASIT could not be determined from the available evidence. The results of 2 trials that directly compared SLIT with injection ASIT were insufficient to permit conclusions. Patient groups in each trial were small (10-15 patients per arm), and each was of short duration. Neither trial followed up patients after immunotherapy was terminated, and thus neither trial speaks to the persistence of possible therapeutic effects.

2005 Update

A search of the literature was performed for the period of 2003 through May 2005. No additional published articles were identified that would prompt reconsideration of the policy statement, which remains unchanged. A number of randomized placebo-controlled trials were identified, (3-5) however, as noted in the 2003 TEC assessment, the relevant comparison group is the gold standard of injection ASIT. One controlled trial comparing SLIT with injection ASIT in 75 patients was identified. (6) This trial randomized patients to one of three groups, SLIT, ASIT or placebo. Thus there were only 25 patients in each group. There was no significant difference in the outcomes in either group. Therefore, the limitations noted in the TEC assessment remain and the policy statement is unchanged.

2006 Update

An updated search of the literature based on MEDLINE through May 2006 returned three new randomized trials of sublingual immunotherapy and a March 2006 Practice Parameter for food allergies from the American Academy of Allergy, Asthma and Immunology (AAAAI).  In a randomized, double-blind, placebo controlled trial, Enrique and colleagues randomly assigned 22 patients with hazelnut allergy to receive SLIT or placebo. (7) Outcome measures included double-blind food challenge test before and following two to three months of maintenance therapy.  In addition, IgE and serum cytokines were measured.  The oral food challenge test for patients in the active SLIT group showed significant improvement from baseline (p=0.02) while the placebo group showed a non-statistically significant improvement.  IgE levels did not differ significantly between groups following treatment.  The study demonstrated that in the short term, SLIT resulted in significant increases in the threshold sensitivity to hazelnut allergen.  The treatment was tolerated well.  What the study did not demonstrate is whether SLIT provides long term protection against hazelnut or other food allergies.  In another randomized, double-blinded, placebo-controlled trial, Sensi and colleagues randomly assigned 24 children with dust mite allergy to SLIT or placebo. (8) Placebo assigned patients were unblinded after one year and offered SLIT.  All patients received maintenance SLIT for at least 2 years.  During the third trimester of the first year when patients were still randomized, the rhinitis and medication scores were significantly lower in the active SLIT group versus the placebo SLIT group.  Asthma scores were not significantly different.  As patients completed two and three years of SLIT immunotherapy, their rhinitis, allergy and asthma scores improved significantly as well as the down-regulation of inflammatory markers (nasal and sputum eosinophils and nasal tryptase).  The study results merit further validation in a larger, randomized clinical trial with long term follow-up.  In a randomized, non-blinded, non-placebo-controlled trial, Marogna and colleagues compared SLIT plus standard medication management to standard medication management alone for the treatment of birch pollinosis. (9) Following three years of therapy the outcome measures in the SLIT group improved significantly.  However, this study was not blinded, had a significant number of drop-outs and did not conduct an intent-to-treat analysis.  Evidence on whether SLIT may reduce use of rescue medications remains conflicting and inconclusive.  None of the new studies reviewed for the 2006 update compared SLIT to ASIT; therefore conclusions concerning the effect of SLIT compared to the standard of care cannot be made.  Due to the above concerns, the policy criteria for SLIT are unchanged.

The 2006 AAAAI’s “Food Allergy: Practice Parameter” section on management of food allergy states that immunotherapy with food allergens has not been shown to be consistently effective or safe in the management of patients with food allergy. (10)

2007 Update

Literature search results performed through May 2007 did not change the policy statement.  Trials continue to be reported comparing sublingual immunotherapy with no treatment or to various dosages of sublingual immunotherapy.  Trials have still not been reported comparing SLIT to standard subcutaneous injection immunotherapy.  As noted above, these comparisons are needed to adequately evaluate SLIT.  A recent review also commented that there is no allergy extract approved for this use (by the FDA) in the United States. (11)

2008 Update

Nineteen non-US (17 European, 2 Asian) randomized placebo-controlled studies were identified, 8 of them in children. These studies report SLIT use for grass pollen, birch pollen, house dust mites, cat dander, and latex allergens in allergic rhinoconjunctivitis, atopic dermatitis, and asthma over a median of 9 months (range, 10 days to 3 years). Two meta-analyses related to asthma were published, one in children (12) and another in children and adults (13). A significant effect (using standardized mean difference) for symptoms (n=441) and medication use (n=366) was found in the analyses of SLIT use in children with asthma, although effect on medication use was driven by 2 studies. (12) Asthma parameters (n=876) showed small but significant improvements (using standardized mean difference) in the Cochrane meta-analysis of adults and children with asthma as well. (13) However, when just symptoms were analyzed (n=303), there was a non-significant improvement using SLIT over placebo. Only one direct comparison to ASIT was identified. (14) This was a 1-month, randomized, non-blinded trial of SLIT versus ASIT in 47 patients with birch allergy in which 34 patients (72%) completed the trial. No differences were noted in symptom and medication scores. Immunoglobulin levels were varied; they were not significantly different for IgE and were significantly increased for IgG4 for ASIT but not SLIT. Despite extensive study, questions regarding SLIT remain. These include optimal dosing, duration of treatment, and the use of multiple allergens, and, ideally, a comparison to ASIT and placebo.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.01.17
2. TEC Assessment: Sublingual Immunotherapy for Allergies. 2003, Tab 4
3. Bowen T, Greenbaum J Charbonneau Y et al. Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Ann Allergy Asthma Immunol 2004;93:425-30
4. Smith H, White P, Annila I et al. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol 2004;114:831-7
5. Bufe A, Ziegler-Kirbach E, Stoeckmann E et al. Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms; a double blind placebo-controlled study. Allergy 2004;59:498-504
6. Khinchi MS, Pouslen LK, Carat F et al. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double blind, double dummy study. Allergy 2004;59:45-53
7. Enrique E, Pineda F, Malek T et al. Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allerg Clin Immunol 2005;116:1073-9
8. Marcucci F, Sensi L, Di Cara C et al. Three-year follow-up of clinical and inflammation parameters in children undergoing sub-lingual immunotherapy. Ped Allerg Immunol 2005;16:519-526
9. Marogna M, Spadolini I, Massolo A et al. Clinical, functional, and immunologic effects of sublingual immunotherapy in birch pollinosis: A 3-year randomized controlled study. J Allerg Clin Immunol 2005;115:1184-8
10. Chapman JA, Bernstein IL, Lee RE et al. Food Allergy: a Practice Parameter. Ann All, Asthma, Immunol 2006;96:S1-S68
11. Cox LS, Linnemann DL, Nolte H et al. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 2006; 117(5):1021-35
12. Penagos M, Passalacqua G, Compalati E et al. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest 2008; 133(3): 599-609
13. Calamita Z, Saconato H, Pelá AB et al. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006; 61(10):1162-72
14. Mauro M, Russello M, Incorvaia C et al. Comparison of efficacy, safety and immunologic effects of subcutaneous and sublingual immunotherapy in birch pollinosis: a randomized study. Eur Ann Allergy Clin Immunol. 2007; 39(4):119-22

Cross References

Allergy Testing, Regence Medical Policy Manual, Laboratory, Policy No. 1

Diagnosis and Management of Idiopathic Environmental Intolerance, i.e., Clinical Ecology, Regence Medical Policy Manual, Medicine 37

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