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Sublingual Immunotherapy - Is There a Role?

Is the US Ready for Sublingual Immunotherapy?


Linda Cox, MD

Linda Cox, MD runs a solo adult and pediatric allergy and immunology practice in Ft. Lauderdale, Florida and is assistant clinical professor of medicine at University of Miami School of Medicine and Nova Southeastern University School of Osteopathic Medicine. She is a past president of the Broward County Medical Association and of the Florida Allergy Asthma and Immunology Society. Dr Cox has been chair of the American Academy of Allergy, Asthma and Immunology's immunotherapy and allergy diagnostics committee since 2004, and is the current chair of the American College of Allergy, Asthma and Immunology's immunotherapy and diagnostic committee. Dr. Cox chaired the AAAAI/ACAAI Task Force on Sublingual Immunotherapy which recently completed a comprehensive review of the literature on sublingual immunotherapy, and which will be submitted for publication in the near future. Dr Cox is also ch air of the AAAAI's Rhinitis, Sinusitis and Ocular Diseases (RSOD) Interest Section , in which capacity she has been actively assisting with the planning of the 2006 Annual Meeting.

Abstract

Introduction
Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is being viewed with increased interest by US allergists. In light of this the ACAAI and AAAAI Immunotherapy & Allergy Diagnostics Committees formed a Joint Task Force with the purpose of providing a comprehensive updated report on SLIT for the North American allergy community. Members of the SLIT task force include academic and community-based allergists. The information in this paper is derived from the Joint Task Force's report. In addition, due to the 'speculative' nature of the presentation - "Is the US ready for sublingual immunotherapy" some of the research information was obtained through personal communications.

The SLIT Task Force reviewed 103 articles with references through October 2005. The committee was divided into work groups that reviewed dosing, efficacy, immunologic response, safety, and practical considerations. Each work group reviewed each of the articles and extracted those articles that were relevant to their section. The focus of this presentation will be on practical considerations related to implementing SLIT in the US, focusing on issues such as costs, safety and adherence. There will also be some discussion of the other topics reviewed because they impact considerably on the practical consideration issues.

Sublingual Immunotherapy in the US
 In parts of Europe sublingual is the predominant route of immunotherapy but in the US, aside from growing interest, SLIT has not received widespread acceptance. This is possibly because it has been associated with a low-dose form of immunotherapy called provocation-neutralization, discussed in the "Immunotherapy procedures that have not been proven effective" section of the "Immunotherapy for aeroallergen disease" chapter or the "Unconventional and unproven theories" chapter in Middleton's Allergy textbook. (1)

An application for a new CPT code (new category 3 - emerging technology) for sublingual immunotherapy extract preparation in mid-2003 prompted the JCAAI to contact the ACAAI and AAAAI Immunotherapy Committees for comments, and subsequently lead to the development of an ACAAI and AAAAI SLIT Joint Task Force in early 2004 (Jay Portnoy and Linda Cox co-chairs, Hal Nelson, Larry Borish, Bob Lanier and Ira Finegold) which was assigned the task of working with AAOA, representing the otolaryngology allergy community, to write guidelines for studies to properly validate SLIT in the USA.

The Task Force felt no action was needed until an FDA approved formulation for SLIT was developed. At around the same time the AAAAI Immunotherapy Committee discussed SLIT in a conference call and came up with the following 'questions to be answered' as well as a similar decision that no action was needed until an FDA approved formulation for SLIT was developed.

In November of 2004, Greer Laboratories (Lenoir, NC) began a safety and dosing study of standardized allergenic extracts/vaccines administered by the sublingual-oral route with the intent to obtain FDA approval for a SLIT formulation. At this time the ACAAI and AAAAI Immunotherapy and Allergy Diagnostics Committees began the Joint Task Force comprehensive review project.

SLIT Costs: How much will the treatment cost, who will pay for it and how much are they (insurers, patients and/or government) willing to pay?

Allergen dosing
It is difficult to predict the likely cost of SLIT without having a clear concept of what dose and dosing frequency is required to achieve optimal efficacy. In the SLIT Joint Task Force review the dosing regimens varied from daily to once weekly. The individual sublingual allergen doses varied between 10 ng Fel d 1 (2) and 314 mcg Amb b 1 (3) per dose and cumulative monthly doses (CMD) between 0.017 and more than 500 times the customary subcutaneous maintenance dose recommended by the Joint Task Force Allergen Immunotherapy Practice Parameters (JTFAIPP) and the WHO Position Paper on Al­lergen Immunotherapy (4, 5).

The optimal maintenance dosing frequency of SLIT has not been established. Dosing regimens varied from daily (2, 3, 6-16), three times a week (17), twice weekly (18) to once weekly. (19) One 4-year open study of various allergens compared one drop daily (6 mcg Der p 1 CMD) with 5 drops 3 times a week (13 mcg Der p 1 CMD), and demonstrated that the daily lower dose regimen resulted in a greater magnitude of decrease in skin prick end-point titration reactivity (0<.001), a higher rate of no drug use (p = .013) and at least 50% reduction in drug consumption compared with pretreatment use (p = .001). (7)

Another study compared 3 dosing regimens with an open control group. There were two pre- and co-seasonal regimens. The higher dose administered was 0.4 mcg major grass allergen daily (12 mcg CMD) while the lower dose administered was 0.3 mcg 3 times week (5.1 mcg CMD) (20). In addition, there was one pre-seasonal regimen. There was a significant improvement in symptoms and drug intake in all SLIT groups compared with the open control group (p < .0001). The best clinical results were seen in the 2 pre- and co-seasonal regimens (p= < .0001) with greater improvement in drug intake scores (p = .026), paradoxically, in the 3 times a week regimen with the lower cumulative maintenance dose.

Only two randomized-controlled (RC) studies were specifically designed to compare the response to different doses. (6, 21). One randomized-controlled study compared 2 maintenance dose regimens administering 85 and 375 times the usual SCIT dose, (24 drops of 300 IR vs. 40 drops of 100 IR per week) and found greater improvement in symptom- medication scores in the higher dose group (p = .024)(21). The other dose response study was a randomized, placebo controlled multi-center, multi-country study of 855 patient with grass-induced allergic rhinitis who were treated with either placebo or one of 3 treatment doses ( 2,500 , 25,000 and 75,000 SQ-T units of P hleum pratense ) daily for a mean duration of 18 weeks. (6) There was a significant improvement in medication and symptoms scores only in the highest dose treatment group, 75,000 SQ-T (equivalent to 15 mcg Phl p 5 or a cumulative monthly dose 22.5 times that recommended by the same company for SCIT).

Table 1

855 patients with seasonal allergic rhinitis treated with one of three sublingual doses of Phleum pratense or placebo tablets for mean duration of 18 weeks (6) P value versus placebo

Treatment group

Medication Scores

Symptoms Scores

2,500 SQ-T (~0.5 mcg Phl p 5)

P = .38

P = .96

25,000 SQ-T (~ 5 mcg Phl p 5)

P = .96

P = .46

75,000 SQ-T (~15 mcg Phl p 5)

Reduced by 28% (p = .047)

Reduced by 16% (p = .0071)

If only pts treated with 75,000 SQ-T for at least 8 weeks were considered:

Reduced by 29% (p = .012)

Reduced by 21% (p = .002)

How much will the treatment cost?
In the above study as an example, the effective SLIT dose was equivalent to 15 mcg of major grass allergen administered daily which is in the 5 to 20 mcg range recommended for maintenance subcutaneous immunotherapy (SCIT). Using this dose and schedule, the ALK-Abello January 15 2006 list price for standardized grass (the company that sponsored the study) was used, and the recommended maintenance dose for standardized grass is 8000 BAU per dose (5).

Standardized grass 100,000 BAU/ml $89.90 US per 10 ml = $8.9/ml
4,000 BAU = $0.359 US per dose x 30 days = $10.78 per month

In comparison with SCIT, the maintenance cost for the allergen extract (CPT code 95165) would be $0.359 per dose if administered on a monthly basis with greater costs during the build-up phase. SCIT would have the additional administration fee cost (~ 95115 single injection, 95117 multiple injection- ~ $14- $20–reimbursement varies by location and insurer)

Polysensitized patients: Virtually all of the studies reviewed by the SLIT Joint Task Force utilized single allergen and none employed non-cross reacting allergens. Polysensitized patients appear to be 'the rule' rather than the exception in the US. A 3 year prospective open study of polysensitized patients designed to evaluate the efficacy of SLIT treatment with multiple pollen allergens demonstrated significant improvement in medication and symptom scores compared with baseline. (Personal communication Martin Kagi, MD Zurich, Switzerland).

Adding dust mite and cat sensitivity to the above example, and using the same catalogue for list price:

Cat 10,000 BAU/ml = $127.0 per 10 ml = $12.7/ml
2000 BAU (2000-3000 BAU recommended maintenance dose)5 = $2.5 per dose x 30 days= $ 76.2 per month
Dust mite: 10,000 AU/ml = $126.0 per 10 ml = $12.6 /ml
2600 AU (600 AU D. pteronssinus. 2000 AU D. farinae recommended maintenance dose)5 = $3.2 per dose x 30 days= $98.28 per month

Total SLIT extract cost for a cat, dust mite and grass allergic patient in the above example would be: $185.26 per month or $2223.12 per year.

In comparison, SCIT costs:
Build-up phase: ~28 dose increments (JTFAIPP sample build-up) x $20 (95117 for administration)= $560 plus $172.9 (95165 extract preparation): Total= $732 for build-up phase ~ 6 months
Maintenance: monthly administration: $20 (95117 for administration) + $6.17 (95165 extract)= $26.17 per month

The above example is only speculative and based on the one placebo-controlled dose response SLIT study's dose and schedule as well as the current list price for the company (ALK-Abello) who sponsored the study.

Who will pay for it?
Currently there is no CPT code for sublingual immunotherapy. Definition of immunotherapy from the The American Medical Association's Current Procedural Terminology 2005 manual (CPT) (22):

"Immunotherapy (densitization, hyposensitization) is defined as the parenteral administration of allergenic extracts as antigens at periodic intervals, usually on an increasing dosage scale to a dosage which is maintained as maintenance therapy. Indications for immunotherapy are determined by appropriate diagnostic procedures coordinated with clinical judgment and knowledge of the natural history of allergic diseases.

The CPT code 95165 used to bill for preparation of antigens for allergen immunotherapy is defined as: "Professional services for the supervision of preparation and provision of antigens for allergen immunotherapy single or multiple antigens (specify number of doses)" and included in the group of codes (95115-95199) which are described as “professional services necessary for allergen immunotherapy." (22).

Considering the CPT definition of immunotherapy as the "parenteral administration of allergenic extracts", it can be inferred that the 95165 CPT code is intended for preparation of allergen extracts that will be administered by means of the parenteral route. Some insurers will reimburse for SLIT utilizing a CPT for unlisted services (see below Kansas BCBS Blue Shield Report excerpt):

How much are they (insurers, patients and/or government) willing to pay?
Current state of US health care: Health care coverage purchased by employers with little input from consumers/patients/employees. The concept of managed care providing 'complete medical coverage' from hospital bills to prescription medication is waning and health care is moving toward health savings accounts and "consumer directed health care" ( Donald Fisher June 25, 2005 Allergy Partners Annual meeting). This translates into patients who will have a greater say in health care decisions as well as more responsibility for their health care costs. With patients determining how their health care dollars are spent, factors such as time/convenience, one of the advantages of SLIT, may become more important. On the other hand, the increased treatment costs may make SLIT too costly for individuals in lower incomes or on ‘tighter' budgets.

Safety
The US has been struggling with a medical malpractice 'crisis' for several years. In response to the crisis many physicians practice 'defensive' medicine reluctant to take any risks in patient treatment including new or novel treatments. SLIT would represent a novel form of immunotherapy. It is generally administered in the home setting, which accounts for its greater convenience compared with SCIT. However, the home setting does not have trained personel and equipment available to assess, treat and document adverse reactions.

Below is an excerpt from a response to questions regarding potential SLIT liability issues.

"Regarding your question on allergist liability in connection with home administration of SLIT, malpractice liability requires a showing of negligence and negligence is usually measured against either the standard of care of what a reasonably prudent physician would do. So if the allergist had met the standard of practice in preparation of the SLIT and had provided the patient with proper instructions and given informed consent, then the allergist would generally not be liable. But in the case of a new therapy, where the standard of practice is not yet established, it might be hard for the allergist to demonstrate that they had acted consistent with accepted standard of care. Sorry not to be more concrete - this is always a fact specific determination. Certainly risk is minimized by properly informing the patient and documenting it." (Personal communication, Rebecca Burke for JCAAI)

In the SLIT Joint Task Force review there were 66 sublingual immunotherapy studies utilizing unmodified allergen extracts that provided some information about SLIT-related adverse events.

Table 2: Sublingual Immunotherapy Serious Adverse Reactions:

In 58 studies, 3,984 patients treated with a total of 1,019,826 doses in 58 studies there were 14 probably SLIT-related serious adverse events

Author

Number of SAE patients

Details

Calderon (21)

1

1 mild uvula edema hospitalized for observation in the highest dose group (~ 15 mcg Phl p 5)

Fiocchi (23)

1

Severe (4/4) vomiting

Gozalo (28)

1

1 severe asthma: treatment beta- agonist and systemic steroids

Grosclaude (26)

2

2 persistent asthma

Hirsch (25)

1

One drop-out because of worsening of asthma and generalized weakness for weeks with 1 episode of severe bronchial obstruction.

Mitsch (24)

3

Severe abdominal pain when SLIT was taken with antibiotics. (1x)

'Severe' worsening of their allergy (2x)

Pradalier (16)

1

Generalized urticaria for 48 hours

Rolinck-Werninghaus (17)

1

Asthmatic crisis requiring hospitalization

Tari (29)

3

Severe Asthma (3)

Lima (11)

2

Motorbike accident

Epiglottitis

Total number of SAE

16 (allergy-SAE: 14)

 

Total of asthma exacerbations

8

 

Total doses given

1,019,826

Allergy SAE: 1.4/100,000 doses

Total treatment years

5,377

1 allergic SAE per 384 treatment years

Number of patients

3,984

1 SAE per 249 patients

Only allergy exacerbations SAE

14

1 treatment related allergic SAE per 285 pts

1 asthma exacerbation per 498 patients

Safety in very young children:

JTFAIPP Summary statement 53: Children < 5 years of age may have difficulty cooperating with an immunotherapy program ( refers to SCIT ). Therefore the physician should carefully consider the benefits and risks of immunotherapy and individualize treatment in patients < 5 years of age. (A)

One of the other purported advantages of SLIT over SCIT is greater safety. Currently in the US, SCIT is generally not initiated in children < 5 years. The greater safety of SLIT may make allergen immunotherapy a feasible option for this age population.

In the SLIT Task Force review there were two observational and one post-marketing survey SLIT studies specifically designed to assess safety of SLIT in young children. (23, 30, 31 ). In the first study, thirty-three children with intermittent (12 patients)  or mild persistent (17 patients) asthma or persistent rhinitis (33 patients),  aged 1 year 11 months to 3 years 10 months (mean 3 years 2 months) were treated with a monomeric allergoid (Lofarma,various allergens, 4 drops of 3000 AU/ml daily) (30). The mean follow-up was 22.3 months and approximately 22,200 doses were administered. Two children experienced one episode of abdominal pain (5% of patients; 0.071% per 1000 doses). One was mild and the other was characterized as moderate, requiring a temporary dose adjustment. The parents' assessment in 21 children was highly improved, moderately improved in nine, slightly improved in nine and unchanged in two children.

In the second study, sixty-five children aged 38-80 months (mean ± SD, 60 ± 10 months) were treated with SLIT to various pollens or dust mite for a mean 246 ±161 days. (23) The target maintenance dose was 300 IR three times a week (“300 times higher than standard dose recommended” with SCIT). The investigators compared two subgroups: 38-60 months (33 pts, 52 ± 6 months) and 61 to 80 months (32 patients, 70 ± 10.6 months). There were six AEs (4 urticaria, 1 gastrointestinal and 1 orolabial itch) in five (15%) patients in the younger group and seven AEs (2 urticaria, 3 gastrointestinal, and 2 orolabial itch) in six (18%) patients in the older group. Six AEs occurred during the build-up phase and 7 in the maintenance phase. The severity of the AEs ranged from mild to moderate and none resulted in discontinuation of treatment.

The third study was a post-marketing survey of 126 children aged 3 to 5 years (mean age 4.2 years) with allergic rhinitis and/or asthma treated for 2 years with SLIT to various allergens. (31) Side-effects were recorded by the parents in diary cards. The total number of doses was 39,000. Nine side effects were reported in seven children (5.6% of patients and 0.2 per 1000 doses). All side-effects occurred during the induction phase. There were two local (oral itching) side-effects that required no treatment. There were 7 systemic reactions: One was an episode of mild abdominal pain that did not require treatment. The remaining six cases were moderate abdominal pain with diarrhea, which were controlled by a dose reduction achieved by changing the SLIT method from sublingual-swallow to sublingual-spit.

Adherence
Another factor to consider with SLIT is how adherence will be monitored. Adherence can potentially impact the efficacy and safety of the treatment. Insurers considering reimbursement for SLIT have expressed concern about the former (personal communication Tracy Woody, Greer Laboratories ) whereas prescribing physicians should consider both safety and efficacy and the patient's likely adherence with this home-based treatment.

Few of the studies reviewed provided information about treatment adherence. Only one multi-center, observational study was specifically designed to provide a quantitative measure of SLIT adherence. (32) Eighty-six patients with allergic rhinitis and/or asthma prescribed SLIT for a single relevant allergen (41 HDM, 45 pollens) were treated with a monomeric allergoid prepared as a soluble tablet for a mean of 18 ± 2 weeks (pollen) or one year (HDM). Adherence was assessed through unscheduled telephone interviews after one year of treatment for HDM treated patients or at the beginning of the pollen season for the pollen treated group. During the interview, patients were asked to count the remaining tablets. The count of the taken/expected tablets was 5,080/5,248 (96.8 %) in the HDM group and 3,952/4,050 (97.6%) in the pollen group. Omitted doses were reported in 11 patients with most postponing 1-2 doses because of concurrent illness or forgetfulness. One patient skipped multiple doses due to work schedule. In a randomized 4 year open study of 511 patients with allergic rhinitis and/or asthma to various allergens adherence was assessed by measuring with a pipette the remaining volume of extract in the returned vials and comparing it with the amount expected to be consumed during a given treatment period. (33) At the end of the observational year 311 patients were randomized to the SLIT group and 192 patients to the medication only group. Adherence to SLIT over the 3-year period was excellent (>80%) in 195 out of 271 (72%) patients, good (from 60 to 80%) in 49 out of 271 (18%) patients and poor or insufficient in 27 out of 271 (10%) of patients.

Since this treatment is administered at home with no direct medical supervision, prescribing physicians would need to provide specific instructions on how to manage adverse reactions, unplanned treatment interruptions, situations in which the dose should be withheld and dosing adjustments for any or all of these variables. In addition to assessing a patient's likely adherence to SLIT, physicians should consider the patient's ability to follow these instructions before prescribing this treatment.

Is the US ready for sublingual immunotherapy?
 What questions, raised by the AAAAI Immunotherapy and Allergy Diagnostic Committee 2003 conference call have been answered?

Sublingual immunotherapy reference list

  1. Middleton E, Reed C, Ellis E et al Allergy principles and practice. Fourth edition Mosby 1993
  2. Sanchez Palacios A, Schamann F, Garcia JA Sublingual immunotherapy with cat epithelial extract. Personal experience. Allergol Immunopathol (Madr) 2001; 29: 60-65.
  3. Bowen T, Greenbaum J, Charbonneau, et al. Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Ann Allergy Asthma Immunol 2004; 93: 425-430 and Andre C, Vatrinet C, Galvain S, Carat F, Sicard H. Safety of sublingual-swallow immunotherapy in children and adults. Int Arch Allergy Immunol. 2000 Mar;121(3):229-34.
  4. Bousquet J, Lockey RF, Malling H-J eds. WHO Position Paper. Al­lergen Immunotherapy: Therapeutic Vaccines for Allergic Diseases. Allergy 1998; 53 (suppl. 44):1–42.
  5. Li JT, Lockey RF, Bernstein IL et al Allergen Immunotherapy: A Practice Parameter. Annals of Allergy, Asthma & Immunology. 2003; 90 (suppl )
  6. Calderón M A , Rak S, Durham S R. Grass Pollen Tablets for Sublingual Immunotherapy in seasonal allergic rhinitis. Abstract AAAAI 2005 meeting
  7. Bordignon V, Parmiani S.Variation of the skin end-point in patients treated with sublingual specific immunotherapy. J Investig Allergol Clin Immunol. 2003;13(3):170-6.
  8. 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
  9. Casanovas M, Guerra F, Moreno C, et al. Double-blind, placebo-controlled clinical trial of preseasonal treatment with allergenic extracts of Olea europaea pollen administered sublingually. J Invest Allergol Clin Immunol. 1994; 4: 305-314.
  10. Clavel R, Bousquet J, Andre C. Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardized five-grass-pollen extract in rhinitis. Allergy 1998; 53: 493-498.
  11. Lima M, Wilson D, Pitkin L, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 2002; 32: 507-514.
  12. Passalacqua G, Albano M, Riccio A, et al. Clinical and immunologic effects of a rush sublingual immuno-therapy to Parietaria species: A double-blind, placebo-controlled trial. J Allergy Clin Immunol. 1999 Nov;104(5):964-8
  13. Sambugaro R, Puccinelli P, Burastero SE, et al. The efficacy of sublingual immunotherapy for respiratory allergy is not affected by different dosage regimens in the induction phase. Allergol Immunopathol (Madr) 2003; 31: 329-337.
  14. Tonnel AB , Scherpereel A, Douay B, et al. Allergic rhinitis due to house dust mites: evaluation of the efficacy of specific sublingual immunotherapy. Allergy 2004; 59: 491-497.
  15. Vourdas D, Syrigou E, Potamianou P, et al. Double-blind, placebo controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization. Allergy 1998; 53: 662-672.
  16. Pradalier A, Basset D, Claudel A, et al. Sublingual-swallow immunotherapy (SLIT) with a standardized five-grass-pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy 1999; 54: 819-828.
  17. Rolinck-Werninghaus C, Wolf H, Liebke C, et al. A prospective, randomized, double-blind, placebo-controlled multicentre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen. Allergy 2004; 59: 1285-1294.
  18. Bahceciler NN, Arikan C, Taylor A, et al. Impact of sublingual immunotherapy on specific antibody levels in asthmatic children allergic to house dust mites. Int Arch Allergy Immunol 2005; 136: 287-294.
  19. Lombardi C, Gargioni S, Venturi S, et al. Controlled study of preseasonal immunotherapy with grass pollen extract in tablets: effect on bronchial hyperreactivity J Investig Allergol Clin Immunol 2001; 11: 41-45
  20. Di Rienzo V, Puccinelli P, Frati F, Parmiani S. Grass pollen specific sublingual/swallow immunotherapy in children: open-controlled comparison among different treatment protocols . Allergol Immunopathol (Madr) 1999; 27: 145-151.
  21. Marcucci F, Sensi L, DiCara G, et al. Dose dependence of immunological response to sublingual immunotherapy. Allergy 2005; 60: 952-956
  22. American Medical Association Current Procedural Terminology CPT 2005 standard edition, AMA. Canonica GW, Compalati E, Fumagalli F, Passalacqua G. Sublingual and oral immunotherapy. Immunol Allergy Clin N Am 2004: (25) 685-704
  23. Fiocchi A, Pajno G, Grutta S. Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol 2005; 95: 254-358
  24. Mitsch A, Drachenberg KJ. Positive results in a primary multicentric study, specific immunotherapy administered sublingually. TW Padiatrie 1996; 9: 628-631
  25. Hirsch T, Sahn M, Loupold W. Double-blind placebo-controlled study of sublingual immunotherapy with house dust mite extract (D. pt.) in children. Pediatr Allergy Immunol 1997; 8: 21 -27.
  26. Grosclaude M, Bouillot P, Alt R, et al. Safety of various dosage regimens during induction of sublingual immunotherapy. A preliminary study. Int Arch Allergy Immunol 2002; 129: 248-253
  27. Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double blind study. Allergol et Immunopathol. 1990; 18: 277-284.
  28. Gozalo F, Martin S, Rico P, et al. Clinical efficacy and tolerance of two year Lolium perenne sublingual immunotherapy. Allergol et Immunopathol 1997; 25: 219-227 .
  29. Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double blind study. Allergol et Immunopathol. 1990; 18: 277-284
  30. Agostinis F, Tellarini L, Canonica GW, et al. Safety of sublingual immunotherapy with a monomeric allergoid in very young children. Allergy 2005; 60: 133.
  31. Di Rienzo V, Minelli M, Musarra Post-marketing survey of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy 2005; 35:560-564
  32. Lombardi C, Gani F, Landi M, et al. Quantitative assessment of the adherence to sublingual immunotherapy. J Allergy Clin Immunol 2004; 113: 1219-1220.
  33. Marogna M, Spadolini I, Massalo A, et al. Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real life: clinical efficacy and more. Allergy 2004; 59: 1205-1210


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