Sublingual Immunotherapy

Sublingual Immunotherapy (SLIT)

 

I have been getting a number of questions about SLIT. This has prompted me to offer a few words on the subject.

 

Immunotherapy for the treatment of allergic disease has mostly been through allergen immunotherapy (aka allergy shots). These are injections under the skin. The injections contain the items that the patient has demonstrated sensitivity towards and was deemed clinically relevant to their condition. The clinical indications for subcutaneous (SQ) allergen immunotherapy are allergic rhinitis, stage 2-4 asthma in patients > 5 years of age, and life-threatening reactions to stinging insects (add urticaria in the adult). This form of therapy is not indicated for hives, atopic dermatitis, or food allergy.

 

Other approaches to immunotherapy have been around for many years. One of these forms of immunotherapy is the use of drops of allergens given orally or sublingual immunotherapy (SLIT).

 

An even more advanced form of immunotherapy is the use of injected anti-IgE for the treatment of moderate to severe asthma. This is a humanized mouse monoclonal antibody directed against IgE, the molecule that mediates allergic reactions.

 

This discussion will focus on oral or sublingual immunotherapy.

 

This form of treatment has been the focus of renewed popularity. Its use is expanding in Europe for the treatment of aeroallergen induced conditions. The specific indications are asthma and allergic rhinitis. It has also become more popular here in the United States- for better or for worse.

 

Sublingual immunotherapy in Europe was in part a response to find a less hazardous method of allergy treatment. Due to increase mortality/morbidity from allergy shots it was recommended that the injections would be given in a hospital setting with up to a 3 hour wait afterwards. This is to make sure that there were no life-threatening reactions to the injection. The taking allergen-drops may be safer and less time-consuming. In this country, we do not have that constraint of location and waiting time for conventional allergen immunotherapy.

 

Currently, research studies are underway using oral immunotherapy for the treatment of specific food allergies especially for peanut, egg, and milk. The product(s) used for the treatment of food allergy and the protocols are not at this time available/approved for clinical practice. The hopes and prayers are that they will be available soon; however there is nothing that is now commercially purchasable or FDA approved for the treatment of food allergy by the use of the oral route of administration. The same holds true for the use of sublingual (oral) immunotherapy for other allergic conditions.

 

There are numerous studies from Europe that demonstrate the efficacy of these programs. Practitioners have taken these studies to either vindicate current practices or to introduce new therapies. They may very well work in select patients and that is great however there are concerns.

 

The research performed in Europe has been done in a very homogeneous (genetic make-up) population of people. It this country we tend to be very heterogeneous- a great mix of genes. It is well known that allergic people in Europe are very different from allergic people here in this country. In Europe individuals tend to be more mono-sensitive- that is sensitive to just one thing. Here it is a rarity to find sensitivity to a single allergen. The sensitivities are to many different allergens according to the skin test reports and to the specific IgE determined by blood testing. The point is that the patients used for studies in Europe may not be representative of patients here. Be careful when comparing populations and their biological responses.

 

Also consider what products were used in the studies for treatment and we need to ask whether or not the same products are available here.

 

The conclusions of a study are valid for the study population, living in a specific environment, having specific exposures, and given a specific manufactured product. Care must be taken in extending the conclusions beyond the limits of the defined study population. A study needs to be done here in this country to make sure the program works, is cost-effective and above all- it is safe in our population.

 

I reviewed the topic of sublingual immunotherapy for a presentation on immunotherapy for asthma. This is what was in the literature regarding SLIT:

  •           1999 21 citations
  •           2004 58 citations
  •           2005 179 citations

There has been significant interest in this decade.

 

A Task Force from the American Academy of Allergy, Asthma, and Immunology (AAAAI) was convened to study this form of therapy for respiratory allergy- allergic rhinitis and asthma. In addition to the report of the task force a meta-analysis was  published last year(2008) on sublingual immunotherapy.

 

The Task Force found only 16 articles that fit the criteria of a valid (good) study. These 16 studies were randomized, controlled and double-blinded. A randomized-controlled-double-blinded study with the appropriate number of patients would be looked at as the optimal way to study a question. To be included in the Task Force review, the study had to define the allergen used, the dose, the inclusion criteria for the study and the outcomes. To qualify as a good study there had to be at least 45 patients. Almost all of the publications were from Europe.

 

The following are features of the review

  • Delivery method- swallowed or spit out
  • Amount- <50% reported in mcg the major allergen used
  • Dose (per injection) – 6/10,000 (0.0006) to 21 times the injected dose
  • Dose (per month) – 0.017 to 500 times a monthly injected dose
  • Frequency- optimal frequency not established- daily or weekly
  • Duration of treatment- 2 months to 5 years
  • Timing- preseason, co-season, pre and co-season, or perennially

Summary- for ragweed as an example, the amount of allergen provided varied in the studies from 0.3 mcg to 9,000 mcg per month. There was a 30,000 fold variation in the dose given either daily or weekly from 2 months to 5 years on the program. That is a huge range in what was shown to be an effective dose. Imagine if that was the dosing range for an antibiotic.

 

As far as the outcomes were concerned, one study showed a decrease in symptom scores for asthma in the second year of treatment for house dust mites.

 

The Task Force concluded

  • Many unanswered question- dose, schedule, timing, mechanism, safety
  • Unable to provide a cost/benefit analysis
  • No CPT code for this treatment (billing purposes)
  • No FDA approved product for SLIT
  • Need for specific instructions for home-based treatment
  • Need for guidance for patient adherence
  • Need for guidance on adverse effects from treatment

 

A ‘meta-analysis’ takes another approach to evaluating the studies on SLIT. This technique brings all the qualifying studies together to increase the total number of patients which helps with finding significant changes in a population under study. A meta-analysis on SLIT for children with asthma was published in 2008. There were 73 published articles that qualified for a review. From this group, only 9 studies fulfilled the selection criteria for the analysis. From these 9 studies there were 441 patients of whom 232 were on SLIT and 209 were given placebo. There was a reduction in symptoms and in medication. Five studies all of which used the house dust mite SLIT had a change in symptom score. Two studies that used house dust mite SLIT had a change for medication usage.

From a meta-analysis it was only house dust mites SLIT that had an effect.

 

Recommendations-

If SLIT is suggest as a form of therapy for your allergic condition you may want to ask a few things.

  • 1. What is the condition for which this treatment is recommended?
  • 2. What is going to be used? What proteins/allergens? Are they relevant to the condition?
  • 3. Where do the extracts come from? Who made them and how?
  • 4. Are these the same materials used in the SLIT studies? Are we comparing apples to apples or are we assuming equal efficacy of a product?
  • 5. How much will be used? What is the protein content of the extract?
  • 6. How often will it be used?
  • 7. How long is the program?
  • 8. What can I (my child) expect from this program (outcomes)?
  • 9. When should we see an effect?
  • 10. Is there any evidence that this particular allergen given as SLIT has worked?
  • 11. Is there any evidence that combinations of SLIT allergens work?
  • 12. Have studies for efficacy and safety been performed in children (related to the age of the child).
  • 13. Will this be covered by insurance? If not, why not?
  • 14. Is it safe? If done at home, what is needed for a reaction?

 

I am skeptical, especially when I look at the literature on this topic (SLIT for respiratory illness).

I am hopeful that this mode of allergen delivery will help with severe food allergy. Just be careful when this therapeutic option is considered. Look at the evidence and ask the questions. SLIT is intriguing. It may be stimulating the protective antibody IgA which coats all of our mucus membranes. I think it is investigational at this time. I await good studies done on our population with a standardization of protocol. Also consider, if you undertake this program as an experiment then I would figure you should be paid for your participation in the experiment and not have to pay for it yourself. Think about it.

In my opinion,

Fred Leickly