Allergy Drops–Are We Closer to Getting Rid of Shots?

Wouldn’t it be nice to put some drops under your tongue and say goodbye to those painful shots for good?  Allergy treatment under the tongue (sublingual drops and now tablets) have actually been around for a long time.  Until recently, the science behind allergy drops has been lacking.  As you read this review, consider the following:

  1. At the present time, there are no products approved by the FDA for this type of therapy.  It is anticipated that products will be approved within the next 3-5 years, but don’t ever try to predict the FDA!
  2. Most allergy care in the US uses multiple allergens in preparation for allergy shots.  This means a combination of trees, grasses, weeds, molds, dust, cat, dog, and sometimes cockroach. How many of you would be satisfied using only grass pollen or dust mite in your allergy treatment?
  3. Oh, the pain of shots!  There are now high frequency vibrational devices that take the pain out of shots right on the spot.  Ask our nurses to help you try it out.  This might make shots easier to tolerate.
  4. I don’t usually include references in my posts, but there’s only 25; the list is very inclusive for a complete up-to-date review of studies in the United States.
  5. I’ve copied the authors introduction, and conclusions for your review.   I enjoy reading future predictions and we’ll have to see how accurate this is. 

Adult and Pediatric Clinical Trials of Sublingual Immunotherapy in the USA

Dai Park, Nora Daher, Michael S Blaiss. Expert Rev Clin Immunol. 2012;8(6):557-564.

Specific allergen immunotherapy has been practiced for allergic rhinoconjunctivitis for over 100 years and is the only treatment option that is disease modifying. In the USA, immunotherapy is usually administered via subcutaneous injection; this is the only route with a US FDA-approved formulation. There is growing interest in developing US-standardized formulations for the sublingual route, but up until recently there have been few US trials. Most of the experience with sublingual immunotherapy (SLIT) comes from Europe, where it is widely used and there is a large body of literature supporting its use. The purpose of this review is to summarize recent adult and pediatric clinical trials of SLIT in the USA. Most of the trials are for inhalant allergies, but there is some early work on SLIT as a novel therapy for food allergies.


Presently, only subcutaneous immunotherapy is approved by the US FDA for inhalant and stinging insect allergies in the USA. Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is being viewed with increased interest by US allergists as an alternative to subcutaneous immunotherapy.

The first published double-blind, placebo-controlled, randomized clinical trial (DBPC-RCT) with inhalant SLIT came from London, UK in 1986.[1] This was followed by numerous studies from Europe in the last two decades, which confirmed the efficacy and safety of SLIT.[2] Some novel studies include the first DBPC-RCT on allergoid SLIT tablets in 1998[3] and the first DBPC-RCT of SLIT successfully treating atopic dermatitis in dust mite-sensitized children.[4]

Important work has also gone into elucidating the underlying mechanism of SLIT. The current thought is that tolerogenicity is induced by oral dendritic cells, which reside on the uppermost layers of oral tissue and in the context of SLIT, capture allergen and produce IL-10 and IL-12 cytokines. This thereby promotes a tolerogenic pathway and a T-cell shift from a Th2 to a Th1 and Treg phenotype. Treg cells further propagate the Th1 pathway by producing IL-10 and TGF-β that negatively feedback on Th2 cytokines and subsequently cause a decrease in IgE levels and an increase in IgG4 levels.[5]

In the USA, there was early work performed on SLIT for cat allergy in 1993;[6] however, this aside, there were no other published DBPC-RCTs until the past few years. Renewed interest may be, in part, due to the advent of two SLIT grass pollen tablets – Grazax®[7,8] and Oralair®,[9] approved for use in Europe in the late 2000s. These SLIT tablets are currently undergoing trials in the USA. Here we review those and other recent US clinical trials for inhalant and food SLIT.

Expert Review & Five-year View

SLIT has been demonstrated in US studies to be efficacious and safe in the limited number of allergens evaluated so far. Hopefully this will lead to FDA approval for this treatment in the near future. It appears from the studies discussed that SLIT by tablet will have a higher likelihood of FDA approval compared with SLIT drops. We should see the development of other common allergens in tablet form for SLIT, including dust mites, tree pollen and cat hair over the next several years. Studies will need to be performed to determine if mixed unrelated allergens given together by the SLIT method will demonstrate clinical efficacy and safety. We may likely see further studies looking at the disease-modifying aspects of SLIT and whether early treatment with SLIT in children at risk for allergy and asthma may prevent their development. Food studies will continue to assess the role of SLIT versus OIT that will hopefully lead to better and safer means of inducing desensitization and tolerance to improve the lives of the increasing growing population of people with food allergy in the USA.

  1. Scadding GK, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite. Clin. Allergy 16(5), 483–491(1986).
  2. Cox LS, Larenas Linnemann D, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: a comprehensive review. J. Allergy Clin. Immunol. 117(5), 1021–1035(2006).
    • A detailed, comprehensive review on Sublingual immunotherapy (SLIT) worldwide and discusses unmet needs.
  3. Passalacqua G, Albano M, Fregonese L et al. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Lancet 351(9103), 629–632(1998).
  4. 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. 120(1), 164–170(2007).
  5. Moingeon P, Mascarell L. Induction of tolerance via the sublingual route: mechanisms and applications. Clin. Dev. Immunol. 2012, 623474(2012).
  6. Nelson HS, Oppenheimer J, Vatsia GA, Buchmeier A. A double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized cat extract. J. Allergy Clin. Immunol. 92(2), 229–236(1993).
  7. Durham SR, Emminger W, Kapp A et al. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J. Allergy Clin. Immunol. 129(3), 717–725.e5(2012).
    • Shows that the grass SLIT tablet, Grazax®, has a sustained disease modifying effect.
  8. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J. Allergy Clin. Immunol. 117(4), 802–809(2006).
  9. Didier A, Worm M, Horak F et al. Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis. J. Allergy Clin. Immunol. 128(3), 559–566(2011).
    • Shows that the grass SLIT tablet, Oralair™, has a sustained disease modifying effect.
  10. Esch RE, Bush RK, Peden D, Lockey RF. Sublingual-oral administration of standardized allergenic extracts: Phase 1 safety and dosing results. Ann. Allergy Asthma Immunol. 100(5), 475–481(2008).
  11. Skoner D, Gentile D, Bush R, Fasano MB, McLaughlin A, Esch RE. Sublingual immunotherapy in patients with allergic rhinoconjunctivitis caused by ragweed pollen. J. Allergy Clin. Immunol. 125(3), 660–6, 666.e1-e666.e4.(2010).
  12. Bush RK, Swenson C, Fahlberg B et al. House dust mite sublingual immunotherapy: results of a US trial. J. Allergy Clin. Immunol. 127(4), 974–81.e1(2011).
  13. Amar SM, Harbeck RJ, Sills M, Silveira LJ, O’Brien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J. Allergy Clin. Immunol. 124(1), 150–156.e1–e5(2009).
  14. Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J. Allergy Clin. Immunol. 127(1), 72–80, 80.e1(2011).
    •• The first study to demonstrate efficacy of grass SLIT tablet in US adults.
  15. Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. J. Allergy Clin. Immunol. 127(1), 64–71, 71.e1(2011).
    •• The first study to demonstrate efficacy of grass SLIT tablet in US children.
  16. Bufe A, Eberle P, Franke-Beckmann E et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J. Allergy Clin. Immunol. 123(1), 167–173.e7(2009).
  17. Cox L, Casale TB, Nayak A et al. A US study of 5-grass pollen allergen extract in adults with grass pollen-induced allergic rhinoconjunctivitis – results of secondary efficacy assessments. J. Allergy Clin. Immunol. 129(2), (Abstract AB46) (2012).
  18. Cox L, Casale T, Nayak A et al. Efficacy and safety of sublingual 300IR 5-grass pollen tablets in adult patients with grass-pollen rhinoconjunctivitis in United States. J. Allergy Clin. Immunol. 127(2), (Abstract AB74) (2011).
  19. Berman G, Nolte H, Maloney J et al. Ragweed allergy immunotherapy tablet reduces nasal and ocular symptoms of allergic rhinoconjunctivitis over the peak ragweed pollen season in North America. J. Allergy Clin. Immunol. 129(2), (Abstract AB249) (2012).
  20. Maloney J, Nolte H, Nekam K et al. Dose-related effects of ragweed allergy immunotherapy tablet on nasal and ocular symptoms of allergic rhinoconjunctivitis during the peak ragweed pollen seasons in Europe and North America. J. Allergy Clin. Immunol. 129(2), (Abstract AB47) (2012).
  21. Nolte H, Maloney J, Bernstein D et al. Efficacy and tolerability of a novel ragweed allergen immunotherapy tablet during peak season in North American and European patients. J. Allergy Clin. Immunol. 129(2), (Abstract AB143) (2012).
  22. Kim EH, Bird JA, Kulis M et al. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J. Allergy Clin. Immunol. 127(3), 640–6.e1(2011).
    • This is the first study to demonstrate efficacy of peanut SLIT in US children.
  23. Narisety SD, Keet C, Guerrerio P et al. A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J. Allergy Clin Immunol. 129(2), (Abstract AB27) (2012).
  24. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J. Allergy Clin. Immunol. 129(2), 448–55, 455.e1(2012).
    • This is the first study to compare the efficacy of oral immunotherapy versus SLIT for cow’s milk allergy in children.
  25. Seopaul S, Keet CA, Frischmeyer-Guerrerio PA et al. Prolonged exposure to sublingual immunotherapy improves safety of oral immunotherapy. J. Allergy Clin. Immunol.129(2), (Abstract AB126) (2012).
  26. Website
    101. A service of the U.S. National Institutes of Health.

#slit, #sublingual-immunotherapy

Can I Prevent an Allergy Shot Reaction?

Risk Factors for Systemic Reactions to Allergen Immunotherapy

Alfredo Iglesias-Cadarso; Pilar Hernández-Weigand

Purpose of review To update safety information regarding allergen-specific immunotherapy (ASIT) in clinical practice and highlight the risk factors associated with the adverse reactions, product and each dose.
Recent findings Efforts in recent years have focused on increasing our understanding of the efficacy and safety of ASIT, especially the sublingual variety (SLIT), in multicenter studies. Moreover, new Clinical Practice Guidelines (CPGs) and an international consensus concerning ASIT have been published recently. Although no deaths as a result of subcutaneous immunotherapy or SLIT have been reported in the last 2 years, systemic reactions mainly arising from administration errors still appear. Recent studies support the safety of new forms of specific immunotherapy.
Summary An understanding of the risk factors for each patient, product and dose, and the implementation of CPGs are the main factors that could improve the safety of ASIT. The standardization of all procedures for prescribing and administering ASIT, and the systematic collection of standardized safety data in a multicenter database (postmarketing surveillance), may be required to generate new information on the safety of ASIT.

Why Do We Even Care About Safety of Allergy Shots?

Allergen-specific immunotherapy (ASIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), has been shown to be effective for the treatment of allergic respiratory disease in randomized controlled trials and meta-analyses.  Indeed, SCIT is the treatment of choice for preventing anaphylaxis in patients with systemic reactions to hymenoptera (bee stings).

The greatest drawback to the more widespread use of ASIT is the associated risk of severe side-effects, as the dose which has been shown to be well tolerated and effective in a group of patients may not be so for a specific patient. Here again, everyone is different and what may be the best dose for one patient, may cause an adverse reaction for someone else.

Systemic reactions are those which produce symptoms and signs far from the administration site. They may be immediate systemic reaction (ISR), appearing in the first 30 min postadministration, or delayed systemic reaction (DSR), occurring after the first 30 min, with the former tending to be more severe.

The incidence of systemic reactions has been estimated at between 1 and 34% of patients and around 0.2–0.3% of doses, depending on the type of study, patient, diagnosis, extract or treatment scheme.  

Historical reviews of ASIT-related mortalityhighlighted severe or poorly controlled asthma and administration errors as the main causes of fatal systemic reactions. These findings led to the drafting of Clinical Practice Guidelines (CPGs) for ASIT treatment,and their subsequent updates, in the 1990s. Adherence to such guidelines is the main reason behind the reduced frequency and severity of systemic reactions in the past 20 years. The statistics regarding mortality and systemic reactions prior to these CPGs are no longer applicable.

Let’s look at some individual factors that increase your chances of a systemic reaction to an allergy shot!

  • What do you put in my serum? No specific allergen is currently thought to produce higher mortality or a greater chance of a large local reaction.
  • Very few fatal reactions to pure hymenoptera venom immunotherapy (VIT) have been reported. Indeed, several studieshave found a lower incidence of systemic reactions with hymenoptera vaccines, with bee vaccines being tolerated worse than wasp vaccines.
  • Systemic reactions appear to be more frequent when aqueous extracts are used.  This is presumably due to the fact that the allergen is absorbed very quickly after it’s injected.

Dose-related Risk Factors

  • Administration errors are the main identifiable and avoidable cause of ASIT-related systemic reactions, including SLIT. (SLIT is the oral allergy drops)
  • Any delay in the treatment of a systemic reaction increases its severity. This is why I instruct my nurses to give epinephrine first, then call.
  • Although CPGs provide recommendations to avoid such errors, they continue to occur with a greater than expected frequency. 
  • I could write a book on the types of errors that occur with the dose of allergy shots.  Would this be a best-seller or what?
  • Research has shown that a large local reaction does not predict the occurance of a more severe systemic reaction; a concept that can be difficult to grasp for patients.  (see below)

Dosing Scheme

In the case of SCIT with airborne allergens, the use of fast regimens (rush and cluster) has been associated with a higher number of systemic reactions, although more recent studies have shown their safety to be similar to that of conventional schemes. Patients tend to like the rapid schedule because they can avoid the prolonged build-up of conventional treatment. 

Omalizumab (Xolair) has been used to reduce the systemic reaction incidence in patients receiving SCIT with inhaled allergens and VIT (venom shots),  with good results.

It is possible, but not confirmed, that systemic reactions increase during the pollen season, but patients generally do not decrease their dose at this time.

Prior Reactions

Together with poorly controlled asthma, the presence of a prior systemic reaction during AIT is the main risk factor associated with a new systemic reaction. 

There is currently no evidence that the dose adjustments recommended in clinical guidelines reduce recurrent systemic reaction in a patient.

Premedication with antihistamines or omalizumab has been shown to be useful in some studies, although such treatment is not recommended as standard.

Local reactions do not predict the appearance of a systemic reaction, although some studies have suggested them to be a risk factor.  The dose adjustments subsequent to major local reactions recommended in the clinical guidelines do not reduce the frequency of future systemic reactions. For additional information regarding the safety of allergy shots, refer to the reference below:

  • Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127:S1-S55.
    •• Latest and extended update of the Joint Task Force (AAAAI-ACAAI) on Practice Parameters concerning all aspects of allergen-specific immunotherapy.

#adverse-drug-reaction, #allergen-immunotherapy, #allergy, #clinical-trial, #health, #immunotherapy, #scit, #slit, #sublingual-immunotherapy, #symbiosis-centre-for-information-technology

Best Immunotherapy for Allergic Rhinitis and Asthma?: Conclusion & Future Perspective

I didn’t think that all of you wanted to read the full article so here’s the link for the “brainiacs” in the group! Comparing drops to shots!

Conclusion & Future Perspective

The  clinical efficacy of SCIT (typical shots)  is well established for both rhinitis and asthma.  SLIT (sublingual drops) has also been validated in regards to rhinitis and asthma.   Two recent meta-analyses in children showed that sublingual delivery of allergen vaccination constitutes a safe and effective alternative to the injectable route to reduce allergic respiratory symptoms and drug intake.  Assessment of possible long-term benefits, including long-term disease remissions, suppression of new allergic sensitizations, and reduction of progression from rhinitis to asthma in children, as has been shown for the subcutaneous route, are future requirements for “proof” of benefits for sublingual drops. 

The immunological effects of SLIT and how these relate to clinical efficacy are yet incompletely understood. Large-scale trials have confirmed the induction of allergen-specific IgG antibodies to be dose dependent. There is no early suppression of allergen-specific IgE antibodies and a transient early increase in specific IgE antibodies as in SCIT.

Current models of SCIT propose the induction of antigen-specific Tregs (cell type in the body), which then orchestrate the observed antibody and mucosal changes observed during treatment. As of yet there is only scarce evidence that such mechanisms operate during SLIT. Comparative clinical studies of sublingual and subcutaneous treatment yielded heterogeneous results demonstrating efficacy of both modes, but SLIT to be a safer approach.

In conclusion, understanding of the interaction of allergen and antigen-presenting cells within the oral mucosa may allow improved targeting of SLIT vaccines. In the near future the combination of allergen products with adjuvants may improve efficacy of immunotherapy via the sublingual route.

So here’s the bottom line:

  • Sublingual drops are not yet approved by the FDA and I can’t bill insurance for the product like allergists now do for subQ shots. 
  • Why not use Rapid immunotherapy to achieve maintenance in ONE month, followed by MONTHLY shots instead of weekly?  With this method, you get the best of both worlds–good, proven benefits at a convenient dosing schedule. 
  • Sublingual drops have to be given multiple days per week and compliance isn’t all that impressive. 

This issue isn’t going away, so stay tuned!

#allergen, #allergy, #clinical-trial, #food-and-drug-administration, #immunoglobulin-e, #slit, #sublingual-immunotherapy, #symbiosis-centre-for-information-technology