Clinical Information & Research

The following clinical information is designed for educational purposes only and is used to help educate our potential providers (non-allergy physicians) on building clinical knowledge regarding our low-dose semi-custom Compounded Sublingual Immunotherapy vaccine for long term efficacy and immune modulation.   

Click Here to jump to Clinical Studies listed below.

General Summary: Desensitization

The best argument in favor of allergy testing is that once the offending allergen is identified, a specific treatment such as desensitization immunotherapy can be given to induce immune tolerance, reduce IgE antibody production, and provide long term (if not permanent) relief from allergies without further need for allergy medications.

Common Terminology & Therapy Fundamentals

Immunotherapy Synonyms 
Desensitization, Tolerance, Systemic Immunotherapy (SIT), Hyposensitization, Allergy Vaccination, Sublingual Immunotherapy (SLIT) [a.k.a. Allergy Drops], Subcutaneous Immunotherapy (SCIT) [a.k.a. Allergy Shots].

Three specific treatments for the allergic patient:
  1. Symptomatic Therapy: Medication although useful, will only suppress symptoms but do little to modify the long-term disease process (Does not provide immune modulation). 6.7 billion dollar market/year market. Examples would be anti-histamine (8.8% effective), nasal steroid sprays (18.8% effective), nasal decongestant, steroid shot. This treatment all by itself will never modulate the immune system, can cause side effects, and can be expensive.
  2. Allergen Avoidance (food) and Allergy Trigger Reduction: As allergies play such a significant role in triggering allergic rhinitis and asthma, it makes sense to try allergen avoidance measures as a first-line prevention strategy. To be a successful intervention, however, it is important to create a low allergen environment in patients’ homes, and, unfortunately, the majority of single interventions have failed to achieve a sufficient reduction in allergen load to lead to a clinical improvement. Almost all current asthma and rhinitis guidelines advocate allergen avoidance, but avoidance only applies to exposure patients can CONTROL (example – indoor antigen exposure to dust mites, cockroach, animal dander, molds, fungi). Exposure to outdoor seasonal allergens is all but impossible to avoid without wearing a breathing filter (mask). Avoidance is also only effective once allergen triggers are identified. This leads to the question: How can one be told what allergens to avoid if the allergens responsible for the allergy symptoms have been identified? This is the reason for allergy testing (blood or skin) in the office. Once triggers have been identified, patients are given possible lifestyle modulations that can decrease possible exposure to help reduce overall inflammation below the patient’s symptom threshold.

     

  3. Allergen Systemic ImmunoTherapy (SIT): Given either orally (SLIT) or by injection (SCIT). When one considers the expense of long term allergy medication, immunotherapy must be viewed as a cost-effective treatment option and long term tolerance/resistance/elimination of allergy symptoms.
 
How immunotherapy works at a cellular level?

The exact immuno-modulatory mechanism by which desensitization immunotherapy switches off allergies is uncertain. It was hypothesised that specific “IgE blocking” antibodies were produced, as during successful immunotherapy an initial increase in specific IgE was followed by an IgE fall and compensatory rise in IgG (a blocking antibody). Researchers then postulated that specific IgG4 antibodies where induced towards the offending allergen. An associated reduction in mucosal mast cell numbers and a decrease in antigen-induced eosinophil migration to the site of inflammation are noted during immunotherapy. The latest “hot” hypothesis is that immunotherapy modulates the T-helper cells, causing switching from predominantly TH2 (IgE inducing) to predominantly TH1 (IgG inducing) subsets and as a result of this, allergen IgE count drops with successful immunotherapy.


Who will benefit from allergen immunotherapy?
Allergen immunotherapy should only be considered to treat type I IgE-mediated allergy that has been confirmed either by allergen skin prick testing or radio- allergosorbent testing (Finger-stick IgE-Blood-Drop Cards). Another equally important consideration is whether the patient is likely to be compliant and adhere to this regular treatment regime for three years. The ideal candidate is a severely allergic person who is unable to avoid the offending allergen in daily life and in whom drug therapy has failed to control the allergy or in whom drug side-effects have become intolerable or have lowered the quality of life for the patient. The patient must be carefully evaluated to determine whether the severity of the disease justifies this kind of treatment by balancing the relative benefits, risks, cost and inconvenience of immunotherapy versus drug therapy.
 
Immunotherapy Options: SCIT vs SLIT

Traditional immunotherapy (SCIT), although successful in improving symptoms, is inconvenient, expensive and painful. For that reason, there has been a great deal of interest in delivering immunotherapy via non-traditional routes such as sublingual (oral) or nasal mucosa. There is increasing evidence that both traditional and non-traditional immunotherapy results in the immediate and long-term improvement of symptoms.

Here are the basics of each therapy.
 
SCIT: Injection immunotherapy – Procedure of Choice by Allergy Specialists
 
The injections should be given in the presence of a doctor and because of the anaphylaxis risk to a patient, resuscitation equipment must always be available with adrenaline 1:1000, 0,5ml drawn up ready for injection. At each visit, the patient should be assessed for any intercurrent febrile illnesses, sudden increased exposure to the allergen or any delayed adverse reaction to the last injection. If there has been a problem, the next dose may need to be modified or omitted. The manufacturers dose schedule for each extract should be regarded as a guideline, and frequently will have to be modified in the light of events occurring during the course of treatment.
The injection of allergen extract is given subcutaneously into the outer portion of the upper arm once a week. Always use a one milliliter finely calibrated syringe and first draw back on the syringe so as to prevent intravenous injection. Dosage starts at 20SQ Units and usually increases to a maintenance dose of 100 000 SQ Units.
 
The injection dose is doubled weekly until a state of tolerance to the allergen is achieved, (maintenance usually occurs at 15 weeks). Grass pollen immunotherapy should be commenced pre-seasonally to so as to reach the maintenance dose before the pollen season starts. Thereafter maintenance injections are given 4 to 6-weekly for a period of 3 years to complete the immune modulating process. During the grass pollen season, allergists usually reduce the maintenance dose by 25%. If an injection is missed the next dose may need to be proportionally reduced. The patient should be observed for at least one hour after each injection to ensure an adverse reaction does not occur. All forms of sport, exercise, alcohol and hot baths should be avoided for 6 – 8 hours afterwards as the increased blood circulation could precipitate an anaphylactic reaction. Contact with the relevant allergens immediately after the injection should be avoided as this may also trigger an adverse reaction. Changing from one injection vaccine manufacturer to another should be done with extreme caution and we usually recommend a temporary reduction in dosage over the transition period.
 
Common Adverse Reactions to SCIT (anaphylaxis risk)
 
Most adverse reactions to subcutaneous immunotherapy are attributed to errors in dosage and timing. Special care should therefore be taken to ensure that the patient receives the correct dose at the correct time. Adverse reactions are most likely to occur during the initial induction phase of immunotherapy. Non-specific reactions such as excessive tiredness and headache are quite often reported but of no clinical significance. However, dizziness, itching and repeated clearing of the throat often precedes a systemic reaction. The routine use of “pre-med” antihistamines before immunotherapy should be discouraged as they will suppress an immediate adverse reaction but the patient may then go on to have a delayed systemic reaction later on (at home!).
 
If a small local reaction (less than 5cm diameter of swelling) occurs, continue the schedule as normal. If a larger area of swelling (greater than 5cm) occurs, then treat with an oral anti-histamine and maintain the same dose at the next injection. A mild systemic reaction is indicated by intense itching, erythema, rhinitis, localized edema and is treated by antihistamines and a stepwise reduction of the next dose. A more severe systemic reaction includes; laryngeal edema and respiratory distress and is promptly treated with intra-muscular adrenaline 1:1000 0,5ml solution. The adrenaline injection may need to be repeated after 5 minutes if no improvement occurs. Oxygen and intravenous fluids may need to be administered with intravenous hydrocortisone 200mg and antihistamines in the case of generalized anaphylaxis. A tourniquet can be applied to the limb above the site of allergen injection and a further injection of adrenaline given to the allergen injection site will delay further absorption of allergen. If these severe reactions occur, the desensitization immunotherapy program should possibly be abandoned.
 
NOTE: These risks are found only in SCIT. They are not recognized with SLIT.
 
So the key question to ask is why would clinicians still treat with a potential lethal therapy (allergy shots) for a disease that is not deadly…especially when there is a safer, more convenient, more compliant and therefore more effective route of therapy.
 

SLIT: Sublingual Immunotherapy – Procedure of Choice by Non-Allergists & ENT

The procedure is very safe and far less likely than injection immunotherapy to cause any adverse reaction (SLIT side-effects include headache and oral itching). In 1996, The World Health Organization considers SLIT as “a viable alternative to allergy shots.”…but why doesn’t anyone else out (in the U.S.) there know about it?

Drops: An oral allergy treatment administered in drops under the tongue is a safe and effective alternative to injections for adults who are allergic to environmental seasonal inhalant allergens (pollens from trees, weeds, grass) and common indoor environmental inhalants (molds, fungi, animals dander and insects). Widely used in Europe, but not yet approved by the U.S. Food and Drug Administration, sublingual allergen immunotherapy (SLIT) can be a more convenient and tolerable treatment approach that leads to greater patient compliance.

The sublingual method has a superior safety profile over allergy shots (no known records of anaphylaxis or fatalities in Europe or the US), and the adherence rate (compliance) has been tracked as being 90% because no injections are involved and the, vaccine is administered at home (more convenient), and costs only $70 per month out of pocket. In Europe, SLIT represents the majority of new IT prescriptions, and its use has also been increasing in the United States

This treatment involves taking a numbered drop (AllergywoRx drops are a 30-day dose of weekly increasing dosage drops and a monthly increase of antigen concentration) containing the proprietary semi-specific allergen mixture under the tongue on a daily basis for 2 minutes per dose to induce immune tolerance. SLIT negates the need for distressing injections and the one hour wait after the injection in the allergy clinic, as well as the additional costs associated with driving to and from the allergists office every week. These drops can safely be administered at home.
Results from extensive clinical studies on SLIT have been very encouraging but patient commitment is essential and the drops must be taken every day for a minimum of 12 months to derive maximal benefit.

Tablet: Grazax oral tablet desensitization immunotherapy is now available for adults in the UK as a treatment for grass pollen induced hayfever and allergic rhino-conjunctivitis. Each tablet contains an extract of Timothy Grass (Phleum Pratense) 75000SQ-T. The first dose must be administered under the supervision of a medical doctor (with 20-30 minutes observation), and all subsequent doses can safely be taken at home. The treatment involves taking one tablet daily and allowing it to dissolve under the tongue over one minute before swallowing. Treatment should commence 2 months before the grass pollen season and continued throughout the grass pollen season for maximal benefit. The treatment is stopped in the autumn/winter and then recommence 2 months prior to each subsequent grass pollen season. The only drawback is cost – each tablets cost well over $60 per month, and ONLY treats for grass allergies.

 
Outcome & benefits of successful immunotherapy

The success of injection immunotherapy is dependent on the patient receiving regular injections (COMPLIANCE) of the highest tolerated dose of the biologically standardized vaccine for at least 3-7 years for injection therapy (and weekly office visits), or 1-2 years for drop therapy. Only limited knowledge exists about the optimal duration of immunotherapy and the duration of the therapeutic response achieved and it varies from patient to patient based on the number and severity of the allergic sensitivity.

Successful immunotherapy program will reduce the severity of an allergic disorder, improve the quality of life of allergy sufferer and diminish the risk and cost of pharmacotherapy. The ideal end point to signify successful immunotherapy is a negative skin prick test or a significant fall in allergen specific IgE to negligible levels.

Unfortunately, only a minority of patients will achieve this end point (due to lack of compliance from allergy shots at 25-30%) despite the procedure producing a good clinical and symptomatic response. In Europe, immunotherapy via allergy drops (with a 90% compliance) is a popular adjunct to allergy shots and anti-allergy pharmacotherapy and is often used to augment asthma treatment.

As with any therapy, patient compliance is key to a successful outcome. Studies show that sublingual and subcutaneous therapy are both equally efficacious, so then it comes down to convenience (the more convenient the therapy is, the more compliant the patient will be), cost (affordability of therapy), safety (risk vs benefit) and effectiveness (better patient outcomes).

FDA Response to SLIT

Why would FDA approve SCIT for use in the US when SCIT has a proven record of causing near- death or actual fatalities while SLIT has a proven recorded occurrences fatalities or near-death events? The truth is that according to new FDA guidelines, SLIT is considered an “off-label use of prescribed medication”. This occurrence happens daily in a primary care setting when a drug with intended use is prescribed for another use.

However, that is NOT the case when discussing SLIT since the intended use of which the medication was made is still intended to treat allergies and asthma. The difference here is the “application” of the medication. The manufacturers of SCIT raw materials are the same manufacturers of the SCIT materials because the raw materials are the same antigens. The only different is SCIT administration is done through a needle (that has a known history of causing anaphylaxis and death), and SLIT is dropped under the tongue for a slower absorption rate (which has no history of anaphylaxis or death). Let me close by saying this: where does a patient suffering from a heart attack put the dissolvable pill of nitroglycerine? Under the tongue! Why? Its a rapid and safe administration of therapy.

Clinical Studies

Allergen-Specific Immunotherapy for Pediatric Asthma and Rhinoconjunctivitis: A Systematic Review
Pediatrics: Official Journal of the American Academy of Pediatrics, 2013

Evidence supports the effectiveness of both SCIT and SLIT for remediation of asthma and hay fever in pediatric patients.

 

Sublingual Immunotherapy for Allergic Rhinitis and Conjunctivitis
Immunotherapy, 2013

SLIT has shown dependable efficacy in minimizing symptoms and allergy drug usage in allergic rhinitis and likely in concurring asthma for all related antigens. Further, due to the complex mechanism of action, SLIT significantly alters the immune reaction, thus, its effects endure long-term. Additionally, SLIT,* as well as SCIT, ** can lessen the chances for asthma in pediatric allergic rhinitis sufferers. According to this finding, SLIT is affirmed as an operable substitute for SCIT in the remediation of allergic rhinoconjunctivitis, with a very positive safety record and the plausibility of extending its usage to additional diseases.

 

Mechanisms of Allergen-Specific Immunotherapy: Multiple Suppressor Factors at Work in Immune Tolerance to Allergens
Journal of Allergy and Clinical Immunology, 2014

This study confirms the efficacy of both sublingual immunotherapy and subcutaneous immunotherapy in changing the immune response.

 

Efficacy of Sublingual Immunotherapy Versus Subcutaneous Injection Immunotherapy in Allergic Patients
Journal of Environmental and Public Health, 2012

These findings indicate that SCIT and SLIT demonstrate similar effectiveness. SLIT empirically betters symptom scores for asthma and hay fever while reducing the need for allergy drugs. With the heightened risks and challenges in treating asthmatic patients and children, these outcomes imply that SLIT should be regarded as the first-line treatment option for these patients, considering allergy shots for low-responders only.

 

Quality of Life Improvement with Sublingual Immunotherapy: A Prospective Study of Efficacy
Journal of Allergy, 2012

Statistically appreciable relief of symptoms and heightened quality of life are demonstrated during the first four months of sublingual immunotherapy treatment.  Reduced symptom scores sustain or continue to reduce after this time frame.

 

Allergen Immunotherapy in Allergic Respiratory Disease: From Mechanisms to Meta-Analyses
Chest Journal: Official Publication of the American College of Chest Physicians, 2012

Sublingual immunotherapy is well-accepted by patients with only limited side effects in some patients (slight mouth itching or swelling).  We are aware of just six cases of anaphylactic reaction that have ever occurred in reaction to SLIT.  Additionally, a  financial analysis of SLIT vs. pharmacotherapy for environmental allergens shows SLIT to be cost-efficient.

 

High-Dose Sublingual Immunotherapy with Single-Dose Aqueous Grass Pollen Extract in Children is Effective and Safe: A Double-Blind, Placebo-Controlled Study
Journal of Allergy and Clinical Immunology, 2012

This research affirmed that this usage of sublingual immunotherapy markedly lowered symptoms and medication usage in pediatric patients who had a history of allergies to grass pollen.   SLIT had substantial influence on allergen-specific antibodies, and the therapy was well-tolerated by children. Overall, SLIT appeared to be a viable treatment alternative in children with grass pollen allergies.

 

A Prospective Study on the Safety of Sublingual Immunotherapy in Pregnancy
Allergy, 2012

SLIT can be safely used in the course of pregnancy.  Additionally, it is safe to start a pregnant woman on SLIT, even if she is using the therapy for the first time.

 

The Current Role of Sublingual Immunotherapy in the Treatment of Allergic Rhinitis in Adults and Children
Journal of Asthma and Allergy, 2011

SLIT is supported by substantial research affirming its potency and safety.  In some parts of Europe, the treatment is prescribed more frequently than subcutaneous immunotherapy.  In addition to having a more favorable safety profile than SCIT, sublingual immunotherapy has also been shown to have higher compliance rates because it does not need to be taken under medical supervision.  It has also been shown to be more cost-efficient because patients do not have to pay for the administration of shots.

 

Sublingual Immunotherapy in Allergic Rhinitis
Asia Pacific Allergy, 2011

In Europe, sublingual immunotherapy is frequently used instead of subcutaneous immunotherapy due to several benefits:  it is not as invasive as shots, it does not need to be taken under physician supervision, and it has a higher safety profile.  In 2008, the British Society for Allergy and Clinical Immunology affirmed sublingual immunotherapy  as a safe option for allergic rhinitis and asthma, and in 2009, the World Allergy Organization Position Paper about SLIT highlighted its potency and safety.

 

Safety of Sublingual Immunotherapy
Journal of Biological Regulators and Homeostatic Agents, 2011

Sublingual immunotherapy is established as an accepted alternative to traditional shot therapy and is broadly used in European healthcare. Sublingual treatment is especially appealing for kids since it is painless.   There are no deaths linked to sublingual immunotherapy, and while two instances of anaphylactic reaction have been linked to it, adverse reactions to SLIT have been classified as mild.

 

Sublingual Immunotherapy for Allergic Rhinitis
Cochrane Database of Systematic Reviews, 2010

Sublingual immunotherapy is a safe remediation which substantially lessens symptoms and the need for medications in hay fever sufferers.

 

Sublingual Immunotherapy: Clinical Indications in the WAO-SLIT Position Paper
World Allergy Organization Journal, 2010

Sublingual immunotherapy is indicated in the care of hay fever for both adult and pediatric patients.   In children, SLIT may prevent the onset and progression of asthma. Sublingual immunotherapy is also indicated for asthma that is linked to rhinitis,  whereas it is not the primary treatment option for remediation of isolated asthma. SLIT is deemed to be safe for home administration (though the first dose should be given in a clinical setting).

 

Undertreatment of Allergy: Exploring the Utility of Sublingual Immunotherapy
Otolaryngology-Head and Neck Surgery, 2009

Traditional subcutaneous immunotherapy (SCIT or allergy shots) is effective but has also been linked to serious negative effects, must be given under medical supervision, and is not recommended for certain groups of people. On the other hand, sublingual immunotherapy is used throughout Europe, offering most of the advantages of immunotherapy and also heightened safety, patient acceptance, and convenience. This overview examines findings from a collection of clinical research and concludes that SLIT may be a fitting choice to help remedy the undertreatment of allergies in the U.S.

 

Comparison of Sublingual Immunotherapy vs. Inhaled Budesonide in Patients (PDF)
Annals of Allergy, Asthma and Immunology, 2009

This study examines people whose asthma is triggered by grass pollens.  Over time, sublingual immunotherapy was just as effectual as inhaled budesonide in treating asthma symptoms and offered a further advantage in addressing rhinitis and bronchial hyper-responsiveness.

 

Meta-analysis of the Efficacy of Sublingual Immunotherapy in the Treatment of Allergic Asthma in Pediatric Patients
Chest Journal: Official Publication of the American College of Chest Physicians, 2008

Sublingual immunotherapy with standardized allergenic extracts decreases symptoms as well as drug requirements in pediatric patients  allergy-related asthma.

 

The Safety of Sublingual Immunotherapy with one or Multiple Pollen Allergens in Children
Allergy, 2008

The use of an increased number of antigens for sublingual immunotherapy does not increase side effects in children.

 

Preventive Effects of Sublingual Immunotherapy in Childhood
Annals of Allergy, Asthma and Immunology, 2008

In daily medical practice, sublingual immunotherapy decreased the development of sensitivities to new antigens and mild asthma and reduced bronchial hyperreactivity in pediatric patients who exhibited respiratory allergies.

 

Sublingual Immunotherapy: What Have We Learned From the ‘Big Trials’?
Current Opinion in Allergy and Clinical Immunology, 2008

SLIT is an effective and favorably-tolerated therapy for adult seasonal hay fever sufferers. Current clinical research and examination of lasting effects will shape its continuing role in allergy remediation.

 

Effects of Sublingual Immunotherapy on Allergic Inflammation
Inflammation and Allergy Drug Targets, 2008

Allergen specific immunotherapy (AIT) has a marked effect on tissue inflammation resulting from allergies that endures after the treatment’s end. Further, AIT is the only treatment capable of changing the course of allergic progression. Anti-inflammatory mechanisms observed with use of high antigen doses proved to be equitable between SLIT (allergy drops) and SCIT (allergy shotes).  Biopsy results show that the pathophysiology of the oral mucosa, and in particular mucosal dendritic cells, plays a key part in helping patients build up immunity to the antigens being treated for.

 

Sublingual Immunotherapy: Past, Present, Paradigm for the future? A Review of the Literature
Otolaryngology-Head and Neck Surgery, 2007

Americans are becoming increasingly interested in sublingual immunotherapy. The benefits of SLIT include a highly favorable safety profile as well as a high degree of patient acceptance/tolerability, easier and better access to immunotherapy, and a more child-friendly administration route.

 

Post-Marketing Survey on the Safety of Sublingual Immunotherapy in Children Below the Age of 5 Years
Clinical and Experimental Allergy, 2005

Sublingual immunotherapy has been found to be safe in pediatric patients 5 years old and younger.

Position Papers

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