Immunotherapy, by whatever route, treats the cause of allergies by giving increasing doses of the substances to which a person is allergic. This, in turn, increases tolerance to those allergens and ultimately reduces symptoms. It is truly functional medicine in that it gets to the root cause of allergies instead of simply trying to control the symptoms. When done well and thoroughly, it can be highly effective.
In the US, subcutaneous injections are the only form of immunotherapy that most doctors and patients know. This is unfortunate because “allergy shots” are extremely inconvenient, costly and sometimes dangerous. For the most part, injections are given by specialists, and this relatively simple treatment has been carved out of primary care. With shots as the only option, a very small percentage of Americans who might benefit from immunotherapy get the relief they need.
Fortunately, shots are not the only option.
Outside the US, Sublingual Immunotherapy (SLIT) is the most common method of treating allergies. It is supported by a large body of science showing that in most cases it is equivalent or even superior to subcutaneous injections in efficacy and safety. SLIT is also vastly more convenient, and ideally suited to the primary care setting.
My own clinical experience with SLIT has been highly satisfactory, and I predict it will soon become the norm in this country. Prestigious centers such as Johns Hopkins Sinus Center are already offering SLIT, and one can envision its rapid expansion into the primary care arena. SLIT is patient-friendly functional medicine at its finest!
History of Sublingual Immunotherapy
The concept of immunotherapy originated in the early 1900s, based on the idea of vaccination against infectious agents. An attempt at vaccination against “airborne toxins” led to the subcutaneous route of allergen administration1. This line of thinking ultimately became the standard American approach to allergy treatment, with allergists primarily overseeing and administering subcutaneous immunotherapy (SCIT). Early attempts at oral, nasal and bronchial immunotherapy were either not successful or fraught with complications.
Things changed in 1986, when the British Committee for the Safety of Medicines reported several deaths caused by SCIT and raised concerns about the safety and the risk/benefit ratio2. About the same time cheaper drugs (anti-histamines, inhaled steroids) became widely available. Interest in alternative routes for IT, beyond injections, began to increase. That same year the first randomized controlled trial with SLIT was published3. SLIT was soon confirmed to be effective in several controlled studies, in both adults and children4,5.
By 1993, the European Academy of Allergy and Clinical Immunology (EAACI) published a position paper recognizing SLIT as a “promising route” for desensitization6. A few years later, the EAACI declared that “use of SLIT in clinical practice is justified because of the ascertained efficacy and the favorable safety profile”7. There is ample data proving safety of SLIT in adults and children over age 5.8-9 The World Health Organization accepted its use in adults in 199810.
In 2004 the first metanalysis showed SLIT was effective for allergic rhinitis11 and another study showed that it actually helps prevent asthma12. Additional papers in 2006-2008 bolstered the idea that SLIT is significantly effective for rhinitis and asthma in adults and children13-17. Since then, there have been many large trials in adults and children weighing in favor of SLIT18-23.
How Immunotherapy Works
All forms of immunotherapy involve a “recalibration” of the portion of the immune system that is hypersensitive.
The allergic response in hay fever and asthma is the type-1 hypersensitivity reaction that involves an allergen binding to specific IgE receptors on mast cells. This triggers mast cell degranulation and release of histamine and leukotrienes that cause blood vessel dilation and leaking, leading to the symptoms of swelling, itching, and inflammation.
Mast cells are most abundant in the skin and respiratory tract, which explains why allergy symptoms present there. It also explains why side effects to allergy shots include pain, redness and swelling at the injection site and possible anaphylaxis.
The T-helper (Th)-1 pathway is responsible for defense against intracellular pathogens, and a pathologic response in this pathway is associated with autoimmune disease and cell-mediated allergies. The Th2 pathway is responsible for defense against extracellular pathogens, and it is here that asthma and IgE-mediated allergies present when the Th2 system goes awry.
Note that Th3 or T-regulatory (T-reg) cells control both the Th1 or Th2 pathways. In particular, T-reg cells secrete interleukin-10 (IL-10), which leads to immunosuppression and reduces inflammation. The Th1 and Th2 pathways also exert negative feedback on one another; up-regulation of one will down-regulate the other.
While there is much research needed to fully understand the mechanisms of SLIT, there is a consensus that it works by inducing a population of IL-10 producing T-reg cells, triggering a Th1 immune response and increasing IgG4. This ultimately inhibits allergen-IgE binding to B cells, reduces eosinophil activity, and reduces cellular adhesion molecules.
Unlike SCIT, in which allergen is exposed to primed mast cells in the skin, SLIT delivers the allergen directly to antigen-presenting cells in the tissue underneath the tongue. These cells “present” the allergen to the immune system, bypassing and ultimately down-regulating the Th2 pathway.
Effectiveness of SLIT
During the last 3 years there have been numerous well-designed, well-powered studies using standardized grass pollen sublingual tablets. The general effect of SLIT was a significant reduction in symptom severity and medication use. The first metanalysis of SLIT for allergic rhinitis included 22 trials and nearly 1,000 patients, and showed significant reduction in both symptoms and medication requirements24.
A metanalysis of SLIT for asthma, which included 25 trials and over 1,000 patients, indicated that it is beneficial, though the magnitude of the effect is small. However, the authors note that SLIT is a safe alternative to subcutaneous injections and that it gives improvements in symptoms, medication use, pulmonary function, and overall well-being25.
A metanalysis of SLIT for allergic rhinitis in children, which included 10 trials and 484 patients, showed that, SLIT with standardized extracts is effective 26 compared with placebo. There is also a metanalysis of 9 SLIT trials for asthma in children, representing 441 patients, and showing that SLIT reduces symptom scores and rescue drug use in kids with allergic asthma27.
SLIT vs. SCIT?
Comparison of SLIT with SCIT reveals that sublingual and injection therapies are equally effective according to subjective clinical parameters. Both give highly significant reductions of symptoms and medication use28. It is interesting that even though the clinical outcomes were equivalent, objective parameters (total specific IgG, specific IgG4, skin reactivity) changed only in patients treated with injection therapy. The clinical efficacy of SLIT is not statistically different from SCIT, and both treatments are clinically effective compared with placebo.
All things being equal, SLIT may be favorable owing to its advantageous safety profile 29. Some studies even give SLIT the edge over SCIT for allergic rhinitis30.
Safety of SLIT
The safety of SLIT over SCIT is well worth noting. In a comprehensive review of 104 articles on SLIT31, there were 66 studies that provided some information on safety and tolerance, representing 4,378 patients who got nearly 1.2 million total doses. There were no fatalities or anaphylactic events reported, and only 1.4 significant adverse events (SAE) per 100,000 SLIT doses.
Mild reactions in the oral mucosa were the most common non-serious AE, occurring in about 75% of patients, most frequently during the escalation phase. Moderate AEs occurred in 0.056% of SLIT doses. These included gastrointestinal symptoms, hay fever symptoms, and itching. A total of 21% of SLIT patients reported AEs compared with 11.7% of placebo patients. The most common SLIT-related serious AEs were asthmatic reactions, followed by abdominal pain/vomiting, uvula edema and urticaria lasting 48 hours; all were rare.
By comparison, according to the World Allergy Organization, there are an estimated 3.4 fatal and 22.8 near-fatal reactions caused by subcutaneous allergy shots every year. Local reactions at the injection site, such as redness, swelling, and warmth, are common, with about 10-20% of users experiencing large (>25mm) reactions.
Safe use of SLIT depends on identifying risk factors for side effects, which would include asthma, especially if not optimally controlled, and previous significant reaction to allergy shots. Safety of SLIT in children has been shown down to age 3 and several studies have shown safety of multi-allergen mixtures. Safety of SLIT in pregnant and nursing women is unknown at this time.
SLIT in Primary Care
Before initiating immunotherapy, it is important to: 1) Demonstrate the presence of IgE-mediated disease; 2) Document that a specific sensitivity is involved; 3) Document the severity and duration of symptoms; and 4) Ensure availability of standardized, high-quality vaccines32-34.
After 16 years of administering subcutaneous immunotherapy in my office I am very familiar with its protocols, successes, and risks. SCIT does work well in controlling asthma and hay fever. However, we’ve seen a fair share of significant adverse reactions including anaphylaxis, which is why I got interested in the sublingual option.
Our protocol for SLIT involves taking a detailed initial history along with respiratory allergen testing by either serum RAST or skin tests. We then inform the patient about the risks and benefits of SLIT, educate them on home use, administer a 60 day supply of allergen drops and include an epinephrine kit for safety and peace of mind (though the risk of anaphylaxis is almost nil).
We instruct patients to take the drops under the tongue daily. During the first 10 days, called the “escalation phase,” the dosage is gradually increased. After that, in the “maintenance phase,” the patient takes a fixed number of drops per day.
Our allergen supplier is Wellness Pharmacy of Birmingham Alabama. A leader in compounding since 1964, Wellness has been able to formulate a universal allergen extract that contains 70 individual allergens, and goes to great lengths to safeguard extract compatibility and stability, ensuring a consistent standard of excellence in the allergen product.
They also provide packaging and distribution of the allergen drops, either mailing directly to our office or to the patient’s home. This is a nice contrast to SCIT, which obliges the physician to mix allergens and make the serial dilutions.
In terms of treatment duration, some patients note symptom improvement within 3-4 months after starting SLIT, but it is recommended that treatment continue for 3-5 years in order to confer lasting immunity.
Massive Potential Cost Savings
Treatment for allergies is big business! In 2005, roughly 22 million Americans spent $11 billion on doctors' bills, prescription drugs, and other medical care to relieve allergy symptoms, according to the Agency for Healthcare Research and Quality (AHRQ). Visits to doctors and hospitals accounted for $4 billion. The remaining roughly $7 billion was spent mostly on prescription drugs. Much of that expenditure could have been avoided if people had better access to effective immunotherapy. SLIT is a very viable option.
Unfortunately, most insurance plans do not cover SLIT, and the FDA considers it an "off-label" use. Hopefully, that will change as more physicians and patients become aware of it’s therapeutic and fiscal potential. When compared with the cost of allergy shots, SLIT may be a more economical choice and is certainly more convenient to the patient.
SLIT has potential to treat other allergic reactions such as IgE-mediated food allergies, atopic dermatitis, and honeybee allergies. Key topics for future research include: evaluation of optimal dosing and duration of treatment, efficacy and safety of no build-up regimens, duration of pre-seasonal induction, efficacy of SLIT in asthma, and use of mixtures of unrelated allergens.
Sublingual immunotherapy has been a valuable addition to my practice, and I believe it has the potential to greatly improve the management of allergies and related conditions in the US.
Scott Rollins, MD, is Board Certified with the American Board of Family Medicine and the American Board of Anti-Aging and Regenerative Medicine. He specializes in rural family medicine and emergency services, bioidentical hormone replacement, thyroid and adrenal disorders, fibromyalgia and other complex medical conditions. In 2004 he was awarded “Family Physician of the Year” by the Colorado Academy of Family Practice. He is founder and medical director of the Integrative Medicine Center of Western Colorado, and also serves as Medical Director of Physician Consulting, Inc.
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