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Our Evidence Base

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Evidence-Based Medicine (EBM) guides our allergy diagnostic and treatment system

AllergiEnd™ aims to enhance the quality of life of individuals and populations through research, evidence based diagnostics, innovative intervention promotion and distribution while enhancing the physician practice.

The AllergiEnd™ diagnostic system and immunotherapy methods are ‘state-of-the-science’ for achieving meaningful, long-term allergy and asthma improvements throughout the population we serve.

Evidence-based medicine (EBM) is the conscientious, explicit and judicious use of current best evidence in making decisions about health strategies to promote the health of individuals, communities, and populations. The practice of EBM means integrating local expertise with the best available external evidence yielded by systematic research.

EBM requires conducting cross-disciplinary literature searches, applying rules of evidence and appraisal of study quality, and selecting the most effective programs.

EBM asks the practitioner to present to the purchaser ‘patient’ a reliable summary of the area, including its strengths, weaknesses, and recommendations.

In practice, clinicians contextualize the best available research evidence by integrating it with their individual clinical expertise and their patient’s values and expectations. The incorporation of patient values and clinical expertise in EBM partly recognizes the fact that many aspects of health care depend on individual factors. These include variations in individual physiology and pathology, and quality-of-life and value-of-life judgments. These factors are only partially subjected to scientific inquiry and sometimes even cannot be assessed in controlled experimental settings. Application of available evidence is therefore dependent on patient circumstances and preferences, and remains subject to input from personal, political, philosophical, religious, ethical, economic, and aesthetic values. This has led to a shift from the original term Evidence ‘Based’ Medicine to Evidence ‘Informed’ Healthcare, to emphasize that decisions need not necessarily be based or complying with the evidence.

EBM has evolved from the critical need to bridge the gap between research and practice. EBM applies research information (evidence) to clinical practice, emphasizing the importance of the use of quantitative (as well as qualitative) evidence in the “art” of clinical decision making. It aims to make decision making more structured and objective by better reflecting the evidence from research. By introducing the use of research information in clinical decision making, particularly from clinical epidemiology, EBM has driven a transformation of clinical practice and medical education. 

References for our approaches by category

The list of allergy and immunotherapy references and summaries below are produced for your satisfaction, detailing our tireless efforts, but can never be considered exhaustive given the nature of science today. This research informs our diagnostic system and immunotherapy method’s design with the best possible evidence for effectiveness.

We cross a very broad body of evidence and continue to weigh the subjective hypothesis-based approaches with empirically tested research findings. In each of our entries on this web page, we’ve attempted to give you a very brief idea of the article’s subject matter. We have provided information at the end regarding its author, title and publication so that you may easily search and read it in its entirety. As always, we are open to discussion and encourage your questions and comments through our various forums.

Let’s start by discussing what EBM is and what it is not

In a 1996 article for BMJ, authors from the US, Canada and UK discussed the origins, definition and practical implications of evidenced-based medicine and how its usage equips clinicians to make the best decisions in terms of individual patient care. By integrating individual clinical expertise with the best available clinical evidence derived from systematic research, the authors suggest that patient-centered, compassionate care can be achieved.

The article suggests that the best doctors utilize both evidence and clinical expertise to maximize best-practice techniques. The evolution of this technique in terms of medical education programs results in clinicians becoming even more successful in the treatment of their patients.

Sackett D, Rosenberg W, Gray J, Haynes, B, Richardson W. Evidence-based medicine: What it is and what it isn’t.       BMJ. 1996; 312: 71-72.

Allergy and Asthma Prevalence 

Antihistamine use as a result of allergy symptoms increases a person’s sleepiness 

The nine authors of this study published in American Journal of Respiratory and Critical Care Medicine examined the high incidence of excessive sleepiness and sleep-disordered breathing as potential risk factors in motor vehicle accidents involving commercial drivers. Antihistamine and narcotic analgesic use increased the risk even further. A questionnaire and anthropormorphic measurement group made up one sample population of drivers while voluntary laboratory polysomnography testing was employed with the other testing group.

Ninety-nine of the drivers tested in the questionnaire group were males with the median age of 42.4 years while the median age of the polysomnography group was 45 years. Eighty four percent of the drivers were overweight or obese. Sixty percent of the drivers had sleep-disordered breathing and 16% had obstructive sleep apnea syndrome compared to just 24% and 4% of working males in occupations other than commercial drivers. For drivers averaging less than seven hours of sleep per night, vigilance and reaction time was reduced significantly. The authors noted that the chronic sleepiness reported by commercial drivers was comparable to the safety risks associated with talking on a cell phone while driving, driving over the legal blood alcohol limit and driving late at night after 2:00 am.

Howard M, Desai A, Gunstein R, et al. Sleepiness, Sleep-Disordered Breathing, and Accident Risk Factors in Commercial   Vehicle Drivers. Am J Resir Crit Care Med. 2004;170: 1014-1021.

Inflammatory disorders are actually on the rise due to better human hygiene

Due to humankind moving to richer, more industrialized areas, the “hygiene hypothesis” suggests that a reduced pattern of exposure to certain microorganisms has led to increases in certain inflammatory disorders secondary to disordered regulation of the immune system. Human adaption to new environments has become more technological in nature than genetic.

The author of this paper which was published in Immunology in 2008 explored the idea that like the brain, the immune system requires certain inputs in order to learn. Individuals suffering from allergic disorders, some autoimmune diseases and possibly also inflammatory bowel disease tend to be greater in number in industrialized rather than developing countries where exposure to parasitic worms (helminths) and saprophytic bacteria happens on frequent basis due to contaminated water and poor hygiene in the food delivery system.

In addition to allergic reactions, the author explored the effect of these factors on inflammatory disease processes including cancer, atherosclerosis, Alzheimer’s disease, depression and anxiety. In relation to multiple environmental changes, the author suggested that additional exploration to help unravel the mysterious molecular mechanism of action may lead to the creation of new medications for prophylaxis and treatment.

Rook G. Review series on helminths, immune modulation and the hygiene hypothesis: The broader implications of the hygiene hypothesis. Immunology. 2008; 126: 3-11.

Epinephrine administration is critical in the early stages of allergic reaction

A committee of anaphylaxis experts put together by the World Allergy Organization in 2008 reviewed all medical literature from 1966 to present and determined that there were no contraindications to the use of epinephrine in either immunologic or nonimmunologic anaphylactic episodes. In fact, the danger of not initiating epinephrine when available far outweighed any risk to an individual experiencing an attack.

The article published in World Allergy Organization Journal indicated that the acute and potentially lethal multi-system allergic reaction known as anaphylaxis occurs as part of a clinical continuum that may begin with minor cutaneous symptoms and progress within minutes to respiratory and cardiovascular distress. Immediate treatment of patients with appropriate intramuscular doses of epinephrine may prevent more severe anaphylaxis from occurring. The authors indicated that food, medications, insect stings and allergen immunotherapy injections are the most common provoking factors and that the prevalence of anaphylaxis may be increasing.

Unfortunately, many allergic individuals either don’t carry epinephrine auto-injectors due to cost or a poor understanding of when and how to use them. One study reviewed cited that only 50-75% of patients prescribed epinephrine carry it with them and only 30-40% of these patients are able to demonstrate proper technique. Consensus of all the evidence in available literature clearly recommended a “sooner rather than later” approach to initial dosage during an allergic episode in patients at risk in order to avoid potential fatalities.

Kemp S, Lockey R, Simons F. Epinephrine: The Drug of Choice for Anaphylaxis – A Statement of the World Allergy Organization. WAO Journal. 2008; Supplement 2: S18-S26.

Reduced genetic diversity leads to greater risk of allergies

Various inflammatory conditions such as asthma, allergic and inflammatory bowel diseases, type 1 diabetes, cancer, depression and obesity are being linked to reduced biodiversity and alteration in gut and skin microbiology secondary to climate change and a more urban lifestyle in developed countries. This 2013 multi-authored article for the World Allergy Organization discussed the concept that microbe-rich environments offer protection against human autoimmune and allergic dysfunction.

Variability among living organisms can be noted by genetic diversity observed within naturally functioning ecosystems. A recent study found that the annual prevalence rate of most disease was ten percent lower for cultures of people living within a one kilometer radius of a green space such as parks and forests which act as a buffer between stressful life-events and health. Compared with urban areas, forest environments are associated with lower cortisol, pulse rate, blood pressure and sympathetic nerve activity levels. Additionally, various human immune cells require interaction with microbes for normal development and function. The reduced abundance and diversity of these microbes may lead to the body’s failure to regulate and restore appropriate immune and inflammatory responses.

The paper looked extensively at the effect of gut and skin bacterial flora on immune tolerance and human health. Early environmental exposure to this microbiota is associated with protection of allergy in children. Likewise, early-life exposure to antibiotics may disrupt the metabolic homeostasis and increase the risk of allergies and inflammatory conditions. Healthy immigrants begin to show immunomodulation shaped by cultural adaptation within ten years of arriving in a more urban area with a high prevalence of disease.

Environmental factors can cause epigenetic changes and thus modify disease susceptibility in individuals, but the induction of immune tolerance can play an essential role in offsetting the dysregulation of the body’s immune system. Lifestyle factors such as physical exercise, healthy diet, probiotics, connection with nature and a global allergy plan may all have a positive impact on human health.

Haahtela T, Holgate S, Pawankar R, et al. The biodiversity hypothesis and allergic disease: world allergy organization position statement. World Allergy Organization Journal. 2013; 6:3.

Allergy Diagnosis 

Beta-blockers are not a huge concern with allergy testing

The two authors of this 2010 paper for Allergy, Asthma and Clinical Immunology reviewed patient charts from an Ontario allergy clinic for data collected between the years of 2004-2008 for the first known study to specifically address the concerns of beta-blocker usage and skin prick allergy testing. Of the 191 patients taking beta-blockers when allergy skin testing occurred, no adverse events were noted.

The authors discussed the concern that beta-blockers may amplify the effects of anaphylaxis thereby contraindicating their usage during allergy skin testing. Reasons cited include a possible worsening of anaphylaxis severity, difficulty of anaphylaxis treatment and an increased incidence of anaphylaxis itself.

They noted that while there may be an increased risk of anaphylaxis in patients undergoing immunotherapy, the degree of risk is likely smaller to that of patients undergoing allergy skin testing. Despite their positive findings, the authors cited the need for larger multi-center prospective studies and advised that caution be employed whenever testing patients taking beta-blocker medications.

Fung I, Kim H. Skin prick testing in patients using beta-blockers: a retrospective analysis. Allergy, Asthma Clinical Immunology. 2010; 6:2.

Sedatives and antidepressants may interfere with allergy skin testing

Five authors retrospectively reviewed skin-prick test results of patients taking antihistamines as well as other medications such as sedatives and antidepressants which had antihistaminic properties. The study published in the 2010 issue of Allergy and Asthma Proceedings revealed that both types of medications could negatively affect skin testing.

For the more common, non-sedating antihistamines, discontinuation of usage within three days of testing was acceptable. For the TCA class of drugs (amitriptyline and nortriptyline), seven days was the recommended length of time to discontinue usage so as not to elicit histamine response in the allergy testing client. Additionally, their findings suggested that if possible, patients taking benzodiazepines, mirtazapine and quetiapine should temporarily discontinue treatment before skin testing. Many other medications are listed specifically in detail in the study which the authors determined would not necessarily interfere with the skin prick testing results.

Shah K, Rank M, Dave S, et al. Predicting which medication classes interfere with allergy skin testing. Allergy Asthma Proc. 2010; 31: 477-482.

Multi-headed skin prick tests helpful in allergy diagnosis

Four authors conducted a comprehensive review of current methodology through a critical analysis of data for this 2008 article for Allergologia et immunothologia. They discussed the origins of skin testing techniques dating as far back as 1865 and related the procedures to clinical practice today in terms of airborne and food allergen sensitivity in patients. They cited that proper documentation is critical as is a thorough review of the patient’s symptoms and prior history when selecting which seasonal allergens to test.

They explained that both histamines and enzymes play a role in the typical wheal and flare reaction seen with skin-prick testing. When examining patient sensitivity to food sources, the clinician’s decision to test with commercial extract versus fresh food sample (using the prick-prick technique) should also be considered since fresh food sensitivity usually exceeds 90% and can even reach 100%.

The authors emphasize that the goal for the allergist is to minimize false positive reactions while reducing patient discomfort during testing. Multi-headed testing devices are particularly useful with pediatric patients since several areas can be examined at once. Location of testing is also a big decision since an area such as the back is 20% more reactive than the forearm.

Skin results should generally be read at 20 minutes post prick. Measuring the papule area either by planimetry, directly via image-processing programs or from a traced copy is advised for accuracy. Standardization of the findings via computer or ultrasound evaluation reduce inter-observer variations. Contraindications, adverse reactions and other variability factors such as medication usage prior to testing are all also discussed in the article in detail.

Antunes J, Borrego L, Romeira A, Pinto P. Skin prick tests and allergy diagnosis. Allergol Immunopathol. 2009;37(3): 155-64.

Primary care physicians can now conduct effective screening of allergy sensitivity with the appropriate testing devices and education

This 2008 monograph published in Annals of Allergy, Asthma & Immunology provided a general overview of allergy diagnostics for primary care health professionals who do not possess formal training in the specialty. The authors emphasized that allergy skin tests and blood tests should only be used as an adjunct to an extensive review of a patient’s clinical history and physical examination. These tests merely indicate the presence of allergen specific IgE and do not necessarily determine clinical allergy, so they should only be utilized as confirmatory tools based on a physician’s assessment of many other factors.

Most allergic patients are sensitive to multiple allergens. Determining which are of the highest importance is not an easy task for the primary care physician. Panels of laboratory blood tests designed for geographical regions and seasons do exist, yet so do many issues with test performance and standardization. Fewer adverse reactions have been noted in response to prick or puncture (percutaneous) testing versus intradermal testing particularly when dealing with asthmatic patients and assessing food allergies. Many types of prick and puncture testing devices are available with a multi-head design allowing ten or more tests to be completed with one application. Though standardization and quality assurance methods need further development, the primary care physician now has several viable tools to help identify allergic patterns in patients which may warrant a referral to an allergy, asthma and immunology specialist for further testing or treatment if indicated.

Cox L, Williams B, Sicherer, S et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy, Asthma Immunol. 2008;101:508-592.

Sublingual Immunotherapy 

Sublingual immunotherapy is helpful in treating asthma and rhinitis in children

Five authors for the Italian Journal of Pediatrics reviewed studies which addressed the clinical efficacy of SLIT in the pediatric population. Factors examined included feasibility issues such as patient compliance and cost-effectiveness as well as safety.

Negative reactions to SLIT treatment such as localized itching, tingling and swelling in the mouth and mild gastrointestinal reactions were minimal compared to reported SCIT reactions. Additionally, higher patient compliance and better clinical outcomes at a reduced cost were noted by parents of children receiving SLIT as compared to traditional European drug treatment.

The authors’ analysis of the existing literature up to 2009 supported the use of SLIT to treat the symptoms of asthma and rhinitis related to seasonal allergies in pediatric patients. The authors suggested that additional research was needed in regards to perennial allergens.

Marseglia G, Incorvaia C, Rosa M, Frati F, Marcucci F. Sublingual immunotherapy in children: facts and needs. Italian Journal of Pediatrics. 2009; 35:31.

Sublingual immunotherapy may reduce the need for rescue medication

The physician author for this article from The Journal of Allergy Clinical Immunology explained that based on studies conducted up to 2007, allergists were still learning how conventional immunotherapy works. SLIT was found to be beneficial both in regards to symptom management and reduced rescue medication requirements. However, additional research was still needed to determine exactly how this positive outcome occurred. Active buccal dendritic cells capable of interacting with lymphocytes as well as altered IgG and T-cell responses were discussed by the author as possible explanations as to how positive immune mechanisms might be induced by SLIT.

Frew A. How does sublingual immunotherapy work? J Allergy Clin Immuno. 2007;120: 533-536.

Children with pollen or grass related rhinitis respond well to sublingual immunotherapy

The use and efficacy of SLIT in the pediatric population suggests that it might be the most effective treatment for selected atopic children with pollen or grass related rhinitis and mild to moderate persistent asthma with mono-sensitivity to House dust mite. Pediatricians appreciate the ease of delivery and low risk of serious side-effects of fatal anaphylaxis compared to SCIT delivery.

At the time of this article’s 2009 publication in Paediatric Respiratory Reviews, about 85% of all children receiving immunotherapy in Italy received it via sublingual route. Although no form of SLIT has yet been approved by the FDA in the USA, several clinical trials examining its effects are being conducted. The authors suggest that the mechanism of SLIT action of specific immunity in the mucosal areas is thought to be key in the process.

Campbell D. Sublingual immunotherapy for children: Are we there yet? Defining its role in clinical practice. Pediatric Respiratory Reviews. 2009;10:69-74.

Sublingual-swallow immunotherapy may be used safely in children younger than five years old

In an attempt to assess the safety of high-dose SLIT in children younger than five years, eight Italian physicians conducted this observational, multicenter and minimization study within a group of pediatric patients younger than seven years who were experiencing symptoms associated with rhinoconjunctivitis and/or asthma. Sixty-five children were administered SLIT with a cumulative dosage 300 times higher than the standard SCIT dose.

The authors of this study published in the 2005 Annals of Allergy, Asthma & Immunology indicated that the dosage was tolerated in 54 of the 65 cases without adverse reactions. Though this pilot study involved a selected population of patients, the authors summarized that there was no reason to forbear the assessment of safety and efficacy of SLIT in patients aged five and younger.

Fiocchi A, Pajno G, Grutta S et al. Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol. 2005;95:254-258.

Efficacy of sublingual immunotherapy is notable particularly with multiple allergens

The author of this 2012 clinical study for Journal of Environmental and Public Health utilized the method of a retrospective chart review of his own private practice’s allergy patients. He suggested that the prevalent problem of allergic disease which affects up to one-third of the general population in industrialized countries may be treated effectively in equal ways by both SLIT and SCIT methods. However, in regards to treating asthmatic and young patients, his results indicated considering SLIT as the main treatment modality with SCIT for treatment failures.

Ninety-three charts met the author’s study inclusion criteria. Of these, 43 were on SLIT (reflecting the majority of children and asthmatics examined) and 50 were on SCIT.  Many factors were repeatedly and statistically compared including pre and post treatment symptom averages, medication usage and peak flow meter determinations. As SLIT had been added to the physician’s practice later than SCIT, the SCIT patients had been treated for a longer period of time. In the author’s clinical experience, the ability to use SLIT with multiple antigens enabled his practice to treat many more clients that otherwise might have been unable to receive care.

Saporta D. Efficacy of Sublingual Immunotherapy versus Subcutaneous Injection Immunotherapy in Allergic Patients. Journal of Environmental and Public Health. 2012.

Systemic reactions to sublingual immunotherapy are less severe compared to subcutaneous route 

This Journal of Allergy and Clinical Immunology 2013 article provides an updated systematic review methodology and reporting of studies including adults or children with moderate to severe seasonal allergic reactions with or without asthma. Statistical methods examining SLIT or SCIT versus placebo and also via indirect comparison of head-to-head trials were considered.

Most adverse events to treatment were local reactions which resolved spontaneously although some less common systemic reactions were moderate to severe. The six authors noted that 19% of systemic reactions after SCIT treatment were considered severe compared with just 2% of SLIT reactions. In studies conducted after 2007, the probability of SLIT being more effective than SCIT shifted slightly. All in all, there was still not enough significant data available to conclusively indicate that one method was more effective than the other.

Dretze J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, Meads C. Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: A systematic review and indirect comparison. J Allergy Clin Immunol. 2013; 1361-1365.

Sublingual immunotherapy is more economically beneficial long-term than other treatments

This informative study looked at 50 patients treated with SLIT against house mite sensitivity and compared their results with a control group of 20 patients receiving treatment with symptomatic drugs so that the economic relevance of each method could be assessed. The six medical doctors and two Pharm D authors of this paper which was originally published in the Annal of Allergy, Asthma & Immunology in 2009 followed patients for five consecutive years.

Subjects were all between the ages of eight and 50 years with persistent allergic asthma for at least two years. Additionally, all patients were both skin prick test and radioallergosorbent test positive to Dermatophagoides.

The authors found that although the initial cost of SLIT was higher, the mean annual cost to SLIT patients was significantly lower even after two years of stopping their three year course of treatment. The long-lasting symptomatic relief and cost to the patient and the healthcare system indicated that SLIT was more economically advantageous than SCIT. Additionally, this study showed particularly good results in terms of patient tolerance with 90% of those individuals followed demonstrating no adverse events or severe reactions.

Ariano R, Berto P, Incorvaia, C et al. Economic evaluation of sublingual immunotherapy vs symptomatic treatment in allergic asthma. Ann Allergy Asthma Immunol. 2009;103:254-259.

Immunotherapy for allergic rhinitis has advantages over pharmacological treatment

The MD co-authors of this 2011 overview published in Immunology Allergy Clinics North America noted that although SLIT and SCIT are prescribed nearly equally in Europe, the lack of FDA- approved formulation in the US along with an unknown effective dose amount are reported as the most common reason practicing allergists say they are reluctant to use SLIT. The historical background of both treatments as well as issues such as efficacy of single and multi-allergens are examined in depth through several charts and tables. The authors indicated that based on their review of the existing research, both SCIT and SLIT offer protection against the development of asthma along with other new allergen sensitizations.

SCIT adverse reactions may be local or systemic ranging in severity from mild rhinitis to life-threatening anaphylaxis depending on factors such as dose, type of extract, induction schedule, premeditation and patient selection. The incidence of systemic adverse reactions to SLIT is significantly lower and no deaths have been reported secondary to SLIT. While no clear predictors for serious SLIT adverse reactions have been identified, previous systemic reactions to SCIT and SLIT as well as a history of asthma appear to be patient risk factors.

Complex immunologic mechanisms associated with SLIT and SCIT are still under investigation but appear to be similar. The cost effectiveness of both methods also needs more review but both approaches show advantages compared to pharmacotherapy. In terms of persistent clinical benefits even after the discontinuation of treatment despite a relatively high level of patient non-compliance, immunotherapy shows exceptional promise.

Cox L, Wallace D. Specific Allergy Immunotherapy for Allergic Rhinitis: Subcutaneous and Sublingual. Immunol Allergy Clin N Am. 2011;31:561-599.

Noninjection routes for immunotherapy are particularly effective with pediatric population

Two physicians offered a review of the allergen specific immunotherapy options for both SCIT and SLIT methods through 2003 for this article published in Journal of Allergy and Clinical Immunology. They included the history of non-injection methods such as local bronchial immunotherapy (no longer used) and local nasal immunotherapy (declining in usage) as well as oral immunotherapy (rarely used) as a basis of comparison for the advantages of SCIT and SLIT.

With their primary emphasis being on SLIT, the physicians noted that although no relevant direct absorption could be demonstrated through the sublingual mucosa, it was still the most widely used non-injection route for immunotherapy in Europe. SLIT was particularly effective within the pediatric population showing clinical effects both on rhinitis and asthma symptoms.

More research was needed regarding the effective doses for SLIT as the literature at the time indicated a wide range of values anywhere from three to 375 times the allergen amount used in SCIT. While too high amounts led to gastrointestinal symptoms, doses that were too low were found to be ineffective.

Canonica G, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol. 2003; 437-448.

Sublingual immunotherapy protocals can have long-lasting effects on house dust mite sensitivity

This 2011 review for Immunology Allergy Clinical North America of existing research examined multiple views on the exact mechanisms with which SLIT may exert its effects. The most accepted hypothetical method of absorption described by the authors suggests an allergen uptake in the submucosal dendritic cells with a migration to the local regional lymphoid tissues along with the submandibular and cervical lymph nodes. Allergen specific T cells react to the dendritic cells’ presentation of peptide matter which results in induction of regulatory T cells and Th1 cells and the inhibition of Th2 cells. In response, B cells produce protective antibody responses such as the secretion of allergen-specific IgG4 and IgA and the later inhibition of IgE. Additionally, this hypothesis suggests that regulatory T cells may suppress other inflammatory cells such as eosinophils, mast cells and basophils by cytokine secretion or direct cell-to-cell contact.

Significant evidence suggests that both local mucosa and lymphoid tissues play dominant roles in SLIT and that the oral Langerhans cell is very involved in the process. Increasing evidence for a functional role of IgG antibodies also exists but needs further study along with SLIT’s effect on T-cell proliferation, cytokine secretion and the proliferation of regulatory T cells due to researchers varying their usage of different allergens, doses and treatment regimens in existing studies.

Long-lasting tolerance and symptomatic improvement even after the discontinuation of treatment is a major advantage of both SCIT and SLIT compared with pharmacologic treatments. One particular open study the co-authors cited showed that the beneficial effect of house dust mite SLIT could last for up to seven years after a three year treatment course.

Scadding G, Durham S. Mechanisms of Sublingual Immunotherapy. Immunol Allergy Clin N Am. 2011;31:191-209.

Sublingual immunotherapy is effective in the treatment of allergic rhinoconjuntivitis and asthma

Eight authors participated in this 2013 comprehensive review of the existing medical literature for the Journal of the American Medical Association with the primary objective of examining the effectiveness and safety of the off-label usage of SLIT for allergic rhinoconjunctivitis and asthma in the US. The team examined 63 randomized controlled trials written in the English language prior to December 2012. The study included 5131 participants between the ages of four and 74 years. Researchers evaluated the strength of evidence for each comparison and outcome by grading the risk of bias, consistency, magnitude of effect and directness of the evidence.

Though the authors concluded that high-quality studies were still needed to evaluate optimal SLIT dosing strategies, moderate overall evidence supported the effectiveness of SLIT for the treatment of allergic rhinitis. High evidence existed in support of SLIT in terms of improving asthma symptoms. They concluded that the evidence was of moderate strength in support of treating allergic conjunctivitis, of decreasing medication usage and of improving disease specific quality of life.

Yin S, Erekosima N, Kim J et al. Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjuntivitis and Asthma: A Systematic Review. JAMA. 2013;309:1278-1288.

Increased safety is noted with the use of sublingual immunotherapy for allergic respiratory diseases

Since its first description in 1986, SLIT has appeared to be a good clinical alternative to SCIT because of its safety profile. The 2009 publication of the World Allergy Organization position paper stimulated additional randomized, double-blind, placebo-controlled trials. The co-authors of this 2011 literature review for Immunological Allergy Clinical North America included all of these along with a look at other big trials and meta-analyses. They noted that continual challenges exist in regards to the heterogeneity of the existing trials in terms of dosage, regimen, type and concentration of extracts, duration, inclusion criteria and measurements.

In regards to asthma, particularly in children, the authors noted apparent positive effects with SLIT compared to SCIT. When comparing the efficacy of SLIT to SCIT and medications, however, the results of the literature were inconclusive. The long-lasting, beneficial clinical effects of SLIT were still seen four to five years after discontinuation of treatment.

The authors found that the safety of SLIT was overall superior to SCIT with no fatalities reported in 23 years of trials and extensive clinical use. However, no universal system yet exists for reporting and grading side effects.  Additionally, no consensus on the best administration regimen, the usefulness of a buildup phase of dosing or the optimal dosing schedule for SLIT has been established either.

Passalacqua G, Canonica G. Sublingual Immunotherapy for Allergic Respiratory Diseases: Efficacy and Safety. Immunol Allergy Clin N Am. 2011;31:265-277.

High-dose sublingual immunotherapy for house dust mite allergies causes no systemic reactions in US trial

This 2010 randomized, placebo-controlled SLIT feasibility study is one of the few US trials reported. Its objective is to compare the safety and physiologic effects of low versus high doses of the Dermatophagoides farinae vaccine for dust-mite sensitivity in 21 adults with allergic rhinitis with or without mild intermittent asthma who completed an eighteen month enrollment period.

Subjects received daily doses using a metered-dose pump. The solution was held under the tongue for two minutes. Clinical assessments, adverse effects, symptom and medication scoring, immunoglobulin measurements, allergen bronchoprovocation and environmental house dust mite allergen levels were all monitored closely via statistical analysis.  Results concluded that despite mild-to-moderate local adverse effects such as oral lesions and gastrointestinal symptoms in 57% of the high dose group, high-dose SLIT was generally safe as it produced no systemic reactions. The high-dose of 4200 AU D farina vaccine induced a potentially protective immune response associated with an increase in the bronchial threshold to allergen challenge while the low-dose of 60 AU of SLIT had no significant effect.

Bush R, Swenson C, Fahlberg B, Evans M, Esch R, Busse W. House dust mite sublingual immunotherapy: Results of a US trial. J Allergy Clin Immunol. 2011;127: 974-981.

Sublingual immunotherapy shows new promise for sufferers of peanut allergies

A large panel of investigators assessed the safety, efficacy and immunologic effects of peanut SLIT in this ground-breaking, multicenter, randomized, placebo-controlled first-ever trial of peanut SLIT. This 2012 study was published in the January 2013 issue of the Journal of Allergy Clinical Immunology. Forty subjects aged 12 to 37 years with a median age of 15 years were randomized 1:1 and tested daily across five sites to peanut or placebo SLIT.

After 44 weeks, 70% of the 20 subjects receiving peanut SLIT were compared with the placebo group and found to be responders. Responders were those individuals who could consume either a cumulative dose of 5 g or a 10-fold increase in the amount of peanut powder compared to their baseline oral food challenge without dose-limiting symptoms.

After this point, the study was unblinded for its second phase. For an additional 120 weeks, initially active-treated subjects received lower dose peanut SLIT treatment while the placebo-treated subjects received 164 weeks of higher dose peanut SLIT after crossover to active therapy. End point titration skin prick testing, immunologic studies of basophil activation and immunoglobulins and statistical analysis were used.

The study demonstrated that treatment with peanut SLIT induced a statistically significant degree of desensitization in a majority of patients compared with placebo as well as originally randomized to placebo subjects who crossed over to receive a higher dose peanut SLIT. The modest desensitization effect to 5 g of peanut powder at 44 weeks might not provide clinically relevant protection, but a subset of patients challenged again after 68 weeks of SLIT demonstrated incremental and statistically significant increases in successfully consumed dosages of 5 to 10 g of peanut powder. Accidental injections of peanut proteins are 100 mg in general so these results were encouraging in terms of reduced reactivity with longer periods of SLIT. The authors noted the limitations and issues with their study and indicated that further investigation of SLIT as treatment for food allergy was most definitely warranted.

Fleischer D, Burks A, Vickery B et al. Sublingual immunotherapy for peanut allergy: A randomized, double-blind, placebo-controlled mulitcenter trial. J Allergy Clin Immunol. 2013; 131:119-127.

Sublingual immunotherapy has less death risk compared to subcutaneous immunotherapy

It has been estimated that over one billion dollars a year is spent on the management of allergic rhinitis which affects between 5-22% of Americans. Two John Hopkins University physicians explored multiple studies prior to 2011 for this article published in Otolaryngol Clinical North America. They concluded that SLIT was efficacious in treating allergic rhinitis in adults and children and suggested the need for future US based studies.

One of the most consistent changes in inflammatory mediators noted was the reduction in serum eosinophil cationic protein (ECP) and several studies indicated a reduction of this in both adults and children receiving SLIT for 6 to 24 months. The improved safety profile of SLIT over SCIT in terms of systemic reactions was indicated by the authors to be a rate of 0.6% for SCIT compared to 0.056% for SLIT. Additionally, the prevalence of death was noted to be 1 per 2.5 million for SCIT versus no reported deaths for SLIT. Common sense home safety precautions for use with children were discussed in detail.

The authors stated that the optimal dosage, timing and length of treatment for SLIT are still not as clearly defined as they are for SCIT. They hoped that more information would soon be available regarding standardization along with FDA approval so that SLIT is viewed as a reasonable treatment option for patients.

Pajno G. Sublingual Immunotherapy. J Allergy Clin Immunol. 2007; 119:796-801.

Optimism existes for the future of sublingual immunotherapy 

The author took an in-depth look at some of the unmet needs of SLIT research including the challenge for manufacturers to achieve standardized vaccines, the inconsistent measurement of clinical efficacy and safety, and the issue of early intervention in young children with Ig-E mediated disorders. At present, each supplier of SLIT uses its own standardization process, so comparing the amounts of allergens present in extracts of allergens such as grass pollen is not yet possible.

At the time of this article’s publication in Journal of Allergy and Clinical Immunology in 2007, studies comparing directly the efficacy of SLIT to SCIT were not yet in place. Likewise, the issues of using SLIT in young children required further research particularly in regards to rather early intervention might ward off further allergy progression as in the notion of “atopic march.” The author stated that allergy patients with multiple sensitizations as well as those with food sensitivities have reason for optimism if current focused research progresses.

Pajno G. Sublingual immunotherapy: The optimism and the issues. J Allergy Clin Immunol. 2007; 119:796-801.




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