The year 2011 marks the 100th anniversary of allergen-specific immunotherapy, and for this reason JACI has published a series of articles in the first issue of this year to provide a comprehensive overview of the current status and progress. 100 years ago British doctors Leonard Noon and John Freeman published an article in The Lancet on the treatment of AR caused by allergy to pollen, marking the beginning of AIT for allergic diseases. However, there are still some misconceptions or misconceptions about allergen immunotherapy and its usefulness in allergic rhinitis over the past 100 years.
Due to the lack of standardized clinical research methods for trials in this area, misconceptions persisted until the 1850’s. Leonard Noon and John Freeman used the scientific method of clinical research and are considered pioneers of allergen immunotherapy. Their reports led more young physicians to strive for comprehensive therapies in the current medical situation. Admittedly, the clinical efficacy of AIT is also diverse. aIT involves the routine administration of specific, semi-purified allergen extracts to reduce the patient’s allergic response to naturally exposed allergens.
The molecular cellular theory of the mechanism of action of AIT is currently well studied, and the induction of regulatory T-cell production to alter peripheral T-cell tolerance is a key step in altering the immune response, which can induce a shift from a Th2 cell activation-based response pattern to a Th1 cell pattern. From a historical point of view, allergen immunotherapy by subcutaneous injection of allergen extracts once or twice a month is the preferred treatment option. However, subcutaneous immunotherapy has a lower systemic risk and potential for allergic reactions, and other routes of administration (with a particular emphasis on sublingual immunotherapy) are being investigated for safety and efficacy.
However, 100 years of clinical trials have made it difficult to reach a consensus on the optimal regimen for selected allergen extracts and routes of administration (based on dosing frequency, dose per allergen, duration of treatment, cumulative dose). Therefore, this article briefly reviews some persistent misconceptions, cites some adequate medical and scientific evidence, and dispels these misconceptions.
Misconception 1: Allergic rhinitis is an unimportant disease.
In fact, AR is under-diagnosed and under-treated, and his symptoms are more complex than many doctors or even patients think. In a large European study, it was reported that 2/3 of AR patients have at least one symptom that seriously affects sleep quality and daily life, learning, memory, social adaptation, overall quality of life, and low quality sleep is a troublesome problem.
In a French study, 44% of AR patients were reported to feel tired and tended to be depressed and anxious. In another European-wide study, 1/3 of patients were prone to impatience and 12% suffered from persistent or intermittent depression. The study also highlighted the association of disease severity with comorbidities (including fatal asthma). One third of the AR patients surveyed were diagnosed with comorbid asthma, and 3/4 of the patients with asthma had comorbid AR of moderate to severe severity.
We recognize that the national social security system does not cover all costs of AR. When faced with challenges such as the global financial crisis, rarer and more serious diseases (e.g., cancer and neurodegenerative diseases), AR is insignificant compared to them. However, the most immediate consequence of ignoring AR is that people’s treatment, health and functioning are substandard. In a Danish study, 83% of patients with moderate-to-severe rhinitis were inadequately treated (i.e., they received only antihistamines or even no treatment at all).
Misconception 2: AIT is used in all patients with AR.
International guidelines and the ARIA consensus (guidelines related to AR and asthma diagnosis and treatment) clearly state that AIT is a second-line drug when medication is ineffective or intolerable or when the patient refuses medication or has adverse side effects. The guidelines state that AIT is particularly appropriate for patients with moderate-to-severe AR who are ineffective at symptomatic treatment, do not accept or are unwilling to use pharmacotherapy.
This has a good evidence that AIT is appropriate for patients with clinical symptoms. For example, a causal analysis, in a cohort of patients with AR treated with sublingual immunotherapy with pollen found that compared to a blank placebo-controlled study, patients with mild, moderate, and severe degrees of disease activity achieved clinical efficacy scores of 15%, 26%, and 37%, respectively (symptom efficacy scores based on placebo control group).
In similar pediatric trials, classified as mild, moderate, and severe disease, the different efficacy was 10%, 33%, and 34%, respectively, compared to placebo controls; therefore, the greater the initial symptom score the better the treatment efficacy. Using a different approach, Durhum et al. came to the same conclusion that the more severe the symptoms, the better the effect of sublingual immunotherapy with pollen.
Misconception 3: Sublingual immunotherapy for allergic rhinitis is not particularly effective.
Numerous meta-analyses (e.g. 12), systematic evaluations, high-quality clinical trials, and randomized double-blind placebo-controlled trials have found sublingual immunotherapy (SLIT) to be highly effective in hay fever. It is hard to believe why the erroneous view can exist. Studies published before the 1880s (smaller study populations and non-optimal experimental designs) had conflicting results and may be responsible for the lingering suspicion.
The reason for the skepticism regarding the efficacy of SLIT is that very little is known about the mechanism of action of AIT. The efficacy of allergen immunotherapy in the treatment of hay fever is unquestionable and the knowledge of how AIT works is well established. We are confident that the remaining questions about the efficacy of AIT in the treatment of AR caused by other allergens will be resolved in time through effective clinical trials.
Misconception 4: AIT has no short-term clinical efficacy.
The fact that AIT treatment is recommended to last several years leads to the misconception that it takes several years for this treatment to become effective, and Noon and Freeman documented clinical efficacy in patients after a few weeks to 8 months of treatment. The vast majority of recent large-scale trials involving pre-treatment in the first 2 to 4 months of the pollen season have achieved substantial clinical efficacy.
The difference in clinical efficacy scores between the DBPC (randomized double-blind blank-controlled) trial of taking Harvest Pollen tablets during pollen season exposure, after one week, one month, two months, and four months of treatment initiation, respectively, and the placebo control group, showed that efficacy was significant after 1 month. Therefore, SLIT begins to have clinical efficacy a few weeks after administration of the drug.
Misconception 5: The efficacy of AIT therapy does not persist after discontinuation of the drug.
This misconception differs from the previous view that SIT has neither short- nor long-term efficacy; AIT is clearly different from allopathic medicine because it produces lasting clinical effects when subsequent treatment is discontinued. For example, a study involving 257 hay fever subjects (who were treated with daily sublingual pollen extracts and a blank control) found clinical improvement and associated immunological changes lasting for at least two years.
In addition AIT treatment increased in efficacy from one period to another, with patients showing similar, sustained reductions in symptoms and medication scores one year after treatment discontinuation (mean reductions of 26% and 29%, respectively). Recent large-scale clinical trials have demonstrated that late efficacy observations correlate with the previous three phases of treatment, that sustained treatment is required to achieve late efficacy, and that (at least for modern allergen agents) single-phase treatment and one year of treatment are ineffective.
As with other long-term regimens, therefore, AIT also requires good patient compliance to be effective. In addition, allergens, unlike pollen extracts, still need to be studied. However, AIT is a disease-modifying treatment modality that does not require antihistamines and hormonal medications in the future.
Misconception 6: AIT is not indicated for patients with multiple allergies.
This misconception is slightly less sensible than saying “antihistamines are not indicated for patients with multiple allergies”. AIT has been shown to be effective in patients with multiple allergies in numerous well-documented clinical trials. It is difficult to achieve such an effective overall treatment effect with high efficacy in a small number of patients. Certainly, causal analysis confirmed that sensitization status was not a significant covariate of placebo-controlled efficacy in the two large trials.
Misconception 7: Home self-administration of SLIT is not safe.
It is clear that sublingual preparations of inhaled allergens have a clear safety profile and are perhaps the best route of treatment for allergic diseases. A recent review of 11-point case reports found that systemic allergic reactions (non-fatal) to SLIT were caused by non-compliance with standard routine practice. In fact, this involved non-standard extracts, rapid ingestion, drug overdose and hasty discontinuation of the drug by the patient due to severe adverse reactions to prior SCIT treatment.
The authors counted 1 billion units of SLTI dosing being commonly taken between 2000 and 2010 (i.e., 1 in 1 million SLIT-treated patients with systemic allergic reactions or 1 in 56,000 patients after years of treatment.) This reliable safety profile may be due to the rapid local occurrence of antigen capture, with small numbers of antigen-presenting cells and mast cells in the sublingual tissue. However, all physicians administering SIT therapy (and, of course, all patients receiving it) should be aware of the risk of tachyphylactic allergic reactions and know how to recognize and treat (or seek treatment for) them promptly.
Misconception 8: Allergic disease is lifelong with the patient.
Reliable epidemiological evidence suggests that allergic respiratory disease changes with age, with children developing and/or showing atopy in the first few years or even months of life. Overall, the “allergic process” means that many patients with AR will develop allergic asthma (AA) (and vice versa). Of course, some patients are born with a combination of allergic diseases (essentially in adolescence).
In the year in which the natural course of AA and AR progresses, the introduction of disease-modifying treatments, such as the introduction of AIT for the treatment of genetic allergic diseases, is now the treatment guideline, and for safety and compliance reasons AIT treatment is appropriate for children over 5 years of age. However, with the early views on allergic diseases, we believe that clinical trials of AIT in children under 5 years of age are theoretically justified. There is a need to develop allergy prevention strategies (currently, the best is breastfeeding) and to test new, child-friendly minimal doses (e.g., allergen patches) that have the potential to promote strong evidence of hay fever AIT for food allergy.
In summary.
Allergic rhinitis is an idiosyncratic, under-diagnosed, and under-treated, chronic allergic respiratory disease. If physicians ignore the severity of symptoms, AR remains morbid and the quality of life is extremely low. noon and Freeman’s seminal paper in 1911 prompted an enthusiastic but empirical and sometimes unethical clinical practice in the field of allergen immunotherapy research in the first half of the 20th century. As a result, AR allergen immunotherapy has suffered from an enduring “misbelief” caused by poor methodology.
Despite becoming the recommended treatment guideline, AIT is not accepted by physicians. However, DBPC trials, meta-analyses, systematic reviews, and high-quality clinical trials have dispelled the misconception that AIT is the only treatment for allergic modulation of immunity. With proper screening of patients, modern in the treatment of common allergen-induced AR, there is no doubt that AIT is safe and effective.