New Directions in Immunotherapy

Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for initiating and adhering to treatment.     

Allergen immunotherapy: 100 years, but it does not look like

Allergen immunotherapy (AIT) is the only treatment able to act on the causes and not merely on the symptoms of allergy. AIT was introduced 100 years ago but remained an empirical treatment for more than 40 years, when the first controlled trial in 1954 opened the era of scientific evidence. A major advance was the introduction of venom immunotherapy to prevent anaphylaxis from insect stings in 1978. Concerning inhalant allergens, currently AIT may be administered in two forms, subcutaneous (SCIT), and sublingual immunotherapy (SLIT). A large number of trials, globally analyzed in a number of meta-analyses, gave sound evidence to the efficacy and safety of SCIT and SLIT in allergic rhinitis and asthma. Adverse systemic reactions are still a drawback for SCIT while safety and tolerability of SLIT are very good, provided recommended doses and schedules of administration are used A significant advance for SLIT development was the registration in Europe of the standardized quality tablets. New applications, such as food allergy and atopic dermatitis, as well as new routes of administration, are currently under evaluation. After 100 years of use, AIT has a central role in the management of allergy and the ongoing improvement seems able to warrant to AIT an even brighter future.     

The role of immunotherapy in the management of childhood asthma

Subcutaneous immunotherapy (SCIT) is still questioned as a safe and efficacious way of treating allergic asthma in children. In a Cochrane review published in 2010 it was, however, concluded that SCIT has significant and beneficial effects on symptoms and medication use in both children and adults with mostly mild asthma. Only a few studies have been performed to specifically study if SCIT in children with moderate asthma reduces the need for inhaled corticosteroids. There are conflicting results that illustrate the problem of the heterogeneity of the asthma disease and the fact that allergies may play different roles on the severity and symptoms of the disease. Furthermore, children with severe allergic asthma are often sensitized to multiple allergens, which makes SCIT both complicated and less safe to administer. On the other hand, if the child suffers from asthmatic symptoms despite adherence to pharmacotherapy, omalizumab or a combination of omalizumab and allergen immunotherapy might be useful. There is a need for more studies on this combination before it can be considered as an additional therapy in children with asthma and severe allergies. Sublingual immunotherapy (SLIT) has also been shown to improve asthma symptoms and medication use. SLIT is safe although its efficacy compared with SCIT has been studied very little. Another approach is to try to prevent asthma by treating children with SCIT for allergic rhinoconjunctivitis before asthma has developed. The most attractive prospect, however, is to find ways of preventing asthma by vaccination against the most common viruses, particularly rhinovirus. There is evidence that there are children at high risk of developing asthma in whom a viral infection can also enhance the risk of allergen sensitization. So far this vaccination has not been achievable although research is in progress.     

Subcutaneous versus sublingual immunotherapy for allergic rhinitis and/or asthma

Subcutaneous allergen-specific immunotherapy has long been used in allergic rhinitis and/or asthma and has been recognized to be efficacious. However, owing to the inconvenience of injection and the risk of serious side effects, alternative concepts inspiring the search for effective noninjective routes, namely sublingual administration of allergens, have emerged. Sublingual immunotherapy (SLIT) appears to be associated with a lower incidence of systemic reactions. The clinical efficacy of subcutaneous immunotherapy (SCIT) is well established for both rhinitis and asthma. Meta-analyses relating to its efficacy on asthma and rhinitis are available. SLIT has also been validated in this respect. Comparative clinical studies of SLIT versus SCIT are scarce demonstrating both routes to be clinically efficient. Knowledge of the exact mechanism of action of SLIT has been increasing in the last decade. In addition, recent studies have proved similarities of the immunological changes with the treatment of both routes. Further comparative clinical and immunological studies of SLIT versus SCIT are needed to confirm the long-term efficacy and to complete the knowledge of immunological mechanisms of both routes. Moreover, better understanding of the interaction of allergen and oral mucosal dendritic cells during SLIT may allow improved targeting of SLIT vaccines.     

Allergen immunotherapy in allergic respiratory diseases: from mechanisms to meta-analyses

Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG(4) and IgA(2,) which can then result in an "immune deviation" from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state.     

One century of allergen-specific immunotherapy for respiratory allergy

Among the treatments available for respiratory allergy, which include allergen avoidance and pharmacotherapy, specific immunotherapy (SIT) is the only treatment able to not only act on the symptoms of allergy but also act on the causes. SIT is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects and was introduced one century ago. SIT remained an empirical treatment for more than 40 years, but the first controlled trial in 1954 paved the way for the scientific era. At present, SIT may be administered in two forms: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). A large number of trials, globally analyzed in several meta-analyses, evaluated the efficacy and safety of SCIT and SLIT in allergic rhinitis and asthma. Current available data give solid evidence to the clinical efficacy of both SCIT and SLIT in allergic rhinitis and asthma. Providing the recommended doses and administration schedules are adhered to, the safety and tolerability are very good; however, adverse systemic reactions remain a drawback for SCIT. After one century of use, accumulating evidence surrounds SIT and the central role in the management of respiratory allergy.     

Subcutaneous and sublingual immunotherapy in children: Complete update on controversies,dosing, and efficacy

For this review, articles on immunotherapy dosing in pediatric respiratory allergy were identified via PubMed, through congressional abstracts for 2008, in reference lists of recent review articles, and via personal communication with experts. In pediatric subcutaneous immunotherapy (SCIT), doses shown to be effective, mostly in aluminium-adsorbed preparations administered every 6 weeks, contain 20 μg of group 5 major allergen, 12 μg Bet v 1, 15 μg Fel d 1, and 5 to 20 μg Der p 1. Evidence indicates that SCIT prevents new sensitizations and asthma onset 7 years after discontinuation and reduces symptoms 12 years after a 5-year SCIT course, even though skin reactivity returns. Consistent evidence of effect exists for sublingual immunotherapy in pediatric respiratory allergy with daily 15-to 25-μg grass group 5 major allergen and 6 μg Bet v 1. Der p/f doses of 0.8/0.4 μg three times weekly (up to 27/57 μg daily) demonstrate inconsistent findings. Evidence of effect exists for SCIT in pediatric allergic rhinitis and asthma as treatment and preventive management. Evidence of effect exists for sublingual immunotherapy in pediatric allergic rhinoconjunctivitis and seasonal asthma. Similar results are doubtful for perennial asthma.     

One hundred years of immunotherapy: review of the first landmark studies

In 2011, one hundred years of allergen immunotherapy was celebrated. Several landmark studies date from the first decades of experience with this treatment and are still cited today, often without analysis of the original articles. Original articles of the oldest landmark studies on subcutaneous immunotherapy (SCIT) and sublingual immunotherapy were sought and reviewed in detail, together with some publications on their authors' historical background. Details that might be of importance to the present allergists are highlighted in this article. Study design, preparation of allergen extracts used for immunotherapy and clinical findings of the following studies are discussed. For the European school, Noon 1911 was the first report of successful application of grass pollen extract; Frankland 1954 was the first double-blind placebo-controlled randomized trial (DBPC-RCT) in SCIT. For the European school: Noon published the first report of successful application of grass pollen extract (1911); Frankland was the first double-blind placebo-controlled randomized trial (DBPC-RCT) in SCIT (1954). For the American line: Clowes published the first successful trial of ragweed SCIT (1913); Cooke used skin prick testing as diagnostic method (1915); Loveless used venom immunotherapy with purified venom (not whole body extract) (1956); in 1961/1968 Johnstone showed in a DBPC-RCT dose-effect of an allergen mix and highly significant asthma reduction after up to 14 yrs of treatment of asthmatic children; Lowell and Franklin did the first DB-RCT demonstrating ragweed pollen efficacy as part of a multi-allergen mix and 1967 ragweed pollen extract dose response. We discuss the first studies for SLIT in 1927 from Black (oral-IT versus SCIT) and 1986 from Scadding, DBPC-RCT with house dust mite extract. We conclude that an in-depth review of investigators' observations, methods, and thoughts, however, can also be enriching for investigators in the field today.     

Current and Emerging Therapies for IgE-Mediated Food Allergy

Food allergies are a growing clinical problem leading to increased health care utilization and decreases in patient quality of life. Current treatment recommendations include strict dietary avoidance of the offending food as well as use of self-injectable epinephrine in case of accidental exposure with allergic reaction. Although many individuals will eventually outgrow their food allergies, a substantial number will not. Significant effort has been made to find novel treatments that protect patients from food-triggered reactions as well as to develop immune-modulating therapies that could lead to tolerance. In this review, three therapies that have shown the most promise for the treatment of food allergies are highlighted: oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy.     

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特异性免疫治疗(SIT)是变态反应疾病特有的病因治疗方法,是除避免接触变应原外能够影响变态反应疾病自然进程的惟一治疗手段。针对目前SIT特别是皮下注射免疫治疗(SCIT)存在的问题,国内外变态反应学者进行了大量研究,文章对SIT新的给药途径、新的适应证、变应原提取液制剂的改进、合并应用Anti-IgE治疗及cDNA免疫治疗等方面的研究进展进行了简要综述并对其临床应用前景进行了展望。     

Sublingual immunotherapy in pediatric allergic rhinitis and asthma: Efficacy,safety, and practical considerations

Specific allergen immunotherapy (SIT) is the only disease-modifying treatment for allergic rhinitis and asthma. Subcutaneous immunotherapy (SCIT) is the only method with a US Food and Drug Administration (FDA)-approved formulation, but safety concerns limit administration to medical facilities. Sublingual immunotherapy (SLIT), under investigation in the United States, appears to have a more favorable safety profile, which may expand its use to populations generally not treated with SIT (eg, young children). This paper reviews SLIT studies that were specifically limited to the pediatric population. Most demonstrated evidence of clinical efficacy, but approximately 29% failed to demonstrate efficacy in symptom and medication scores in the first treatment year. Efficacy was seen in a broad range of allergen doses, but optimal dose range has not been established. SLIT appeared to be well tolerated in children as young as 2 years, but serious adverse reactions, including anaphylaxis, were reported. SLIT is a promising immunotherapy that may expand the population receiving SIT because of the convenience of home administration due to its favorable safety profile. However, questions remain unanswered, including optimal therapeutic dose.     

Subcutaneous allergen immunotherapy for allergic disease: examining efficacy, safety and cost-effectiveness of current and novel formulations

Subcutaneous immunotherapy (SCIT) is a unique therapy for allergic disease because it provides symptomatic relief while modifying the allergic disease by targeting the underlying immunological mechanism. Its efficacy and safety have been established in the treatment of asthma, allergic rhinitis/rhinoconjunctivitis and stinging insect hypersensitivity in numerous controlled clinical trials. This review evaluates a spectrum of clinical factors, ranging from efficacy to cost-effectiveness, which should be considered in evaluating SCIT. The evidence for SCIT safety and efficacy for these conditions is reviewed in an evaluation of the systematic reviews and meta-analyses. The evidence for the persistent and preventive effects of SCIT is also examined. An overview of the SCIT outcomes measures utilized in clinical trials is presented. The cost-effectiveness of SCIT compared with conventional medication treatment, novel indications and formulations for SCIT are also explored in this review.     

Immunotherapy Safety: What Have We Learned from Surveillance Surveys?

Subcutaneous allergen immunotherapy (SCIT) is beneficial for the treatment of allergic rhinitis, asthma, and in preventing stinging insect anaphylaxis, but is not without risks. Four retrospective surveillance surveys and one on-going national prospective study have attempted to characterize the incidence and risk factors for fatal and non-fatal SCIT reactions. These studies have contributed significantly to currently recommended SCIT safety guidelines. Recent surveillance studies indicate stable SR rates, and a possible decline in the incidence of fatal reactions since the implementation of evidence-based safety guidelines. This review will provide a detailed summary of the evidence from surveillance studies for risk factors associated with SCIT reactions, including: uncontrolled asthma, prior systemic reactions, dosing during peak pollen seasons, epinephrine being delayed or not given, dosing or administration errors, inadequate waiting times, reactions occurring more than 30 min after injections, injections given in medically unsupervised settings, concomitant beta-blocker and angiotensin-converting enzyme inhibitor (ACEi) use, and accelerated build-up regimens.     

Allergie à lˈarachide

Peanut allergy, which is frequent in the United States and was much less so in Europe up to the mid-eighties, has become a major problem in many industrialized countries. Peanut consumption is high in Eastern Europe, the United Kingdom, The Netherlands, Germany and France. The frequency of peanut allergy is between 0.5 and 0.7% in the general population. Two million Americans are now thought to be affected. In France peanuts are one of the most frequent allergens, lying second (27.4%) to egg in food allergies in children, and holding first place in food allergies in children aged over 3 years. Sensitization occurs through ingestion, contact even if indirect, and inhalation. The symptoms, which affect the skin and the respiratory or gastrointestinal tract, appear a few minutes to a few hours after exposure. Serious reactions (anaphylactic shock, life-threatening reactions, sudden death) have been described. Asthma has a significantly higher association with peanut allergy than with other allergies, taken overall. As with other food allergies, diagnosis is based on history, prick-tests, screening for specific serum IgE and food challenge whose modalities (labial and oral challenge) are debated. For the time being, elimination is the only form of treatment. The development of a modified allergen as immunogenic as possible but practically without allergenic effects should give immunotherapy new impetus. Patients with severe peanut allergy should carry a card or wear a distinctive bracelet indicating their condition as well as an emergency kit including in particular epinephrine.     

Immunotherapy: when to initiate treatment in children.

Although immunotherapy has documented short- and long-term benefits with regard to treatment of allergies and asthma as well as reducing development of new allergies and preventing progression of allergic rhinitis to asthma, the age to begin subcutaneous allergen immunotherapy appears established at the age of 5 years by published guidelines for treatment. The rationale for this age limit was examined and found to not reflect actual immunotherapy practice. Reasons for considering a downward revision are explored in this article. The conclusions from this review of past data and some recent studies with young children, especially with asthma, suggest that there is a need to consider beginning allergen immunotherapy earlier than the age of 5 years in more children.     

Pneumologische Allergologie II

Management of respiratory allergies comprises prevention of exposure to allergens, pharmacologic treatment with controllers and relievers and specific immunotherapy (SIT). Omalizumab is an immunomodulating agent the use of which is confined to asthma which cannot otherwise be treated. Avoiding exposure to tobacco smoke is easily implemented and effective. Controlling airway inflammation primarily by inhaled glucocorticosteroids is of high significance and is already to be applied at step 2 in a 5-step treatment. In managing allergic rhinitis topical glucocorticosteroids are likewise of high significance. The SIT as a causal approach is proven in either form of application in treatment of rhinitis but the efficacy in asthma is still limited. Concerning sublingual immunotherapy (SLIT) in treatment of asthma a conclusive appraisal is not yet permitted.     

Immunotherapy with Alternaria alternata: present and future

The prevalence of fungal allergies is greater than previously believed; consequently, such processes have been underestimated as potential causes of respiratory tract disease. Most patients sensitized to fungi exhibit perennial symptoms, though their intensity increases in the summer and autumn months. Skin reactions to the antigens of Alternaria alternata are associated with a high risk of allergic respiratory conditions in the presence of spores of this fungus -fundamentally in children and young adults- with a special form of presentation as life-threatening asthma. Very few controlled studies have examined the efficacy and safety of fungal extract immunotherapy -the main problem being the lack of standardized extracts for the diagnosis and treatment of such patients. In the year 2005 a tolerance study was made in children in relation to a depot extract containing the predominant antigen of Alternaria, with two different regimens (short and cluster). Tolerance was found to be good, with a 0.95 % incidence of local reactions and a 0.95 % incidence of grade 2 systemic reactions. Few studies involving sublingual immunotherapy have been conducted to date.     

吸烟与支气管哮喘研究进展

吸烟是支气管哮喘(简称哮喘)发病的危险因素之一。吸烟的哮喘患者在临床表型、影像学表现和气道炎症方面与普通哮喘患者不同。吸烟可加速肺功能下降,加重哮喘病情。吸烟哮喘患者气道重塑更严重。吸烟降低哮喘患者激素治疗敏感性。