J investing allergol clin immunol 2011
Published 17.12.2019 в Mohu leaf placement tips for better
Here, we review approaches that are currently in clinical trials, including oral, sublingual, and epicutaneous immunotherapy, immunotherapy combined with anti-IgE, and Chinese herbal medicine as well as approaches that are in preclinical or early clinical investigation, including modified protein immunotherapy, adjuvants, DNA vaccines, and helminth administration.
We discuss the importance of fully exploring the risks and benefits of any treatment before it is taken to general clinical practice and the need for clarity about the goals of treatment. Introduction Food allergy is defined as an immunologically mediated response that occurs repeatedly on exposure to a food 1. Although food allergy encompasses both IgE-mediated disease, typically characterized by acute symptoms such as hives or respiratory distress, and non-IgE—mediated conditions, such as milk-protein proctocolitis and eosinophilic gastrointestinal diseases, this review focuses on IgE-mediated allergy.
There are currently no approved treatments for food allergy except for avoidance of the allergenic food and treatment of accidental reactions. While much childhood food allergy is outgrown, a substantial proportion of even milk and egg allergy persists into adulthood, and some food allergies, such as peanut, tree nuts, and shellfish, are usually persistent 1.
Although mortality from food-related anaphylaxis is rare, estimated to be approximately 1. Moreover, avoidance diets can leave food-allergic children at nutritional risk 7. It is estimated that food allergy costs the US almost 25 billion dollars per year in direct and indirect expenses 8. For all of these reasons, effective treatment for food allergy would be highly desirable. However, while potential treatments are under active investigation, it is still not at all clear what the best approach may be.
Further, there is lack of consensus as to what the goals of therapy should be: while the ability to incorporate the food into the diet would be ideal, some would argue that simply minimizing the risk of reaction with accidental exposure would be of sufficient value to justify treatment. These questions are vital because we need criteria by which to evaluate novel treatments, especially if they carry risk of serious adverse reactions. In fact, whether the emerging therapies for food allergy are sufficiently beneficial to justify any significant risk remains to be determined.
Pathophysiology of food allergy IgE-mediated food allergy is characterized by Th2-dominant immunologic responses, with allergen-specific IgE present in circulating forms and bound to mast cells and basophils. The predominant mechanism by which food allergy develops remains controversial, with some studies suggesting that primary sensitization through skin contact may be even more important than exposure via the gut 9.
Active gastrointestinal tolerogenic mechanisms appear to be important in preventing food allergy in general, as children with genetic defects in generating regulatory T cells frequently have severe allergic disease 10 , APCs in the gut, particularly DCs, clearly direct these T cell responses and are themselves responsive to the context in which they receive antigen.
Abnormal function of both DCs and T cells has been linked to food allergy 12 — Contextual clues that influence DC responses include costimulatory signals through a variety of receptors, including the TLRs. These signals come from multiple sources, including those associated with tissue damage, commensal bacteria, and the allergen itself 20 , Responses to these signals may vary considerably due to genetic predisposition Although basic science has been helpful in understanding the mechanisms by which potential treatments for food allergy might work, to date, the most promising therapies have not come as a result of these discoveries but instead from clinical observation and the modification of therapies previously developed for other allergic diseases.
For example, immunotherapy, discussed at length below, was first described as a treatment for IgE-mediated allergic disease in 23 , more than 50 years before the discovery of IgE Some therapies, such as the recombinant peanut vaccine described below, emerged from basic science and appeared effective in animal models, but failed when tested in humans.
Still other approaches, such as DNA vaccines, which appear promising in animal models, may be difficult or impossible to safely translate to humans. In the following sections, we will first review approaches that are under active clinical investigation, after which we will review potential approaches that are in preclinical or early clinical investigation.
Current clinical investigations Current clinical investigations are summarized in Table 1. For venom and aero allergies, immunotherapy using intact, and often rather crude, allergens remains the only disease-modifying therapy available.
Although sublingual delivery is emerging as a treatment option for inhalant allergens, especially in Europe, most immunotherapy has traditionally been provided by s. Limited study of s. Table 1 Selected recent clinical studies Oral and sublingual immunotherapy.
Published case reports of sublingual immunotherapy or oral immunotherapy for the treatment of food allergy date back to at least through the s 26 — 29 , but the first randomized, placebo-controlled study of either method was not published until In recent years, there has been a proliferation of small and medium-sized studies of these methods 28 , 30 — 74 , but small sample sizes and variable study designs have made interpretation of the evidence difficult.
A Cochrane review of milk oral immunotherapy 75 up to October found five trials that met their quality criteria, with a total of patients. Of these trials, only three were blinded with a placebo arm, and each study used a different protocol. These findings are similar to other controlled studies of oral immunotherapy.
Eosinophilic esophagitis has been reported in some studies, and it is not clear how frequently undiagnosed disease may complicate immunotherapy. Fewer studies have been done with sublingual immunotherapy, but thus far it appears that efficacy is much less than with oral immunotherapy.
However, sublingual immunotherapy appears to be safer than oral immunotherapy, with significantly fewer multi-system, gastrointestinal, and lower respiratory reactions It is likely that the differences between oral immunotherapy and sublingual immunotherapy, with regard to both efficacy and safety, primarily represent differences in the antigen doses that are used, given that typical sublingual immunotherapy maintenance doses are under 10 mg compared with 1 to 4 grams for oral immunotherapy.
Improved sublingual immunotherapy efficacy might therefore be possible if higher doses were used, and in theory, an ideal sublingual immunotherapy dose might achieve efficacy similar to oral immunotherapy at far lower — and therefore safer — doses, given the high density of tolerogenic APCs in the sublingual space However, significantly higher sublingual immunotherapy doses will not be possible unless more concentrated extracts or alternative delivery systems, such as the tablets that have been formulated for grass pollen sublingual immunotherapy 78 , are developed.
Until then, maximum sublingual immunotherapy dosing will remain limited by the concentration of the available aqueous extracts and the volume of liquid that can be safely administered sublingually. The mechanisms of action underlying oral immunotherapy and sublingual immunotherapy are not entirely clear, although it is likely that a combination of suppressive mechanisms, anergy, and deletion of reactive T cells is important refs.
With treatment, allergen-specific IgE tends to rise initially and then fall marginally by the completion of treatment. Specific IgG4 levels increase, and markers of basophil activation and mast cell reactivity as evidenced by skin test responses typically decrease 47 , 53 , Although these changes occur in most subjects, especially with oral immunotherapy, and may be associated with more positive outcomes, the data thus far do not allow for any of these measures to be used as reliable biomarkers of clinical response.
Figure 1 Potential mechanisms by which specific immunotherapy to food may act. Multiple cellular responses to immunotherapy may contribute to reduced immune activation, including deletion of effector Th2 cells, desensitization of mast cells and basophils, and induction of tolerogenic DCs. In addition, immunotherapy may promote allergen-specific Tregs, which in turn suppress effector T cells, reduce activation of mast cells and basophils, and trigger B cells to first increase IgG4 production and then decrease IgE production, leading to decreased activation of mast cells and basophils.
Although the persistence of desensitization after avoidance of the allergen has only been assessed in a few studies, the results are sobering overall. This concept is very important because if sustained protection is not the norm, the long-term safety of food immunotherapy after treatment may be far more problematic than the known short-term risks during treatment. While ongoing consumption of the problem food may afford protection for most, this does not appear to always be the case and, even if it were, this is something that can be difficult to achieve, even in the research setting Anti-IgE therapy.
Anti-IgE agents such as TNX and omalizumab, which is licensed for the treatment of asthma, have been shown to increase the food challenge threshold to peanut. These treatments have the advantage over immunotherapy that they are non—allergen specific and thus may be effective for those who are allergic to multiple foods. However, their effects are dependent on continued injections of the antibody 81 , 82 , and this treatment is very expensive.
In conjunction with s. Two small, uncontrolled studies of omalizumab combined with rush food oral immunotherapy, where dose escalation was performed at a more rapid pace than usual using either peanut or milk, have recently been published. However, normal levels of serum tryptase in the first sample do not exclude anaphylaxis. Other biomarkers, such as histamine and its metabolites, chymase, carboxypeptidase, cysteinyl leukotrienes, prostaglandins, or platelet-activating factor, have lower and variable positive predictive values for a diagnosis of anaphylaxis than serum tryptase [ 42 ].
The identification of agents which trigger the anaphylactic reaction is essential for prevention of new exposure and recurrence. In general, diagnostic testing should be performed 3—4 weeks after the acute episode to allow time for the recovery of mast cell activity [ 43 , 44 ]. The etiological diagnosis can be supported by serologic methods, e.
These techniques offer interesting alternatives in the diagnosis of potential triggers of anaphylaxis. Although in vitro tests are safer, their sensitivity and specificity remain to be determined. The main in vivo tests currently used to investigate allergy and hypersensitivity reactions are skin tests and provocation tests [ 41 ], which follow standard methods and practice parameters and should be requested, performed, and interpreted by experienced professionals.
Co-factors, or augmenting factors, such as concomitant asthma, exercise, or specific drugs e. Co-factors may lead to more severe reactions or to anaphylaxis with lower doses of allergen. Physical exercise is one of the best-known augmenting factors in anaphylaxis. In fact, food-dependent exercise-induced anaphylaxis is considered a distinct clinical syndrome [ 46 ].
In general, the mechanisms underlying the role of co-factors in anaphylaxis remain poorly understood [ 48 ]. Table 2 Most common co-factors of anaphylaxis Full size table Acute management of anaphylaxis Anaphylaxis is a life-threatening medical emergency, and prompt evaluation and intervention are critical for its management. All health professionals should be prepared to identify and treat patients with anaphylaxis.
An apparently mild presentation may unpredictably progress to fatal anaphylactic shock in minutes [ 49 ]. The severity of an anaphylactic episode can differ from one patient to another, and even in the same patient from one episode to another [ 50 ]. They should not be placed seated, standing, or in the upright position.
In cases of vomiting or dyspnoea, the patient should be placed in a comfortable position with the lower limbs elevated. Help should be requested as soon as possible. When indicated, supplemental oxygen and intravenous fluid should be administered and, if necessary, cardiopulmonary resuscitation should be performed [ 53 ]. Biphasic anaphylaxis is defined as recurrence of anaphylaxis hours after recovery of the initial symptoms, with no further exposure to the trigger [ 1 ].
Given that biphasic anaphylaxis is not uncommon [ 21 , 54 ], patients overcoming symptoms should undergo monitoring and medical supervision in a centre with trained staff, an ED, and hospital beds available. The duration of monitoring must be tailored to the severity of symptoms [ 55 ].
Pharmacologic treatment of anaphylaxis: epinephrine as the drug of choice Evidence supporting the use of different medications for the treatment of anaphylaxis is based on observational, epidemiologic, pharmacologic, and animal models, as well as on post-mortem studies [ 56 ]. The severity of anaphylaxis makes epinephrine difficult to assess in prospective, randomized, double-masked, placebo-controlled trials [ 57 ].
Epinephrine is the medication of choice for the immediate treatment of anaphylaxis [ 58 ] and is the only drug that exerts a vasoconstrictor effect, thus reverting airway mucosal edema and hypotension [ 59 ]. Additionally, it has inotropic and chronotropic cardiac effects, bronchodilator activity and a stabilization effect on mast cells and basophils [ 60 , 61 ].
Evidence has shown that delayed injection of epinephrine is associated with higher hospitalization and mortality rates [ 62 , 63 ]. In contrast, prompt pre-hospital administration of epinephrine is associated with better outcomes [ 64 , 65 ]. Epinephrine should be injected by the intramuscular route in the vastus lateralis muscle outer thigh due to its vasodilator effect in skeletal muscle, which facilitates rapid absorption and pharmacologic effects.
In contrast, it acts as a vasoconstrictor in the subcutaneous tissue, potentially delaying its absorption [ 66 , 67 , 68 ]. The dose of epinephrine for the treatment of anaphylaxis in a health centre is 0. The maximum dose is 0. With an EAI, patients weighing between 7. The epinephrine injection can be repeated once or twice at 5—15 min intervals in patients who do not respond to the first dose, in patients whose reaction is progressing rapidly, or in biphasic anaphylaxis [ 69 ].
A third dose of epinephrine is needed less frequently [ 70 , 71 ]. Lack of response to epinephrine is an indicator of the need for admission to the intensive care unit, where the patient can receive further care, such as intravenous infusion of epinephrine [ 72 ]. Administration of therapeutic doses of epinephrine, as used in anaphylaxis, may induce adverse effects, including transient anxiety, headache, dizziness, tremor, pallor, and palpitations.
These symptoms are similar to those caused physiologically by increased endogenous epinephrine levels. However, the adverse effects cannot be dissociated from the beneficial effects of epinephrine [ 57 , 60 , 61 , 73 ].
Less frequently, usually due to overdosing or the administration of an intravenous bolus, epinephrine may cause ventricular arrhythmias, pulmonary oedema, malignant hypertension, and intracranial haemorrhage, although these effects are very rare in children and healthy adults [ 59 , 61 , 74 , 75 ].
There is no absolute contraindication to epinephrine in the treatment of anaphylaxis [ 50 ]. However, the risk—benefit ratio should be assessed in patients with cardiovascular disease [ 76 ]. The heart is a potential target organ in anaphylaxis, and acute coronary syndrome can occur during anaphylaxis in the absence of epinephrine [ 77 ]. Second-line drugs for the treatment of anaphylaxis Antihistamines both anti-H1 and anti-H2 and corticosteroids are second-line medications for the treatment of anaphylaxis, since they are not life-saving and, therefore, should not be used as initial or only treatment [ 58 , 78 , 79 ].
There is no evidence that supports the use of H1-antihistamines in anaphylaxis. H1-antihistamines relieve itching, flushing, and urticaria, but they do not act on airway obstruction or hypotension. Their onset of action is slower than that of epinephrine. Moreover, recommendations for anaphylaxis, including the doses administered, are extrapolated from those used in urticaria.
A limited number of first-generation H1-antihistamines is available in parenteral form for use in anaphylaxis. These drugs frequently cause mild side effects e. Severe adverse effects e. Second-generation H1-antihistamines are more secure; however, they are not available for parenteral use. Nevertheless, antihistamines are still the most frequently wrongly used drugs for the treatment of anaphylactic reactions in the ED [ 58 , 80 , 81 ].
There is evidence that the effect of H2-antihistamines, when administered concurrently with H1-antihistamines, could be enhanced in skin symptoms, although their role in anaphylaxis remains unclear [ 79 , 82 ]. Corticosteroids are traditionally administered to prevent biphasic or protracted anaphylaxis, although these effects have never been proven.
Their use in asthma indicates that the onset of pharmacological action may take several hours after administration. Therefore, corticosteroids have little or no effect on initial symptoms or signs [ 78 ]. Inhaled beta-2 adrenergic agonists, such as salbutamol or terbutaline, may play a role in anaphylaxis by relieving bronchospasm, in addition to the effect of epinephrine. However, the administration of these drugs should never delay the administration of epinephrine [ 2 ].
Long-term management of anaphylaxis Management of anaphylaxis continues after resolution of the acute episode. The key to preventing future anaphylactic reactions is a confirmed etiological diagnosis and the avoidance of triggers. In some cases, long-term etiologic treatments may provide protection in case of accidental exposures, such as allergen-specific immunotherapy in cases of Hymenoptera venom-induced anaphylaxis. Finally, the patient should know how to treat new symptoms in case they re-appear [ 2 , 3 , 4 , 5 , 83 ].
All patients who experience an episode of anaphylaxis should be advised that their specific triggers must be identified. Important differences between the etiological diagnosis suspected in the ED and the definitive cause of anaphylaxis have been reported in recent studies in adults and children [ 28 , 84 , 85 ].
The triggers of anaphylaxis can be identified by allergy specialists, who will also provide information on possible cross-reacting agents and safe alternatives, especially in the case of drug hypersensitivity. Such an approach has proven useful for reducing the risk of severe anaphylaxis [ 86 ]. It is usually accepted that the optimal time for testing is around 4 weeks after the acute episode [ 5 ]. Given the unpredictable nature of anaphylaxis, patients should be prepared to act whenever necessary, especially when health care professionals are not present.
International guidelines consider written action plans to be a useful tool for optimizing outcome [ 2 , 3 , 4 , 5 ]. An anaphylaxis action plan is a written document that can guide the patient and caregivers in the event that he or she experiences an allergic reaction in the community Table 3. The several available action plan models have improved outcomes for other allergic diseases, such as asthma, and thus have the potential to reduce the frequency and severity of reactions, as well as the anxiety felt by patients and their caregivers [ 91 ].
Table 3 Summary of data that should be included in a personalized anaphylaxis emergency action plan Full size table EAIs are the preferred method for administration of epinephrine in the community setting. Given that handling of ampoules, needles, and syringes by patients or their relatives is often subject to error, the EAI could be preferable when commercially available [ 2 , 3 , 4 , 5 ]. Currently, EAIs administer three doses, namely, 0.
Self-injectable epinephrine may also be used in health care settings [ 92 ]. Self-injectable epinephrine should be prescribed to patients with a history of anaphylaxis and a high probability of recurrence, especially when triggered by foods or insects and in patients with idiopathic anaphylaxis. Patients living in isolated areas without access to medical services, and patients with mastocytosis, should also receive EAIs Table 4 [ 2 , 3 , 4 , 5 ]. Table 4 Indications for prescription of epinephrine auto-injectors Full size table Specific patients with no history of anaphylaxis should also keep an EAI at home.
These cases include patients with previous generalized skin reactions after exposure to trace amounts of food and those who are allergic to triggers that are difficult to avoid owing to their ubiquity e. The number of devices prescribed should be considered.
General indications for prescribing 2 or more EAIs include high body weight, fear of possible misuse, a history of biphasic or protracted reactions in the past, and concomitant severe asthma Table 4 [ 93 ]. Nevertheless, prescription of an EAI must be based on objective data from the medical history after the risk—benefit ratio has been properly assessed. Carrying an EAI has been associated with impaired quality of life [ 94 ]. There is growing evidence on the benefits of education with the aim of reducing the morbidity and mortality of anaphylaxis, although long-term benefits have yet to be clarified [ 95 , 96 ].
Education should begin after the resolution of the acute episode, before discharge, and ED health professionals should be well prepared to provide correct guidance. Patients should be taught how to recognize anaphylaxis symptoms, when to inject epinephrine and seek medical assistance, and how to recognize and avoid possible co-factors, which may multiply the risk for severe anaphylaxis [ 50 ].
In the last few years, Internet and social media have become highly accessible information sources for health-related queries [ 97 ]. The few studies that have focused on the impact of these technologies in patients with anaphylaxis tend to describe the beneficial effects, as in other allergic diseases.
The use of Internet, social media, and mobile applications may play a role in future approaches to education in anaphylaxis [ 98 , 99 , ].
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