EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy.

Hymenoptera venom allergy is a potentially life-threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic-allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life-threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H1 -antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence-based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta-analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom-allergic children and adults to prevent further moderate-to-severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence-based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence.

Allergen immunotherapy for insect venom allergy: a systematic review and meta-analysis.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy. METHODS: We undertook a systematic review, which involved searching 15 international biomedical databases for published and unpublished evidence. Studies were independently screened and critically appraised using established instruments. Data were descriptively summarized and, where possible, meta-analysed. RESULTS: Our searches identified a total of 16 950 potentially eligible studies; of which, 17 satisfied our inclusion criteria. The available evidence was limited both in volume and in quality, but suggested that venom immunotherapy (VIT) could substantially reduce the risk of subsequent severe systemic sting reactions (OR = 0.08, 95% CI 0.03-0.26); meta-analysis showed that it also improved disease-specific quality of life (risk difference = 1.41, 95% CI 1.04-1.79). Adverse effects were experienced in both the build-up and maintenance phases, but most were mild with no fatalities being reported. The very limited evidence found on modelling cost-effectiveness suggested that VIT was likely to be cost-effective in those at high risk of repeated systemic sting reactions and/or impaired quality of life. CONCLUSIONS: The limited available evidence suggested that VIT is effective in reducing severe subsequent systemic sting reactions and in improving disease-specific quality of life. VIT proved to be safe and no fatalities were recorded in the studies included in this review. The cost-effectiveness of VIT needs to be established.

No cases of perioperative allergy to local anaesthetics in the Danish Anaesthesia Allergy Centre.

BACKGROUND: Local anaesthetics (LA) are often suspected as possible causes of allergic reactions. The Danish Anaesthesia Allergy Centre (DAAC) is the national reference centre for investigation of perioperative allergic reactions. The purpose of this study was to investigate the incidence of IgE-mediated immediate type perioperative allergic reactions to LA. METHODS: In the period 2004-2013, a total of 409 patients (244 women/165 men; median age 49 years, range 1-86 years) were investigated in DAAC on suspicion of allergy associated with anaesthesia and surgery. A total of 162 (40%) patients were exposed to one or more LA. Suspected allergy to LA was investigated by prick test, intradermal test and subcutaneous provocation with the suspected drug. Patients with positive skin tests still underwent subcutaneous provocation, as false positive skin tests can occur. RESULTS: A total of 203 test series with LA were carried out on 162 patients (89 women/73 men; mean age 49 years, range 2-85 years) with the following drugs: Lidocaine n = 80 (49%), bupivacaine n = 82 (51%), ropivacaine n = 31 (19%) and mepivacaine n = 10 (6%). All 162 patients had negative subcutaneous provocation for all tested LA (95% CI: 0-1.8%). Investigations revealed another allergen in 52 of 162 patients. CONCLUSION: None of the 162 patients with suspected perioperative allergic reactions and exposure to LA reacted on subcutaneous provocation with the relevant LA. Thus, no patients have been diagnosed with allergy to LA in DAAC in the period 2004-2013 and allergy to LA must be considered very rare in this population.

Self-medication of anaphylactic reactions due to Hymenoptera stings-an EAACI Task Force Consensus Statement.

An anaphylactic reaction due to a Hymenoptera sting is a clinical emergency, and patients, their caregivers as well as all healthcare professionals should be familiar with its recognition and acute management. This consensus report has been prepared by a European expert panel of the EAACI Interest Group of Insect Venom Hypersensitivity. It is targeted at allergists, clinical immunologists, internal medicine specialists, pediatricians, general practitioners, emergency department doctors, and any other healthcare professional involved. The aim was to report the scientific evidence on self-medication of anaphylactic reactions due to Hymenoptera stings, to inform healthcare staff about appropriate patient self-management of sting reactions, to propose indications for the prescription of an adrenaline auto-injector (AAI), and to discuss other forms of medication. First-line treatment for Hymenoptera sting anaphylaxis is intramuscular adrenaline. Prescription of AAIs is mandatory in the case of venom-allergic patients who suffer from mast cell diseases or with an elevated baseline serum tryptase level and in untreated patients with a history of a systemic reaction involving at least two different organ systems. AAI prescription should also be considered in other specific situations before, during, and after stopping venom immunotherapy.

Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper.

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation.

No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut†.

BACKGROUND: Propofol is thought to be a potential cause of allergic reactions in patients allergic to egg, soy or peanut, since current formulations contain an emulsion that includes egg lecithin and soybean oil. However, other than six case reports lacking in confirmatory evidence of an allergic reaction, there is no evidence linking the two types of allergies. The aim of this study was to examine the frequency of propofol allergy and to investigate if patients with specific immunoglobulin E (IgE) to egg, soy or peanut tolerated propofol. METHODS: Study A examined the frequency of propofol allergy in 273 patients systematically investigated for suspected perioperative allergic reactions. Of these, 153 had been exposed to propofol and underwent skin tests and intravenous provocation. Study B retrospectively investigated propofol exposure and tolerance in 520 adult patients with a positive specific IgE to egg, soy or peanut. RESULTS: Four of the 153 propofol-exposed patients (2.6%) investigated in study A were diagnosed with propofol allergy. Of these, three tested positive only on intravenous provocation. None of the four had allergic symptoms when eating egg, soy or peanut and none had detectable levels of specific IgE to egg or soy in their serum. In study B we found no signs of allergic reactions towards propofol in 171 retrieved anaesthetic charts from 99 patients with specific IgE to egg, soy or peanut. CONCLUSION: No connection between allergy to propofol and allergy to egg, soy or peanut was found. The present practice of choosing alternatives to propofol in patients with this kind of food allergy is not evidence based and should be reconsidered.

Clinical and diagnostic features of perioperative hypersensitivity to cefuroxime.

INTRODUCTION: The Danish Anaesthesia Allergy Centre (DAAC) investigated 89 adult patients with suspected perioperative cefuroxime-associated hypersensitivity reactions between 2004 and 2013. The goals were to determine whether the time to index reaction after cefuroxime exposure could be used to implicate cefuroxime as the cause of the reactions and explore different test modalities in diagnosing cefuroxime hypersensitivity. METHOD: Skin tests, in vitro tests, and titrated provocations were used to determine cefuroxime hypersensitivity. Patients were deemed cefuroxime positive on the basis of at least two positive tests and/or a positive provocation. RESULTS: One or more tests were positive for cefuroxime in 24 of 89 (27.0%) patients. One was only specific IgE positive and was deemed cefuroxime negative. Twenty-three (25.8%) were deemed cefuroxime positive. There were four specific IgE-, 4 histamine release test-, 13 skin test-, and 14 provocation positive patients. There were eight (34.8%) patients who were only provocation positive. Data on time to index reaction after cefuroxime exposure were available for 80 patients (22 in the positive group and 58 in the negative group), 22 of 22 (100%) of positive patients reacted in <15 min vs. only 38 of 58 (65.5%) of negative patients. CONCLUSION: All patients with confirmed hypersensitivity to cefuroxime reacted within 15 min of administration, but so did 65.5% of Cefuroxime negative patients, making timing of administration an unreliable predictor of causation in the perioperative setting. Provocations were always positive when carried out in skin test positive patients; however, eight patients had positive provocations only, highlighting the need for provocation in skin test negative patients.

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper.

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.

Standardized testing with chlorhexidine in perioperative allergy--a large single-centre evaluation.

BACKGROUND: Perioperative allergic reactions to chlorhexidine are often severe and easily overlooked. Although rare, the prevalence remains unknown. Correct diagnosis is crucial, but no validated provocation model exists, and other diagnostic tests have never been evaluated. The aims were to estimate (i) the prevalence of chlorhexidine allergy in perioperative allergy and (ii) the specificity and sensitivity for diagnostic tests for chlorhexidine allergy. METHODS: We included all patients investigated for suspected perioperative allergic reactions in the Danish Anaesthesia Allergy Centre during 2004-2012. The following tests were performed: specific IgE (Immunocap® ; Phadia AB, Sweden), histamine release test (HR) (RefLab ApS, Denmark), skin prick test (SPT) and intradermal test (IDT). Positivity criteria were as follows: specific IgE >0.35 kUA/l; HR class 1-12; SPT mean wheal diameter ≥3 mm; IDT mean wheal diameter ≥ twice the diameter of negative control. Chlorhexidine allergy was post hoc defined as a relevant clinical reaction to chlorhexidine combined with two or more positive tests. Based on this definition, sensitivity and specificity were estimated for each test. RESULTS: In total, 22 of 228 patients (9.6%) met the definition of allergy to chlorhexidine. Estimated sensitivity and specificity were as follows: specific IgE (sensitivity 100% and specificity 97%), HR (sensitivity 55% and specificity 99%), SPT (sensitivity 95% and specificity 97%) and IDT (sensitivity 68% and specificity 100%). CONCLUSIONS: In patients investigated for suspected perioperative allergic reactions, 9.6% were diagnosed with allergy to chlorhexidine. Using our definition of chlorhexidine allergy, the highest combined estimated sensitivity and specificity was found for specific IgE and SPT.

Transfusion-associated anaphylaxis during anaesthesia and surgery--a retrospective study.

BACKGROUND AND OBJECTIVES: Transfusion-associated anaphylaxis (TAA) is a severe adverse reaction reported to occur in 1:9000-90,000 transfusions. According to the Danish Registration of Transfusion Risks (DART), the frequency is 1:300,000 transfusions, which suggests insufficient reporting of TAA in Denmark. Our aims were to identify possible cases of TAA, to characterize their symptoms and tryptase levels and to investigate the reporting of TAA to the haemovigilance systems. MATERIAL AND METHODS: We reviewed 245 patients with suspected allergic reactions during anaesthesia and surgery, investigated at the Danish Anaesthesia Allergy Centre (DAAC). Based on the outcome of this investigation, the patients were classified as DAAC positive (confirmed hypersensitivity to identified agent, n = 112), or DAAC negative (no confirmed hypersensitivity, n = 133). Data on case history, details of blood transfusion and results of laboratory and clinical investigations were collected. TAA cases were identified according to the recommendations of the International Society of Blood Transfusion (ISBT). RESULTS: Ten possible TAA cases (30% of all transfused patients) were identified, all DAAC negative. The frequency of elevated serum tryptase, hypotension and male sex was significantly higher among these cases compared with the remaining DAAC negative (P < 0·05), but not different from the DAAC-positive patients. One case had been reported to the Blood Bank haemovigilance system and none to DART. CONCLUSION: We identified unreported cases of possible TAA, which resembled the DAAC-positive patients with respect to elevated tryptase and symptoms. By applying the ISBT criteria of adverse transfusion reactions, we conclude that TAA during anaesthesia and surgery is likely to be underreported in Denmark.

Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper.

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.

Tolerability and efficacy of house dust mite AIT.

Sublingual immunotherapy based on grass pollen allergy immunotherapy tablets is an efficacious and well-tolerated treatment for rhinoconjunctivitis, and subcutaneous house dust mite (HDM) immunotherapy is effective against allergic asthma. Three studies have investigated a new ALK tablet for HDM allergy: two studies on tolerability in adults and children, and one on efficacy and safety in adults and adolescents with asthma. Treatment was well tolerated, mainly with mild-to-moderate local reactions pertaining to the administration site, such as temporary oral pruritus. The primary efficacy endpoint was a significant reduction in inhaled corticosteroid dose compared to baseline after 1 year of daily treatment. A positive therapeutic effect on asthma was demonstrated by a reduction of more than 80 µg/day inhaled budesonide for a group receiving six developmental units daily compared to the placebo group.

Optimizing diagnostic tests for persulphate-induced respiratory diseases.

BACKGROUND: Persulphates from hair bleaching products are considered the major cause of occupational-rhinitis and asthma in hairdressers. The specific inhalation challenge (SIC) is considered 'reference standard' for diagnosing persulphate-induced asthma and rhinitis; however, the currently validated method of performing SIC with persulphate powder is time consuming with a duration of up to 4 days. The value of skin prick tests (SPTs) and histamine release tests (HRTs) with persulphates is unknown. The aim of this study was to establish a novel rapid SIC with persulphate powder to test for both rhinitis and asthma simultaneously in 1 day. In addition, we assessed the suitability of SPTs and HRTs for detecting persulphate-induced respiratory diseases. METHODS: The study population included 19 hairdressers with a history of work-related rhinitis and/or asthma symptoms, 12 symptomatic controls (10 with concurrent allergic asthma and rhinitis and two with non-allergic asthma), and 40 healthy controls. A previous severe asthmatic reaction and/or anaphylactic reaction to persulphates was considered an exclusion criterion for hairdressers. The 19 hairdressers and 12 symptomatic controls had SIC performed with 3 × 5 min exposures to potassium persulphate powder in a provocation chamber. All participants, including the 40 healthy controls, were subjected also to SPTs and HRTs with three persulphate salts at concentrations of 2-20 % and 0.03-1 %, respectively. RESULTS: None of the symptomatic controls had a nasal or bronchial response to SIC with potassium persulphate. Six hairdressers presented a nasal and two a bronchial response. No severe reactions occurred. No positive SPTs were recorded, neither among hairdressers, symptomatic controls, nor healthy controls. All three groups showed nonspecific non-IgE mediated histamine release to persulphates in HRT. CONCLUSIONS: The proposed method for performing SIC showed a high specificity for detecting persulphate-induced asthma and rhinitis. The rapid SIC was able to produce positive nasal and bronchial responses in symptomatic hairdressers without any severe reactions occurring. SPTs and HRTs cannot predict asthma or rhinitis caused by persulphates.

[Allergy to dust mites]. / Allergi for husstøvmider.

House dust mites are the most important indoor allergens in our region. During recent years more dwellings have become infested, most likely as a result of increased indoor humidity due to reduced ventilation. Among Danish adults, 14% have developed IgE against mites. The allergens are stable and can remain for years. Keeping the humidity low (< 45%) during winter months is the most important limiting factor for mite growth. It can be accomplished by ventilation and heating. If bedding, pillow, eiderdown and covering mattress are washedat temperatures > 55 degrees C mites are killed and allergens removed. In addition mattress covers seem to be useful, although guidelines for quality assessment are lacking. Reduction in mite exposure will reduce development of allergy in all age groups especially in the newborn period. Immunotherapy can be offered in rhinitis and moderate asthma when sufficient allergen reduction cannot be accomplished.

[Insect stings and visits to emergency departments]. / Insektstik og skadestuebesøg.

For four representative hospitals, emergency room contacts were registered during 1988, 1989 and 1990. A total of 2,935 of these contacts were due to insect stings, equivalent to approximately 9,000 p.a. in the whole of Denmark. For insect sting allergics and for others with severe reactions to insect stings it is important to realize that stings can occur during whole year and during day as well as at night. However, 59% were stung in July or in August and 46% between 3 and 9 p.m. Stings on head or hands were most common. Only 2% required admission and only 5% were controlled in out-patient clinics or by doctors outside hospitals. This means that surprisingly few patients were referred for allergy testing and possibly immunotherapy.

[Diagnosis of allergy in bee-keepers. A 1-year prospective study]. / Allergidiagnostik hos biavlere. En etårs prospektiv undersøgelse.

Thirty-six Danish bee-keepers were clinically investigated by means of a questionnaire before and after the bee season 1990. Their serum was assayed for IgE and IgG antibody reacting with bee venom, and skin prick tests were performed prior to the season. Thirty-six percent had previously reacted abnormally, either with a systemic reaction (SR) (25%) or a large local reaction (LLR) (11%). Retrospectively, eight of the nine bee-keepers with SR had upon re-exposure developed a normal reaction, in spite of the fact that seven of them had specific IgE and/or a positive prick test at subsequent examination. At follow up 38% of the persons who had previously had a SR reacted with a SR or a LLR on the first sting in the season. Two of eight with previous SR reacted with SR during the observation period in spite of a negative prick test and no specific IgE. Of the bee-keepers who had previously only reacted normally there were no systemic of large localised reactions during the observed period, although six showed signs of IgE-sensitization. The results confirm the problems of identifying patients where immunotherapy is superfluous in the group with previous SR and IgE sensitization.

[Allergy to insect stings]. / Insektstiksallergi.

Components in the insect venom and probably also in their saliva may have direct toxic effects or may cause sensitization and may result in allergic reactions to subsequent stings. In Denmark, only the stings of honey bees and wasps (yellow jackets) are of clinical significance and it is important to be aware that these insects contain separate allergenic components. Clinical manifestations following stings are observed from all of the organ systems on the whole. The commonest are itching of the skin, urticaria, possibly angioedema and slight generalized symptoms with vertigo, headache and fatigue. Life-threatening reactions may also occur and one or two fatal cases are registered annually in Denmark. It may be difficult to decide whether an allergic or a toxic reaction is involved on the basis of the symptoms. Possible IgE-sensitization must therefore be assessed by means of a prick test and measurement of specific IgE. The main treatment in cases of acute systemic reactions is adrenaline which may possibly be supplemented with antihistamine and corticosteroid. In cases of massive local reactions and urticaria, antihistamines will, as a rule, prove sufficient. Hyposensitization with insect venom preparations eliminates the future risk for systemic insect sting reactions practically entirely and this must be recommended for patients with demonstrated IgE-sensitizing and generalized reactions. At present, treatment should be continued for three to five years and protection lasts for a series of years after cessation of treatment.

[House dust mite allergens and mite allergy in Copenhagen dwellings. A cross-sectional study]. / Støvmideallergener og mideallergi i københavnske boliger. En tvaersnitsundersøgelse.

The aim of the study was to investigate the influence of various environmental factors on occurrence of house dust mite allergens and the influence of allergen exposure on mite allergy. Ninety-two persons from a population study filled in a questionnaire, were skin prick and lung function tested and dust samples were collected from their mattresses for analyses. Two out of five patients with asthma had a positive skin reaction to house dust mite allergen in contrast to five out of 87 non-asthmatics. Fifty-nine per cent of the dust samples contained (group 1) mite allergen > 2 micrograms/g dust. Such mattresses were older (median 7 years, range 1-22) than mattresses with less allergen (median 4 years, range 1-20). In the six bedrooms reported to be humid or mouldy, mattresses contained high concentration of mite allergens. No other parameter investigated could predict the allergen contents. In almost all cases dust analyses are crucial to be able to advise patients with house dust mite allergy.