Different phenotypes of drug-induced anaphylaxis—Data from the European Anaphylaxis Registry

Background Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment. Methods Data from the European Anaphylaxis Registry (2007–2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly. Results Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use. Conclusion The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines.Peer Reviewe

International consensus on (ICON) anaphylaxis

ICON: Anaphylaxis provides a unique perspective on the principal evidence-based anaphylaxis guidelines developed and published independently from 2010 through 2014 by four allergy/immunology organizations. These guidelines concur with regard to the clinical features that indicate a likely diagnosis of anaphylaxis -- a life-threatening generalized or systemic allergic or hypersensitivity reaction. They also concur about prompt initial treatment with intramuscular injection of epinephrine (adrenaline) in the mid-outer thigh, positioning the patient supine (semi-reclining if dyspneic or vomiting), calling for help, and when indicated, providing supplemental oxygen, intravenous fluid resuscitation and cardiopulmonary resuscitation, along with concomitant monitoring of vital signs and oxygenation. Additionally, they concur that H1-antihistamines, H2-antihistamines, and glucocorticoids are not initial medications of choice. For self-management of patients at risk of anaphylaxis in community settings, they recommend carrying epinephrine auto-injectors and personalized emergency action plans, as well as follow-up with a physician (ideally an allergy/immunology specialist) to help prevent anaphylaxis recurrences. ICON: Anaphylaxis describes unmet needs in anaphylaxis, noting that although epinephrine in 1 mg/mL ampules is available worldwide, other essentials, including supplemental oxygen, intravenous fluid resuscitation, and epinephrine auto-injectors are not universally available. ICON: Anaphylaxis proposes a comprehensive international research agenda that calls for additional prospective studies of anaphylaxis epidemiology, patient risk factors and co-factors, triggers, clinical criteria for diagnosis, randomized controlled trials of therapeutic interventions, and measures to prevent anaphylaxis recurrences. It also calls for facilitation of global collaborations in anaphylaxis research. In addition to confirming the alignment of major anaphylaxis guidelines, ICON: Anaphylaxis adds value by including summary tables and citing 130 key references. It is published as an information resource about anaphylaxis for worldwide use by healthcare professionals, academics, policy-makers, patients, caregivers, and the public

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime

Hymenoptera Venom Immunotherapy (printer-friendly)

Abstract and Introduction Abstract Subcutaneous venom immunotherapy is the only effective treatment for patients who experience severe hymenoptera sting-induced allergic reactions, and the treatment also improves health-related quality of life. This article examines advances in various areas of this treatment, which include the immunological mechanisms of early and long-term efficacy, indications and contraindications, selection of venom, treatment protocols, duration, risk factors for systemic reactions in untreated and treated patients as well as for relapse following cessation of treatment. Current and future strategies for improving safety and efficacy are also examined. However, although progress in the past few years has been fruitful, much remains to be accomplished. Introduction Hymenoptera stings can induce allergic systemic and occasionally fatal reactions. The offending hymenoptera belong to the suborder Aculeate, which are made up of the Apoidea (Apis mellifera and Bombus species) and Vespidae (Vespinae and Polistinae subfamilies) superfamilies, [1] Detailed clinical features of insect sting reactions and their pathogenesis are described elsewhere. Authors and Disclosures Classification by HL Mueller Grade I -Generalized urticaria, itching, malaise and anxiety Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 1 of 22 6/4/2011 9:10 μμ In the USA, the prevalence of SRs to hymenoptera sting in the general population ranges from 0.5 to 3.3%. European epidemiological studies from the last decade report a prevalence of 0.3-8.9% for SRs, with anaphylaxis reported in 0.3-42.8% of cases. To date, there is no existing parameter that enables clinicians to predict who will have a future reaction and whether it will be a LLR or generalized anaphylaxis. Several concomitant factors, which include the environment, genetics and individual elements, may account for the occurrence of a SR in any one patient. [11] Mechanisms of Action of VIT The underlying immunological mechanisms of VIT are continuously being elucidated. Different mechanisms involving specific cell populations, play a role in the different phases of VIT, [10] The proposal of blocking antibodies has been Grade II -Any of the above plus two or more of the following: angioedema, chest constriction, nausea, vomiting, diarrhea, abdominal pain and dizziness Grade III -Any of the above plus two or more of the following: dyspnea, wheezing, stridor, dysarthria, hoarseness, weakness, confusion and feeling of impending disaster Grade IV -Any of the above plus two or more of the following: fall in blood pressure, collapse, loss of consciousness, incontinence and cyanosis Classification by J Ring Grade I -Generalized skin symptoms (e.g., flush, generalized urticaria and angioedema) Grade II -Mild to moderate pulmonary, cardiovascular and/or gastrointestinal symptoms Grade III -Anaphylactic shock and loss of consciousness Grade IV -Cardiac arrest and apnea Adapted from Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 2 of 22 6/4/2011 9:10 μμ re-evaluated on the basis of observations of altered specificity and affinity during immunotherapy and effects on memory B cells and antigen-presenting cells. Very early effects of VIT are also associated with an early decreased mediator release from mast cells and basophils, although the mechanism of this desensitization effect is, as yet, unknown. [24] Indications & Contraindications Indications for VIT are based on the history of a SR, a positive venom skin or specific IgE, knowledge of the natural history and established risk factors for a severe outcome. Patient History The history is especially important as diagnostic tests with venoms are positive in 10-20% of asymptomatic individuals. The patient is asked to describe his/her symptoms and course of the sting reaction, number of stings, cues to the type of insect involved and individual risk factors for anaphylaxis. In general, cutaneous manifestations are more common in children than in adults, respiratory symptoms occur with equal frequency in approximately 40% of children and adults, while cardiovascular signs and symptoms are common in adults, whereas these are infrequent in children. Diagnostic Testing The decision to commence VIT requires confirmation of allergic sensitivity to venom allergens by positive venom skin tests and/or detection of venom-specific IgE antibodies in the serum. The European Academy of Allergology and Clinical Immunology (EAACI) [1] However, some patients reported having only manifest sensitization in the first week after being stung. Even at venom concentrations of 100 µg/ml, the sensitivity of the skin prick test is lower than that of the intradermal test, which has to be used in order to confirm the negative result (from a concentration of 0.001 up to 1 µg/ml). [1] Skin tests with hymenoptera venoms are generally safe; nevertheless, SRs do occur, although these are very rare. [2] Hymenoptera venom products, such as lyophilized protein extract for honey bee, bumble bee, yellow jacket and Polistes wasp venoms, are commercially available in many countries, the latter two being mixtures of the clinically relevant species. Due to incomplete cross-reactivity between venoms of the European and American species of Polistes, [1] If in vitro tests are negative in approximately 20% of positive skin tests, [1] Indeed, the most reactive skin tests often occur in patients with only LLRs, while almost 25% of patients who are referred for evaluation of a sting SR are intradermal skin-test positive only at the 1 µg/ml concentration, thus demonstrating the importance of testing with the full diagnostic range of venoms. [32] Double positivity to both bee and vespid venoms in diagnostic tests has been observed in 25-40% of HVA patients, the majority of whom have a single-positive history and are unable to identify the culprit insect. Double positivity may arise from double sensitization, cross-reactivity between epitopes on hyaluronidase in the two venoms or to cross-reactivity between cross-reactive carbohydrate determinants (CCDs) of venoms and common allergens. [34] Specific IgE to the recombinant nonglycosylated major allergen, Api m 1, was detected in 99% of cases of whole bee venom-positive allergy, while sIgE to Ves v 5 was present in 96% of whole Vespula venom-positive allergic patients when tested by ADVIA Centaur, thus reducing the double positivity to 17%. [36] On the other hand, there are those patients with a clear history of a SR but negative skin and in vitro radioallergosorbent test (RAST) results. [44] Finally, live insect sting challenges should not be used as a diagnostic tool in untreated patients, as the absence of systemic symptoms does not rule out the possibility of a SR to a future sting. [46] Natural History & Risk Factors Reaction severity, confirmation of venom IgE sensitivity, current knowledge of the natural history of HVA and risk factors form the selection criteria for suitable VIT candidates, when deciding whether to start VIT and for how long to treat them for. In general, the risk of recurrence of SRs is linked to the severity of the previous reaction: the more serious the initial reaction, the greater the risk of recurrence. Linking the estimated risk of a future SR with reaction severity, age and sting interval, adults and children with LLRs are a low-risk category for a SR (5-15%) when re-stung. [50] Other risk factors associated with the occurrence of a severe field-sting SRs in untreated patients are represented by an increased baseline tryptase concentration, Contrary to previous findings, [10] Venom immunotherapy is indicated in HVA patients with mast-cell diseases as the treatment can reduce SRs, albeit to a lesser extent than in otherwise healthy subjects with HVA; [25] Venom immunotherapy is able to reduce the severity and duration of LLRs and its efficacy improves over a period of 2-4 years. [57] Although VIT is not usually recommended in patients with such reactions, as the risk of a subsequent systemic sting reaction is low, physicians may consider it as a treatment option when confronted with extremely anxious patients with HRQL impairment or highly exposed subjects who require repeated per annum corticosteroid shots. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 5 of 22 6/4/2011 9:10 μμ Contraindications In Europe, the standards for practical allergen-specific immunotherapy [45] Untreated patients with anaphylaxis should not be given β-blockers, except under circumstances where the administration of these drugs is urgently required as in the case of certain heart rhythm disorders. Administration of VIT to patients receiving β-blockers (even in eye drops) is contraindicated as they can aggravate anaphylactic reactions and also interfere with treatment. However, if the cardiac risk in venom allergic patients outweighs the risk of a systemic reaction during VIT, then VIT is appropriate for use in subjects receiving β-blockers but must be performed in an emergency care setting. [60] Severe allergic reactions, including anaphylaxis, have been described in patients on angiotensin-converting enzyme (ACE)-inhibitors subsequent to being stung or receiving immunotherapy. [25] Currently, there are no data to support or exclude the potentially harmful role of angiotensin-receptor blockers in patients with anaphylaxis in general, or in HVA-untreated patients. [61] As regards the other contraindications, such as serious immunological diseases and cancer, the European guidelines need to be reviewed in order to cater for cases of severe sting allergic reactions, particularly where there is a high risk of sting exposure, a history of a near-fatal sting reaction and perhaps for mast-cell diseases given the treatment's life-saving potential. Indeed, in some selected cases the advantages of VIT might outweigh the potential negative effects. Venom immunotherapy should not be begun during pregnancy, but well-tolerated maintenance VIT may be continued in order to prevent the risk of further SRs in the mother as well as in the fetus. [59] Selection of Venoms Selection is based on the identification of the hymenoptera species that is involved, on the results of the diagnostic tests and on venom cross-reactivity. In North America, allergists and immunologists believe it prudent to prescribe VIT with any venom, which gives a positive skin test, or sIgE result, since there have been cases where VIT was tailored towards the primary culprit insect but the patients subsequently reacted to an insect to which they had previously been sensitized. In Europe, the geographical distribution of each species and the ample cross-reactivity among venoms of Vespula, Dolichovespula and Vespa, usually makes treatment with Vespula venom alone sufficient in the temperate European climate. Double diagnostic positivities to wasp (Polistes) and yellow jacket (Vespula species) venoms have been observed in Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 6 of 22 6/4/2011 9:10 μμ more than 50% of vespid allergic patients. Owing to the incomplete cross-reactivity between vespinae and paper wasps (Polistes) in the Mediterranean area, patients who test positive to both venoms should be treated with both, unless RAST-inhibition reveals cross-reactivity. [10] The same approach is used in the Gulf states of the USA, where Polistes is common as a species. [31] A weaker cross-reactivity between European and American paper wasps was recently demonstrated. [27] The species P. dominulus and Polistes gallicus are European paper wasps; P. dominulus has spread to northeastern USA and has also been reported in Australia. The species Polistes exclamans, Polistes annularis and Polistes fuscatus are indigenous to North America and are not present in Europe. All these findings raise the need to introduce, at least in Europe, the P. gallicus or P. dominulus extract (the latter only recently being available in some European countries) into clinical practice for diagnostic and therapeutic purposes to replace the American Polistes species mixture presently being used. [55] V. crabro venom has some antigens in common with Vespula venom; however, a third of V. crabro-allergic individuals have positive skin and sIgE tests restricted to only V. crabro venom. Italy, it is a common practice to use V. crabro extract for both diagnostic and therapeutic purposes. Dual positivity of diagnostic tests with Vespula and honeybee is also frequent, especially in some European countries where bee venom allergy is more frequent than vespid venom allergy. [33] Honeybee and bumblebee venoms show high cross-reactivity. [1] Immunotherapy with honeybee venom alone may be sufficient in nonprofessionally exposed bumblebee-allergic patients with bee venom primary sensitization, whose reaction is most likely due to cross-reactivity. In occupationally exposed patients, who are frequently stung by bumblebees, purified bumblebee venom for immunotherapy, when available, is recommended owing to the low or absent cross-reactivity with honeybee venom. [47] In the USA, whole-body fire ant extract immunotherapy, which contain sufficient venom allergens to provide reasonable clinical protection is used; fire ant venoms are available in Australia (Jack Jumper) where a very successful controlled trial was performed. [69] By contrast, allergic reactions to ants are rare in Europe, Efficacy Subcutaneous VIT is probably the most effective allergen treatment currently available to physicians. The efficacy of VIT has been confirmed in prospective controlled and uncontrolled studies [72] The recommended maintenance dose is 100 µg of venom, both in children and adults. This dose was originally proposed because it was believed to be equivalent to two stings. Indeed, between 50 and 140 µg venom are delivered by a bee sting compared with up to 3 µg by that of a Vespula sting and up to 17 µg by that of a Polistes sting. [4] For the first time, a recent paper demonstrated the efficacy of a P. dominulus extract after a field sting. [65] A dose of 200 µg is recommended when a SR follows an insect sting in spite of VIT with 100 µg and in highly exposed populations, such as beekeepers. [51] Most American patients receive mixed vespid venoms, with an injectable maintenance dose of 300-400 µg, which provides approximately 98% protection. [68] Some authors have demonstrated that VIT efficacy in mastocytosis sufferers may be reduced. [75] Box 2 presents risk factors currently known to predispose a patient to a SR at sting challenge or an in-field sting during VIT. Treatment Protocol Many treatment protocols for the VIT induction phase have been designed. [10] They vary with respect to the number of injections, venom doses and time needed to reach the final dose [ Question marks indicate the existence of discordant data on these topics. [76] They performed two different protocols, a rush protocol in 62 inpatients, and a modified rush protocol in 670 outpatients, thereby demonstrating that by starting with 1 µg of venom there was no SR. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 9 of 22 6/4/2011 9:10 μμ If two or more venoms are required, they should be administered in separate protocols a few days apart. While the build-up phase of VIT should be performed by an allergist, in some countries, maintenance treatment is eventually continued by the general practitioners. In Europe, VIT may be performed with nonpurified aqueous (NPA), purified aqueous (PA) extracts and purified aluminium hydroxide adsorbed (PAHA) preparations (so-called 'depot' extracts) of yellow jacket and honeybee venoms, administered by subcutaneous injection. Purified venom extracts do not contain vasoactive amines (e.g., dopamine, histamine and serotonin) and have a reduced presence of small peptides (e.g., apamine, kinins and mast-cell degranulating peptide in the final product). [77] Polistes species and P. dominulus PA and PAHA extracts for diagnostic and therapeutic purposes are not currently commercially available in Europe. The efficacy of PA and depot extracts is supported by studies using both sting challenge and in-field stings, and is comparable to that of nonpurified preparations. [31] The NPA and PA extracts can be used for ultrarush, rush, clustered and maintenance phases, while PAHA preparations are only administered for the conventional build-up and maintenance schedule. Many European specialists switch to depot preparations following the up-dosing phase. [77] The general consensus is that the maintenance interval should be kept at 4 weeks for the first year, extended to 6 weeks in the second year, and then to 8 weeks if VIT is continued for more than 5 years, provided that the treatment is tolerated. [77] A longer interval is not recommended for honeybee allergic patients since beekeepers with less than ten stings a year were those who developed SRs most frequently. Side Effects Although highly effective, patient compliance with VIT may be impaired by LLRs and SRs, Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 10 of 22 6/4/2011 9:10 μμ some European countries, only selected allergy centers usually opt for treatment. However, some studies demonstrate that the side effects of VITs are less frequent than those caused by subcutaneous immunotherapy for inhalant allergens. [2] The literature reports a large variation (0-46%) in the incidence of VITs side effects, In a European, multicenter study, published in 2000, a greater risk of SRs was demonstrated during the incremental phase of VIT in female patients, in subjects receiving bee venom vaccines and in patients undergoing the rapid incremental phase, but not in patients with a history of a severe, original SR. [85] Similar findings for several of these parameters were observed in a previously conducted, larger, retrospective study in the USA, which reported that SRs were most likely to occur at venom doses between 1 and 50 µg and at maintenance dosage. [87] However, there may be a difference between honeybee and vespid venoms with respect to the tolerability of the different protocols. [91] At present, ultrarush protocols should only be used by specialists who are experienced in managing VIT and preferably only in an emergency care setting, particularly in bee venom allergic patients. Even though there are good theoretical grounds for the contraindication of β-blockers during immunotherapy, this does not seem to apply to VIT. [60] ACE-inhibitors may possibly contribute to the onset of SRs during VIT in some highly selected patients, [52] However, risk factors for adverse reactions in these patients (e.g., type of mastocytosis and protocol) require further evaluation. [91] Question marks indicate the existence of discordant data on these topics. ymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 11 of 22 6/4/2011 9:10 μμ In general, repeated anaphylactic reactions are rare. In these cases, it should be assumed that VIT will not prevent further SRs following a sting. Moreover, treatment should be continued for approximately 6 months with the highest tolerated dose of insect venom (injection interval 1-2 weeks) and then renewed attempt at dose increase. [45] In conclusion, risk factors for VIT-induced SRs must be taken into account and patients with one or more risk factor should be treated and monitored with special care. How can VIT Safety be Improved? Pretreatment with a H1 antihistamine has been demonstrated to reduce the number and severity of LLRs and mild SRs to VIT, such as urticaria and angioedema. Pretreatment with a combination of H1 antihistamine and a corticosteroid have not yet been performed in honeybee and vespid VIT, except in patients with mast-cell diseases. [52] In a prospective, double-blind, randomized, placebo-controlled pilot study the occurrence of local reactions following VIT was significantly delayed by pretreatment with the leukotriene antagonist montelukast. [96] Pretreatment with anti-IgE monoclonal antibodies may permit more rapid and higher doses of allergen immunotherapy while improving its safety. Moreover, this pretreatment could play an important role in insect-venom allergic patients who are intolerant to VIT. There are several case reports of bee venom allergic patients, [99] Until now, the optimal time for its administration during VIT (should it be administered 6 months, 2 weeks, 1 week or 1 h before VIT?), the appropriate dosage (should we use the the recommended dose of 150 or 300 mg?), the long-term effects (should omalizumab be discontinued after first administration or administered before each shot?) and the best incremental protocol of VIT (should the protocol be conventional or rush/ultrarush?) to be used are still unknown. It is important to underline that omalizumab is not approved for the prevention of anaphylaxis and it must be prescribed as off-label. In addition, taking into account its high cost, omalizumab should be limited to patients with repeated severe SAR to VIT injections preventing reaching the maintenance dose. Although the object of a certain amount of criticism, [101] Even though LLRs are not an indication for VIT, in a placebocontrolled, double-blind study on bee venom SLIT in patients with a history of LLRs, the diameter of LLR to a bee sting challenge was reduced by more than 50% in 57% of active-treated patients. [102] H

Honeybee Venom Immunotherapy: A Comparative Study Using Purified and Nonpurified Aqueous Extracts in Patients with Normal Basal Serum Tryptase Concentrations

In this study, we compared a purified aqueous extract and the corresponding nonpurified aqueous preparation under the same build-up protocol in bee venom allergic patients with a normal baseline mast cell tryptase concentration. Eighty patients with a history of a systemic reaction were enrolled for immunotherapy using a 5-day rush protocol. Patients treated with the purified extract and those treated with the non purified aqueous extract who developed a systemic reaction underwent maintenance therapy with the purified aluminium hydroxide adsorbed preparations. Patients treated with the nonpurified aqueous extract who did not experience a systemic reaction during the rush phase underwent the maintenance phase with that extract. Systemic reactions during the build-up phase occurred significantly more often in patients treated with nonpurified aqueous extract than in those treated with the corresponding purified aqueous preparations. During the one-year maintenance phase, no systemic reactions occurred in either of the groups. Neither age nor baseline mast cell tryptase concentration presented a significant correlation with the occurrence of a systemic reaction during the treatment, while the type of extract did. In conclusion, nonpurified aqueous extracts induced more frequent systemic reactions than the purified aqueous preparations, during the same rush protocol. The efficacy seemed to be comparable