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Relationship Between Anaphylaxis and Use of Beta-Blockers and Angiotensin-Converting Enzyme Inhibitors: A Systematic Review and Meta-Analysis of Observational Studies.

Tejedor-Alonso MAFarias-Aquino EPérez-Fernández EGrifol-Clar EMoro-Moro MRosado-Ingelmo A.

J Allergy Clin Immunol Pract. 2019 Mar;7(3):879-897.e5. doi: 10.1016/j.jaip.2018.10.042. Epub 2018 Nov 5.

Reasons for recommending the article:

For a number of years, the evidence regarding the role of beta-blockers and ACE inhibitors as factors increasing the severity of anaphylaxis has been controversial. This has impact upon clinical practice, and whether to withhold these types of medications in patients at risk of anaphylaxis or even prior to some common procedures, such as diagnostic challenges. In this meta-analysis it is shown that despite there seems to be an associated risk, but the quality of evidence is low, owing to underlying conditions. Therefore, practitioners must also bear in mind the possible effects due to the withdrawal of these drugs.


BACKGROUND: Beta-blockers (BBs) and angiotensin-converting enzyme inhibitors (ACEIs) have been associated with an increased risk and severity of anaphylaxis. However, the evidence supporting these findings is contradictory.

OBJECTIVE: We carried out a systematic review and meta-analysis of studies that assess the influence of BBs and ACEIs on anaphylaxis.

METHODS: We searched PubMed/MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Web of Science for relevant observational studies. We searched for studies where the presence and severity of anaphylaxis were compared between patients taking BBs, ACEIs, both types of drug, or neither type of drug. We performed a meta-analysis using a random-effects model.

RESULTS: A total of 21 studies met the study criteria. Of these, 15 assessed the severity and 9 the incidence of anaphylaxis. The studies brought together 22,313 anaphylaxis episodes for the severity studies and 18,101 anaphylaxis episodes for the studies of new cases of anaphylaxis. BBs and ACEIs increased the severity of anaphylaxis (BBs, odds ratio [OR] 2.19, 95% confidence interval [CI] 1.25-3.84; ACEIs, OR 1.56, 95% CI 1.12-2.16), but not the presence of new cases of anaphylaxis (BBs, OR 1.40, 95% CI 0.91-2.14; ACEIs, OR 1.38, 95% CI 0.39-4.86). It was not possible to perform an analysis adjusted for cardiovascular diseases, because only 1 study each for BBs and ACEIs, respectively, had adjusted data.

CONCLUSIONS: The quality of evidence showing that the use of BBs and ACEI increases the severity of anaphylaxis is low owing to differences in the control of confounders arising from the concomitant presence of cardiovascular diseases.

Assessing severity of anaphylaxis: a data-driven comparison of 23 instruments.

Eller EMuraro ADahl RMortz CGBindslev-Jensen C.

Clin Transl Allergy. 2018 Aug 1;8:29. doi: 10.1186/s13601-018-0215-x. eCollection 2018.

Reasons for recommending the article:

Currently, no instrument has widely  been accepted to score anaphylaxis severity. In this interesting paper, more than 20 different severity scoring systems have been applied to over 2800 challenge outcomes. It clearly highlights major differences and poor translatability between them. Many scoring systems have been developed to be applied in anaphylaxis triggered by a specific cause. There is a need to establish a universal tool which may be used in all cases.


BACKGROUND: The severity of an allergic reaction can range from mild local symptoms to anaphylactic shock. To score this, a number of instruments have been developed, although heterogeneous in design and purpose. Severity scoring algorithms are therefore difficult to compare, but are frequently used beyond their initial purpose. Our objective was to compare the most used severity scoring instruments by a data-driven approach on both milder reactions and anaphylaxis.

METHODS: All positive challenges to foods or drugs (n = 2828) including anaphylaxis (n = 616) at Odense University Hospital, Denmark from 1998 to 2016 were included and severity was scored according to Sampson5. Based on recommendations from an expert group, the symptoms and values from Sampson5 were for all reactions and anaphylaxis only translated and compared by kappa statistics with 22 instruments, ranging from 3 to 6 steps.

RESULTS:For milder reactions, there was a significant correlation between the number of steps in an instrument and the number of challenges that could be translated, whereas all instruments were good to identify food anaphylaxis. Some instruments scored reactions more severely than Sampson5, other scored them milder and some scored food and drug challenges differently. Instruments for hymenoptera reactions were difficult to apply on food and drug reactions, and thus distributed severity differently. Algorithms hampered the translation between instruments, and 7 instruments were poor concerning drug anaphylaxis, including the only instrument developed specifically for drug reactions.

CONCLUSION:The distributions of severity differed between the 23 instruments in both food and drug allergy, and thus rendering translation especially between scoring systems with 3 and 5 grades difficult. Fine-graded and simple instruments are preferred for comparison especially among milder reactions, and instruments applied to non-intended situations may not reflect a true severity picture.

Phenotypes, endotypes and biomarkers in anaphylaxis: current insights.

Sala-Cunill AGuilarte MCardona V.

Curr Opin Allergy Clin Immunol. 2018 Oct;18(5):370-376. doi: 10.1097/ACI.0000000000000472.

Reasons for recommending the article:

This review takes a look into the different mechanisms involved in the development of anaphylaxis, and their link to a variety of causes and clinical pictures. It helps us realize the complexity of such reactions and the current limitations we have in order to explore these pathways in clinical practice, and subsequently, of potential preventive and therapeutic targets to manage anaphylaxis.


PURPOSE OF REVIEW: The aim of the review is to describe the different clinical pictures of anaphylaxis(phenotypes), in relation to the underlying mechanisms and potential biomarkers, to describe anaphylaxis endotypes. This may aid in achieving a better understanding, management and outcomes of such severe reactions.

RECENT FINDINGS: Different anaphylaxis phenotypes have been outlined, ranging from the classical type-I-like to those suggestive of cytokine-storm-like or complement-mediated reactions. Underlying mechanisms differ and biomarkers of cells and systems involved are being identified (tryptase, IL-6, bradykinin etc.)

SUMMARY: Identifying specific phenotypes/endotypes will allow the application of precision medicine in patients with anaphylaxis, providing insights to the most appropriate approach in each case.

Myths, facts and controversies in the diagnosis and management of anaphylaxis.

Anagnostou KTurner PJ.

Arch Dis Child. 2019 Jan;104(1):83-90. doi: 10.1136/archdischild-2018-314867. Epub 2018 Jun 16.

Reasons for recommending the article:

This is an easy read and very interesting paper, debunking 10 different popular myths in anaphylaxis, from ‘Anaphylaxis often results in death’ to ‘MMR and influenza vaccinations are contraindicated in patients with previous anaphylaxis to egg’. It is appropriate to be read not only by allergists, but also by other physicians such as family doctors or pediatricians.


Anaphylaxis is a serious systemic allergic reaction that is rapid in onset and may cause death. Despite numerous national and international guidelines and consensus statements, common misconceptions still persist in terms of diagnosis and appropriate management, both among healthcare professionals and patient/carers. We address some of these misconceptions and highlight the optimal approach for patients who experience potentially life-threatening allergic reactions.

Twenty Years' Experience with Anaphylaxis-Like Reactions to Local Anesthetics: Genuine Allergy is Rare.

Trautmann AGoebeler MStoevesandt J.

J Allergy Clin Immunol Pract. 2018 Nov - Dec;6(6):2051-2058.e1. doi: 10.1016/j.jaip.2018.04.005. Epub 2018 Apr 12.

Reasons for recommending the article:

Local anesthetics (LA) are usual suspects in many adverse drug reactions, and it is a common belief that they frequently cause allergy. This paper shows that true LA-allergy is a very rare condition. Therefore, to overcome unnecessary avoidance of LA, and to correctly diagnose the reactions and possible triggers, it is important to refer patients to experienced specialists.


BACKGROUND: Anaphylaxis-like reactions occur within minutes after the application of local anesthetics (LA), most commonly during dental interventions. Impressive symptoms including respiratory distress or loss of consciousness frequently give rise to a suspicion of allergy and may prompt patients and treating physicians to refuse future LA injections.

OBJECTIVE: Nonallergic mechanisms are responsible for the majority of LA-induced immediate-type reactions. In view of the preponderance of nonallergic reactions, the question arises whether genuine LA allergy may be missed during routine testing procedures.

METHODS: We retrospectively evaluated clinical data and test results from patients referred to our allergy clinic within the past 20 years for diagnostic workup of LA-induced immediate-type reactions.

RESULTS: Of 402 evaluated patients, 29 had an episode of acute urticaria within 30 minutes after LA injections, and the remaining 373 had a history of mainly subjective cutaneous, respiratory, cardiovascular, and neurological complaints. Of the patients reporting urticaria with or without angioedema, 14 were diagnosed with a spontaneous episode of urticaria, 13 had allergic or nonallergic reactions to other agents, and 2 had IgE-mediated LA allergy. LA allergy was definitely excluded by 771 subcutaneous provocation tests with skin test negative LA, thereby demonstrating the high predictive value of negative intradermal testing.

CONCLUSIONS: Skin testing and provocative LA challenge are useful to exclude LA allergy, and this testing procedure seems to be appropriate to identify the extremely rare cases with IgE-mediated LA allergy.

Epinephrine in Severe Allergic Reactions: The European AnaphylaxisRegister.

Grabenhenrich LBDölle SRuëff FRenaudin JMScherer KPföhler CTreudler RKoehli AMahler VSpindler TLange LBilò MBPapadopoulos NGHourihane JOBLang RFernández-Rivas MChristoff GCichocka-Jarosz EWorm M.

J Allergy Clin Immunol Pract. 2018 Nov - Dec;6(6):1898-1906.e1. doi: 10.1016/j.jaip.2018.02.026. Epub 2018 Mar 30.

Reasons for recommending the article:

No matter how many anaphylaxis guidelines we have, and despite enormous efforts to implement them, this paper shows that the use of intramuscular epinephrine (adrenaline) in anaphylaxis is still far from optimal. There seems to be some improvement in the use by health-care professionals, but autoinjection by patients or carers remains extremely low. Are we correctly informing and educating patients at risk of anaphylaxis on the use of epinephrine? Should we search new ways to address this? These issues warrant a thorough reflection by health professional and patient organizations.


BACKGROUND: Current guidelines recommend intramuscular administration of epinephrine as the first-line drug for the emergency treatment of severe allergic reactions (anaphylaxis), but no randomized trial evidence supports this consensus.

OBJECTIVE: We aimed to assess anaphylaxis treatment practices over 10 years, covering several European regions, all allergen sources, and all age groups.

METHODS: The European Anaphylaxis Register tracks elicitors, symptoms, emergency treatment, diagnostic workups, and long-term counseling for anaphylaxis incidents through web-based data entry from tertiary allergy specialists, covering information from the emergency respondent, patient, tertiary referral, and laboratory/clinical test results.

RESULTS: We analyzed 10,184 anaphylaxis incidents. In total, 27.1% of patients treated by a health professional received epinephrine and, in total, 10.5% received a second dose. Successful administration was less frequent in German-speaking countries (minimum 19.6%) than in Greece, France, and Spain (maximum 66.7%). Over the last decade, epinephrine administration from a health professional almost doubled to reach 30.6% in 2015-2017, half of which was applied intramuscularly. A total of 14.7% of lay- or self-treated cases were treated with an autoinjector. Of those without treatment, 22.4% carried a device for administration. No change in successful administration by lay emergency respondents was found over the last 10 years. Of the reaction and patient characteristics analyzed, only clinical severity considerably influenced the likelihood of receiving epinephrine, with 66.9% of successful administrations in near-fatal (grade IV) reactions.

CONCLUSIONS: Despite clear recommendations, only a small proportion of anaphylaxis incidents are treated with epinephrine. We demonstrated a slight increase in treated patients when handled by professionals, but stagnation in lay- or self-treated anaphylaxis. The reaction circumstances, the respondent's professional background, and patient characteristics did not explain which reactions were treated.

Mast cell activation test in the diagnosis of allergic disease and anaphylaxis.

Bahri RCustovic AKorosec PTsoumani MBarron MWu JSayers RWeimann A, Ruiz-Garcia MPatel NRobb AShamji MHFontanella SSilar MMills ENCSimpson ATurner PJBulfone-Paus S.

J Allergy Clin Immunol. 2018 Aug;142(2):485-496.e16. doi: 10.1016/j.jaci.2018.01.043. Epub 2018 Mar 5.

Reasons for recommending the article:

Mast cells are the key players in anaphylactic reactions. This new technique explores the possibility of studying their activation as a tool to diagnose clinically relevant allergic sensitization. In this paper we can appreciate its performance in peanut allergic subjects, which seems extremely promising. Further research in other forms of anaphylaxis (different food triggers, drugs or hymenoptera) will be extremely interesting.


BACKGROUND: Food allergy is an increasing public health issue and the most common cause of life-threatening anaphylactic reactions. Conventional allergy tests assess for the presence of allergen-specific IgE, significantly overestimating the rate of true clinical allergy and resulting in overdiagnosis and adverse effect on health-related quality of life.

OBJECTIVE: To undertake initial validation and assessment of a novel diagnostic tool, we used the mast cell activation test (MAT).

METHODS: Primary human blood-derived mast cells (MCs) were generated from peripheral blood precursors, sensitized with patients' sera, and then incubated with allergen. MC degranulation was assessed by means of flow cytometry and mediator release. We compared the diagnostic performance of MATs with that of existing diagnostic tools to assess in a cohort of peanut-sensitized subjects undergoing double-blind, placebo-controlled challenge.

RESULTS: Human blood-derived MCs sensitized with sera from patients with peanut, grass pollen, and Hymenoptera (wasp venom) allergy demonstrated allergen-specific and dose-dependent degranulation, as determined based on both expression of surface activation markers (CD63 and CD107a) and functional assays (prostaglandin D2 and β-hexosaminidase release). In this cohort of peanut-sensitized subjects, the MAT was found to have superior discrimination performance compared with other testing modalities, including component-resolved diagnostics and basophil activation tests. Using functional principle component analysis, we identified 5 clusters or patterns of reactivity in the resulting dose-response curves, which at preliminary analysis corresponded to the reaction phenotypes seen at challenge.

CONCLUSION: The MAT is a robust tool that can confer superior diagnostic performance compared with existing allergy diagnostics and might be useful to explore differences in effector cell function between basophils and MCs during allergic reactions.

The urgent need for a harmonized severity scoring system for acute allergic reactions.

Muraro AFernandez-Rivas MBeyer KCardona VClark AEller EHourihane JOJutel MSheikh AAgache IAllen KJAngier EBallmer-Weber BBilò MBBindslev-Jensen CCamargo CA JrCianferoni ADunn Galvin AEigenmann PAHalken SHoffmann-Sommergruber KLau SNilsson CPoulsen LKRueff FSpergel JSturm GTimmermans FTorres MJTurner Pvan Ree RWickman MWorm MMills ENCRoberts G.

Allergy. 2018 Sep;73(9):1792-1800. doi: 10.1111/all.13408. Epub 2018 Jun 17.

Reasons for recommending the article:

Scoring anaphylaxis severity is difficult, as shown by the numerous grading systems which are currently available. A universally accepted system, applicable in all circumstances and settings is a long-awaited need. In this paper, there is a proposal on the development of a tool which is both data-driven but which also feeds on other perspectives (patients, professionals, etc.).


The accurate assessment and communication of the severity of acute allergic reactions are important to patients, clinicians, researchers, the food industry, and public health and regulatory authorities. Severity has different meanings to different stakeholders with patients and clinicians rating the significance of particular symptoms very differently. Many severity scoring systems have been generated, most focusing on the severity of reactions following exposure to a limited group of allergens. They are heterogeneous in format, none has used an accepted developmental approach, and none has been validated. Their wide range of outcome formats has led to difficulties with interpretation and application. Therefore, there is a persisting need for an appropriately developed and validated severity scoring system for allergic reactions that work across the range of allergenic triggers and address the needs of different stakeholder groups. We propose a novel approach to develop and then validate a harmonized scoring system for acute allergic reactions, based on a data-driven method that is informed by clinical and patient experience and other stakeholders' perspectives. We envisage two formats: (i) a numerical score giving a continuum from mild to severe reactions that are clinically meaningful and are useful for allergy healthcare professionals and researchers, and (ii) a three-grade-based ordinal format that is simple enough to be used and understood by other professionals and patients. Testing of reliability and validity of the new approach in a range of settings and populations will allow eventual implementation of a standardized scoring system in clinical studies and routine practice.

Factors increasing the risk for a severe reaction in anaphylaxis: An analysis of data from The European Anaphylaxis Registry.

Worm MFrancuzik WRenaudin JMBilo MBCardona VScherer Hofmeier KKöhli ABauer AChristoff GCichocka-Jarosz EHawranek THourihane JO'Lange LMahler VMuraro APapadopoulos NGPföhler CPoziomkowska-GÄ™sicka IRuëff FSpindler TTreudler RFernandez-Rivas MDölle S.

Allergy. 2018 Jun;73(6):1322-1330. doi: 10.1111/all.13380. Epub 2018 Mar 8.

Reasons for recommending the article:

When assessing patients at risk of a future anaphylaxis, we need to make decisions regarding potential factors which may determine severity and to decide upon measures to prevent and handle them. This paper, based on date extracted from a very large anaphylaxis registry identifies a number of factors, some of which may be modified in order to reduce the risk of future anaphylaxis severity.


BACKGROUND: Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase the severity of anaphylaxis and therefore need to be recognized and avoided.

OBJECTIVE: To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis.

METHODS: Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis.

RESULTS: We identified higher age and concomitant mastocytosis (OR: 3.1, CI: 2.6-3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise (OR: 1.5, CI: 1.3-1.7), male sex (OR: 1.2, CI: 1.1-1.3), and psychological burden (OR: 1.4, CI: 1.2-1.6) were more often associated with severe reactions. Additionally, intake of beta-blockers (OR: 1.9, CI: 1.5-2.2) and ACE-I (OR: 1.28, CI: 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis.

CONCLUSION: Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.

Bioavailability and Cardiovascular Effects of Adrenaline Administered by Anapen Autoinjector in Healthy Volunteers.

Duvauchelle TRobert PDonazzolo YLoyau SOrlandini BLehert PLecomte JMSchwartz JC.

J Allergy Clin Immunol Pract. 2018 Jul - Aug;6(4):1257-1263. doi: 10.1016/j.jaip.2017.09.021. Epub 2017 Nov 3.

Reasons for recommending the article:

Despite epinephrine autoinjectors are recommended for the first line treatment of anaphylaxis, especially by patients and carers, little is known about the pharmacokinetics of the drug when using these devices. This is an interesting paper which compares the performance of one device (Anapen) to that of an injection with a prefilled syringe. Regulatory bodies will probably be requesting similar studies for other devices. Even a head-to-head comparison would be very interesting! It is a must-read for all allergists.


BACKGROUND: The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability.

OBJECTIVE: To assess the adequacy of Anapen, which has a relatively short needle length (10.5 mm), through a comparison of the depot localization, plasma pharmacokinetics, and cardiovascular responses of adrenaline delivered via Anapen versus a prefilled syringe with a 25.4-mm needle, which is generally used for intramuscular injections.

METHODS: This randomized, open-label, crossover study compared the impact of adrenaline administration at 2 sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, we studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline level was evaluated by ultra performance liquid chromatography-mass spectrometry (UPLC-MS), and heart rates were measured using a Holter monitor.

RESULTS: Intramuscular injections were given with both devices at both thigh sites in nonobese men, but not in overweight women. Adrenaline levels showed a double peak, with parallel changes in the heart rate. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 minutes postinjection, with maximum concentration and area under the curve significantly higher with Anapen than with prefilled syringes; the magnitude of the second peak did not differ among the various conditions. Unexpectedly, in overweight women treated with Anapen, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous, and the overall bioavailability was enhanced.

CONCLUSIONS: Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis.

Action Plan to Reach the Global Availability of Adrenaline Auto-Injectors.

Kase Tanno L, Demoly P; Joint Allergy Academies.

J Investig Allergol Clin Immunol. 2018 Nov 13:0. doi: 10.18176/jiaci.0346. [Epub ahead of print]

Reasons for recommending the article:

The availability of epinephrine autoinjectors is limited to a small number of countries, while the occurrence of anaphylaxis is globally increasing. In this paper the authors review the current status of availability and propose an ambitious action plan to improve the situation.  Efforts should align all stakeholders to reach such goal.


Adrenaline is the first-line treatment for anaphylaxis and, therefore, listed as an essential medication for the treatment of anaphylaxis by the World Health Organization (WHO). However, the availability of auto-injector (AAI) forms for use in the first-aid treatment is limited to only 32% of all 195-world countries, mostly high-income countries. The key issues leading to the lack of availability of AAIs include cost but also national regulations, lack of regional evidence about the value of epinephrine and the limited accurate data about the epidemiology of anaphylaxis. For these reasons, regional and international allergy academies support the initiatives to narrow these gaps. Our WHO Collaborating Centre is deeply involved in this process and the purpose of this document is serving as baseline to reach: (I) an adequate access to AAI in affordable cost for all patients/societies and (II) the development of disease/patient-specific approaches. Therefore, we propose a 5 steps action plan (gather accurate anaphylaxis epidemiological data and AAI consumption indicators, confirm partnerships, strengthen awareness and include AAI into the WHO Model List of Essential Medicine), which should be considered in combination. A prioritized research agenda should encapsulate all these steps in the frame a global initiative against anaphylaxis. More than calling for the global availability of AAIs for best management of anaphylaxis, we propose an action plan as baseline of a global initiative against anaphylaxis. We strongly believe the combined efforts are a strong public health and societal move, leading to optimal care of allergic patients and best practice of allergology

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